Review Article Anti-Inflammatory Effects of Heparin and Its...

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Review Article Anti-Inflammatory Effects of Heparin and Its Derivatives: A Systematic Review Sarah Mousavi, 1 Mandana Moradi, 2 Tina Khorshidahmad, 3 and Maryam Motamedi 3 1 Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran 2 Faculty of Pharmacy, Zabol University of Medical Sciences, Zabol, Iran 3 Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran Correspondence should be addressed to Sarah Mousavi; [email protected] Received 24 February 2015; Accepted 24 April 2015 Academic Editor: Berend Olivier Copyright © 2015 Sarah Mousavi et al. is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background. Heparin, used clinically as an anticoagulant, also has anti-inflammatory properties. e purpose of this systematic review was to provide a comprehensive review regarding the efficacy and safety of heparin and its derivatives as anti-inflammatory agents. Methods. We searched the following databases up to March 2012: Pub Med, Scopus, Web of Science, Ovid, Elsevier, and Google Scholar using combination of Mesh terms. Randomized Clinical Trials (RCTs) and trials with quasi-experimental design in clinical setting published in English were included. Quality assessments of RCTs were performed using Jadad score and Consolidated Standards of Reporting Trials (CONSORT) checklist. Results. A total of 280 relevant studies were reviewed and 57 studies met the inclusion criteria. Among them 48 studies were RCTs. About 65% of articles had score of 3 and higher according to Jadad score. Twelve studies had a quality score > 40% according to CONSORT items. Asthma (=7), inflammatory bowel disease (=5), cardiopulmonary bypass (=8), and cataract surgery (=6) were the most studied disease condition. Forty studies use unfractionated heparin (UFH) for intervention; the remaining studies use low molecular weight heparin (LMWH). Conclusion. Despite the conflicting results, heparin seems to be a safe and effective anti-inflammatory agent; although it is shown that heparin can decrease the level of inflammatory biomarkers and improves patient conditions, still more data from larger rigorously designed studies are needed to support use of heparin as an anti-inflammatory agent in clinical setting. However, because of the association between inflammation, atherogenesis, thrombogenesis, and cell proliferation, heparin and related compounds with pleiotropic effects may have greater therapeutic efficacy than compounds acting against a single target. 1. Introduction Heparin is a highly sulfated glycosaminoglycan (GAG) that is found in the mast cells of most mammals. e endogenous GAGs are highly acidic and actively charged. Heparin is the most sulfated, and acidic GAGs enable it to bind to different component such as coagulating and fibrinolysing proteins, many growth factors, and immune response proteins such as cytokines and chemokines [1, 2]. Heparin is mostly known for its anticoagulant properties, so commercially form of heparin including unfractionated heparin (UFH) and low molecular weight heparin (LMWH) used currently in treatment and prevention of thrombotic events like deep vein thrombosis, pulmonary emboli, acute coronary syndromes, and ischemic cerebrovascular events as well as prevention of thrombosis in extracorporeal circuits and hemodialysis [3, 4]. Apart from its anticoagulant effects, there are several studies which have shown that heparin possesses various anti-inflammatory and immunomodulatory properties and the mechanisms of anti- inflammatory actions of heparin have been discussed recently [5, 6]. But the exact benefit and safety of heparin and its derivatives as anti-inflammatory agents in clinical setting have not definitely proved yet. Our objective was to system- atically review and summarize the literature supporting anti- inflammatory role of heparin to provide evidence about the clinical effectiveness and safety of heparin in inflammatory conditions. Hindawi Publishing Corporation Advances in Pharmacological Sciences Volume 2015, Article ID 507151, 14 pages http://dx.doi.org/10.1155/2015/507151

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Review ArticleAnti-Inflammatory Effects of Heparin and Its DerivativesA Systematic Review

Sarah Mousavi1 Mandana Moradi2 Tina Khorshidahmad3 and Maryam Motamedi3

1Department of Clinical Pharmacy and Pharmacy Practice Faculty of Pharmacy and Pharmaceutical SciencesIsfahan University of Medical Sciences Isfahan Iran2Faculty of Pharmacy Zabol University of Medical Sciences Zabol Iran3Faculty of Pharmacy Tehran University of Medical Sciences Tehran Iran

Correspondence should be addressed to Sarah Mousavi smousavipharmmuiacir

Received 24 February 2015 Accepted 24 April 2015

Academic Editor Berend Olivier

Copyright copy 2015 Sarah Mousavi et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Background Heparin used clinically as an anticoagulant also has anti-inflammatory properties The purpose of this systematicreview was to provide a comprehensive review regarding the efficacy and safety of heparin and its derivatives as anti-inflammatoryagents Methods We searched the following databases up to March 2012 Pub Med Scopus Web of Science Ovid Elsevierand Google Scholar using combination of Mesh terms Randomized Clinical Trials (RCTs) and trials with quasi-experimentaldesign in clinical setting published in English were included Quality assessments of RCTs were performed using Jadad score andConsolidated Standards of Reporting Trials (CONSORT) checklist Results A total of 280 relevant studies were reviewed and 57studies met the inclusion criteria Among them 48 studies were RCTs About 65 of articles had score of 3 and higher according toJadad score Twelve studies had a quality score gt 40 according to CONSORT items Asthma (119899 = 7) inflammatory bowel disease(119899 = 5) cardiopulmonary bypass (119899 = 8) and cataract surgery (119899 = 6) were the most studied disease condition Forty studies useunfractionated heparin (UFH) for intervention the remaining studies use low molecular weight heparin (LMWH) ConclusionDespite the conflicting results heparin seems to be a safe and effective anti-inflammatory agent although it is shown that heparincan decrease the level of inflammatory biomarkers and improves patient conditions still more data from larger rigorously designedstudies are needed to support use of heparin as an anti-inflammatory agent in clinical setting However because of the associationbetween inflammation atherogenesis thrombogenesis and cell proliferation heparin and related compounds with pleiotropiceffects may have greater therapeutic efficacy than compounds acting against a single target

1 Introduction

Heparin is a highly sulfated glycosaminoglycan (GAG) thatis found in the mast cells of most mammalsThe endogenousGAGs are highly acidic and actively charged Heparin is themost sulfated and acidic GAGs enable it to bind to differentcomponent such as coagulating and fibrinolysing proteinsmany growth factors and immune response proteins such ascytokines and chemokines [1 2] Heparin ismostly known forits anticoagulant properties so commercially form of heparinincluding unfractionated heparin (UFH) and low molecularweight heparin (LMWH) used currently in treatment andprevention of thrombotic events like deep vein thrombosispulmonary emboli acute coronary syndromes and ischemic

cerebrovascular events as well as prevention of thrombosis inextracorporeal circuits and hemodialysis [3 4] Apart fromits anticoagulant effects there are several studies which haveshown that heparin possesses various anti-inflammatory andimmunomodulatory properties and the mechanisms of anti-inflammatory actions of heparin have been discussed recently[5 6] But the exact benefit and safety of heparin and itsderivatives as anti-inflammatory agents in clinical settinghave not definitely proved yet Our objective was to system-atically review and summarize the literature supporting anti-inflammatory role of heparin to provide evidence about theclinical effectiveness and safety of heparin in inflammatoryconditions

Hindawi Publishing CorporationAdvances in Pharmacological SciencesVolume 2015 Article ID 507151 14 pageshttpdxdoiorg1011552015507151

2 Advances in Pharmacological Sciences

2 Methods

21 Search Strategy A comprehensive literature search wasconducted in PubMed Scopus Web of Science OvidElsevier and Google Scholar from inception to March2012 using the following Mesh keywords (1) heparin (2)UFH (3) anticoagulants (4) dalteparin (5) enoxaparin (6)nadroparin (7) tinzaparin (8) heparinoids (9) inflamma-tion (10) inflammatory process (11) anti-inflammation (12)inflammation mediators (13) inflammatory bowel diseaseand (14) anti-inflammatory agents All keywords from 1 to8 were separately combined with each keyword from 9 to14 in all databases Articles were initially scanned based ontitles and abstracts by two reviewers (Sarah Mousavi andMandana Moradi) and related articles were retrieved in fulland assessed for eligibility by two reviewers (Sarah Mousaviand Mandana Moradi) The reference list of each eligiblestudy was checked to identify additional studies

22 Inclusion Criteria All Randomized Clinical Trials(RCTs) and studies with quasi-experimental design whichevaluated efficacy using inflammatory biomarkers levelsand safety (significant hemorrhage or thrombocytopenia)of anti-inflammatory effects of heparin and heparin-relatedderivatives (LMWH or other heparinoids) with an Englishabstract regardless of rout of administration (intravenoussubcutaneous topical or inhaler) age gender race andethnic origin of participants were included

23 Exclusion Criteria The following were excluded studiesbased on animal models preclinical and biological studiesletters and editorials report published as meeting abstractonly where insufficient data were reported to allow inclusion

24 Data Extraction and Quality Assessment Data from eacheligible study were extracted individually and compared bytwo authors (Sarah Mousavi and Mandana Moradi) usingstandard form that included study design setting samplesize duration and follow up dosing regimen interventiontype and outcomes Disagreements were resolved throughdiscussion if necessary they consulted a third person Anarrative synthesis was conducted

Quality assessment of clinical trials included in the anal-ysis were performed utilizing the Jadad score a previouslyvalidated instrument that assesses trials based on appro-priate randomization blinding and description of studywithdrawals or dropouts [7] The description of this score isas follows (1) whether it is randomized (yes = 1 point no =0) (2) whether randomization was described appropriately(yes = 1 point no = 0) (3) whether it is double-blind (yes = 1point no = 0) (4) whether the double-blindingwas describedappropriately (yes = 1 point no = 0) (5) whether withdrawalsand dropouts were described (yes = 1 point no = 0) Thequality score ranges from 0 to 5 points a low-quality reportscore is le2 and a high-quality report score is at least 3

The Consolidated Standards of Reporting Trials (CON-SORT) checklist was also used for randomized trials as it is

Citations identified in literature search

Full text review

Articles included in systematic review

Excluded

Excluded (n = 13)

(n = 553)

(n = 70)

(n = 57)

(ii) Title and abstract screening (n = 210)

(i) No outcome of interest (n = 11)(ii) Nonclinical study (n = 2)

(i) Duplicate citations (n = 275)

Figure 1 Flow diagram of literature search process

strongly endorsed by prominent journals and leading edi-torial organizations [8] Total possible score for CONSORTchecklist was considered as 74 two points for adequatedescription one point for inadequate description and zerofor no description

25 Statistical Methods To summarize and extract datathe database was designed by Microsoft office Access 2007(MicrosoftCorporation RedmondWA) A narrative synthe-sis was conducted and data were extracted into tables andsummarized

3 Results

Following Initial screening of mentioned databases total of553 citations (275 duplicates) were extracted but only 70 ofthem were potentially eligible for investigation of our objec-tives (according to our proposed inclusion criteria) based ontitles and abstracts The full text screening excluded other13 citations and the remaining 57 papers were consideredrelevant for data extraction and following analysis The flowchart of studiesrsquo selection processes is as shown in Figure 1

31 Study and Patient Characteristic Sample sizes rangedfrom 8 to 555 patients in 57 studies that met the criteriato be included Research designs mostly were randomizedcontrolled trial (119899 = 48) and the remaining (119899 = 9) had quasi-experimental designs using pre-post studies (119899 = 6)

Tables 1 and 2 [9ndash62] list the characteristics of theincluded studies The most studied clinical conditions wascardiopulmonary bypass (119899 = 12) followed by Asthma(119899 = 8) inflammatory bowel disease (IBD) (119899 = 5) acutecoronary syndrome (ACS) (119899 = 8) and ophthalmologicaldisease (119899 = 8) Other less common studied conditions wereas follows burn cystic fibrosis allergic rhinitis superficial

Advances in Pharmacological Sciences 3

Table1Summaryandfin

ding

sofcom

mon

studied

diseases

Clinicalsetting

Heparin

preparation

Mod

eof

administratio

nCom

parator

Num

bero

fpatie

nts

Clinicalou

tcom

eLabo

ratory

outcom

eStud

ydesig

n

Exercise-in

duced

Asthma[

9]UFH

Inhaler

Crom

olyn

sodium

orplacebo

12Sign

ificantlyredu

ctionof

exercise-in

ducedasthma

Heparin

hadno

effecto

nhistam

ine-indu

ced

bron

chocon

strictio

n

Sing

le-blin

drand

omized

crossoverc

linicaltrial

Asthma[

10]

UFH

Inhaler

Placebo

8

Sign

ificant

redu

ctionof

late

asthmaticrespon

seaft

erallergen

administratio

n(119875

0005)

mdashRa

ndom

izeddou

ble-blind

crossoverc

linicaltrial

Atop

icasthma

[11]

Heparin

(IVX-

0142)

Nebulizer

Placebo

19Nosig

nificantd

ecreasein

early

(119875006)

andlate(119875

024)a

sthm

aticrespon

semdash

Rand

omized

single-blind

placebo-controlled

crossovertria

l

Asthma[

12]

LMWH

Nebulizer

mdash24

Effectiv

easa

nadd-on

therapyto

stand

ard

treatment

Redu

ctionin

eosin

ophil(119875

000

06)and

lymph

ocyte(119875

0049)

inbron

choalveolar

lavageNochangesinIL-5

orEC

Pconcentrations

inserum

Quasi-experim

ental

(pretest-

posttestd

esign)

Allergicasthma

[13]

UFH

Inhaler

Placebo

25

Heparin

inhalatio

nsig

nificantly

redu

ced

bron

chialhyperreactiv

ity(119875lt005)

mdashRa

ndom

izeddou

ble-blind

placebo-controlled

crossovertria

l

Asthma[

14]

UFH

Inhaler

mdash12

Transie

nt(time-depend

ent)

inhibitory

rolein

allergic

reactio

ns

Increasedthem

ethacholine

PC20

value(119875005)

but

didno

tprevent

anincrease

inRa

wandor

adecreasein

SGAW

Rand

omizeddou

ble-blind

placebo-controlled

crossovertria

l

Asthma

(children)

[15]

UFH

Inhaler

Placebo

14

Sing

ledo

seof

heparin

significantly

(1198750005)

redu

cedbron

chial

hyperreactivity

Provocationtestused

leuk

otrie

neD4

Rand

omizeddou

ble-blind

placebo-controlled

crossovertria

l

Asthma[

16]

UFH

Inhaler

Placebo

23Sign

ificant

redu

ctionof

bron

chialhyperreactiv

ityto

histam

inea

ndleuk

otrie

nemdash

Rand

omizeddou

ble-blind

placebocontrolled

crossovertria

l

IBD[17]

UFH

IVSC

Hydrocortiso

ne+

prednisolone

20(12in

control

grou

p)

Clinicalactiv

ityindexsto

olfre

quencyand

endo

scop

icandhisto

pathological

gradingweres

imilarin

both

treatmentg

roup

s

CRPand1205721a

cid

glycop

rotein

didno

tchange

Openlabelrando

mized

crossoverc

linicaltrial

4 Advances in Pharmacological Sciences

Table1Con

tinued

Clinicalsetting

Heparin

preparation

Mod

eof

administratio

nCom

parator

Num

bero

fpatie

nts

Clinicalou

tcom

eLabo

ratory

outcom

eStud

ydesig

n

IBD[18]

UFH

SCmdash

17

Histologyim

proved

significantly

inulcerativ

ecolitispatie

nts(UFH

iseffectiv

einulcerativ

ecolitis

butn

otCr

ohndisease)

CRP(11987500119

)and

ESR

(11987500096)

significantly

redu

cedin

ulcerativ

ecolitis

butn

otCr

ohndisease

Quasi-experim

ental

(pretest-

posttestd

esign)

IBD[19

]UFH

IVMethylpredn

isolone

25(13in

control

grou

p)

Noeffecto

fheparinalso

increasedbleeding

Nochange

inCR

PRa

ndom

izeddou

ble-blind

parallel-g

roup

trial

IBD[20]

Enoxaparin

+sta

ndard

treatment

SCAminosalicylate+

corticosteroid

34(18in

control

grou

p)

Sign

ificant

improvem

entin

diseases

everity

inbo

thgrou

ps(1198750001)

NodifferenceE

SRC

RPandfib

rinogen

and

coagulation

Rand

omized

controlled

trial

IBD[21]

Nadroparin

SCmdash

25

Endo

scop

icand

histo

logicalsignof

inflammationsig

nificantly

improved

mdashQuasi-experim

ental

(Non

-rando

mized

clinical

trial)

Cataractsurgery

[22]

UFH

Intraocular

lens

(IOL)

Polymethylm

ethacrylate

524

mdash

Heparin

surfa

cemod

ificatio

nredu

cedthe

cellu

lard

epositcompared

tocontrolgroup

Rand

omizeddou

ble-blind

parallelgroup

clinicaltria

l

Cataractsurgery

[23]

UFH

Intraocular

lens

(IOL)

Polymethylm

ethacrylate

58(31in

control

grou

p)

Posto

perativ

einfl

ammation

decreasedsig

nificantly

inheparin

grou

p(119875002)

Giant

cellandcelldepo

sitdecreasedsig

nificantly

(119875lt005)

Rand

omizeddou

ble-blind

clinicaltria

l

Cataractsurgery

(pediatric)[24]

UFH

Irrig

ation

Balanced

saltsolutio

n33

(19in

control

grou

p)

Heparin

irrigationredu

ced

numbero

fpostoperativ

einflammatoryrelated

complication

Anteriorc

hamberreaction

inclu

ding

fibrin

form

ation

was

lower

inheparin

grou

p

Rand

omized

prospective

doub

le-blin

dtrial

Cataractsurgery

(pediatrics)[25]

Enoxaparin

Irrig

ation

Notre

atment

40(20in

each

grou

p)

Increase

offlare

andcell

depo

sitaft

ersurgery(1and

3mon

ths)(119875099)

Increase

inlargec

ell

depo

sits

Rand

omizeddou

ble-blind

controlledtrial

Cataractsurgery

[26]

UFH

Irrig

ation

Regu

larirrigation

solutio

n72

Sign

ificant

redu

ctionof

inflammationin

thee

arly

(days1ndash3)p

ostoperativ

eperio

d(119875lt001)

mdashRa

ndom

ized

controlled

trial

Cardiopu

lmon

ary

bypass(pediatric)

[27]

Heparin-

coated

circuit

(119899=11)

mdashNon

-heparin-coated

circuit(119899=10)

21

Decreaseo

fsystemic

inflammatoryrespon

sewith

theu

seof

heparin

-bon

ded

oxygenators

Sign

ificantlydecreased

levelsof

IL-6IL-8term

inal

complem

entcom

plex

neutroph

ilsand

elastase

inheparin

coated

circuit

Rand

omized

controlled

trial

Cardiopu

lmon

ary

bypass[28]

Heparin-

coated

circuit

plusmnaprotin

inmdash

Uncoatedcircuitplusmn

aprotin

in200(4

grou

ps)

Aprotin

inandheparin

had

noeffecto

ncytokine

release

TNF-120572IL-6andIL-8

and

myeloperoxidase

didno

tchange

Rand

omizeddou

ble-blind

clinicaltria

l

Advances in Pharmacological Sciences 5

Table1Con

tinued

Clinicalsetting

Heparin

preparation

Mod

eof

administratio

nCom

parator

Num

bero

fpatie

nts

Clinicalou

tcom

eLabo

ratory

outcom

eStud

ydesig

n

Cardiopu

lmon

ary

bypass[29]

UFH

mdashUncoatedcircuit

51(26in

each

grou

p)

Decreased

pulm

onary

vascular

resistanceind

exandpu

lmon

aryshun

tfractio

nandincreased

PaO2FIO2ratio

Lower

levelsof

phosph

olipaseA

2and

complem

entactivation(119875

0001)

Rand

omizeddou

ble-blind

clinicaltria

l

Cardiopu

lmon

ary

bypass[30]

Heparin-

coated

circuit

mdashNon

-heparin-coated

circuit

16(9

incontrol

grou

p)mdash

Nosig

nificantd

ifference

betweengrou

psregarding

granulocytee

lasta

seIL-6

IL-8

Quasi-experim

ental

(pretest-

posttestd

esign)

Cardiopu

lmon

ary

bypass[31]

Heparin

concentration-

based

syste

m

mdashAc

tivated

clotting

time-based

managem

ent

200(100

incontrol

grou

p)

Noeffecto

npo

stoperativ

ebloo

dloss

Sign

ificant

redu

ctionof

neutroph

ilactiv

ationand

fibrin

olysisandthrombin

generatio

n(119875lt005)

Rand

omized

controlled

trial

Cardiopu

lmon

ary

bypass(pediatric)

[32]

Heparin-

coated

circuit

mdashNon

-heparin-coated

circuit

19(10in

control

grou

p)

Improvem

ento

fthe

biocom

patib

ilityof

CPB

durin

gheartsurgery

Levelsof

complem

ent

factor

C3a(119875lt0001)a

ndIL-6

(1198750005)significantly

redu

cedin

heparin

-coated

circuit

Rand

omized

controlled

trial

Cardiopu

lmon

ary

bypass(pediatric)

[33]

Heparin-

coated

circuit

mdashNon

-heparin-coated

circuit

34(12in

control

grou

p)

Nodifferences

indu

ratio

nof

intubatio

nintensivec

are

unitor

hospita

lstayor

posto

perativ

eblood

loss

IL-6IL-8andTN

F-120572we

resig

nificantly

lower

inheparin

grou

p(119875lt001

119875lt001and119875lt005

resp)

Rand

omized

controlled

trial

Cardiopu

lmon

ary

bypass[34]

Heparin-

coated

circuit

(heparin

+aprotin

in)

mdashNon

-heparin-coated

circuit(heparin

+aprotin

in)

30(15in

each

grou

p)

Nosig

nificantd

ifferences

betweenthetwogrou

psin

term

sofb

leedingand

transfu

sionalrequirements

thetim

espent

ona

ventilatoror

indu

ratio

nof

stayin

theintensiv

ecare

unit(ICU

)

Levelsof

IL-6C

RPand

neutroph

ilcoun

tdid

not

change

byheparin

-coated

circuitMon

ocytec

ount

increasedin

heparin

-coatedcircuit

Rand

omized

controlled

trial

Coron

aryartery

bypassgraft

ing

(CABG

)[35]

Heparin-

coated

circuit

mdashNon

-heparin-coated

circuit

18(9

ineach

grou

p)mdash

Redu

ctionof

levelsof

IL-8

andTN

F-120572andincrease

ofneutroph

ilelastase

Rand

omized

controlled

trial

CRP

C-Re

activ

eProteinC

PBC

ardioPu

lmon

aryB

ypassEC

PEo

sinop

hilC

ationicP

roteinE

SRE

rythrocyteSedimentatio

nICUIntensiv

eCareU

nitILinterleuk

inIV

intravenou

sSC

sub

cutaneou

sSG

AW

SpecificA

irway

Con

ductanceT

NFTu

mor

Necrosis

Factorand

UFH

unfractionatedheparin

6 Advances in Pharmacological Sciences

Table2Summaryandfin

ding

sofo

ther

studied

diseases

Clinicalsetting

Heparin

preparation

Mod

eof

administratio

nCom

parator

Num

bero

fpatie

nts

Clinicalou

tcom

eLabo

ratory

outcom

eStud

ydesig

n

Pancreatitisa

fter

ERCP

[36]

UFH

SCSalin

esolution

105(54in

control

grou

p)

Rateof

posto

perativ

epancreatitisw

asno

tsig

nificantb

etweenbo

thgrou

ps

mdashRa

ndom

ized

placebo-controlledclinical

trial

Acutec

oron

ary

synd

rome(AC

S)[37]

UFH

SCEn

oxaparin

201

mdashNosig

nificantd

ifference

betweenCD

4ligandand

PAI-1inbo

thgrou

ps

Openlabelrand

omized

clinicaltria

l

Skin

orpu

lmon

ary

allergy[38]

UFH

IVnebulizer

Normalsalin

eplacebo

25Sign

ificant

inhibitio

nof

mastcell-m

ediatedallergic

inflammation(119875004)

mdashDou

ble-blind

placebo-controlled

crossoverc

linicaltrial

COPD

[39]

UFH

IVmdash

37(18in

control

grou

p)

Sign

ificant

improvem

entin

bron

chospasm

and

bron

chialsecretio

ns(58

respon

serate)

mdashRa

ndom

ized

placebo-controlledclinical

trial

COPD

[40]

Nadroparin

SCCon

ventionaltreatment

66(33in

each

grou

p)

Decreaseo

fdurationof

mechanicalventilationand

leng

thof

hospita

land

ICU

stay(119875lt001)

Sign

ificant

decrease

inlevelsof

CRPIL-6and

fibrin

ogen

Rand

omized

controlled

trial

Ischem

icstroke

[41]

UFH

IVAs

pirin

167(97in

control

grou

p)

Early

onsetinitia

tionof

heparin

might

improve

recovery

after

stroke

Rise

ofsV

CAM-1at48

hwas

significantly

lower

inpatie

ntstreated

with

UFH

(119875lt001)

Quasi-experim

ental

(con

trolledob

servational

study)

Lign

eous

conjun

ctivitis[42]

UFH

Topical

Alpha

chym

otrypsin

orste

roid

17(12in

control

grou

p)

Intensivea

ndearly

useo

ftopicalh

eparin

may

improvetherapy

results

indisease

mdashQuasi-experim

ental

(non

rand

omized

Clinical

trial)

Endo

toxemia

(indu

cedby

lipop

olysaccharide

inhealthysubjects)

[43]

UFH

IVLM

WHor

placebo

30(10in

each

grou

p)mdash

Noeffecto

nTN

F-120572IL-6

and8CR

PandE-selectin

Rand

omized

doub

le-blin

ded

placebo-controlledparallel

grou

ptrial

Mechanical

ventilatio

n[44]

UFH

Nebulizer

Normalsalin

e(placebo)

50(25in

each

grou

p)

Fewer

days

onmechanical

ventilatio

nbette

rPao2Fio2ratio

mdashDou

ble-blindrand

omized

placebo-controlledtrial

Percutaneous

coronary

interventio

n[45]

Bivalirud

inIV

UFH

+eptifi

batid

e63

(29in

control

grou

p)mdash

Increase

inIL-6

andCR

Paft

er1d

ayD

ecreaseinCR

Pin

bivalirud

ingrou

paft

er30

days

(1198750002)

Rand

omized

controlled

trial

Cysticfib

rosis

(adu

lts)[46

]UFH

Inhaler

mdash12

(6in

control

grou

p)Spiro

metry

parametersd

idno

tchang

eIL-6

redu

cedaft

ertre

atment

Quasi-experim

ental

(pretest-

posttestd

esign)

Advances in Pharmacological Sciences 7Ta

ble2Con

tinued

Clinicalsetting

Heparin

preparation

Mod

eof

administratio

nCom

parator

Num

bero

fpatie

nts

Clinicalou

tcom

eLabo

ratory

outcom

eStud

ydesig

n

Cysticfib

rosis

(adu

lts)[47]

UFH

Inhaler

Placebo

14Noeffecto

nFE

V1

Noeffecto

nsputum

inflammatorymarkers

Rand

omizeddou

ble-blind

placebo-controlled

crossovertria

l

Hem

odialysis

patie

nts[48]

UFH

IVSC

LMWHandno

drug

33

LMWHdecreased

oxidatives

tressand

inflammationwhereas

heparin

increasedthem

CRPTN

F-120572sup

eroxide

dism

utaseMDAincreased

inheparin

grou

pbu

tcomparabletoLM

WH

grou

p

Quasi-experim

ental

(pretest-

posttestd

esign)

Stableangina

[49]

Heparin

+Aspirin

(119899=15)

mdashArgatroban+As

pirin

(119899=12)2

7

Nodifferencein

inflammatoryrespon

seaft

erangiop

lasty

Fibrinogen

decreased

significantly

inargatro

ban

grou

pNodifferenceinvon

Willberand

factor

between

both

grou

psPAI-1

increasedin

argatro

ban

grou

p

Rand

omized

controlled

trial

Phacoemulsifi

catio

n[50]

Heparin

Coatedlenses

Polymethylm

ethacrylate

lenses

367

Heparin

coated

lenses

redu

cedsig

nificantly

inflammationearly

posto

peratio

n(119875005)

mdashRa

ndom

izeddou

ble-blind

multic

enterparallelgroup

trial

Allergicrhinitis[51]

UFH

Intranasal

mdash10

mdashRe

ductionof

eosin

ophil

catio

nicp

rotein

inthen

asal

wash

Quasi-experim

ental

(pretest-

posttestd

esign)

Phacom

orph

icglaucoma[

52]

Dalteparin

Irrig

ation

Balanced

saltsolutio

n46

(23in

each

grou

p)

Sign

ificant

decrease

ofpo

stoperativ

einfl

ammation

indalteparin

grou

pmdash

Rand

omizeddou

ble-blind

clinicaltria

l

Burn

[53]

Dalteparin

SCNotre

atment

24mdash

Decreaseo

fnitricoxide

synthetase

activ

itysig

nificantly

Quasi-experim

ental

(non

rand

omized

clinical

trial)

Unstablec

oron

ary

artery

disease[54]

Enoxaparin

(119899=46)

Dalteparin

(119899=48)

SCUFH

(119899=47)

68

VonWillberand

factor

may

have

progno

sticv

aluebut

otherb

iologicalvariables

didno

tpredictou

tcom

e

CRPfib

rinogenV

onWillberand

factor

increased

over

first2days

despite

medicaltre

atment

Enoxaparin

(13

)and

dalteparin

(19)reduced

releaseo

fVon

Willberand

factor

Openlabelrand

omized

clinicaltria

l

ST-Elevated

Myocardial

Infarctio

n(STE

MI)

[55]

Enoxaparin

SCUFH

34(17in

each

grou

p)

Both

heparin

and

enoxaparin

show

anti-inflammatoryeffects

inST

EMIp

atients

Serum

AmyloidA(119875002)

CRP(119875002)and

ferritin

(119875001)redu

cedin

heparin

grou

pIL-6

(1198750002)SA

A(1198750009)CR

P(119875001)

weres

ignificantly

decreased

inenoxaparin

grou

pTh

eoveralld

ifference

between

grou

pswas

notsignificant

Openlabelrand

omized

clinicaltria

l

8 Advances in Pharmacological Sciences

Table2Con

tinued

Clinicalsetting

Heparin

preparation

Mod

eof

administratio

nCom

parator

Num

bero

fpatie

nts

Clinicalou

tcom

eLabo

ratory

outcom

eStud

ydesig

n

Coron

aryartery

disease[56]

Dalteparin

SCPlacebo

555(285

incontrolgroup

)

Dalteparin

redu

ced

coagulationandso

MyocardialInfarctionbu

thasn

otinflammatory

activ

ity

Noeffectson

IL-6

C-reactiv

eprotein

and

fibrin

ogen

Rand

omizeddou

ble-blind

parallel-g

roup

multic

entre

trial

Stablecoronary

artery

disease[57]

Enoxaparin

SCSo

dium

chlorid

e62

(31ineach

grou

p)

Bymob

ilizing

vesselbo

und

MPO

eno

xaparin

improves

endo

thelialfun

ction

Sign

ificant

increase

ofMPO

levels

Rand

omizeddou

ble-blind

placebo-controlledtrial

Acutec

oron

ary

synd

romea

ndPC

I[58]

Tirofib

an(highdo

se)+

enoxaparin

Tirofib

an(highdo

se)+

UFH

60(30in

each

grou

p)

Thec

ombinatio

nof

tirofi

ban(highdo

se)+

enoxaparin

redu

ced

inflammationaft

erPC

I

Vonwillberand

CRP

D-dim

erand

prothrom

bin

fragmentw

eres

ignificantly

lower

inenoxaparin

grou

pthan

UFH

Openlabelrando

mized

controlledtrial

Superficialveno

usthrombo

phleb

itis

[59]

Dalteparin

SCIbup

rofen

72(37in

dalteparin

grou

p)

Sign

ificant

redu

ctionof

pain

form

baselin

etoday14

offollo

w-upNodifference

onthrombo

sisprogression

after

3mon

ths

mdashRa

ndom

izeddou

ble-blind

controlledtrial

Superficialveno

usthrombo

sis[60]

Nadroparin

SCNaproxen

117(39in

control

grou

p)

Nadroparin

redu

ced

symptom

andsig

nsof

thrombo

sedsuperficial

vein

bette

rthannaproxen

(1198750007)

mdashRa

ndom

izedopenlabel

clinicaltria

l

Superficialveno

usthrombo

sis[61]

Nadroparin

SCNadroparin

+acem

etacin

50

Sign

ificant

symptom

improvem

entinbo

thgrou

ps(1198750001)Th

ecombinatio

ngrou

pwas

bette

r

mdashRa

ndom

ized

controlled

trial

Periton

eald

ialysis

patie

nts[62]

Tinzaparin

Intraperito

neal

Isoton

icsalin

e21

Redu

ctionof

localand

syste

micinflammationin

periton

eald

ialysis

patie

nts

Redu

cedlevelsof

CRP(119875

0032)

andfib

rinogen

(119875

004

2)andIL-6

(1198750007)

indialysate

Rand

omizeddou

ble-blind

placebo-controlled

crossovertria

l

COPD

Chron

icObstructiv

ePu

lmon

aryDise

aseCR

PC-

Reactiv

eProtein

CPB

Cardio

Pulm

onaryBy

passE

CPE

osinop

hilC

ationicProtein

ERCP

End

oscopicRe

trogradeCh

olangiop

ancreatographyE

SR

ErythrocyteSedimentatio

nICUIntensiv

eCa

reUnitILinterleuk

inIV

intravenou

sLM

WHlow

molecular

weighth

eparinM

DAm

alon

dialdehydePAIPlasminogen

Activ

ator

InhibitorSC

sub

cutaneou

ssV

CAMSolub

leVa

scular

CellA

dhesionMoleculeTN

FTu

mor

Necrosis

Factorand

UFH

unfractionatedheparin

Advances in Pharmacological Sciences 9

Table 3 Summary of numbers and percentages of adequatelyreported items in each trial according to CONSORT checklist andJadad score

Trials Jadadscore

Adequately reporteditems (119899119873)

Percentage()

Abdollahi et al [52] 4 2974 392Ahmed et al [9] 3 2074 27Ang et al [17] 2 2474 324Ashraf et al [27] 2 2274 297Becker et al [37] 3 2874 378de Vroege et al [29] 3 2674 351Defraigne et al [28] 4 2874 378Derhaschnig et al [43] 3 3274 432Dixon et al [44] 4 5074 675Duong et al [11] 3 3074 405Gu et al [71] 2 1674 216Jerzynska et al [13] 3 2074 27Keating et al [45] 2 2174 284Koster et al [31] 2 2674 351Montalescot et al [54] 3 3574 473Nasiripour et al [55] 2 3474 46Oldgren et al [56] 3 2774 365Olsson et al [32] 2 2574 338van Ophoven et al [79] 2 2774 365Ozawa et al [33] 2 2774 365Ozkurt et al [24] 3 1874 243Paparella et al [72] 2 2274 297Polosa et al [67] 3 2374 311Rathbun et al [59] 5 4474 595Rudolph et al [57] 3 3174 412Serisier et al [47] 5 4574 608Stelmach et al [16] 3 3174 412Suzuki et al [49] 2 2374 31Vancheri et al [51] 4 2274 297Vasavada et al [25] 5 5274 702Walters et al [58] 3 3274 432Zezos et al [20] 3 3774 50

thrombophlebitis and hemodialysis Unfractionated heparin(UFH) was used in forty studies as subcutaneous intra-venous inhaler or heparin-coated circuits while others usedenoxaparin (119899 = 3) dalteparin (119899 = 4) nadroparin (119899 = 4)and tinzaparin (119899 = 1)

Table 3 provides information on the adequately reporteditems according to Jadad score andCONSORT items Amongthese 32 papers 11 (354) scored 2 and the remaining studiesscored 3 or higher according to Jadad score and just threestudies fulfill the criteria of Jadad score Calculated qualityscores according to CONSORT checklist range from 21 to70 in our object studies with twelve studies scoring greaterthan 40 The following characteristics were not exactlyreported in more than half of the trials identification as

a randomized trial in the title information about the settingand location of studies determination of sample size alloca-tion and implementation of randomization participant flowrecruitment and follow-up subgroup analysis limitations ofstudy harms registration number access to full trial protocoland funding source

4 Discussion

We discuss evidence from clinical studies supporting an anti-inflammatory role for heparin and heparin-related deriva-tives

41 Asthma Asthma is a chronic inflammatory disorderof airways characterized by bronchial hyperresponsivenessresulting in episodic bronchospasm Several studies in 1960sdescribed subjective improvement of symptoms in asthmaticpatients using intravenous heparin for the first time [3963] Inhaled heparin or its derivatives have been shown topossess antiasthmatic properties in various clinical modelsallergen induced [38 64] exercise [9] adenosine [6] anddistilled water challenge models [65] Seven randomizedcontrolled crossover trials studied anti-inflammatory effectsof heparin in exercise-induced or allergen-induced asthmahaving sample size range from 8 to 25 in 5 trials

Heparin inhalation reduced bronchial hyperreactivity ina single-blind randomized crossover trial (119899 = 12) byAhmed et al [9] Heparin inhalation (1000 120583kg) preventsexercise-induced asthma (119875 lt 005) without preventionof histamine-induced bronchoconstriction Stelmach et al[66] provoke challenge tests with histamine or leukotrieneD4 before and after inhalation of heparin showed that hep-arin (5000 Iu) decreases histamine and leukotriene-inducedbronchial hyperreactivity compared to placebo significantly(119875 0043 and 0005) but changes in Forced Expiratory Vol-ume (FEV 1) were not significant (119875 0064) The inhibitoryeffects of inhaled heparin in the airways in the absence ofbronchodilation might be related to suppressive action onmast cell degranulation A randomized double-blind studyin 10 subjects with asthma showed that heparin inhalationattenuates airway response to adenosine 51015840-monophosphate(AMP) but not to methacholine (119875 lt 001) suggestingthe theory that heparin acts more likely in association tomodulation of mediator release compared to a direct effecton smooth muscle [67]

Our results showed that inhaled enoxaparin was usedjust in a pre-post study of 24 asthmatic patients measur-ing inflammatory biomarkers and showed a reduction ineosinophil (119875 0006) and lymphocytes of bronchoalveolarlavage without any significant change in IL-5 or EosinophilCationic Protein (ECP) concentrations [12] Therefore itseems that enoxaparin could be a valuable add on treatmentin asthma like UFH Duong et al [11] evaluated IVX-0142nebulizer a heparin-derived hypersulfated disaccharide inasthma and showed nonsignificant decrease in early and lateasthmatic response

Performed studies did not show any adverse events orharms with heparin or related compounds except increase in

10 Advances in Pharmacological Sciences

the plasma partial thromboplastin time reported by Ahmedet al [9]

All in one considering the results of these studies wecan conclude that heparin and its derivatives could have anti-inflammatory effects and could be considered along withother treatments in asthma

42 Cardiopulmonary Bypass Contact and interaction ofblood with foreign surfaces during cardiopulmonary bypass(CPB) cause systemic inflammatory response syndrome(SIRS) through activation of several humoral cascadesincluding cytokines such as IL-6 IL-8 and Tumor NecrosisFactor-120572 (TNF-120572) [68] The inflammatory response can beattenuated by promoting the biocompatibility of the CPBcircuit Use of heparin-treated surfaces in CPB circuits hasbeen shown to decrease activation of leukocytes and thecomplement cascades [5] As a result need to inotropicsupport postoperative time of mechanical ventilation andrate of acute lung injury decrease and patients durationof hospital stay shortens which reflects the positive effectof heparin in CPB circuits [69 70] Twelve studies whoseendpoints were the effects of heparin-bonded circuits oninflammatory markers were included in our analysis and inthe majority of these trials [27 29 32ndash35 71] heparin-coatedcircuit significantly decreased the level of cytokines such asIL-6 IL-8 TNF-120572 complement complex neutrophils andelastase compared to non-heparin-coated circuit

Defraigne et al [28] randomized 200 patients in 4 groupsheparin-coated circuit with or without aprotinin administra-tion and uncoated circuit with or without aprotinin adminis-tration They measured IL-6 IL-8 TNF-120572 myeloperoxidase(MPO) and elastase level and concluded that cytokine releaseand neutrophil activation were not attenuated by heparin-coated circuit or by the administration of aprotinin Misawaet al [30] evaluated cytokines level under normothermicCPB in a small observational controlled study (119899 = 19 9 incontrol group) Levels of IL-6 IL-8 and ICAM-1 (indicatorof endothelial damage) were not different between study andcontrol group However as mentioned before most studiesindicate the favorable effect of heparin-coated circuit oninflammatory responses in CPB

Paparella et al [72] compared two doses of heparin and300 Iukg and 600 Iukg in 40 patients undergoing CPB in anRCT and showed that IL-6 and TNF-120572 plasma levels were inassociation to heparin dose It seems that lower heparin dosehad small influence on proinflammatory cytokines releasehowever higher doses make a better regulatory effect oncoagulation system

The side effects of heparin-coated circuits were notreported In these studies just a number of included studiesreported a decrease in platelet levels in both groups (coatedand noncoated circuit) No major events including hemor-rhage were reported

43 Inflammatory Bowel Diseases (IBD) Hypercoagulablestate may be an important contributing factor in the patho-genesis of IBD especially ulcerative colitis (UC) [73] A num-ber of studies evaluate the effects of heparin administrationon UC but the results obtained are controversial [17 19]

Bloom et al [74] did not find any favorable effect of LMWHtinzaparin over placebo in the treatment of active UC ina double-blind randomized placebo controlled multicentertrial (119899 = 100) evaluating mean change in colitis activity asthe primary endpoint Ang et al [17] compared heparin tohydrocortisone plus prednisolone in 20 patients (UC 119899 = 17Crohnrsquos colitis 119899 = 3) in open-label randomized crossovertrial whichmeasured endpoints clinical disease activity stoolfrequency and 120572

1acid glycoprotein and endoscopic and

histopathological grading indicate the efficacy and safety ofheparin compared to corticosteroids (119875 gt 005) in contrastthe study by Panes et al [19] did not show the efficacy ofheparin in UC compared to methylprednisolone

Zezos et al [20] compared enoxaparin with standardtreatment (aminosalicylate + corticosteroids) in 34 patientswith active UC The inflammatory biomarkers includingC-Reactive Protein (CRP) Erythrocyte Sedimentation Rate(ESR) and fibrinogen did not show any difference in studygroup compared to control and both groups showed similarrate of disease improvement (119875 gt 005) furthermorecoagulation factors did not change from one to anotherAuthors concluded that enoxaparin is a safe adjuvant but hasno additive benefit over standard treatment of UC

Generally the studies show conflicting results The hep-arin and LMWHs showed efficacy in regard of disease activityand also well tolerated but inflammatory markers did notchange significantly Therefore the improvement in diseaseactivity might be the result of heparinrsquos anticoagulant effects

44 Acute Coronary Syndrome (ACS) Inflammation has akey role in the pathogenesis of coronary artery plaquedestabilization and rupture leading to acute coronary syn-dromes (ACS) [75] Leukocyte activation monocyte andneutrophil infiltration result in local and systemic inflam-matory responses [76] Heparin and LMWHs are commonlyused in ACS to prevent clot formation they also seem tohave desirable effects on inflammatory markers level basedon sparse data

We found 8 studies about heparin and LMWHs in CADsevaluating anti-inflammatory effects as their endpoints Old-gren et al [56] found that dalteparin administration inpatients with unstable CAD (119899 = 555) did not affect IL-6C-Reactive Protein (CRP) and fibrinogen levels although itreduced coagulation activity and mortality rate in long termso it is concluded that these effects are not related to its anti-inflammatory properties Walters et al [58] compared highdose of tirofibanenoxaparin (119899 = 30) with tirofibanheparin(119899 = 30) in an open-label randomized controlled trial in highrisk percutaneous interventionThey found that combinationof high dose of tirofiban with enoxaparin significantly atten-uate inflammatory process (decreased levels of CRP and vonWillebrand factor) compared to tirofiban and heparin

The ARMADA study [54] evaluated anti-inflammatoryeffects of heparin and enoxaparin in Non-ST-ElevatedMyocardial Infarction (Non-STEMI) and reported thatinflammatory markers (CRP and von Willebrand factor)are affected more by LMWH compared to UFH Howeverbecause of the small sample size of the study (119899 = 68)

Advances in Pharmacological Sciences 11

it did not acquire sufficient statistical power to prove anyeffects on defined outcomes Nasiripour et al [55] found thatboth enoxaparin and heparin reduce inflammatory markersin STEMI patients at the same level however this study hadthe same limitations of sample size (119899 = 34) and power too

In summary considering heparins as the main stay treat-ment of ACS its effects are more pronounced as anticoagu-lating than as an anti-inflammatory agent in this pathologicalcondition

45 Cataract Surgery Postoperative inflammation isobserved in cataract surgery especially in children Newertechniques as lensectomy and phacoemulsification cause lesscomplication but still pose potential risks [77 78] It hasbeen suggested that a heparin surface-modified intraocularlens (IOL) or augmenting the irrigating solution withheparin during cataract surgery may reduce the incidence ofpostoperative inflammation Borgioli et al [22] confirm thishypothesis that heparin surface-modified IOL will reducethe inflammatory response compared to conventional IOLat least in short term period (3 months) in a large (524patients) double-blind multicenter trial A similar study byColin et al [23] (119899 = 58) confirms their results howeverthe power of Borgioli et al study was higher Heparinizedlenses showed also more anti-inflammatory effects duringlong term follow-up (1 year) Heparinized irrigating solutionwas used during cataract surgery in two different studies andinflammation decrease observed in the early postoperativeperiod of both studies (Kohnen et al [26] and Ozkurt et al[24]) Therefore it seems that heparin in both forms haveanti-inflammatory effects in cataract surgery

Vasavada et al [25] used enoxaparin irrigation solutionin 20 children undergoing bilateral cataract surgery butthey did not find any beneficial effect in early postoperativeinflammation This study acquired the highest quality in thestudy quality assessment process based on Jadad score andCONSORT items (5274 702) It is worth noticing that themajority of itemsmentioned in the CONSORT checklist wereadequately reported and covered in this paper

Potential mechanisms of anti-inflammatory effects ofheparin have been discussed completely in a review by Young[6] Binding of heparin to different mediators involved inthe immune system response (cytokines and chemokines)acute phase proteins and complement complex proteinsmay contribute to the anti-inflammatory activity of heparinNeutralizing of cytokines at the inflammation site is anotherpossible mechanism In most of the studies level of cytokinessuch as IL-6 IL-8 TNF-120572 and CRP was decreased afterheparin administration which can confirm this mechanismalso heparin and LMWHs inhibit adhesion of leukocytesand neutrophils to endothelial cells by binding to p-selectinand consequently prevent release of oxygen radicals andproteolytic enzymes Other possible mechanisms are as fol-lows inhibition of nuclear factor 120581B (NF-120581B) and inductionof apoptosis by modulation of activity of TNF-120572 and NF-120581B In a double-blind placebo-controlled trial (119899 = 62)in patients with stable coronary artery disease followingadministration of 1mgkg subcutaneous enoxaparin plasmalevels of myeloperoxidase (MPO) increased significantly

(119875 lt 0001) and subsequently endothelial function improved(119903 = 067 119875 lt 0001) through MPO binding to endotheliumand depleting vascular nitric oxide [57] This study confirmsanother possible mechanism of heparins anti-inflammatoryeffects

5 Conclusion

As we discussed heparins potential effects as anti-inflamma-tory agents supported by several clinical trials in varioussetting Heparin and its related derivatives have been shownto benefit patients with asthma and patients undergoingcardiopulmonary bypass and cataract surgery In otherinflammatory diseases such as IBD (ulcerative colitis) thestudies are heterogeneous and incongruent Most studies didnot report any unwanted event with heparins when they usedthem as anti-inflammatory agents whether through systemicor through local (as inhaler or irrigation or heparin-coatedcircuit) administration However because the majority ofthese trials did not pose optimal quality scores we cannotdraw a definite conclusion on the efficacy of heparin and itsderivatives as anti-inflammatory agents

The present review included studies which measuredinflammatory markers as their endpoints and in most ofthem these markers were decreased though not significantlyTo come to a definite conclusion further double-blindrandomized placebo-controlled clinical trials with a largersample size are needed However because the inflammationatherogenesis thrombogenesis and cell proliferation areassociated with each other the pleiotropic effects of heparinand related compounds may have greater therapeutic effectthan compounds that are directed against a single target

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

[1] B Casu ldquoHeparin structurerdquo Pathophysiology of Haemostasisand Thrombosis vol 20 supplement 1 pp 62ndash73 1990

[2] J Hirsh R Raschke T EWarkentin J E Dalen DDeykin andL Poller ldquoHeparin mechanism of action pharmacokineticsdosing considerations monitoring efficacy and safetyrdquo Chestvol 108 no 4 supplement pp 258Sndash275S 1995

[3] J Fareed D A Hoppensteadt and R L Bick ldquoAn update onheparins at the beginning of the new millenniumrdquo Seminars inThrombosis and Hemostasis vol 26 no 3 pp 5ndash21 2000

[4] J Hirsh ldquoDrug therapy heparinrdquo The New England Journal ofMedicine vol 324 no 22 pp 1565ndash1574 1991

[5] R J Ludwig ldquoTherapeutic use of heparin beyond anticoagu-lationrdquo Current Drug Discovery Technologies vol 6 no 4 pp281ndash289 2009

[6] E Young ldquoThe anti-inflammatory effects of heparin and relatedcompoundsrdquo Thrombosis Research vol 122 no 6 pp 743ndash7522008

12 Advances in Pharmacological Sciences

[7] A R Jadad R A Moore D Carroll et al ldquoAssessing the qualityof reports of randomized clinical trials is blinding necessaryrdquoControlled Clinical Trials vol 17 no 1 pp 1ndash12 1996

[8] K F Schulz D G Altman and D Moher ldquoCONSORT 2010statement updated guidelines for reporting parallel grouprandomised trialsrdquo International Journal of Surgery vol 9 no8 pp 672ndash677 2011

[9] T Ahmed J Garrigo and I Danta ldquoPreventing bronchocon-striction in exercise-induced asthma with inhaled heparinrdquoTheNewEngland Journal ofMedicine vol 329 no 2 pp 90ndash95 1993

[10] Z Diamant M C Timmers H Van Der Veen C P PageF J Van Der Meer and P J Sterk ldquoEffect of inhaled heparinon allergen-induced early and late asthmatic responses inpatients with atopic asthmardquo American Journal of Respiratoryand Critical Care Medicine vol 153 no 6 pp 1790ndash1795 1996

[11] M Duong D Cockcroft L-P Boulet et al ldquoThe effect ofIVX-0142 a heparin-derived hypersulfated disaccharide on theallergic airway responses in asthmardquo Allergy vol 63 no 9 pp1195ndash1201 2008

[12] A M Fal M Kraus-Filarska J Miecielica and J MalolepszyldquoMechanisms of action of nebulized low-molecular-weightheparin in patients with bronchial asthmardquo The Journal ofAllergy and Clinical Immunology vol 113 no 2 supplement pS36 2004

[13] J Jerzynska I Stelmach P Majak and P Kuna ldquoThe effectof inhaled heparin on airway responsiveness to histamine andmetacholine in asthmatic childrenrdquo Journal of Allergy andClinical Immunology vol 109 no 1 supplement 1 p S39 2002

[14] A F Kalpaklioglu Y S Demirel S Saryal and Z MisirligilldquoEffect of pretreatment with heparin on pulmonary and cuta-neous responserdquo Journal of Asthma vol 34 no 4 pp 337ndash3431997

[15] I Stelmach J Jerzynska A Brzozowska and P Kuna ldquoTheeffect of inhaled heparin on postleukotriene bronchoconstric-tion in children with asthmardquo Journal of Allergy and ClinicalImmunology vol 109 no 1 supplement 1 p S39 2002

[16] I Stelmach J Jerzynska W Stelmach et al ldquoThe effect ofinhaled heparin on airway responsiveness to histamine andleukotriene D4rdquo Allergy and Asthma Proceedings vol 24 no 1pp 59ndash65 2003

[17] Y S Ang N Mahmud B White et al ldquoRandomized compar-ison of unfractionated heparin with corticosteroids in severeactive inflammatory bowel diseaserdquo Alimentary PharmacologyandTherapeutics vol 14 no 8 pp 1015ndash1022 2000

[18] C Folwaczny B Wiebecke and K Loeschke ldquoUnfractionedheparin in the therapy of patients with highly active inflamma-tory bowel diseaserdquo The American Journal of Gastroenterologyvol 94 no 6 pp 1551ndash1555 1999

[19] J Panes M Esteve E Cabre et al ldquoComparison of heparinand steroids in the treatment of moderate and severe ulcerativecolitisrdquo Gastroenterology vol 119 no 4 pp 903ndash908 2000

[20] P Zezos G Papaioannou N Nikolaidis et al ldquoLow-molecular-weight heparin (enoxaparin) as adjuvant therapy in the treat-ment of active ulcerative colitis a randomized controlledcomparative studyrdquoAlimentary Pharmacology andTherapeuticsvol 23 no 10 pp 1443ndash1453 2006

[21] A A Vrij J M Jansen E J Schoon H C Hemker and RW Stockbrugger ldquoLow molecular weight heparin treatmentin steroid refractory ulcerative colitis clinical outcome andinfluence on mucosal capillary thrombirdquo Scandinavian Journalof Gastroenterology Supplement vol 36 no 234 pp 41ndash47 2001

[22] D M Borgioli D J Coster R F T Fan et al ldquoEffect of heparinsurface modification of polymethylmethacrylate intraocularlenses on signs of postoperative inflammation after extracap-sular cataract extraction one-year results of a double-maskedmulticenter studyrdquoOphthalmology vol 99 no 8 pp 1248ndash12551992

[23] J Colin S Roncin and M Wenzel ldquoEfficacy of heparinsurface-modified IOLs in reducing postoperative inflammatoryreactions in patients with exfoliation syndromemdasha double-blind comparative studyrdquo European Journal of Implant andRefractive Surgery vol 7 no 5 pp 266ndash270 1995

[24] Y B Ozkurt A Taskiran N Erdogan B Kandemir and OK Dogan ldquoEffect of heparin in the intraocular irrigating solu-tion on postoperative inflammation in the pediatric cataractsurgeryrdquoClinical Ophthalmology vol 3 no 1 pp 363ndash365 2009

[25] V A Vasavada M R Praveen S K Shah R H Trivedi andA R Vasavada ldquoAnti-inflammatory effect of low-molecular-weight heparin in pediatric cataract surgery a randomizedclinical trialrdquoThe American Journal of Ophthalmology vol 154no 2 pp 252ndash258 2012

[26] T Kohnen B Dick V Hessemer D D Koch and K WJacobi ldquoEffect of heparin in irrigating solution on inflammationfollowing small incision cataract surgeryrdquo Journal of Cataract ampRefractive Surgery vol 24 no 2 pp 237ndash243 1998

[27] S Ashraf Y Tian D Cowan A Entress P G Martin andK G Watterson ldquoRelease of proinflammatory cytokines dur-ing pediatric cardiopulmonary bypass heparin-bonded versusnonbonded oxygenatorsrdquo Annals of Thoracic Surgery vol 64no 6 pp 1790ndash1794 1997

[28] J-O Defraigne J Pincemail R Larbuisson F Blaffart andR Limet ldquoCytokine release and neutrophil activation are notprevented by heparin- coated circuits and aprotinin administra-tionrdquo Annals of Thoracic Surgery vol 69 no 4 pp 1084ndash10912000

[29] R de Vroege W van Oeveren J van Klarenbosch et al ldquoTheimpact of heparin-coated cardiopulmonary bypass circuits onpulmonary function and the release of inflammatory media-torsrdquo Anesthesia and Analgesia vol 98 no 6 pp 1586ndash15942004

[30] Y Misawa K Kawahito H Konishi and K Fuse ldquoCytokinemediated endothelial activation during and after normothermiccardiopulmonary bypass Heparin-bonded versus non heparin-bonded circuitsrdquo ASAIO Journal vol 46 no 6 pp 740ndash7432000

[31] A Koster T Fischer M Praus et al ldquoHemostatic activationand inflammatory response during cardiopulmonary bypassimpact of heparin managementrdquo Anesthesiology vol 97 no 4pp 837ndash841 2002

[32] C Olsson A Siegbahn A Henze et al ldquoHeparin-coatedcardiopulmonary bypass circuits reduce circulating comple-ment factors and interleukin-6 in paediatric heart surgeryrdquoScandinavian Cardiovascular Journal vol 34 no 1 pp 33ndash402000

[33] T Ozawa K Yoshihara N Koyama Y Watanabe N Shionoand Y Takanashi ldquoClinical efficacy of heparin-bonded bypasscircuits related to cytokine responses in childrenrdquo The Annalsof Thoracic Surgery vol 69 no 2 pp 584ndash590 2000

[34] A Parolari F Alamanni T Gherli et al ldquolsquoHigh dosersquo aprotininand heparin-coated circuits Clinical efficacy and inflammatoryresponserdquo Cardiovascular Surgery vol 7 no 1 pp 117ndash127 1999

[35] H Yamada I Kudoh Y Hirose M Toyoshima H Abe andK Kurahashi ldquoHeparin-coated circuits reduce the formation of

Advances in Pharmacological Sciences 13

TNF120572 during cardiopulmonary bypassrdquo Acta AnaesthesiologicaScandinavica vol 40 no 3 pp 311ndash317 1996

[36] O Barkay E Niv E Santo R Bruck A Hallak and F MKonikoff ldquoLow-dose heparin for the prevention of post-ERCPpancreatitis a randomized placebo-controlled trialrdquo SurgicalEndoscopy and Other Interventional Techniques vol 22 no 9pp 1971ndash1976 2008

[37] R C Becker K W Mahaffey H Yang et al ldquoHeparin-associated anti-Xa activity and platelet-derived prothromboticand proinflammatory biomarkers in moderate to high-riskpatients with acute coronary syndromerdquo Journal of Thrombosisand Thrombolysis vol 31 no 2 pp 146ndash153 2011

[38] S D Bowler S M Smith and P S Lavercombe ldquoHeparininhibits the immediate response to antigen in the skin and lungsof allergic subjectsrdquo American Review of Respiratory Diseasevol 147 no 1 pp 160ndash163 1993

[39] J P Boyle R H Smart and J K Shirey ldquoHeparin in thetreatment of chronic obstructive bronchopulmonary diseaserdquoThe American Journal of Cardiology vol 14 no 1 pp 25ndash281964

[40] Y Qian H Xie R Tian K Yu and R Wang ldquoEfficacy of lowmolecular weight heparin in patients with acute exacerbationof chronic obstructive pulmonary disease receiving ventilatorysupportrdquo COPD Journal of Chronic Obstructive PulmonaryDisease vol 11 no 2 pp 171ndash176 2014

[41] A Chamorro A Cervera J Castillo A Davalos J J Aponteand A M Planas ldquoUnfractionated heparin is associated with alower rise of serum vascular cell adhesion molecule-1 in acuteischemic stroke patientsrdquo Neuroscience Letters vol 328 no 3pp 229ndash232 2002

[42] R de Cock L A Ficker J G Dart A Garner and P WrightldquoTopical heparin in the treatment of ligneous conjunctivitisrdquoOphthalmology vol 102 no 11 pp 1654ndash1659 1995

[43] U Derhaschnig T Pernerstorfer M Knechtelsdorfer U Hol-lenstein S Panzer and B Jilma ldquoEvaluation of antiinflamma-tory and antiadhesive effects of heparins in human endotox-emiardquo Critical Care Medicine vol 31 no 4 pp 1108ndash1112 2003

[44] B DixonM J Schultz R Smith J B Fink J D Santamaria andD J Campbell ldquoNebulized heparin is associatedwith fewer daysof mechanical ventilation in critically ill patients a randomizedcontrolled trialrdquo Critical Care vol 14 no 5 article R180 2010

[45] F K Keating H L Dauerman D A Whitaker B E Sobeland D J Schneider ldquoThe effects of bivalirudin compared withthose of unfractionated heparin plus eptifibatide on inflam-mation and thrombin generation and activity during coronaryinterventionrdquo Coronary Artery Disease vol 16 no 6 pp 401ndash405 2005

[46] M Ledson M Gallagher C A Hart and M Walshaw ldquoNeb-ulized heparin in Burkholderia cepacia colonized adult cysticfibrosis patientsrdquo European Respiratory Journal vol 17 no 1 pp36ndash38 2001

[47] D J Serisier J K Shute P M Hockey B Higgins J Conwayand M P Carroll ldquoInhaled heparin in cystic fibrosisrdquo EuropeanRespiratory Journal vol 27 no 2 pp 354ndash358 2006

[48] O K Poyrazoglu A Dogukan M Yalniz D Seckin andA L Gunal ldquoAcute effect of standard heparin versus lowmolecular weight heparin on oxidative stress and inflammationin hemodialysis patientsrdquo Renal Failure vol 28 no 8 pp 723ndash727 2006

[49] S Suzuki T Matsuo H Kobayashi et al ldquoAntithrombotictreatment (argatroban vs heparin) in coronary angioplastyin angina pectoris effects on inflammatory hemostatic and

endothelium-derived parametersrdquoThrombosis Research vol 98no 4 pp 269ndash279 2000

[50] S D Trocme and H-I Li ldquoEffect of heparin-surface-modifiedintraocular lenses on postoperative inflammation after pha-coemulsification a randomized trial in a United States patientpopulationrdquo Ophthalmology vol 107 no 6 pp 1031ndash1037 2000

[51] C Vancheri C Mastruzzo F Armato et al ldquoIntranasal heparinreduces eosinophil recruitment after nasal allergen challenge inpatients with allergic rhinitisrdquo Journal of Allergy and ClinicalImmunology vol 108 no 5 pp 703ndash708 2001

[52] A Abdollahi M-T Naini H Shams and R Zarei ldquoEffect oflow-molecular-weight heparin on postoperative inflammationin phacomorphic glaucomardquo Archives of Iranian Medicine vol5 no 4 pp 225ndash229 2002

[53] R T S Lakshmi T Priyanka J Meenakshi K R MathangiV Jeyaraman and M Babu ldquoLow molecular weight heparinmediated regulation of nitric oxide synthase during burnwound healingrdquo Annals of Burns and Fire Disasters vol 24 no1 pp 24ndash29 2011

[54] G Montalescot C Bal-dit-Sollier D Chibedi et al ldquoCompar-ison of effects on markers of blood cell activation of enoxa-parin dalteparin and unfractionated heparin in patients withunstable angina pectoris or non-ST-segment elevation acutemyocardial infarction (the ARMADA study)rdquo The AmericanJournal of Cardiology vol 91 no 8 pp 925ndash930 2003

[55] S Nasiripour K Gholami SMousavi et al ldquoComparison of theeffects of enoxaparin and heparin on inflammatory biomarkersin patients with ST-segment elevated myocardial infarction aprospective open label pilot clinical trialrdquo Iranian Journal ofPharmaceutical Research vol 13 no 2 pp 583ndash590 2014

[56] J Oldgren C Fellenius K Boman et al ldquoInfluence of prolongeddalteparin treatment on coagulation fibrinolysis and inflam-mation in unstable coronary artery diseaserdquo Journal of InternalMedicine vol 258 no 5 pp 420ndash427 2005

[57] T K Rudolph V Rudolph A Witte et al ldquoLiberation of vesseladherent myeloperoxidase by enoxaparin improves endothelialfunctionrdquo International Journal of Cardiology vol 140 no 1 pp42ndash47 2010

[58] D L Walters M J Ray P Wood E J Perrin J H N Bettand C N Aroney ldquoHigh-dose tirofiban with enoxaparin andinflammatory markers in high-risk percutaneous interventionrdquoEuropean Journal of Clinical Investigation vol 40 no 2 pp 139ndash147 2010

[59] S W Rathbun C E Aston and T L Whitsett ldquoA randomizedtrial of dalteparin compared with ibuprofen for the treatmentof superficial thrombophlebitisrdquo Journal of Thrombosis andHaemostasis vol 10 no 5 pp 833ndash839 2012

[60] J P Titon D Auger P Grange et al ldquoTherapeutic managementof superficial venous thrombosis with calcium nadroparinDosage testing and comparison with a non-steroidal anti-inflammatory agentrdquo Annales de Cardiologie et d Angeiologievol 43 no 3 pp 160ndash166 1994

[61] H Uncu ldquoA comparison of low-molecular-weight heparin andcombined therapy of low-molecular-weight heparin with ananti-inflammatory agent in the treatment of superficial veinthrombosisrdquo Phlebology vol 24 no 2 pp 56ndash60 2009

[62] J A Sjoslashland R S Pedersen J Jespersen and J GramldquoIntraperitoneal heparin ameliorates the systemic inflamma-tory response in PD patientsrdquo NephronmdashClinical Practice vol100 no 4 pp c105ndashc110 2005

[63] N L Fine C Shim and M H Williams Jr ldquoObjectiveevaluation of heparin in the treatment of asthmardquo AmericanReview of Respiratory Disease vol 98 no 5 pp 886ndash887 1968

14 Advances in Pharmacological Sciences

[64] ZDiamantM C Timmers H van derVeen C P Page F J vander Meer and P J Sterk ldquoEffect of inhaled heparin on allergen-induced early and late asthmatic responses in patients withatopic asthmardquo American Journal of Respiratory and CriticalCare Medicine vol 153 no 6 I pp 1790ndash1795 1996

[65] C M E Tranfa A Vatrella R Parrella G Pelaia F Bariffiand S A Marsico ldquoEffect of inhaled heparin on water-inducedbronchoconstriction in allergic asthmaticsrdquoEuropean Journal ofClinical Pharmacology vol 57 no 1 pp 5ndash9 2001

[66] I Stelmach J Jerzynska A Brzozowska and P Kuna ldquoTheeffect of inhaled heparin on postleukotriene bronchoconstric-tion in children with asthmardquo Polski Merkuriusz Lekarski vol12 no 68 pp 95ndash98 2002

[67] R Polosa S Magrı C Vancheri et al ldquoTime course of changesin adenosine 51015840-monophosphate airway responsiveness withinhaled heparin in allergic asthmardquo Journal of Allergy andClinical Immunology vol 99 no 3 pp 338ndash342 1997

[68] J Butler GM Rocker and SWestaby ldquoInflammatory responseto cardiopulmonary bypassrdquo The Annals of Thoracic Surgeryvol 55 no 2 pp 552ndash559 1993

[69] J M Redmond A M Gillinov R S Stuart et al ldquoHeparin-coated bypass circuits reduce pulmonary injuryrdquoThe Annals ofThoracic Surgery vol 56 no 3 pp 474ndash479 1993

[70] S Svenmarker E Sandstrom T Karlsson et al ldquoClinical effectsof the heparin coated surface in cardiopulmonary bypassrdquoEuropean Journal of Cardio-Thoracic Surgery vol 11 no 5 pp957ndash964 1997

[71] Y J Gu W van Oeveren C Akkerman P W Boonstra RJ Huyzen and C R H Wildevuur ldquoHeparin-coated circuitsreduce the inflammatory response to cardiopulmonary bypassrdquoThe Annals of Thoracic Surgery vol 55 no 4 pp 917ndash922 1993

[72] D Paparella O O Al Radi Q H Meng T Venner K Teohand E Young ldquoThe effects of high-dose heparin on inflamma-tory and coagulation parameters following cardiopulmonarybypassrdquo Blood Coagulation and Fibrinolysis vol 16 no 5 pp323ndash328 2005

[73] S Danese A Papa S Saibeni A Repici A Malesci andM Vecchi ldquoInflammation and coagulation in inflammatorybowel disease the clot thickensrdquo The American Journal ofGastroenterology vol 102 no 1 pp 174ndash186 2007

[74] S Bloom S Kiilerich M R Lassen et al ldquoLow molecularweight heparin (tinzaparin) vs placebo in the treatment of mildto moderately active ulcerative colitisrdquo Alimentary Pharmacol-ogy ampTherapeutics vol 19 no 8 pp 871ndash878 2004

[75] P Libby ldquoCoronary artery injury and the biology of atheroscle-rosis inflammation thrombosis and stabilizationrdquo AmericanJournal of Cardiology vol 86 no 8 2000

[76] N T Mulvihill and J B Foley ldquoInflammation in acute coronarysyndromesrdquo Heart vol 87 no 3 pp 201ndash204 2002

[77] N A JamesonW V Good and C S Hoyt ldquoInflammation aftercataract surgery in childrenrdquoOphthalmic Surgery vol 23 no 2pp 99ndash102 1992

[78] R M Sinskey P A Amin and R Lingua ldquoCataract extractionand intraocular lens implantation in an infant with amonocularcongenital cataractrdquo Journal of Cataract amp Refractive Surgeryvol 20 no 6 pp 647ndash651 1994

[79] A van Ophoven A Heinecke and L Hertle ldquoSafety andefficacy of concurrent application of oral pentosan polysulfateand subcutaneous low-dose heparin for patients with interstitialcystitisrdquo Urology vol 66 no 4 pp 707ndash711 2005

Submit your manuscripts athttpwwwhindawicom

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The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

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Volume 2014

ToxinsJournal of

VaccinesJournal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AntibioticsInternational Journal of

ToxicologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Drug DeliveryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in Pharmacological Sciences

Tropical MedicineJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AddictionJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Autoimmune Diseases

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anesthesiology Research and Practice

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Pharmaceutics

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MEDIATORSINFLAMMATION

of

Page 2: Review Article Anti-Inflammatory Effects of Heparin and Its …downloads.hindawi.com/journals/aps/2015/507151.pdf · 2019. 7. 31. · Review Article Anti-Inflammatory Effects of Heparin

2 Advances in Pharmacological Sciences

2 Methods

21 Search Strategy A comprehensive literature search wasconducted in PubMed Scopus Web of Science OvidElsevier and Google Scholar from inception to March2012 using the following Mesh keywords (1) heparin (2)UFH (3) anticoagulants (4) dalteparin (5) enoxaparin (6)nadroparin (7) tinzaparin (8) heparinoids (9) inflamma-tion (10) inflammatory process (11) anti-inflammation (12)inflammation mediators (13) inflammatory bowel diseaseand (14) anti-inflammatory agents All keywords from 1 to8 were separately combined with each keyword from 9 to14 in all databases Articles were initially scanned based ontitles and abstracts by two reviewers (Sarah Mousavi andMandana Moradi) and related articles were retrieved in fulland assessed for eligibility by two reviewers (Sarah Mousaviand Mandana Moradi) The reference list of each eligiblestudy was checked to identify additional studies

22 Inclusion Criteria All Randomized Clinical Trials(RCTs) and studies with quasi-experimental design whichevaluated efficacy using inflammatory biomarkers levelsand safety (significant hemorrhage or thrombocytopenia)of anti-inflammatory effects of heparin and heparin-relatedderivatives (LMWH or other heparinoids) with an Englishabstract regardless of rout of administration (intravenoussubcutaneous topical or inhaler) age gender race andethnic origin of participants were included

23 Exclusion Criteria The following were excluded studiesbased on animal models preclinical and biological studiesletters and editorials report published as meeting abstractonly where insufficient data were reported to allow inclusion

24 Data Extraction and Quality Assessment Data from eacheligible study were extracted individually and compared bytwo authors (Sarah Mousavi and Mandana Moradi) usingstandard form that included study design setting samplesize duration and follow up dosing regimen interventiontype and outcomes Disagreements were resolved throughdiscussion if necessary they consulted a third person Anarrative synthesis was conducted

Quality assessment of clinical trials included in the anal-ysis were performed utilizing the Jadad score a previouslyvalidated instrument that assesses trials based on appro-priate randomization blinding and description of studywithdrawals or dropouts [7] The description of this score isas follows (1) whether it is randomized (yes = 1 point no =0) (2) whether randomization was described appropriately(yes = 1 point no = 0) (3) whether it is double-blind (yes = 1point no = 0) (4) whether the double-blindingwas describedappropriately (yes = 1 point no = 0) (5) whether withdrawalsand dropouts were described (yes = 1 point no = 0) Thequality score ranges from 0 to 5 points a low-quality reportscore is le2 and a high-quality report score is at least 3

The Consolidated Standards of Reporting Trials (CON-SORT) checklist was also used for randomized trials as it is

Citations identified in literature search

Full text review

Articles included in systematic review

Excluded

Excluded (n = 13)

(n = 553)

(n = 70)

(n = 57)

(ii) Title and abstract screening (n = 210)

(i) No outcome of interest (n = 11)(ii) Nonclinical study (n = 2)

(i) Duplicate citations (n = 275)

Figure 1 Flow diagram of literature search process

strongly endorsed by prominent journals and leading edi-torial organizations [8] Total possible score for CONSORTchecklist was considered as 74 two points for adequatedescription one point for inadequate description and zerofor no description

25 Statistical Methods To summarize and extract datathe database was designed by Microsoft office Access 2007(MicrosoftCorporation RedmondWA) A narrative synthe-sis was conducted and data were extracted into tables andsummarized

3 Results

Following Initial screening of mentioned databases total of553 citations (275 duplicates) were extracted but only 70 ofthem were potentially eligible for investigation of our objec-tives (according to our proposed inclusion criteria) based ontitles and abstracts The full text screening excluded other13 citations and the remaining 57 papers were consideredrelevant for data extraction and following analysis The flowchart of studiesrsquo selection processes is as shown in Figure 1

31 Study and Patient Characteristic Sample sizes rangedfrom 8 to 555 patients in 57 studies that met the criteriato be included Research designs mostly were randomizedcontrolled trial (119899 = 48) and the remaining (119899 = 9) had quasi-experimental designs using pre-post studies (119899 = 6)

Tables 1 and 2 [9ndash62] list the characteristics of theincluded studies The most studied clinical conditions wascardiopulmonary bypass (119899 = 12) followed by Asthma(119899 = 8) inflammatory bowel disease (IBD) (119899 = 5) acutecoronary syndrome (ACS) (119899 = 8) and ophthalmologicaldisease (119899 = 8) Other less common studied conditions wereas follows burn cystic fibrosis allergic rhinitis superficial

Advances in Pharmacological Sciences 3

Table1Summaryandfin

ding

sofcom

mon

studied

diseases

Clinicalsetting

Heparin

preparation

Mod

eof

administratio

nCom

parator

Num

bero

fpatie

nts

Clinicalou

tcom

eLabo

ratory

outcom

eStud

ydesig

n

Exercise-in

duced

Asthma[

9]UFH

Inhaler

Crom

olyn

sodium

orplacebo

12Sign

ificantlyredu

ctionof

exercise-in

ducedasthma

Heparin

hadno

effecto

nhistam

ine-indu

ced

bron

chocon

strictio

n

Sing

le-blin

drand

omized

crossoverc

linicaltrial

Asthma[

10]

UFH

Inhaler

Placebo

8

Sign

ificant

redu

ctionof

late

asthmaticrespon

seaft

erallergen

administratio

n(119875

0005)

mdashRa

ndom

izeddou

ble-blind

crossoverc

linicaltrial

Atop

icasthma

[11]

Heparin

(IVX-

0142)

Nebulizer

Placebo

19Nosig

nificantd

ecreasein

early

(119875006)

andlate(119875

024)a

sthm

aticrespon

semdash

Rand

omized

single-blind

placebo-controlled

crossovertria

l

Asthma[

12]

LMWH

Nebulizer

mdash24

Effectiv

easa

nadd-on

therapyto

stand

ard

treatment

Redu

ctionin

eosin

ophil(119875

000

06)and

lymph

ocyte(119875

0049)

inbron

choalveolar

lavageNochangesinIL-5

orEC

Pconcentrations

inserum

Quasi-experim

ental

(pretest-

posttestd

esign)

Allergicasthma

[13]

UFH

Inhaler

Placebo

25

Heparin

inhalatio

nsig

nificantly

redu

ced

bron

chialhyperreactiv

ity(119875lt005)

mdashRa

ndom

izeddou

ble-blind

placebo-controlled

crossovertria

l

Asthma[

14]

UFH

Inhaler

mdash12

Transie

nt(time-depend

ent)

inhibitory

rolein

allergic

reactio

ns

Increasedthem

ethacholine

PC20

value(119875005)

but

didno

tprevent

anincrease

inRa

wandor

adecreasein

SGAW

Rand

omizeddou

ble-blind

placebo-controlled

crossovertria

l

Asthma

(children)

[15]

UFH

Inhaler

Placebo

14

Sing

ledo

seof

heparin

significantly

(1198750005)

redu

cedbron

chial

hyperreactivity

Provocationtestused

leuk

otrie

neD4

Rand

omizeddou

ble-blind

placebo-controlled

crossovertria

l

Asthma[

16]

UFH

Inhaler

Placebo

23Sign

ificant

redu

ctionof

bron

chialhyperreactiv

ityto

histam

inea

ndleuk

otrie

nemdash

Rand

omizeddou

ble-blind

placebocontrolled

crossovertria

l

IBD[17]

UFH

IVSC

Hydrocortiso

ne+

prednisolone

20(12in

control

grou

p)

Clinicalactiv

ityindexsto

olfre

quencyand

endo

scop

icandhisto

pathological

gradingweres

imilarin

both

treatmentg

roup

s

CRPand1205721a

cid

glycop

rotein

didno

tchange

Openlabelrando

mized

crossoverc

linicaltrial

4 Advances in Pharmacological Sciences

Table1Con

tinued

Clinicalsetting

Heparin

preparation

Mod

eof

administratio

nCom

parator

Num

bero

fpatie

nts

Clinicalou

tcom

eLabo

ratory

outcom

eStud

ydesig

n

IBD[18]

UFH

SCmdash

17

Histologyim

proved

significantly

inulcerativ

ecolitispatie

nts(UFH

iseffectiv

einulcerativ

ecolitis

butn

otCr

ohndisease)

CRP(11987500119

)and

ESR

(11987500096)

significantly

redu

cedin

ulcerativ

ecolitis

butn

otCr

ohndisease

Quasi-experim

ental

(pretest-

posttestd

esign)

IBD[19

]UFH

IVMethylpredn

isolone

25(13in

control

grou

p)

Noeffecto

fheparinalso

increasedbleeding

Nochange

inCR

PRa

ndom

izeddou

ble-blind

parallel-g

roup

trial

IBD[20]

Enoxaparin

+sta

ndard

treatment

SCAminosalicylate+

corticosteroid

34(18in

control

grou

p)

Sign

ificant

improvem

entin

diseases

everity

inbo

thgrou

ps(1198750001)

NodifferenceE

SRC

RPandfib

rinogen

and

coagulation

Rand

omized

controlled

trial

IBD[21]

Nadroparin

SCmdash

25

Endo

scop

icand

histo

logicalsignof

inflammationsig

nificantly

improved

mdashQuasi-experim

ental

(Non

-rando

mized

clinical

trial)

Cataractsurgery

[22]

UFH

Intraocular

lens

(IOL)

Polymethylm

ethacrylate

524

mdash

Heparin

surfa

cemod

ificatio

nredu

cedthe

cellu

lard

epositcompared

tocontrolgroup

Rand

omizeddou

ble-blind

parallelgroup

clinicaltria

l

Cataractsurgery

[23]

UFH

Intraocular

lens

(IOL)

Polymethylm

ethacrylate

58(31in

control

grou

p)

Posto

perativ

einfl

ammation

decreasedsig

nificantly

inheparin

grou

p(119875002)

Giant

cellandcelldepo

sitdecreasedsig

nificantly

(119875lt005)

Rand

omizeddou

ble-blind

clinicaltria

l

Cataractsurgery

(pediatric)[24]

UFH

Irrig

ation

Balanced

saltsolutio

n33

(19in

control

grou

p)

Heparin

irrigationredu

ced

numbero

fpostoperativ

einflammatoryrelated

complication

Anteriorc

hamberreaction

inclu

ding

fibrin

form

ation

was

lower

inheparin

grou

p

Rand

omized

prospective

doub

le-blin

dtrial

Cataractsurgery

(pediatrics)[25]

Enoxaparin

Irrig

ation

Notre

atment

40(20in

each

grou

p)

Increase

offlare

andcell

depo

sitaft

ersurgery(1and

3mon

ths)(119875099)

Increase

inlargec

ell

depo

sits

Rand

omizeddou

ble-blind

controlledtrial

Cataractsurgery

[26]

UFH

Irrig

ation

Regu

larirrigation

solutio

n72

Sign

ificant

redu

ctionof

inflammationin

thee

arly

(days1ndash3)p

ostoperativ

eperio

d(119875lt001)

mdashRa

ndom

ized

controlled

trial

Cardiopu

lmon

ary

bypass(pediatric)

[27]

Heparin-

coated

circuit

(119899=11)

mdashNon

-heparin-coated

circuit(119899=10)

21

Decreaseo

fsystemic

inflammatoryrespon

sewith

theu

seof

heparin

-bon

ded

oxygenators

Sign

ificantlydecreased

levelsof

IL-6IL-8term

inal

complem

entcom

plex

neutroph

ilsand

elastase

inheparin

coated

circuit

Rand

omized

controlled

trial

Cardiopu

lmon

ary

bypass[28]

Heparin-

coated

circuit

plusmnaprotin

inmdash

Uncoatedcircuitplusmn

aprotin

in200(4

grou

ps)

Aprotin

inandheparin

had

noeffecto

ncytokine

release

TNF-120572IL-6andIL-8

and

myeloperoxidase

didno

tchange

Rand

omizeddou

ble-blind

clinicaltria

l

Advances in Pharmacological Sciences 5

Table1Con

tinued

Clinicalsetting

Heparin

preparation

Mod

eof

administratio

nCom

parator

Num

bero

fpatie

nts

Clinicalou

tcom

eLabo

ratory

outcom

eStud

ydesig

n

Cardiopu

lmon

ary

bypass[29]

UFH

mdashUncoatedcircuit

51(26in

each

grou

p)

Decreased

pulm

onary

vascular

resistanceind

exandpu

lmon

aryshun

tfractio

nandincreased

PaO2FIO2ratio

Lower

levelsof

phosph

olipaseA

2and

complem

entactivation(119875

0001)

Rand

omizeddou

ble-blind

clinicaltria

l

Cardiopu

lmon

ary

bypass[30]

Heparin-

coated

circuit

mdashNon

-heparin-coated

circuit

16(9

incontrol

grou

p)mdash

Nosig

nificantd

ifference

betweengrou

psregarding

granulocytee

lasta

seIL-6

IL-8

Quasi-experim

ental

(pretest-

posttestd

esign)

Cardiopu

lmon

ary

bypass[31]

Heparin

concentration-

based

syste

m

mdashAc

tivated

clotting

time-based

managem

ent

200(100

incontrol

grou

p)

Noeffecto

npo

stoperativ

ebloo

dloss

Sign

ificant

redu

ctionof

neutroph

ilactiv

ationand

fibrin

olysisandthrombin

generatio

n(119875lt005)

Rand

omized

controlled

trial

Cardiopu

lmon

ary

bypass(pediatric)

[32]

Heparin-

coated

circuit

mdashNon

-heparin-coated

circuit

19(10in

control

grou

p)

Improvem

ento

fthe

biocom

patib

ilityof

CPB

durin

gheartsurgery

Levelsof

complem

ent

factor

C3a(119875lt0001)a

ndIL-6

(1198750005)significantly

redu

cedin

heparin

-coated

circuit

Rand

omized

controlled

trial

Cardiopu

lmon

ary

bypass(pediatric)

[33]

Heparin-

coated

circuit

mdashNon

-heparin-coated

circuit

34(12in

control

grou

p)

Nodifferences

indu

ratio

nof

intubatio

nintensivec

are

unitor

hospita

lstayor

posto

perativ

eblood

loss

IL-6IL-8andTN

F-120572we

resig

nificantly

lower

inheparin

grou

p(119875lt001

119875lt001and119875lt005

resp)

Rand

omized

controlled

trial

Cardiopu

lmon

ary

bypass[34]

Heparin-

coated

circuit

(heparin

+aprotin

in)

mdashNon

-heparin-coated

circuit(heparin

+aprotin

in)

30(15in

each

grou

p)

Nosig

nificantd

ifferences

betweenthetwogrou

psin

term

sofb

leedingand

transfu

sionalrequirements

thetim

espent

ona

ventilatoror

indu

ratio

nof

stayin

theintensiv

ecare

unit(ICU

)

Levelsof

IL-6C

RPand

neutroph

ilcoun

tdid

not

change

byheparin

-coated

circuitMon

ocytec

ount

increasedin

heparin

-coatedcircuit

Rand

omized

controlled

trial

Coron

aryartery

bypassgraft

ing

(CABG

)[35]

Heparin-

coated

circuit

mdashNon

-heparin-coated

circuit

18(9

ineach

grou

p)mdash

Redu

ctionof

levelsof

IL-8

andTN

F-120572andincrease

ofneutroph

ilelastase

Rand

omized

controlled

trial

CRP

C-Re

activ

eProteinC

PBC

ardioPu

lmon

aryB

ypassEC

PEo

sinop

hilC

ationicP

roteinE

SRE

rythrocyteSedimentatio

nICUIntensiv

eCareU

nitILinterleuk

inIV

intravenou

sSC

sub

cutaneou

sSG

AW

SpecificA

irway

Con

ductanceT

NFTu

mor

Necrosis

Factorand

UFH

unfractionatedheparin

6 Advances in Pharmacological Sciences

Table2Summaryandfin

ding

sofo

ther

studied

diseases

Clinicalsetting

Heparin

preparation

Mod

eof

administratio

nCom

parator

Num

bero

fpatie

nts

Clinicalou

tcom

eLabo

ratory

outcom

eStud

ydesig

n

Pancreatitisa

fter

ERCP

[36]

UFH

SCSalin

esolution

105(54in

control

grou

p)

Rateof

posto

perativ

epancreatitisw

asno

tsig

nificantb

etweenbo

thgrou

ps

mdashRa

ndom

ized

placebo-controlledclinical

trial

Acutec

oron

ary

synd

rome(AC

S)[37]

UFH

SCEn

oxaparin

201

mdashNosig

nificantd

ifference

betweenCD

4ligandand

PAI-1inbo

thgrou

ps

Openlabelrand

omized

clinicaltria

l

Skin

orpu

lmon

ary

allergy[38]

UFH

IVnebulizer

Normalsalin

eplacebo

25Sign

ificant

inhibitio

nof

mastcell-m

ediatedallergic

inflammation(119875004)

mdashDou

ble-blind

placebo-controlled

crossoverc

linicaltrial

COPD

[39]

UFH

IVmdash

37(18in

control

grou

p)

Sign

ificant

improvem

entin

bron

chospasm

and

bron

chialsecretio

ns(58

respon

serate)

mdashRa

ndom

ized

placebo-controlledclinical

trial

COPD

[40]

Nadroparin

SCCon

ventionaltreatment

66(33in

each

grou

p)

Decreaseo

fdurationof

mechanicalventilationand

leng

thof

hospita

land

ICU

stay(119875lt001)

Sign

ificant

decrease

inlevelsof

CRPIL-6and

fibrin

ogen

Rand

omized

controlled

trial

Ischem

icstroke

[41]

UFH

IVAs

pirin

167(97in

control

grou

p)

Early

onsetinitia

tionof

heparin

might

improve

recovery

after

stroke

Rise

ofsV

CAM-1at48

hwas

significantly

lower

inpatie

ntstreated

with

UFH

(119875lt001)

Quasi-experim

ental

(con

trolledob

servational

study)

Lign

eous

conjun

ctivitis[42]

UFH

Topical

Alpha

chym

otrypsin

orste

roid

17(12in

control

grou

p)

Intensivea

ndearly

useo

ftopicalh

eparin

may

improvetherapy

results

indisease

mdashQuasi-experim

ental

(non

rand

omized

Clinical

trial)

Endo

toxemia

(indu

cedby

lipop

olysaccharide

inhealthysubjects)

[43]

UFH

IVLM

WHor

placebo

30(10in

each

grou

p)mdash

Noeffecto

nTN

F-120572IL-6

and8CR

PandE-selectin

Rand

omized

doub

le-blin

ded

placebo-controlledparallel

grou

ptrial

Mechanical

ventilatio

n[44]

UFH

Nebulizer

Normalsalin

e(placebo)

50(25in

each

grou

p)

Fewer

days

onmechanical

ventilatio

nbette

rPao2Fio2ratio

mdashDou

ble-blindrand

omized

placebo-controlledtrial

Percutaneous

coronary

interventio

n[45]

Bivalirud

inIV

UFH

+eptifi

batid

e63

(29in

control

grou

p)mdash

Increase

inIL-6

andCR

Paft

er1d

ayD

ecreaseinCR

Pin

bivalirud

ingrou

paft

er30

days

(1198750002)

Rand

omized

controlled

trial

Cysticfib

rosis

(adu

lts)[46

]UFH

Inhaler

mdash12

(6in

control

grou

p)Spiro

metry

parametersd

idno

tchang

eIL-6

redu

cedaft

ertre

atment

Quasi-experim

ental

(pretest-

posttestd

esign)

Advances in Pharmacological Sciences 7Ta

ble2Con

tinued

Clinicalsetting

Heparin

preparation

Mod

eof

administratio

nCom

parator

Num

bero

fpatie

nts

Clinicalou

tcom

eLabo

ratory

outcom

eStud

ydesig

n

Cysticfib

rosis

(adu

lts)[47]

UFH

Inhaler

Placebo

14Noeffecto

nFE

V1

Noeffecto

nsputum

inflammatorymarkers

Rand

omizeddou

ble-blind

placebo-controlled

crossovertria

l

Hem

odialysis

patie

nts[48]

UFH

IVSC

LMWHandno

drug

33

LMWHdecreased

oxidatives

tressand

inflammationwhereas

heparin

increasedthem

CRPTN

F-120572sup

eroxide

dism

utaseMDAincreased

inheparin

grou

pbu

tcomparabletoLM

WH

grou

p

Quasi-experim

ental

(pretest-

posttestd

esign)

Stableangina

[49]

Heparin

+Aspirin

(119899=15)

mdashArgatroban+As

pirin

(119899=12)2

7

Nodifferencein

inflammatoryrespon

seaft

erangiop

lasty

Fibrinogen

decreased

significantly

inargatro

ban

grou

pNodifferenceinvon

Willberand

factor

between

both

grou

psPAI-1

increasedin

argatro

ban

grou

p

Rand

omized

controlled

trial

Phacoemulsifi

catio

n[50]

Heparin

Coatedlenses

Polymethylm

ethacrylate

lenses

367

Heparin

coated

lenses

redu

cedsig

nificantly

inflammationearly

posto

peratio

n(119875005)

mdashRa

ndom

izeddou

ble-blind

multic

enterparallelgroup

trial

Allergicrhinitis[51]

UFH

Intranasal

mdash10

mdashRe

ductionof

eosin

ophil

catio

nicp

rotein

inthen

asal

wash

Quasi-experim

ental

(pretest-

posttestd

esign)

Phacom

orph

icglaucoma[

52]

Dalteparin

Irrig

ation

Balanced

saltsolutio

n46

(23in

each

grou

p)

Sign

ificant

decrease

ofpo

stoperativ

einfl

ammation

indalteparin

grou

pmdash

Rand

omizeddou

ble-blind

clinicaltria

l

Burn

[53]

Dalteparin

SCNotre

atment

24mdash

Decreaseo

fnitricoxide

synthetase

activ

itysig

nificantly

Quasi-experim

ental

(non

rand

omized

clinical

trial)

Unstablec

oron

ary

artery

disease[54]

Enoxaparin

(119899=46)

Dalteparin

(119899=48)

SCUFH

(119899=47)

68

VonWillberand

factor

may

have

progno

sticv

aluebut

otherb

iologicalvariables

didno

tpredictou

tcom

e

CRPfib

rinogenV

onWillberand

factor

increased

over

first2days

despite

medicaltre

atment

Enoxaparin

(13

)and

dalteparin

(19)reduced

releaseo

fVon

Willberand

factor

Openlabelrand

omized

clinicaltria

l

ST-Elevated

Myocardial

Infarctio

n(STE

MI)

[55]

Enoxaparin

SCUFH

34(17in

each

grou

p)

Both

heparin

and

enoxaparin

show

anti-inflammatoryeffects

inST

EMIp

atients

Serum

AmyloidA(119875002)

CRP(119875002)and

ferritin

(119875001)redu

cedin

heparin

grou

pIL-6

(1198750002)SA

A(1198750009)CR

P(119875001)

weres

ignificantly

decreased

inenoxaparin

grou

pTh

eoveralld

ifference

between

grou

pswas

notsignificant

Openlabelrand

omized

clinicaltria

l

8 Advances in Pharmacological Sciences

Table2Con

tinued

Clinicalsetting

Heparin

preparation

Mod

eof

administratio

nCom

parator

Num

bero

fpatie

nts

Clinicalou

tcom

eLabo

ratory

outcom

eStud

ydesig

n

Coron

aryartery

disease[56]

Dalteparin

SCPlacebo

555(285

incontrolgroup

)

Dalteparin

redu

ced

coagulationandso

MyocardialInfarctionbu

thasn

otinflammatory

activ

ity

Noeffectson

IL-6

C-reactiv

eprotein

and

fibrin

ogen

Rand

omizeddou

ble-blind

parallel-g

roup

multic

entre

trial

Stablecoronary

artery

disease[57]

Enoxaparin

SCSo

dium

chlorid

e62

(31ineach

grou

p)

Bymob

ilizing

vesselbo

und

MPO

eno

xaparin

improves

endo

thelialfun

ction

Sign

ificant

increase

ofMPO

levels

Rand

omizeddou

ble-blind

placebo-controlledtrial

Acutec

oron

ary

synd

romea

ndPC

I[58]

Tirofib

an(highdo

se)+

enoxaparin

Tirofib

an(highdo

se)+

UFH

60(30in

each

grou

p)

Thec

ombinatio

nof

tirofi

ban(highdo

se)+

enoxaparin

redu

ced

inflammationaft

erPC

I

Vonwillberand

CRP

D-dim

erand

prothrom

bin

fragmentw

eres

ignificantly

lower

inenoxaparin

grou

pthan

UFH

Openlabelrando

mized

controlledtrial

Superficialveno

usthrombo

phleb

itis

[59]

Dalteparin

SCIbup

rofen

72(37in

dalteparin

grou

p)

Sign

ificant

redu

ctionof

pain

form

baselin

etoday14

offollo

w-upNodifference

onthrombo

sisprogression

after

3mon

ths

mdashRa

ndom

izeddou

ble-blind

controlledtrial

Superficialveno

usthrombo

sis[60]

Nadroparin

SCNaproxen

117(39in

control

grou

p)

Nadroparin

redu

ced

symptom

andsig

nsof

thrombo

sedsuperficial

vein

bette

rthannaproxen

(1198750007)

mdashRa

ndom

izedopenlabel

clinicaltria

l

Superficialveno

usthrombo

sis[61]

Nadroparin

SCNadroparin

+acem

etacin

50

Sign

ificant

symptom

improvem

entinbo

thgrou

ps(1198750001)Th

ecombinatio

ngrou

pwas

bette

r

mdashRa

ndom

ized

controlled

trial

Periton

eald

ialysis

patie

nts[62]

Tinzaparin

Intraperito

neal

Isoton

icsalin

e21

Redu

ctionof

localand

syste

micinflammationin

periton

eald

ialysis

patie

nts

Redu

cedlevelsof

CRP(119875

0032)

andfib

rinogen

(119875

004

2)andIL-6

(1198750007)

indialysate

Rand

omizeddou

ble-blind

placebo-controlled

crossovertria

l

COPD

Chron

icObstructiv

ePu

lmon

aryDise

aseCR

PC-

Reactiv

eProtein

CPB

Cardio

Pulm

onaryBy

passE

CPE

osinop

hilC

ationicProtein

ERCP

End

oscopicRe

trogradeCh

olangiop

ancreatographyE

SR

ErythrocyteSedimentatio

nICUIntensiv

eCa

reUnitILinterleuk

inIV

intravenou

sLM

WHlow

molecular

weighth

eparinM

DAm

alon

dialdehydePAIPlasminogen

Activ

ator

InhibitorSC

sub

cutaneou

ssV

CAMSolub

leVa

scular

CellA

dhesionMoleculeTN

FTu

mor

Necrosis

Factorand

UFH

unfractionatedheparin

Advances in Pharmacological Sciences 9

Table 3 Summary of numbers and percentages of adequatelyreported items in each trial according to CONSORT checklist andJadad score

Trials Jadadscore

Adequately reporteditems (119899119873)

Percentage()

Abdollahi et al [52] 4 2974 392Ahmed et al [9] 3 2074 27Ang et al [17] 2 2474 324Ashraf et al [27] 2 2274 297Becker et al [37] 3 2874 378de Vroege et al [29] 3 2674 351Defraigne et al [28] 4 2874 378Derhaschnig et al [43] 3 3274 432Dixon et al [44] 4 5074 675Duong et al [11] 3 3074 405Gu et al [71] 2 1674 216Jerzynska et al [13] 3 2074 27Keating et al [45] 2 2174 284Koster et al [31] 2 2674 351Montalescot et al [54] 3 3574 473Nasiripour et al [55] 2 3474 46Oldgren et al [56] 3 2774 365Olsson et al [32] 2 2574 338van Ophoven et al [79] 2 2774 365Ozawa et al [33] 2 2774 365Ozkurt et al [24] 3 1874 243Paparella et al [72] 2 2274 297Polosa et al [67] 3 2374 311Rathbun et al [59] 5 4474 595Rudolph et al [57] 3 3174 412Serisier et al [47] 5 4574 608Stelmach et al [16] 3 3174 412Suzuki et al [49] 2 2374 31Vancheri et al [51] 4 2274 297Vasavada et al [25] 5 5274 702Walters et al [58] 3 3274 432Zezos et al [20] 3 3774 50

thrombophlebitis and hemodialysis Unfractionated heparin(UFH) was used in forty studies as subcutaneous intra-venous inhaler or heparin-coated circuits while others usedenoxaparin (119899 = 3) dalteparin (119899 = 4) nadroparin (119899 = 4)and tinzaparin (119899 = 1)

Table 3 provides information on the adequately reporteditems according to Jadad score andCONSORT items Amongthese 32 papers 11 (354) scored 2 and the remaining studiesscored 3 or higher according to Jadad score and just threestudies fulfill the criteria of Jadad score Calculated qualityscores according to CONSORT checklist range from 21 to70 in our object studies with twelve studies scoring greaterthan 40 The following characteristics were not exactlyreported in more than half of the trials identification as

a randomized trial in the title information about the settingand location of studies determination of sample size alloca-tion and implementation of randomization participant flowrecruitment and follow-up subgroup analysis limitations ofstudy harms registration number access to full trial protocoland funding source

4 Discussion

We discuss evidence from clinical studies supporting an anti-inflammatory role for heparin and heparin-related deriva-tives

41 Asthma Asthma is a chronic inflammatory disorderof airways characterized by bronchial hyperresponsivenessresulting in episodic bronchospasm Several studies in 1960sdescribed subjective improvement of symptoms in asthmaticpatients using intravenous heparin for the first time [3963] Inhaled heparin or its derivatives have been shown topossess antiasthmatic properties in various clinical modelsallergen induced [38 64] exercise [9] adenosine [6] anddistilled water challenge models [65] Seven randomizedcontrolled crossover trials studied anti-inflammatory effectsof heparin in exercise-induced or allergen-induced asthmahaving sample size range from 8 to 25 in 5 trials

Heparin inhalation reduced bronchial hyperreactivity ina single-blind randomized crossover trial (119899 = 12) byAhmed et al [9] Heparin inhalation (1000 120583kg) preventsexercise-induced asthma (119875 lt 005) without preventionof histamine-induced bronchoconstriction Stelmach et al[66] provoke challenge tests with histamine or leukotrieneD4 before and after inhalation of heparin showed that hep-arin (5000 Iu) decreases histamine and leukotriene-inducedbronchial hyperreactivity compared to placebo significantly(119875 0043 and 0005) but changes in Forced Expiratory Vol-ume (FEV 1) were not significant (119875 0064) The inhibitoryeffects of inhaled heparin in the airways in the absence ofbronchodilation might be related to suppressive action onmast cell degranulation A randomized double-blind studyin 10 subjects with asthma showed that heparin inhalationattenuates airway response to adenosine 51015840-monophosphate(AMP) but not to methacholine (119875 lt 001) suggestingthe theory that heparin acts more likely in association tomodulation of mediator release compared to a direct effecton smooth muscle [67]

Our results showed that inhaled enoxaparin was usedjust in a pre-post study of 24 asthmatic patients measur-ing inflammatory biomarkers and showed a reduction ineosinophil (119875 0006) and lymphocytes of bronchoalveolarlavage without any significant change in IL-5 or EosinophilCationic Protein (ECP) concentrations [12] Therefore itseems that enoxaparin could be a valuable add on treatmentin asthma like UFH Duong et al [11] evaluated IVX-0142nebulizer a heparin-derived hypersulfated disaccharide inasthma and showed nonsignificant decrease in early and lateasthmatic response

Performed studies did not show any adverse events orharms with heparin or related compounds except increase in

10 Advances in Pharmacological Sciences

the plasma partial thromboplastin time reported by Ahmedet al [9]

All in one considering the results of these studies wecan conclude that heparin and its derivatives could have anti-inflammatory effects and could be considered along withother treatments in asthma

42 Cardiopulmonary Bypass Contact and interaction ofblood with foreign surfaces during cardiopulmonary bypass(CPB) cause systemic inflammatory response syndrome(SIRS) through activation of several humoral cascadesincluding cytokines such as IL-6 IL-8 and Tumor NecrosisFactor-120572 (TNF-120572) [68] The inflammatory response can beattenuated by promoting the biocompatibility of the CPBcircuit Use of heparin-treated surfaces in CPB circuits hasbeen shown to decrease activation of leukocytes and thecomplement cascades [5] As a result need to inotropicsupport postoperative time of mechanical ventilation andrate of acute lung injury decrease and patients durationof hospital stay shortens which reflects the positive effectof heparin in CPB circuits [69 70] Twelve studies whoseendpoints were the effects of heparin-bonded circuits oninflammatory markers were included in our analysis and inthe majority of these trials [27 29 32ndash35 71] heparin-coatedcircuit significantly decreased the level of cytokines such asIL-6 IL-8 TNF-120572 complement complex neutrophils andelastase compared to non-heparin-coated circuit

Defraigne et al [28] randomized 200 patients in 4 groupsheparin-coated circuit with or without aprotinin administra-tion and uncoated circuit with or without aprotinin adminis-tration They measured IL-6 IL-8 TNF-120572 myeloperoxidase(MPO) and elastase level and concluded that cytokine releaseand neutrophil activation were not attenuated by heparin-coated circuit or by the administration of aprotinin Misawaet al [30] evaluated cytokines level under normothermicCPB in a small observational controlled study (119899 = 19 9 incontrol group) Levels of IL-6 IL-8 and ICAM-1 (indicatorof endothelial damage) were not different between study andcontrol group However as mentioned before most studiesindicate the favorable effect of heparin-coated circuit oninflammatory responses in CPB

Paparella et al [72] compared two doses of heparin and300 Iukg and 600 Iukg in 40 patients undergoing CPB in anRCT and showed that IL-6 and TNF-120572 plasma levels were inassociation to heparin dose It seems that lower heparin dosehad small influence on proinflammatory cytokines releasehowever higher doses make a better regulatory effect oncoagulation system

The side effects of heparin-coated circuits were notreported In these studies just a number of included studiesreported a decrease in platelet levels in both groups (coatedand noncoated circuit) No major events including hemor-rhage were reported

43 Inflammatory Bowel Diseases (IBD) Hypercoagulablestate may be an important contributing factor in the patho-genesis of IBD especially ulcerative colitis (UC) [73] A num-ber of studies evaluate the effects of heparin administrationon UC but the results obtained are controversial [17 19]

Bloom et al [74] did not find any favorable effect of LMWHtinzaparin over placebo in the treatment of active UC ina double-blind randomized placebo controlled multicentertrial (119899 = 100) evaluating mean change in colitis activity asthe primary endpoint Ang et al [17] compared heparin tohydrocortisone plus prednisolone in 20 patients (UC 119899 = 17Crohnrsquos colitis 119899 = 3) in open-label randomized crossovertrial whichmeasured endpoints clinical disease activity stoolfrequency and 120572

1acid glycoprotein and endoscopic and

histopathological grading indicate the efficacy and safety ofheparin compared to corticosteroids (119875 gt 005) in contrastthe study by Panes et al [19] did not show the efficacy ofheparin in UC compared to methylprednisolone

Zezos et al [20] compared enoxaparin with standardtreatment (aminosalicylate + corticosteroids) in 34 patientswith active UC The inflammatory biomarkers includingC-Reactive Protein (CRP) Erythrocyte Sedimentation Rate(ESR) and fibrinogen did not show any difference in studygroup compared to control and both groups showed similarrate of disease improvement (119875 gt 005) furthermorecoagulation factors did not change from one to anotherAuthors concluded that enoxaparin is a safe adjuvant but hasno additive benefit over standard treatment of UC

Generally the studies show conflicting results The hep-arin and LMWHs showed efficacy in regard of disease activityand also well tolerated but inflammatory markers did notchange significantly Therefore the improvement in diseaseactivity might be the result of heparinrsquos anticoagulant effects

44 Acute Coronary Syndrome (ACS) Inflammation has akey role in the pathogenesis of coronary artery plaquedestabilization and rupture leading to acute coronary syn-dromes (ACS) [75] Leukocyte activation monocyte andneutrophil infiltration result in local and systemic inflam-matory responses [76] Heparin and LMWHs are commonlyused in ACS to prevent clot formation they also seem tohave desirable effects on inflammatory markers level basedon sparse data

We found 8 studies about heparin and LMWHs in CADsevaluating anti-inflammatory effects as their endpoints Old-gren et al [56] found that dalteparin administration inpatients with unstable CAD (119899 = 555) did not affect IL-6C-Reactive Protein (CRP) and fibrinogen levels although itreduced coagulation activity and mortality rate in long termso it is concluded that these effects are not related to its anti-inflammatory properties Walters et al [58] compared highdose of tirofibanenoxaparin (119899 = 30) with tirofibanheparin(119899 = 30) in an open-label randomized controlled trial in highrisk percutaneous interventionThey found that combinationof high dose of tirofiban with enoxaparin significantly atten-uate inflammatory process (decreased levels of CRP and vonWillebrand factor) compared to tirofiban and heparin

The ARMADA study [54] evaluated anti-inflammatoryeffects of heparin and enoxaparin in Non-ST-ElevatedMyocardial Infarction (Non-STEMI) and reported thatinflammatory markers (CRP and von Willebrand factor)are affected more by LMWH compared to UFH Howeverbecause of the small sample size of the study (119899 = 68)

Advances in Pharmacological Sciences 11

it did not acquire sufficient statistical power to prove anyeffects on defined outcomes Nasiripour et al [55] found thatboth enoxaparin and heparin reduce inflammatory markersin STEMI patients at the same level however this study hadthe same limitations of sample size (119899 = 34) and power too

In summary considering heparins as the main stay treat-ment of ACS its effects are more pronounced as anticoagu-lating than as an anti-inflammatory agent in this pathologicalcondition

45 Cataract Surgery Postoperative inflammation isobserved in cataract surgery especially in children Newertechniques as lensectomy and phacoemulsification cause lesscomplication but still pose potential risks [77 78] It hasbeen suggested that a heparin surface-modified intraocularlens (IOL) or augmenting the irrigating solution withheparin during cataract surgery may reduce the incidence ofpostoperative inflammation Borgioli et al [22] confirm thishypothesis that heparin surface-modified IOL will reducethe inflammatory response compared to conventional IOLat least in short term period (3 months) in a large (524patients) double-blind multicenter trial A similar study byColin et al [23] (119899 = 58) confirms their results howeverthe power of Borgioli et al study was higher Heparinizedlenses showed also more anti-inflammatory effects duringlong term follow-up (1 year) Heparinized irrigating solutionwas used during cataract surgery in two different studies andinflammation decrease observed in the early postoperativeperiod of both studies (Kohnen et al [26] and Ozkurt et al[24]) Therefore it seems that heparin in both forms haveanti-inflammatory effects in cataract surgery

Vasavada et al [25] used enoxaparin irrigation solutionin 20 children undergoing bilateral cataract surgery butthey did not find any beneficial effect in early postoperativeinflammation This study acquired the highest quality in thestudy quality assessment process based on Jadad score andCONSORT items (5274 702) It is worth noticing that themajority of itemsmentioned in the CONSORT checklist wereadequately reported and covered in this paper

Potential mechanisms of anti-inflammatory effects ofheparin have been discussed completely in a review by Young[6] Binding of heparin to different mediators involved inthe immune system response (cytokines and chemokines)acute phase proteins and complement complex proteinsmay contribute to the anti-inflammatory activity of heparinNeutralizing of cytokines at the inflammation site is anotherpossible mechanism In most of the studies level of cytokinessuch as IL-6 IL-8 TNF-120572 and CRP was decreased afterheparin administration which can confirm this mechanismalso heparin and LMWHs inhibit adhesion of leukocytesand neutrophils to endothelial cells by binding to p-selectinand consequently prevent release of oxygen radicals andproteolytic enzymes Other possible mechanisms are as fol-lows inhibition of nuclear factor 120581B (NF-120581B) and inductionof apoptosis by modulation of activity of TNF-120572 and NF-120581B In a double-blind placebo-controlled trial (119899 = 62)in patients with stable coronary artery disease followingadministration of 1mgkg subcutaneous enoxaparin plasmalevels of myeloperoxidase (MPO) increased significantly

(119875 lt 0001) and subsequently endothelial function improved(119903 = 067 119875 lt 0001) through MPO binding to endotheliumand depleting vascular nitric oxide [57] This study confirmsanother possible mechanism of heparins anti-inflammatoryeffects

5 Conclusion

As we discussed heparins potential effects as anti-inflamma-tory agents supported by several clinical trials in varioussetting Heparin and its related derivatives have been shownto benefit patients with asthma and patients undergoingcardiopulmonary bypass and cataract surgery In otherinflammatory diseases such as IBD (ulcerative colitis) thestudies are heterogeneous and incongruent Most studies didnot report any unwanted event with heparins when they usedthem as anti-inflammatory agents whether through systemicor through local (as inhaler or irrigation or heparin-coatedcircuit) administration However because the majority ofthese trials did not pose optimal quality scores we cannotdraw a definite conclusion on the efficacy of heparin and itsderivatives as anti-inflammatory agents

The present review included studies which measuredinflammatory markers as their endpoints and in most ofthem these markers were decreased though not significantlyTo come to a definite conclusion further double-blindrandomized placebo-controlled clinical trials with a largersample size are needed However because the inflammationatherogenesis thrombogenesis and cell proliferation areassociated with each other the pleiotropic effects of heparinand related compounds may have greater therapeutic effectthan compounds that are directed against a single target

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

[1] B Casu ldquoHeparin structurerdquo Pathophysiology of Haemostasisand Thrombosis vol 20 supplement 1 pp 62ndash73 1990

[2] J Hirsh R Raschke T EWarkentin J E Dalen DDeykin andL Poller ldquoHeparin mechanism of action pharmacokineticsdosing considerations monitoring efficacy and safetyrdquo Chestvol 108 no 4 supplement pp 258Sndash275S 1995

[3] J Fareed D A Hoppensteadt and R L Bick ldquoAn update onheparins at the beginning of the new millenniumrdquo Seminars inThrombosis and Hemostasis vol 26 no 3 pp 5ndash21 2000

[4] J Hirsh ldquoDrug therapy heparinrdquo The New England Journal ofMedicine vol 324 no 22 pp 1565ndash1574 1991

[5] R J Ludwig ldquoTherapeutic use of heparin beyond anticoagu-lationrdquo Current Drug Discovery Technologies vol 6 no 4 pp281ndash289 2009

[6] E Young ldquoThe anti-inflammatory effects of heparin and relatedcompoundsrdquo Thrombosis Research vol 122 no 6 pp 743ndash7522008

12 Advances in Pharmacological Sciences

[7] A R Jadad R A Moore D Carroll et al ldquoAssessing the qualityof reports of randomized clinical trials is blinding necessaryrdquoControlled Clinical Trials vol 17 no 1 pp 1ndash12 1996

[8] K F Schulz D G Altman and D Moher ldquoCONSORT 2010statement updated guidelines for reporting parallel grouprandomised trialsrdquo International Journal of Surgery vol 9 no8 pp 672ndash677 2011

[9] T Ahmed J Garrigo and I Danta ldquoPreventing bronchocon-striction in exercise-induced asthma with inhaled heparinrdquoTheNewEngland Journal ofMedicine vol 329 no 2 pp 90ndash95 1993

[10] Z Diamant M C Timmers H Van Der Veen C P PageF J Van Der Meer and P J Sterk ldquoEffect of inhaled heparinon allergen-induced early and late asthmatic responses inpatients with atopic asthmardquo American Journal of Respiratoryand Critical Care Medicine vol 153 no 6 pp 1790ndash1795 1996

[11] M Duong D Cockcroft L-P Boulet et al ldquoThe effect ofIVX-0142 a heparin-derived hypersulfated disaccharide on theallergic airway responses in asthmardquo Allergy vol 63 no 9 pp1195ndash1201 2008

[12] A M Fal M Kraus-Filarska J Miecielica and J MalolepszyldquoMechanisms of action of nebulized low-molecular-weightheparin in patients with bronchial asthmardquo The Journal ofAllergy and Clinical Immunology vol 113 no 2 supplement pS36 2004

[13] J Jerzynska I Stelmach P Majak and P Kuna ldquoThe effectof inhaled heparin on airway responsiveness to histamine andmetacholine in asthmatic childrenrdquo Journal of Allergy andClinical Immunology vol 109 no 1 supplement 1 p S39 2002

[14] A F Kalpaklioglu Y S Demirel S Saryal and Z MisirligilldquoEffect of pretreatment with heparin on pulmonary and cuta-neous responserdquo Journal of Asthma vol 34 no 4 pp 337ndash3431997

[15] I Stelmach J Jerzynska A Brzozowska and P Kuna ldquoTheeffect of inhaled heparin on postleukotriene bronchoconstric-tion in children with asthmardquo Journal of Allergy and ClinicalImmunology vol 109 no 1 supplement 1 p S39 2002

[16] I Stelmach J Jerzynska W Stelmach et al ldquoThe effect ofinhaled heparin on airway responsiveness to histamine andleukotriene D4rdquo Allergy and Asthma Proceedings vol 24 no 1pp 59ndash65 2003

[17] Y S Ang N Mahmud B White et al ldquoRandomized compar-ison of unfractionated heparin with corticosteroids in severeactive inflammatory bowel diseaserdquo Alimentary PharmacologyandTherapeutics vol 14 no 8 pp 1015ndash1022 2000

[18] C Folwaczny B Wiebecke and K Loeschke ldquoUnfractionedheparin in the therapy of patients with highly active inflamma-tory bowel diseaserdquo The American Journal of Gastroenterologyvol 94 no 6 pp 1551ndash1555 1999

[19] J Panes M Esteve E Cabre et al ldquoComparison of heparinand steroids in the treatment of moderate and severe ulcerativecolitisrdquo Gastroenterology vol 119 no 4 pp 903ndash908 2000

[20] P Zezos G Papaioannou N Nikolaidis et al ldquoLow-molecular-weight heparin (enoxaparin) as adjuvant therapy in the treat-ment of active ulcerative colitis a randomized controlledcomparative studyrdquoAlimentary Pharmacology andTherapeuticsvol 23 no 10 pp 1443ndash1453 2006

[21] A A Vrij J M Jansen E J Schoon H C Hemker and RW Stockbrugger ldquoLow molecular weight heparin treatmentin steroid refractory ulcerative colitis clinical outcome andinfluence on mucosal capillary thrombirdquo Scandinavian Journalof Gastroenterology Supplement vol 36 no 234 pp 41ndash47 2001

[22] D M Borgioli D J Coster R F T Fan et al ldquoEffect of heparinsurface modification of polymethylmethacrylate intraocularlenses on signs of postoperative inflammation after extracap-sular cataract extraction one-year results of a double-maskedmulticenter studyrdquoOphthalmology vol 99 no 8 pp 1248ndash12551992

[23] J Colin S Roncin and M Wenzel ldquoEfficacy of heparinsurface-modified IOLs in reducing postoperative inflammatoryreactions in patients with exfoliation syndromemdasha double-blind comparative studyrdquo European Journal of Implant andRefractive Surgery vol 7 no 5 pp 266ndash270 1995

[24] Y B Ozkurt A Taskiran N Erdogan B Kandemir and OK Dogan ldquoEffect of heparin in the intraocular irrigating solu-tion on postoperative inflammation in the pediatric cataractsurgeryrdquoClinical Ophthalmology vol 3 no 1 pp 363ndash365 2009

[25] V A Vasavada M R Praveen S K Shah R H Trivedi andA R Vasavada ldquoAnti-inflammatory effect of low-molecular-weight heparin in pediatric cataract surgery a randomizedclinical trialrdquoThe American Journal of Ophthalmology vol 154no 2 pp 252ndash258 2012

[26] T Kohnen B Dick V Hessemer D D Koch and K WJacobi ldquoEffect of heparin in irrigating solution on inflammationfollowing small incision cataract surgeryrdquo Journal of Cataract ampRefractive Surgery vol 24 no 2 pp 237ndash243 1998

[27] S Ashraf Y Tian D Cowan A Entress P G Martin andK G Watterson ldquoRelease of proinflammatory cytokines dur-ing pediatric cardiopulmonary bypass heparin-bonded versusnonbonded oxygenatorsrdquo Annals of Thoracic Surgery vol 64no 6 pp 1790ndash1794 1997

[28] J-O Defraigne J Pincemail R Larbuisson F Blaffart andR Limet ldquoCytokine release and neutrophil activation are notprevented by heparin- coated circuits and aprotinin administra-tionrdquo Annals of Thoracic Surgery vol 69 no 4 pp 1084ndash10912000

[29] R de Vroege W van Oeveren J van Klarenbosch et al ldquoTheimpact of heparin-coated cardiopulmonary bypass circuits onpulmonary function and the release of inflammatory media-torsrdquo Anesthesia and Analgesia vol 98 no 6 pp 1586ndash15942004

[30] Y Misawa K Kawahito H Konishi and K Fuse ldquoCytokinemediated endothelial activation during and after normothermiccardiopulmonary bypass Heparin-bonded versus non heparin-bonded circuitsrdquo ASAIO Journal vol 46 no 6 pp 740ndash7432000

[31] A Koster T Fischer M Praus et al ldquoHemostatic activationand inflammatory response during cardiopulmonary bypassimpact of heparin managementrdquo Anesthesiology vol 97 no 4pp 837ndash841 2002

[32] C Olsson A Siegbahn A Henze et al ldquoHeparin-coatedcardiopulmonary bypass circuits reduce circulating comple-ment factors and interleukin-6 in paediatric heart surgeryrdquoScandinavian Cardiovascular Journal vol 34 no 1 pp 33ndash402000

[33] T Ozawa K Yoshihara N Koyama Y Watanabe N Shionoand Y Takanashi ldquoClinical efficacy of heparin-bonded bypasscircuits related to cytokine responses in childrenrdquo The Annalsof Thoracic Surgery vol 69 no 2 pp 584ndash590 2000

[34] A Parolari F Alamanni T Gherli et al ldquolsquoHigh dosersquo aprotininand heparin-coated circuits Clinical efficacy and inflammatoryresponserdquo Cardiovascular Surgery vol 7 no 1 pp 117ndash127 1999

[35] H Yamada I Kudoh Y Hirose M Toyoshima H Abe andK Kurahashi ldquoHeparin-coated circuits reduce the formation of

Advances in Pharmacological Sciences 13

TNF120572 during cardiopulmonary bypassrdquo Acta AnaesthesiologicaScandinavica vol 40 no 3 pp 311ndash317 1996

[36] O Barkay E Niv E Santo R Bruck A Hallak and F MKonikoff ldquoLow-dose heparin for the prevention of post-ERCPpancreatitis a randomized placebo-controlled trialrdquo SurgicalEndoscopy and Other Interventional Techniques vol 22 no 9pp 1971ndash1976 2008

[37] R C Becker K W Mahaffey H Yang et al ldquoHeparin-associated anti-Xa activity and platelet-derived prothromboticand proinflammatory biomarkers in moderate to high-riskpatients with acute coronary syndromerdquo Journal of Thrombosisand Thrombolysis vol 31 no 2 pp 146ndash153 2011

[38] S D Bowler S M Smith and P S Lavercombe ldquoHeparininhibits the immediate response to antigen in the skin and lungsof allergic subjectsrdquo American Review of Respiratory Diseasevol 147 no 1 pp 160ndash163 1993

[39] J P Boyle R H Smart and J K Shirey ldquoHeparin in thetreatment of chronic obstructive bronchopulmonary diseaserdquoThe American Journal of Cardiology vol 14 no 1 pp 25ndash281964

[40] Y Qian H Xie R Tian K Yu and R Wang ldquoEfficacy of lowmolecular weight heparin in patients with acute exacerbationof chronic obstructive pulmonary disease receiving ventilatorysupportrdquo COPD Journal of Chronic Obstructive PulmonaryDisease vol 11 no 2 pp 171ndash176 2014

[41] A Chamorro A Cervera J Castillo A Davalos J J Aponteand A M Planas ldquoUnfractionated heparin is associated with alower rise of serum vascular cell adhesion molecule-1 in acuteischemic stroke patientsrdquo Neuroscience Letters vol 328 no 3pp 229ndash232 2002

[42] R de Cock L A Ficker J G Dart A Garner and P WrightldquoTopical heparin in the treatment of ligneous conjunctivitisrdquoOphthalmology vol 102 no 11 pp 1654ndash1659 1995

[43] U Derhaschnig T Pernerstorfer M Knechtelsdorfer U Hol-lenstein S Panzer and B Jilma ldquoEvaluation of antiinflamma-tory and antiadhesive effects of heparins in human endotox-emiardquo Critical Care Medicine vol 31 no 4 pp 1108ndash1112 2003

[44] B DixonM J Schultz R Smith J B Fink J D Santamaria andD J Campbell ldquoNebulized heparin is associatedwith fewer daysof mechanical ventilation in critically ill patients a randomizedcontrolled trialrdquo Critical Care vol 14 no 5 article R180 2010

[45] F K Keating H L Dauerman D A Whitaker B E Sobeland D J Schneider ldquoThe effects of bivalirudin compared withthose of unfractionated heparin plus eptifibatide on inflam-mation and thrombin generation and activity during coronaryinterventionrdquo Coronary Artery Disease vol 16 no 6 pp 401ndash405 2005

[46] M Ledson M Gallagher C A Hart and M Walshaw ldquoNeb-ulized heparin in Burkholderia cepacia colonized adult cysticfibrosis patientsrdquo European Respiratory Journal vol 17 no 1 pp36ndash38 2001

[47] D J Serisier J K Shute P M Hockey B Higgins J Conwayand M P Carroll ldquoInhaled heparin in cystic fibrosisrdquo EuropeanRespiratory Journal vol 27 no 2 pp 354ndash358 2006

[48] O K Poyrazoglu A Dogukan M Yalniz D Seckin andA L Gunal ldquoAcute effect of standard heparin versus lowmolecular weight heparin on oxidative stress and inflammationin hemodialysis patientsrdquo Renal Failure vol 28 no 8 pp 723ndash727 2006

[49] S Suzuki T Matsuo H Kobayashi et al ldquoAntithrombotictreatment (argatroban vs heparin) in coronary angioplastyin angina pectoris effects on inflammatory hemostatic and

endothelium-derived parametersrdquoThrombosis Research vol 98no 4 pp 269ndash279 2000

[50] S D Trocme and H-I Li ldquoEffect of heparin-surface-modifiedintraocular lenses on postoperative inflammation after pha-coemulsification a randomized trial in a United States patientpopulationrdquo Ophthalmology vol 107 no 6 pp 1031ndash1037 2000

[51] C Vancheri C Mastruzzo F Armato et al ldquoIntranasal heparinreduces eosinophil recruitment after nasal allergen challenge inpatients with allergic rhinitisrdquo Journal of Allergy and ClinicalImmunology vol 108 no 5 pp 703ndash708 2001

[52] A Abdollahi M-T Naini H Shams and R Zarei ldquoEffect oflow-molecular-weight heparin on postoperative inflammationin phacomorphic glaucomardquo Archives of Iranian Medicine vol5 no 4 pp 225ndash229 2002

[53] R T S Lakshmi T Priyanka J Meenakshi K R MathangiV Jeyaraman and M Babu ldquoLow molecular weight heparinmediated regulation of nitric oxide synthase during burnwound healingrdquo Annals of Burns and Fire Disasters vol 24 no1 pp 24ndash29 2011

[54] G Montalescot C Bal-dit-Sollier D Chibedi et al ldquoCompar-ison of effects on markers of blood cell activation of enoxa-parin dalteparin and unfractionated heparin in patients withunstable angina pectoris or non-ST-segment elevation acutemyocardial infarction (the ARMADA study)rdquo The AmericanJournal of Cardiology vol 91 no 8 pp 925ndash930 2003

[55] S Nasiripour K Gholami SMousavi et al ldquoComparison of theeffects of enoxaparin and heparin on inflammatory biomarkersin patients with ST-segment elevated myocardial infarction aprospective open label pilot clinical trialrdquo Iranian Journal ofPharmaceutical Research vol 13 no 2 pp 583ndash590 2014

[56] J Oldgren C Fellenius K Boman et al ldquoInfluence of prolongeddalteparin treatment on coagulation fibrinolysis and inflam-mation in unstable coronary artery diseaserdquo Journal of InternalMedicine vol 258 no 5 pp 420ndash427 2005

[57] T K Rudolph V Rudolph A Witte et al ldquoLiberation of vesseladherent myeloperoxidase by enoxaparin improves endothelialfunctionrdquo International Journal of Cardiology vol 140 no 1 pp42ndash47 2010

[58] D L Walters M J Ray P Wood E J Perrin J H N Bettand C N Aroney ldquoHigh-dose tirofiban with enoxaparin andinflammatory markers in high-risk percutaneous interventionrdquoEuropean Journal of Clinical Investigation vol 40 no 2 pp 139ndash147 2010

[59] S W Rathbun C E Aston and T L Whitsett ldquoA randomizedtrial of dalteparin compared with ibuprofen for the treatmentof superficial thrombophlebitisrdquo Journal of Thrombosis andHaemostasis vol 10 no 5 pp 833ndash839 2012

[60] J P Titon D Auger P Grange et al ldquoTherapeutic managementof superficial venous thrombosis with calcium nadroparinDosage testing and comparison with a non-steroidal anti-inflammatory agentrdquo Annales de Cardiologie et d Angeiologievol 43 no 3 pp 160ndash166 1994

[61] H Uncu ldquoA comparison of low-molecular-weight heparin andcombined therapy of low-molecular-weight heparin with ananti-inflammatory agent in the treatment of superficial veinthrombosisrdquo Phlebology vol 24 no 2 pp 56ndash60 2009

[62] J A Sjoslashland R S Pedersen J Jespersen and J GramldquoIntraperitoneal heparin ameliorates the systemic inflamma-tory response in PD patientsrdquo NephronmdashClinical Practice vol100 no 4 pp c105ndashc110 2005

[63] N L Fine C Shim and M H Williams Jr ldquoObjectiveevaluation of heparin in the treatment of asthmardquo AmericanReview of Respiratory Disease vol 98 no 5 pp 886ndash887 1968

14 Advances in Pharmacological Sciences

[64] ZDiamantM C Timmers H van derVeen C P Page F J vander Meer and P J Sterk ldquoEffect of inhaled heparin on allergen-induced early and late asthmatic responses in patients withatopic asthmardquo American Journal of Respiratory and CriticalCare Medicine vol 153 no 6 I pp 1790ndash1795 1996

[65] C M E Tranfa A Vatrella R Parrella G Pelaia F Bariffiand S A Marsico ldquoEffect of inhaled heparin on water-inducedbronchoconstriction in allergic asthmaticsrdquoEuropean Journal ofClinical Pharmacology vol 57 no 1 pp 5ndash9 2001

[66] I Stelmach J Jerzynska A Brzozowska and P Kuna ldquoTheeffect of inhaled heparin on postleukotriene bronchoconstric-tion in children with asthmardquo Polski Merkuriusz Lekarski vol12 no 68 pp 95ndash98 2002

[67] R Polosa S Magrı C Vancheri et al ldquoTime course of changesin adenosine 51015840-monophosphate airway responsiveness withinhaled heparin in allergic asthmardquo Journal of Allergy andClinical Immunology vol 99 no 3 pp 338ndash342 1997

[68] J Butler GM Rocker and SWestaby ldquoInflammatory responseto cardiopulmonary bypassrdquo The Annals of Thoracic Surgeryvol 55 no 2 pp 552ndash559 1993

[69] J M Redmond A M Gillinov R S Stuart et al ldquoHeparin-coated bypass circuits reduce pulmonary injuryrdquoThe Annals ofThoracic Surgery vol 56 no 3 pp 474ndash479 1993

[70] S Svenmarker E Sandstrom T Karlsson et al ldquoClinical effectsof the heparin coated surface in cardiopulmonary bypassrdquoEuropean Journal of Cardio-Thoracic Surgery vol 11 no 5 pp957ndash964 1997

[71] Y J Gu W van Oeveren C Akkerman P W Boonstra RJ Huyzen and C R H Wildevuur ldquoHeparin-coated circuitsreduce the inflammatory response to cardiopulmonary bypassrdquoThe Annals of Thoracic Surgery vol 55 no 4 pp 917ndash922 1993

[72] D Paparella O O Al Radi Q H Meng T Venner K Teohand E Young ldquoThe effects of high-dose heparin on inflamma-tory and coagulation parameters following cardiopulmonarybypassrdquo Blood Coagulation and Fibrinolysis vol 16 no 5 pp323ndash328 2005

[73] S Danese A Papa S Saibeni A Repici A Malesci andM Vecchi ldquoInflammation and coagulation in inflammatorybowel disease the clot thickensrdquo The American Journal ofGastroenterology vol 102 no 1 pp 174ndash186 2007

[74] S Bloom S Kiilerich M R Lassen et al ldquoLow molecularweight heparin (tinzaparin) vs placebo in the treatment of mildto moderately active ulcerative colitisrdquo Alimentary Pharmacol-ogy ampTherapeutics vol 19 no 8 pp 871ndash878 2004

[75] P Libby ldquoCoronary artery injury and the biology of atheroscle-rosis inflammation thrombosis and stabilizationrdquo AmericanJournal of Cardiology vol 86 no 8 2000

[76] N T Mulvihill and J B Foley ldquoInflammation in acute coronarysyndromesrdquo Heart vol 87 no 3 pp 201ndash204 2002

[77] N A JamesonW V Good and C S Hoyt ldquoInflammation aftercataract surgery in childrenrdquoOphthalmic Surgery vol 23 no 2pp 99ndash102 1992

[78] R M Sinskey P A Amin and R Lingua ldquoCataract extractionand intraocular lens implantation in an infant with amonocularcongenital cataractrdquo Journal of Cataract amp Refractive Surgeryvol 20 no 6 pp 647ndash651 1994

[79] A van Ophoven A Heinecke and L Hertle ldquoSafety andefficacy of concurrent application of oral pentosan polysulfateand subcutaneous low-dose heparin for patients with interstitialcystitisrdquo Urology vol 66 no 4 pp 707ndash711 2005

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Page 3: Review Article Anti-Inflammatory Effects of Heparin and Its …downloads.hindawi.com/journals/aps/2015/507151.pdf · 2019. 7. 31. · Review Article Anti-Inflammatory Effects of Heparin

Advances in Pharmacological Sciences 3

Table1Summaryandfin

ding

sofcom

mon

studied

diseases

Clinicalsetting

Heparin

preparation

Mod

eof

administratio

nCom

parator

Num

bero

fpatie

nts

Clinicalou

tcom

eLabo

ratory

outcom

eStud

ydesig

n

Exercise-in

duced

Asthma[

9]UFH

Inhaler

Crom

olyn

sodium

orplacebo

12Sign

ificantlyredu

ctionof

exercise-in

ducedasthma

Heparin

hadno

effecto

nhistam

ine-indu

ced

bron

chocon

strictio

n

Sing

le-blin

drand

omized

crossoverc

linicaltrial

Asthma[

10]

UFH

Inhaler

Placebo

8

Sign

ificant

redu

ctionof

late

asthmaticrespon

seaft

erallergen

administratio

n(119875

0005)

mdashRa

ndom

izeddou

ble-blind

crossoverc

linicaltrial

Atop

icasthma

[11]

Heparin

(IVX-

0142)

Nebulizer

Placebo

19Nosig

nificantd

ecreasein

early

(119875006)

andlate(119875

024)a

sthm

aticrespon

semdash

Rand

omized

single-blind

placebo-controlled

crossovertria

l

Asthma[

12]

LMWH

Nebulizer

mdash24

Effectiv

easa

nadd-on

therapyto

stand

ard

treatment

Redu

ctionin

eosin

ophil(119875

000

06)and

lymph

ocyte(119875

0049)

inbron

choalveolar

lavageNochangesinIL-5

orEC

Pconcentrations

inserum

Quasi-experim

ental

(pretest-

posttestd

esign)

Allergicasthma

[13]

UFH

Inhaler

Placebo

25

Heparin

inhalatio

nsig

nificantly

redu

ced

bron

chialhyperreactiv

ity(119875lt005)

mdashRa

ndom

izeddou

ble-blind

placebo-controlled

crossovertria

l

Asthma[

14]

UFH

Inhaler

mdash12

Transie

nt(time-depend

ent)

inhibitory

rolein

allergic

reactio

ns

Increasedthem

ethacholine

PC20

value(119875005)

but

didno

tprevent

anincrease

inRa

wandor

adecreasein

SGAW

Rand

omizeddou

ble-blind

placebo-controlled

crossovertria

l

Asthma

(children)

[15]

UFH

Inhaler

Placebo

14

Sing

ledo

seof

heparin

significantly

(1198750005)

redu

cedbron

chial

hyperreactivity

Provocationtestused

leuk

otrie

neD4

Rand

omizeddou

ble-blind

placebo-controlled

crossovertria

l

Asthma[

16]

UFH

Inhaler

Placebo

23Sign

ificant

redu

ctionof

bron

chialhyperreactiv

ityto

histam

inea

ndleuk

otrie

nemdash

Rand

omizeddou

ble-blind

placebocontrolled

crossovertria

l

IBD[17]

UFH

IVSC

Hydrocortiso

ne+

prednisolone

20(12in

control

grou

p)

Clinicalactiv

ityindexsto

olfre

quencyand

endo

scop

icandhisto

pathological

gradingweres

imilarin

both

treatmentg

roup

s

CRPand1205721a

cid

glycop

rotein

didno

tchange

Openlabelrando

mized

crossoverc

linicaltrial

4 Advances in Pharmacological Sciences

Table1Con

tinued

Clinicalsetting

Heparin

preparation

Mod

eof

administratio

nCom

parator

Num

bero

fpatie

nts

Clinicalou

tcom

eLabo

ratory

outcom

eStud

ydesig

n

IBD[18]

UFH

SCmdash

17

Histologyim

proved

significantly

inulcerativ

ecolitispatie

nts(UFH

iseffectiv

einulcerativ

ecolitis

butn

otCr

ohndisease)

CRP(11987500119

)and

ESR

(11987500096)

significantly

redu

cedin

ulcerativ

ecolitis

butn

otCr

ohndisease

Quasi-experim

ental

(pretest-

posttestd

esign)

IBD[19

]UFH

IVMethylpredn

isolone

25(13in

control

grou

p)

Noeffecto

fheparinalso

increasedbleeding

Nochange

inCR

PRa

ndom

izeddou

ble-blind

parallel-g

roup

trial

IBD[20]

Enoxaparin

+sta

ndard

treatment

SCAminosalicylate+

corticosteroid

34(18in

control

grou

p)

Sign

ificant

improvem

entin

diseases

everity

inbo

thgrou

ps(1198750001)

NodifferenceE

SRC

RPandfib

rinogen

and

coagulation

Rand

omized

controlled

trial

IBD[21]

Nadroparin

SCmdash

25

Endo

scop

icand

histo

logicalsignof

inflammationsig

nificantly

improved

mdashQuasi-experim

ental

(Non

-rando

mized

clinical

trial)

Cataractsurgery

[22]

UFH

Intraocular

lens

(IOL)

Polymethylm

ethacrylate

524

mdash

Heparin

surfa

cemod

ificatio

nredu

cedthe

cellu

lard

epositcompared

tocontrolgroup

Rand

omizeddou

ble-blind

parallelgroup

clinicaltria

l

Cataractsurgery

[23]

UFH

Intraocular

lens

(IOL)

Polymethylm

ethacrylate

58(31in

control

grou

p)

Posto

perativ

einfl

ammation

decreasedsig

nificantly

inheparin

grou

p(119875002)

Giant

cellandcelldepo

sitdecreasedsig

nificantly

(119875lt005)

Rand

omizeddou

ble-blind

clinicaltria

l

Cataractsurgery

(pediatric)[24]

UFH

Irrig

ation

Balanced

saltsolutio

n33

(19in

control

grou

p)

Heparin

irrigationredu

ced

numbero

fpostoperativ

einflammatoryrelated

complication

Anteriorc

hamberreaction

inclu

ding

fibrin

form

ation

was

lower

inheparin

grou

p

Rand

omized

prospective

doub

le-blin

dtrial

Cataractsurgery

(pediatrics)[25]

Enoxaparin

Irrig

ation

Notre

atment

40(20in

each

grou

p)

Increase

offlare

andcell

depo

sitaft

ersurgery(1and

3mon

ths)(119875099)

Increase

inlargec

ell

depo

sits

Rand

omizeddou

ble-blind

controlledtrial

Cataractsurgery

[26]

UFH

Irrig

ation

Regu

larirrigation

solutio

n72

Sign

ificant

redu

ctionof

inflammationin

thee

arly

(days1ndash3)p

ostoperativ

eperio

d(119875lt001)

mdashRa

ndom

ized

controlled

trial

Cardiopu

lmon

ary

bypass(pediatric)

[27]

Heparin-

coated

circuit

(119899=11)

mdashNon

-heparin-coated

circuit(119899=10)

21

Decreaseo

fsystemic

inflammatoryrespon

sewith

theu

seof

heparin

-bon

ded

oxygenators

Sign

ificantlydecreased

levelsof

IL-6IL-8term

inal

complem

entcom

plex

neutroph

ilsand

elastase

inheparin

coated

circuit

Rand

omized

controlled

trial

Cardiopu

lmon

ary

bypass[28]

Heparin-

coated

circuit

plusmnaprotin

inmdash

Uncoatedcircuitplusmn

aprotin

in200(4

grou

ps)

Aprotin

inandheparin

had

noeffecto

ncytokine

release

TNF-120572IL-6andIL-8

and

myeloperoxidase

didno

tchange

Rand

omizeddou

ble-blind

clinicaltria

l

Advances in Pharmacological Sciences 5

Table1Con

tinued

Clinicalsetting

Heparin

preparation

Mod

eof

administratio

nCom

parator

Num

bero

fpatie

nts

Clinicalou

tcom

eLabo

ratory

outcom

eStud

ydesig

n

Cardiopu

lmon

ary

bypass[29]

UFH

mdashUncoatedcircuit

51(26in

each

grou

p)

Decreased

pulm

onary

vascular

resistanceind

exandpu

lmon

aryshun

tfractio

nandincreased

PaO2FIO2ratio

Lower

levelsof

phosph

olipaseA

2and

complem

entactivation(119875

0001)

Rand

omizeddou

ble-blind

clinicaltria

l

Cardiopu

lmon

ary

bypass[30]

Heparin-

coated

circuit

mdashNon

-heparin-coated

circuit

16(9

incontrol

grou

p)mdash

Nosig

nificantd

ifference

betweengrou

psregarding

granulocytee

lasta

seIL-6

IL-8

Quasi-experim

ental

(pretest-

posttestd

esign)

Cardiopu

lmon

ary

bypass[31]

Heparin

concentration-

based

syste

m

mdashAc

tivated

clotting

time-based

managem

ent

200(100

incontrol

grou

p)

Noeffecto

npo

stoperativ

ebloo

dloss

Sign

ificant

redu

ctionof

neutroph

ilactiv

ationand

fibrin

olysisandthrombin

generatio

n(119875lt005)

Rand

omized

controlled

trial

Cardiopu

lmon

ary

bypass(pediatric)

[32]

Heparin-

coated

circuit

mdashNon

-heparin-coated

circuit

19(10in

control

grou

p)

Improvem

ento

fthe

biocom

patib

ilityof

CPB

durin

gheartsurgery

Levelsof

complem

ent

factor

C3a(119875lt0001)a

ndIL-6

(1198750005)significantly

redu

cedin

heparin

-coated

circuit

Rand

omized

controlled

trial

Cardiopu

lmon

ary

bypass(pediatric)

[33]

Heparin-

coated

circuit

mdashNon

-heparin-coated

circuit

34(12in

control

grou

p)

Nodifferences

indu

ratio

nof

intubatio

nintensivec

are

unitor

hospita

lstayor

posto

perativ

eblood

loss

IL-6IL-8andTN

F-120572we

resig

nificantly

lower

inheparin

grou

p(119875lt001

119875lt001and119875lt005

resp)

Rand

omized

controlled

trial

Cardiopu

lmon

ary

bypass[34]

Heparin-

coated

circuit

(heparin

+aprotin

in)

mdashNon

-heparin-coated

circuit(heparin

+aprotin

in)

30(15in

each

grou

p)

Nosig

nificantd

ifferences

betweenthetwogrou

psin

term

sofb

leedingand

transfu

sionalrequirements

thetim

espent

ona

ventilatoror

indu

ratio

nof

stayin

theintensiv

ecare

unit(ICU

)

Levelsof

IL-6C

RPand

neutroph

ilcoun

tdid

not

change

byheparin

-coated

circuitMon

ocytec

ount

increasedin

heparin

-coatedcircuit

Rand

omized

controlled

trial

Coron

aryartery

bypassgraft

ing

(CABG

)[35]

Heparin-

coated

circuit

mdashNon

-heparin-coated

circuit

18(9

ineach

grou

p)mdash

Redu

ctionof

levelsof

IL-8

andTN

F-120572andincrease

ofneutroph

ilelastase

Rand

omized

controlled

trial

CRP

C-Re

activ

eProteinC

PBC

ardioPu

lmon

aryB

ypassEC

PEo

sinop

hilC

ationicP

roteinE

SRE

rythrocyteSedimentatio

nICUIntensiv

eCareU

nitILinterleuk

inIV

intravenou

sSC

sub

cutaneou

sSG

AW

SpecificA

irway

Con

ductanceT

NFTu

mor

Necrosis

Factorand

UFH

unfractionatedheparin

6 Advances in Pharmacological Sciences

Table2Summaryandfin

ding

sofo

ther

studied

diseases

Clinicalsetting

Heparin

preparation

Mod

eof

administratio

nCom

parator

Num

bero

fpatie

nts

Clinicalou

tcom

eLabo

ratory

outcom

eStud

ydesig

n

Pancreatitisa

fter

ERCP

[36]

UFH

SCSalin

esolution

105(54in

control

grou

p)

Rateof

posto

perativ

epancreatitisw

asno

tsig

nificantb

etweenbo

thgrou

ps

mdashRa

ndom

ized

placebo-controlledclinical

trial

Acutec

oron

ary

synd

rome(AC

S)[37]

UFH

SCEn

oxaparin

201

mdashNosig

nificantd

ifference

betweenCD

4ligandand

PAI-1inbo

thgrou

ps

Openlabelrand

omized

clinicaltria

l

Skin

orpu

lmon

ary

allergy[38]

UFH

IVnebulizer

Normalsalin

eplacebo

25Sign

ificant

inhibitio

nof

mastcell-m

ediatedallergic

inflammation(119875004)

mdashDou

ble-blind

placebo-controlled

crossoverc

linicaltrial

COPD

[39]

UFH

IVmdash

37(18in

control

grou

p)

Sign

ificant

improvem

entin

bron

chospasm

and

bron

chialsecretio

ns(58

respon

serate)

mdashRa

ndom

ized

placebo-controlledclinical

trial

COPD

[40]

Nadroparin

SCCon

ventionaltreatment

66(33in

each

grou

p)

Decreaseo

fdurationof

mechanicalventilationand

leng

thof

hospita

land

ICU

stay(119875lt001)

Sign

ificant

decrease

inlevelsof

CRPIL-6and

fibrin

ogen

Rand

omized

controlled

trial

Ischem

icstroke

[41]

UFH

IVAs

pirin

167(97in

control

grou

p)

Early

onsetinitia

tionof

heparin

might

improve

recovery

after

stroke

Rise

ofsV

CAM-1at48

hwas

significantly

lower

inpatie

ntstreated

with

UFH

(119875lt001)

Quasi-experim

ental

(con

trolledob

servational

study)

Lign

eous

conjun

ctivitis[42]

UFH

Topical

Alpha

chym

otrypsin

orste

roid

17(12in

control

grou

p)

Intensivea

ndearly

useo

ftopicalh

eparin

may

improvetherapy

results

indisease

mdashQuasi-experim

ental

(non

rand

omized

Clinical

trial)

Endo

toxemia

(indu

cedby

lipop

olysaccharide

inhealthysubjects)

[43]

UFH

IVLM

WHor

placebo

30(10in

each

grou

p)mdash

Noeffecto

nTN

F-120572IL-6

and8CR

PandE-selectin

Rand

omized

doub

le-blin

ded

placebo-controlledparallel

grou

ptrial

Mechanical

ventilatio

n[44]

UFH

Nebulizer

Normalsalin

e(placebo)

50(25in

each

grou

p)

Fewer

days

onmechanical

ventilatio

nbette

rPao2Fio2ratio

mdashDou

ble-blindrand

omized

placebo-controlledtrial

Percutaneous

coronary

interventio

n[45]

Bivalirud

inIV

UFH

+eptifi

batid

e63

(29in

control

grou

p)mdash

Increase

inIL-6

andCR

Paft

er1d

ayD

ecreaseinCR

Pin

bivalirud

ingrou

paft

er30

days

(1198750002)

Rand

omized

controlled

trial

Cysticfib

rosis

(adu

lts)[46

]UFH

Inhaler

mdash12

(6in

control

grou

p)Spiro

metry

parametersd

idno

tchang

eIL-6

redu

cedaft

ertre

atment

Quasi-experim

ental

(pretest-

posttestd

esign)

Advances in Pharmacological Sciences 7Ta

ble2Con

tinued

Clinicalsetting

Heparin

preparation

Mod

eof

administratio

nCom

parator

Num

bero

fpatie

nts

Clinicalou

tcom

eLabo

ratory

outcom

eStud

ydesig

n

Cysticfib

rosis

(adu

lts)[47]

UFH

Inhaler

Placebo

14Noeffecto

nFE

V1

Noeffecto

nsputum

inflammatorymarkers

Rand

omizeddou

ble-blind

placebo-controlled

crossovertria

l

Hem

odialysis

patie

nts[48]

UFH

IVSC

LMWHandno

drug

33

LMWHdecreased

oxidatives

tressand

inflammationwhereas

heparin

increasedthem

CRPTN

F-120572sup

eroxide

dism

utaseMDAincreased

inheparin

grou

pbu

tcomparabletoLM

WH

grou

p

Quasi-experim

ental

(pretest-

posttestd

esign)

Stableangina

[49]

Heparin

+Aspirin

(119899=15)

mdashArgatroban+As

pirin

(119899=12)2

7

Nodifferencein

inflammatoryrespon

seaft

erangiop

lasty

Fibrinogen

decreased

significantly

inargatro

ban

grou

pNodifferenceinvon

Willberand

factor

between

both

grou

psPAI-1

increasedin

argatro

ban

grou

p

Rand

omized

controlled

trial

Phacoemulsifi

catio

n[50]

Heparin

Coatedlenses

Polymethylm

ethacrylate

lenses

367

Heparin

coated

lenses

redu

cedsig

nificantly

inflammationearly

posto

peratio

n(119875005)

mdashRa

ndom

izeddou

ble-blind

multic

enterparallelgroup

trial

Allergicrhinitis[51]

UFH

Intranasal

mdash10

mdashRe

ductionof

eosin

ophil

catio

nicp

rotein

inthen

asal

wash

Quasi-experim

ental

(pretest-

posttestd

esign)

Phacom

orph

icglaucoma[

52]

Dalteparin

Irrig

ation

Balanced

saltsolutio

n46

(23in

each

grou

p)

Sign

ificant

decrease

ofpo

stoperativ

einfl

ammation

indalteparin

grou

pmdash

Rand

omizeddou

ble-blind

clinicaltria

l

Burn

[53]

Dalteparin

SCNotre

atment

24mdash

Decreaseo

fnitricoxide

synthetase

activ

itysig

nificantly

Quasi-experim

ental

(non

rand

omized

clinical

trial)

Unstablec

oron

ary

artery

disease[54]

Enoxaparin

(119899=46)

Dalteparin

(119899=48)

SCUFH

(119899=47)

68

VonWillberand

factor

may

have

progno

sticv

aluebut

otherb

iologicalvariables

didno

tpredictou

tcom

e

CRPfib

rinogenV

onWillberand

factor

increased

over

first2days

despite

medicaltre

atment

Enoxaparin

(13

)and

dalteparin

(19)reduced

releaseo

fVon

Willberand

factor

Openlabelrand

omized

clinicaltria

l

ST-Elevated

Myocardial

Infarctio

n(STE

MI)

[55]

Enoxaparin

SCUFH

34(17in

each

grou

p)

Both

heparin

and

enoxaparin

show

anti-inflammatoryeffects

inST

EMIp

atients

Serum

AmyloidA(119875002)

CRP(119875002)and

ferritin

(119875001)redu

cedin

heparin

grou

pIL-6

(1198750002)SA

A(1198750009)CR

P(119875001)

weres

ignificantly

decreased

inenoxaparin

grou

pTh

eoveralld

ifference

between

grou

pswas

notsignificant

Openlabelrand

omized

clinicaltria

l

8 Advances in Pharmacological Sciences

Table2Con

tinued

Clinicalsetting

Heparin

preparation

Mod

eof

administratio

nCom

parator

Num

bero

fpatie

nts

Clinicalou

tcom

eLabo

ratory

outcom

eStud

ydesig

n

Coron

aryartery

disease[56]

Dalteparin

SCPlacebo

555(285

incontrolgroup

)

Dalteparin

redu

ced

coagulationandso

MyocardialInfarctionbu

thasn

otinflammatory

activ

ity

Noeffectson

IL-6

C-reactiv

eprotein

and

fibrin

ogen

Rand

omizeddou

ble-blind

parallel-g

roup

multic

entre

trial

Stablecoronary

artery

disease[57]

Enoxaparin

SCSo

dium

chlorid

e62

(31ineach

grou

p)

Bymob

ilizing

vesselbo

und

MPO

eno

xaparin

improves

endo

thelialfun

ction

Sign

ificant

increase

ofMPO

levels

Rand

omizeddou

ble-blind

placebo-controlledtrial

Acutec

oron

ary

synd

romea

ndPC

I[58]

Tirofib

an(highdo

se)+

enoxaparin

Tirofib

an(highdo

se)+

UFH

60(30in

each

grou

p)

Thec

ombinatio

nof

tirofi

ban(highdo

se)+

enoxaparin

redu

ced

inflammationaft

erPC

I

Vonwillberand

CRP

D-dim

erand

prothrom

bin

fragmentw

eres

ignificantly

lower

inenoxaparin

grou

pthan

UFH

Openlabelrando

mized

controlledtrial

Superficialveno

usthrombo

phleb

itis

[59]

Dalteparin

SCIbup

rofen

72(37in

dalteparin

grou

p)

Sign

ificant

redu

ctionof

pain

form

baselin

etoday14

offollo

w-upNodifference

onthrombo

sisprogression

after

3mon

ths

mdashRa

ndom

izeddou

ble-blind

controlledtrial

Superficialveno

usthrombo

sis[60]

Nadroparin

SCNaproxen

117(39in

control

grou

p)

Nadroparin

redu

ced

symptom

andsig

nsof

thrombo

sedsuperficial

vein

bette

rthannaproxen

(1198750007)

mdashRa

ndom

izedopenlabel

clinicaltria

l

Superficialveno

usthrombo

sis[61]

Nadroparin

SCNadroparin

+acem

etacin

50

Sign

ificant

symptom

improvem

entinbo

thgrou

ps(1198750001)Th

ecombinatio

ngrou

pwas

bette

r

mdashRa

ndom

ized

controlled

trial

Periton

eald

ialysis

patie

nts[62]

Tinzaparin

Intraperito

neal

Isoton

icsalin

e21

Redu

ctionof

localand

syste

micinflammationin

periton

eald

ialysis

patie

nts

Redu

cedlevelsof

CRP(119875

0032)

andfib

rinogen

(119875

004

2)andIL-6

(1198750007)

indialysate

Rand

omizeddou

ble-blind

placebo-controlled

crossovertria

l

COPD

Chron

icObstructiv

ePu

lmon

aryDise

aseCR

PC-

Reactiv

eProtein

CPB

Cardio

Pulm

onaryBy

passE

CPE

osinop

hilC

ationicProtein

ERCP

End

oscopicRe

trogradeCh

olangiop

ancreatographyE

SR

ErythrocyteSedimentatio

nICUIntensiv

eCa

reUnitILinterleuk

inIV

intravenou

sLM

WHlow

molecular

weighth

eparinM

DAm

alon

dialdehydePAIPlasminogen

Activ

ator

InhibitorSC

sub

cutaneou

ssV

CAMSolub

leVa

scular

CellA

dhesionMoleculeTN

FTu

mor

Necrosis

Factorand

UFH

unfractionatedheparin

Advances in Pharmacological Sciences 9

Table 3 Summary of numbers and percentages of adequatelyreported items in each trial according to CONSORT checklist andJadad score

Trials Jadadscore

Adequately reporteditems (119899119873)

Percentage()

Abdollahi et al [52] 4 2974 392Ahmed et al [9] 3 2074 27Ang et al [17] 2 2474 324Ashraf et al [27] 2 2274 297Becker et al [37] 3 2874 378de Vroege et al [29] 3 2674 351Defraigne et al [28] 4 2874 378Derhaschnig et al [43] 3 3274 432Dixon et al [44] 4 5074 675Duong et al [11] 3 3074 405Gu et al [71] 2 1674 216Jerzynska et al [13] 3 2074 27Keating et al [45] 2 2174 284Koster et al [31] 2 2674 351Montalescot et al [54] 3 3574 473Nasiripour et al [55] 2 3474 46Oldgren et al [56] 3 2774 365Olsson et al [32] 2 2574 338van Ophoven et al [79] 2 2774 365Ozawa et al [33] 2 2774 365Ozkurt et al [24] 3 1874 243Paparella et al [72] 2 2274 297Polosa et al [67] 3 2374 311Rathbun et al [59] 5 4474 595Rudolph et al [57] 3 3174 412Serisier et al [47] 5 4574 608Stelmach et al [16] 3 3174 412Suzuki et al [49] 2 2374 31Vancheri et al [51] 4 2274 297Vasavada et al [25] 5 5274 702Walters et al [58] 3 3274 432Zezos et al [20] 3 3774 50

thrombophlebitis and hemodialysis Unfractionated heparin(UFH) was used in forty studies as subcutaneous intra-venous inhaler or heparin-coated circuits while others usedenoxaparin (119899 = 3) dalteparin (119899 = 4) nadroparin (119899 = 4)and tinzaparin (119899 = 1)

Table 3 provides information on the adequately reporteditems according to Jadad score andCONSORT items Amongthese 32 papers 11 (354) scored 2 and the remaining studiesscored 3 or higher according to Jadad score and just threestudies fulfill the criteria of Jadad score Calculated qualityscores according to CONSORT checklist range from 21 to70 in our object studies with twelve studies scoring greaterthan 40 The following characteristics were not exactlyreported in more than half of the trials identification as

a randomized trial in the title information about the settingand location of studies determination of sample size alloca-tion and implementation of randomization participant flowrecruitment and follow-up subgroup analysis limitations ofstudy harms registration number access to full trial protocoland funding source

4 Discussion

We discuss evidence from clinical studies supporting an anti-inflammatory role for heparin and heparin-related deriva-tives

41 Asthma Asthma is a chronic inflammatory disorderof airways characterized by bronchial hyperresponsivenessresulting in episodic bronchospasm Several studies in 1960sdescribed subjective improvement of symptoms in asthmaticpatients using intravenous heparin for the first time [3963] Inhaled heparin or its derivatives have been shown topossess antiasthmatic properties in various clinical modelsallergen induced [38 64] exercise [9] adenosine [6] anddistilled water challenge models [65] Seven randomizedcontrolled crossover trials studied anti-inflammatory effectsof heparin in exercise-induced or allergen-induced asthmahaving sample size range from 8 to 25 in 5 trials

Heparin inhalation reduced bronchial hyperreactivity ina single-blind randomized crossover trial (119899 = 12) byAhmed et al [9] Heparin inhalation (1000 120583kg) preventsexercise-induced asthma (119875 lt 005) without preventionof histamine-induced bronchoconstriction Stelmach et al[66] provoke challenge tests with histamine or leukotrieneD4 before and after inhalation of heparin showed that hep-arin (5000 Iu) decreases histamine and leukotriene-inducedbronchial hyperreactivity compared to placebo significantly(119875 0043 and 0005) but changes in Forced Expiratory Vol-ume (FEV 1) were not significant (119875 0064) The inhibitoryeffects of inhaled heparin in the airways in the absence ofbronchodilation might be related to suppressive action onmast cell degranulation A randomized double-blind studyin 10 subjects with asthma showed that heparin inhalationattenuates airway response to adenosine 51015840-monophosphate(AMP) but not to methacholine (119875 lt 001) suggestingthe theory that heparin acts more likely in association tomodulation of mediator release compared to a direct effecton smooth muscle [67]

Our results showed that inhaled enoxaparin was usedjust in a pre-post study of 24 asthmatic patients measur-ing inflammatory biomarkers and showed a reduction ineosinophil (119875 0006) and lymphocytes of bronchoalveolarlavage without any significant change in IL-5 or EosinophilCationic Protein (ECP) concentrations [12] Therefore itseems that enoxaparin could be a valuable add on treatmentin asthma like UFH Duong et al [11] evaluated IVX-0142nebulizer a heparin-derived hypersulfated disaccharide inasthma and showed nonsignificant decrease in early and lateasthmatic response

Performed studies did not show any adverse events orharms with heparin or related compounds except increase in

10 Advances in Pharmacological Sciences

the plasma partial thromboplastin time reported by Ahmedet al [9]

All in one considering the results of these studies wecan conclude that heparin and its derivatives could have anti-inflammatory effects and could be considered along withother treatments in asthma

42 Cardiopulmonary Bypass Contact and interaction ofblood with foreign surfaces during cardiopulmonary bypass(CPB) cause systemic inflammatory response syndrome(SIRS) through activation of several humoral cascadesincluding cytokines such as IL-6 IL-8 and Tumor NecrosisFactor-120572 (TNF-120572) [68] The inflammatory response can beattenuated by promoting the biocompatibility of the CPBcircuit Use of heparin-treated surfaces in CPB circuits hasbeen shown to decrease activation of leukocytes and thecomplement cascades [5] As a result need to inotropicsupport postoperative time of mechanical ventilation andrate of acute lung injury decrease and patients durationof hospital stay shortens which reflects the positive effectof heparin in CPB circuits [69 70] Twelve studies whoseendpoints were the effects of heparin-bonded circuits oninflammatory markers were included in our analysis and inthe majority of these trials [27 29 32ndash35 71] heparin-coatedcircuit significantly decreased the level of cytokines such asIL-6 IL-8 TNF-120572 complement complex neutrophils andelastase compared to non-heparin-coated circuit

Defraigne et al [28] randomized 200 patients in 4 groupsheparin-coated circuit with or without aprotinin administra-tion and uncoated circuit with or without aprotinin adminis-tration They measured IL-6 IL-8 TNF-120572 myeloperoxidase(MPO) and elastase level and concluded that cytokine releaseand neutrophil activation were not attenuated by heparin-coated circuit or by the administration of aprotinin Misawaet al [30] evaluated cytokines level under normothermicCPB in a small observational controlled study (119899 = 19 9 incontrol group) Levels of IL-6 IL-8 and ICAM-1 (indicatorof endothelial damage) were not different between study andcontrol group However as mentioned before most studiesindicate the favorable effect of heparin-coated circuit oninflammatory responses in CPB

Paparella et al [72] compared two doses of heparin and300 Iukg and 600 Iukg in 40 patients undergoing CPB in anRCT and showed that IL-6 and TNF-120572 plasma levels were inassociation to heparin dose It seems that lower heparin dosehad small influence on proinflammatory cytokines releasehowever higher doses make a better regulatory effect oncoagulation system

The side effects of heparin-coated circuits were notreported In these studies just a number of included studiesreported a decrease in platelet levels in both groups (coatedand noncoated circuit) No major events including hemor-rhage were reported

43 Inflammatory Bowel Diseases (IBD) Hypercoagulablestate may be an important contributing factor in the patho-genesis of IBD especially ulcerative colitis (UC) [73] A num-ber of studies evaluate the effects of heparin administrationon UC but the results obtained are controversial [17 19]

Bloom et al [74] did not find any favorable effect of LMWHtinzaparin over placebo in the treatment of active UC ina double-blind randomized placebo controlled multicentertrial (119899 = 100) evaluating mean change in colitis activity asthe primary endpoint Ang et al [17] compared heparin tohydrocortisone plus prednisolone in 20 patients (UC 119899 = 17Crohnrsquos colitis 119899 = 3) in open-label randomized crossovertrial whichmeasured endpoints clinical disease activity stoolfrequency and 120572

1acid glycoprotein and endoscopic and

histopathological grading indicate the efficacy and safety ofheparin compared to corticosteroids (119875 gt 005) in contrastthe study by Panes et al [19] did not show the efficacy ofheparin in UC compared to methylprednisolone

Zezos et al [20] compared enoxaparin with standardtreatment (aminosalicylate + corticosteroids) in 34 patientswith active UC The inflammatory biomarkers includingC-Reactive Protein (CRP) Erythrocyte Sedimentation Rate(ESR) and fibrinogen did not show any difference in studygroup compared to control and both groups showed similarrate of disease improvement (119875 gt 005) furthermorecoagulation factors did not change from one to anotherAuthors concluded that enoxaparin is a safe adjuvant but hasno additive benefit over standard treatment of UC

Generally the studies show conflicting results The hep-arin and LMWHs showed efficacy in regard of disease activityand also well tolerated but inflammatory markers did notchange significantly Therefore the improvement in diseaseactivity might be the result of heparinrsquos anticoagulant effects

44 Acute Coronary Syndrome (ACS) Inflammation has akey role in the pathogenesis of coronary artery plaquedestabilization and rupture leading to acute coronary syn-dromes (ACS) [75] Leukocyte activation monocyte andneutrophil infiltration result in local and systemic inflam-matory responses [76] Heparin and LMWHs are commonlyused in ACS to prevent clot formation they also seem tohave desirable effects on inflammatory markers level basedon sparse data

We found 8 studies about heparin and LMWHs in CADsevaluating anti-inflammatory effects as their endpoints Old-gren et al [56] found that dalteparin administration inpatients with unstable CAD (119899 = 555) did not affect IL-6C-Reactive Protein (CRP) and fibrinogen levels although itreduced coagulation activity and mortality rate in long termso it is concluded that these effects are not related to its anti-inflammatory properties Walters et al [58] compared highdose of tirofibanenoxaparin (119899 = 30) with tirofibanheparin(119899 = 30) in an open-label randomized controlled trial in highrisk percutaneous interventionThey found that combinationof high dose of tirofiban with enoxaparin significantly atten-uate inflammatory process (decreased levels of CRP and vonWillebrand factor) compared to tirofiban and heparin

The ARMADA study [54] evaluated anti-inflammatoryeffects of heparin and enoxaparin in Non-ST-ElevatedMyocardial Infarction (Non-STEMI) and reported thatinflammatory markers (CRP and von Willebrand factor)are affected more by LMWH compared to UFH Howeverbecause of the small sample size of the study (119899 = 68)

Advances in Pharmacological Sciences 11

it did not acquire sufficient statistical power to prove anyeffects on defined outcomes Nasiripour et al [55] found thatboth enoxaparin and heparin reduce inflammatory markersin STEMI patients at the same level however this study hadthe same limitations of sample size (119899 = 34) and power too

In summary considering heparins as the main stay treat-ment of ACS its effects are more pronounced as anticoagu-lating than as an anti-inflammatory agent in this pathologicalcondition

45 Cataract Surgery Postoperative inflammation isobserved in cataract surgery especially in children Newertechniques as lensectomy and phacoemulsification cause lesscomplication but still pose potential risks [77 78] It hasbeen suggested that a heparin surface-modified intraocularlens (IOL) or augmenting the irrigating solution withheparin during cataract surgery may reduce the incidence ofpostoperative inflammation Borgioli et al [22] confirm thishypothesis that heparin surface-modified IOL will reducethe inflammatory response compared to conventional IOLat least in short term period (3 months) in a large (524patients) double-blind multicenter trial A similar study byColin et al [23] (119899 = 58) confirms their results howeverthe power of Borgioli et al study was higher Heparinizedlenses showed also more anti-inflammatory effects duringlong term follow-up (1 year) Heparinized irrigating solutionwas used during cataract surgery in two different studies andinflammation decrease observed in the early postoperativeperiod of both studies (Kohnen et al [26] and Ozkurt et al[24]) Therefore it seems that heparin in both forms haveanti-inflammatory effects in cataract surgery

Vasavada et al [25] used enoxaparin irrigation solutionin 20 children undergoing bilateral cataract surgery butthey did not find any beneficial effect in early postoperativeinflammation This study acquired the highest quality in thestudy quality assessment process based on Jadad score andCONSORT items (5274 702) It is worth noticing that themajority of itemsmentioned in the CONSORT checklist wereadequately reported and covered in this paper

Potential mechanisms of anti-inflammatory effects ofheparin have been discussed completely in a review by Young[6] Binding of heparin to different mediators involved inthe immune system response (cytokines and chemokines)acute phase proteins and complement complex proteinsmay contribute to the anti-inflammatory activity of heparinNeutralizing of cytokines at the inflammation site is anotherpossible mechanism In most of the studies level of cytokinessuch as IL-6 IL-8 TNF-120572 and CRP was decreased afterheparin administration which can confirm this mechanismalso heparin and LMWHs inhibit adhesion of leukocytesand neutrophils to endothelial cells by binding to p-selectinand consequently prevent release of oxygen radicals andproteolytic enzymes Other possible mechanisms are as fol-lows inhibition of nuclear factor 120581B (NF-120581B) and inductionof apoptosis by modulation of activity of TNF-120572 and NF-120581B In a double-blind placebo-controlled trial (119899 = 62)in patients with stable coronary artery disease followingadministration of 1mgkg subcutaneous enoxaparin plasmalevels of myeloperoxidase (MPO) increased significantly

(119875 lt 0001) and subsequently endothelial function improved(119903 = 067 119875 lt 0001) through MPO binding to endotheliumand depleting vascular nitric oxide [57] This study confirmsanother possible mechanism of heparins anti-inflammatoryeffects

5 Conclusion

As we discussed heparins potential effects as anti-inflamma-tory agents supported by several clinical trials in varioussetting Heparin and its related derivatives have been shownto benefit patients with asthma and patients undergoingcardiopulmonary bypass and cataract surgery In otherinflammatory diseases such as IBD (ulcerative colitis) thestudies are heterogeneous and incongruent Most studies didnot report any unwanted event with heparins when they usedthem as anti-inflammatory agents whether through systemicor through local (as inhaler or irrigation or heparin-coatedcircuit) administration However because the majority ofthese trials did not pose optimal quality scores we cannotdraw a definite conclusion on the efficacy of heparin and itsderivatives as anti-inflammatory agents

The present review included studies which measuredinflammatory markers as their endpoints and in most ofthem these markers were decreased though not significantlyTo come to a definite conclusion further double-blindrandomized placebo-controlled clinical trials with a largersample size are needed However because the inflammationatherogenesis thrombogenesis and cell proliferation areassociated with each other the pleiotropic effects of heparinand related compounds may have greater therapeutic effectthan compounds that are directed against a single target

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

[1] B Casu ldquoHeparin structurerdquo Pathophysiology of Haemostasisand Thrombosis vol 20 supplement 1 pp 62ndash73 1990

[2] J Hirsh R Raschke T EWarkentin J E Dalen DDeykin andL Poller ldquoHeparin mechanism of action pharmacokineticsdosing considerations monitoring efficacy and safetyrdquo Chestvol 108 no 4 supplement pp 258Sndash275S 1995

[3] J Fareed D A Hoppensteadt and R L Bick ldquoAn update onheparins at the beginning of the new millenniumrdquo Seminars inThrombosis and Hemostasis vol 26 no 3 pp 5ndash21 2000

[4] J Hirsh ldquoDrug therapy heparinrdquo The New England Journal ofMedicine vol 324 no 22 pp 1565ndash1574 1991

[5] R J Ludwig ldquoTherapeutic use of heparin beyond anticoagu-lationrdquo Current Drug Discovery Technologies vol 6 no 4 pp281ndash289 2009

[6] E Young ldquoThe anti-inflammatory effects of heparin and relatedcompoundsrdquo Thrombosis Research vol 122 no 6 pp 743ndash7522008

12 Advances in Pharmacological Sciences

[7] A R Jadad R A Moore D Carroll et al ldquoAssessing the qualityof reports of randomized clinical trials is blinding necessaryrdquoControlled Clinical Trials vol 17 no 1 pp 1ndash12 1996

[8] K F Schulz D G Altman and D Moher ldquoCONSORT 2010statement updated guidelines for reporting parallel grouprandomised trialsrdquo International Journal of Surgery vol 9 no8 pp 672ndash677 2011

[9] T Ahmed J Garrigo and I Danta ldquoPreventing bronchocon-striction in exercise-induced asthma with inhaled heparinrdquoTheNewEngland Journal ofMedicine vol 329 no 2 pp 90ndash95 1993

[10] Z Diamant M C Timmers H Van Der Veen C P PageF J Van Der Meer and P J Sterk ldquoEffect of inhaled heparinon allergen-induced early and late asthmatic responses inpatients with atopic asthmardquo American Journal of Respiratoryand Critical Care Medicine vol 153 no 6 pp 1790ndash1795 1996

[11] M Duong D Cockcroft L-P Boulet et al ldquoThe effect ofIVX-0142 a heparin-derived hypersulfated disaccharide on theallergic airway responses in asthmardquo Allergy vol 63 no 9 pp1195ndash1201 2008

[12] A M Fal M Kraus-Filarska J Miecielica and J MalolepszyldquoMechanisms of action of nebulized low-molecular-weightheparin in patients with bronchial asthmardquo The Journal ofAllergy and Clinical Immunology vol 113 no 2 supplement pS36 2004

[13] J Jerzynska I Stelmach P Majak and P Kuna ldquoThe effectof inhaled heparin on airway responsiveness to histamine andmetacholine in asthmatic childrenrdquo Journal of Allergy andClinical Immunology vol 109 no 1 supplement 1 p S39 2002

[14] A F Kalpaklioglu Y S Demirel S Saryal and Z MisirligilldquoEffect of pretreatment with heparin on pulmonary and cuta-neous responserdquo Journal of Asthma vol 34 no 4 pp 337ndash3431997

[15] I Stelmach J Jerzynska A Brzozowska and P Kuna ldquoTheeffect of inhaled heparin on postleukotriene bronchoconstric-tion in children with asthmardquo Journal of Allergy and ClinicalImmunology vol 109 no 1 supplement 1 p S39 2002

[16] I Stelmach J Jerzynska W Stelmach et al ldquoThe effect ofinhaled heparin on airway responsiveness to histamine andleukotriene D4rdquo Allergy and Asthma Proceedings vol 24 no 1pp 59ndash65 2003

[17] Y S Ang N Mahmud B White et al ldquoRandomized compar-ison of unfractionated heparin with corticosteroids in severeactive inflammatory bowel diseaserdquo Alimentary PharmacologyandTherapeutics vol 14 no 8 pp 1015ndash1022 2000

[18] C Folwaczny B Wiebecke and K Loeschke ldquoUnfractionedheparin in the therapy of patients with highly active inflamma-tory bowel diseaserdquo The American Journal of Gastroenterologyvol 94 no 6 pp 1551ndash1555 1999

[19] J Panes M Esteve E Cabre et al ldquoComparison of heparinand steroids in the treatment of moderate and severe ulcerativecolitisrdquo Gastroenterology vol 119 no 4 pp 903ndash908 2000

[20] P Zezos G Papaioannou N Nikolaidis et al ldquoLow-molecular-weight heparin (enoxaparin) as adjuvant therapy in the treat-ment of active ulcerative colitis a randomized controlledcomparative studyrdquoAlimentary Pharmacology andTherapeuticsvol 23 no 10 pp 1443ndash1453 2006

[21] A A Vrij J M Jansen E J Schoon H C Hemker and RW Stockbrugger ldquoLow molecular weight heparin treatmentin steroid refractory ulcerative colitis clinical outcome andinfluence on mucosal capillary thrombirdquo Scandinavian Journalof Gastroenterology Supplement vol 36 no 234 pp 41ndash47 2001

[22] D M Borgioli D J Coster R F T Fan et al ldquoEffect of heparinsurface modification of polymethylmethacrylate intraocularlenses on signs of postoperative inflammation after extracap-sular cataract extraction one-year results of a double-maskedmulticenter studyrdquoOphthalmology vol 99 no 8 pp 1248ndash12551992

[23] J Colin S Roncin and M Wenzel ldquoEfficacy of heparinsurface-modified IOLs in reducing postoperative inflammatoryreactions in patients with exfoliation syndromemdasha double-blind comparative studyrdquo European Journal of Implant andRefractive Surgery vol 7 no 5 pp 266ndash270 1995

[24] Y B Ozkurt A Taskiran N Erdogan B Kandemir and OK Dogan ldquoEffect of heparin in the intraocular irrigating solu-tion on postoperative inflammation in the pediatric cataractsurgeryrdquoClinical Ophthalmology vol 3 no 1 pp 363ndash365 2009

[25] V A Vasavada M R Praveen S K Shah R H Trivedi andA R Vasavada ldquoAnti-inflammatory effect of low-molecular-weight heparin in pediatric cataract surgery a randomizedclinical trialrdquoThe American Journal of Ophthalmology vol 154no 2 pp 252ndash258 2012

[26] T Kohnen B Dick V Hessemer D D Koch and K WJacobi ldquoEffect of heparin in irrigating solution on inflammationfollowing small incision cataract surgeryrdquo Journal of Cataract ampRefractive Surgery vol 24 no 2 pp 237ndash243 1998

[27] S Ashraf Y Tian D Cowan A Entress P G Martin andK G Watterson ldquoRelease of proinflammatory cytokines dur-ing pediatric cardiopulmonary bypass heparin-bonded versusnonbonded oxygenatorsrdquo Annals of Thoracic Surgery vol 64no 6 pp 1790ndash1794 1997

[28] J-O Defraigne J Pincemail R Larbuisson F Blaffart andR Limet ldquoCytokine release and neutrophil activation are notprevented by heparin- coated circuits and aprotinin administra-tionrdquo Annals of Thoracic Surgery vol 69 no 4 pp 1084ndash10912000

[29] R de Vroege W van Oeveren J van Klarenbosch et al ldquoTheimpact of heparin-coated cardiopulmonary bypass circuits onpulmonary function and the release of inflammatory media-torsrdquo Anesthesia and Analgesia vol 98 no 6 pp 1586ndash15942004

[30] Y Misawa K Kawahito H Konishi and K Fuse ldquoCytokinemediated endothelial activation during and after normothermiccardiopulmonary bypass Heparin-bonded versus non heparin-bonded circuitsrdquo ASAIO Journal vol 46 no 6 pp 740ndash7432000

[31] A Koster T Fischer M Praus et al ldquoHemostatic activationand inflammatory response during cardiopulmonary bypassimpact of heparin managementrdquo Anesthesiology vol 97 no 4pp 837ndash841 2002

[32] C Olsson A Siegbahn A Henze et al ldquoHeparin-coatedcardiopulmonary bypass circuits reduce circulating comple-ment factors and interleukin-6 in paediatric heart surgeryrdquoScandinavian Cardiovascular Journal vol 34 no 1 pp 33ndash402000

[33] T Ozawa K Yoshihara N Koyama Y Watanabe N Shionoand Y Takanashi ldquoClinical efficacy of heparin-bonded bypasscircuits related to cytokine responses in childrenrdquo The Annalsof Thoracic Surgery vol 69 no 2 pp 584ndash590 2000

[34] A Parolari F Alamanni T Gherli et al ldquolsquoHigh dosersquo aprotininand heparin-coated circuits Clinical efficacy and inflammatoryresponserdquo Cardiovascular Surgery vol 7 no 1 pp 117ndash127 1999

[35] H Yamada I Kudoh Y Hirose M Toyoshima H Abe andK Kurahashi ldquoHeparin-coated circuits reduce the formation of

Advances in Pharmacological Sciences 13

TNF120572 during cardiopulmonary bypassrdquo Acta AnaesthesiologicaScandinavica vol 40 no 3 pp 311ndash317 1996

[36] O Barkay E Niv E Santo R Bruck A Hallak and F MKonikoff ldquoLow-dose heparin for the prevention of post-ERCPpancreatitis a randomized placebo-controlled trialrdquo SurgicalEndoscopy and Other Interventional Techniques vol 22 no 9pp 1971ndash1976 2008

[37] R C Becker K W Mahaffey H Yang et al ldquoHeparin-associated anti-Xa activity and platelet-derived prothromboticand proinflammatory biomarkers in moderate to high-riskpatients with acute coronary syndromerdquo Journal of Thrombosisand Thrombolysis vol 31 no 2 pp 146ndash153 2011

[38] S D Bowler S M Smith and P S Lavercombe ldquoHeparininhibits the immediate response to antigen in the skin and lungsof allergic subjectsrdquo American Review of Respiratory Diseasevol 147 no 1 pp 160ndash163 1993

[39] J P Boyle R H Smart and J K Shirey ldquoHeparin in thetreatment of chronic obstructive bronchopulmonary diseaserdquoThe American Journal of Cardiology vol 14 no 1 pp 25ndash281964

[40] Y Qian H Xie R Tian K Yu and R Wang ldquoEfficacy of lowmolecular weight heparin in patients with acute exacerbationof chronic obstructive pulmonary disease receiving ventilatorysupportrdquo COPD Journal of Chronic Obstructive PulmonaryDisease vol 11 no 2 pp 171ndash176 2014

[41] A Chamorro A Cervera J Castillo A Davalos J J Aponteand A M Planas ldquoUnfractionated heparin is associated with alower rise of serum vascular cell adhesion molecule-1 in acuteischemic stroke patientsrdquo Neuroscience Letters vol 328 no 3pp 229ndash232 2002

[42] R de Cock L A Ficker J G Dart A Garner and P WrightldquoTopical heparin in the treatment of ligneous conjunctivitisrdquoOphthalmology vol 102 no 11 pp 1654ndash1659 1995

[43] U Derhaschnig T Pernerstorfer M Knechtelsdorfer U Hol-lenstein S Panzer and B Jilma ldquoEvaluation of antiinflamma-tory and antiadhesive effects of heparins in human endotox-emiardquo Critical Care Medicine vol 31 no 4 pp 1108ndash1112 2003

[44] B DixonM J Schultz R Smith J B Fink J D Santamaria andD J Campbell ldquoNebulized heparin is associatedwith fewer daysof mechanical ventilation in critically ill patients a randomizedcontrolled trialrdquo Critical Care vol 14 no 5 article R180 2010

[45] F K Keating H L Dauerman D A Whitaker B E Sobeland D J Schneider ldquoThe effects of bivalirudin compared withthose of unfractionated heparin plus eptifibatide on inflam-mation and thrombin generation and activity during coronaryinterventionrdquo Coronary Artery Disease vol 16 no 6 pp 401ndash405 2005

[46] M Ledson M Gallagher C A Hart and M Walshaw ldquoNeb-ulized heparin in Burkholderia cepacia colonized adult cysticfibrosis patientsrdquo European Respiratory Journal vol 17 no 1 pp36ndash38 2001

[47] D J Serisier J K Shute P M Hockey B Higgins J Conwayand M P Carroll ldquoInhaled heparin in cystic fibrosisrdquo EuropeanRespiratory Journal vol 27 no 2 pp 354ndash358 2006

[48] O K Poyrazoglu A Dogukan M Yalniz D Seckin andA L Gunal ldquoAcute effect of standard heparin versus lowmolecular weight heparin on oxidative stress and inflammationin hemodialysis patientsrdquo Renal Failure vol 28 no 8 pp 723ndash727 2006

[49] S Suzuki T Matsuo H Kobayashi et al ldquoAntithrombotictreatment (argatroban vs heparin) in coronary angioplastyin angina pectoris effects on inflammatory hemostatic and

endothelium-derived parametersrdquoThrombosis Research vol 98no 4 pp 269ndash279 2000

[50] S D Trocme and H-I Li ldquoEffect of heparin-surface-modifiedintraocular lenses on postoperative inflammation after pha-coemulsification a randomized trial in a United States patientpopulationrdquo Ophthalmology vol 107 no 6 pp 1031ndash1037 2000

[51] C Vancheri C Mastruzzo F Armato et al ldquoIntranasal heparinreduces eosinophil recruitment after nasal allergen challenge inpatients with allergic rhinitisrdquo Journal of Allergy and ClinicalImmunology vol 108 no 5 pp 703ndash708 2001

[52] A Abdollahi M-T Naini H Shams and R Zarei ldquoEffect oflow-molecular-weight heparin on postoperative inflammationin phacomorphic glaucomardquo Archives of Iranian Medicine vol5 no 4 pp 225ndash229 2002

[53] R T S Lakshmi T Priyanka J Meenakshi K R MathangiV Jeyaraman and M Babu ldquoLow molecular weight heparinmediated regulation of nitric oxide synthase during burnwound healingrdquo Annals of Burns and Fire Disasters vol 24 no1 pp 24ndash29 2011

[54] G Montalescot C Bal-dit-Sollier D Chibedi et al ldquoCompar-ison of effects on markers of blood cell activation of enoxa-parin dalteparin and unfractionated heparin in patients withunstable angina pectoris or non-ST-segment elevation acutemyocardial infarction (the ARMADA study)rdquo The AmericanJournal of Cardiology vol 91 no 8 pp 925ndash930 2003

[55] S Nasiripour K Gholami SMousavi et al ldquoComparison of theeffects of enoxaparin and heparin on inflammatory biomarkersin patients with ST-segment elevated myocardial infarction aprospective open label pilot clinical trialrdquo Iranian Journal ofPharmaceutical Research vol 13 no 2 pp 583ndash590 2014

[56] J Oldgren C Fellenius K Boman et al ldquoInfluence of prolongeddalteparin treatment on coagulation fibrinolysis and inflam-mation in unstable coronary artery diseaserdquo Journal of InternalMedicine vol 258 no 5 pp 420ndash427 2005

[57] T K Rudolph V Rudolph A Witte et al ldquoLiberation of vesseladherent myeloperoxidase by enoxaparin improves endothelialfunctionrdquo International Journal of Cardiology vol 140 no 1 pp42ndash47 2010

[58] D L Walters M J Ray P Wood E J Perrin J H N Bettand C N Aroney ldquoHigh-dose tirofiban with enoxaparin andinflammatory markers in high-risk percutaneous interventionrdquoEuropean Journal of Clinical Investigation vol 40 no 2 pp 139ndash147 2010

[59] S W Rathbun C E Aston and T L Whitsett ldquoA randomizedtrial of dalteparin compared with ibuprofen for the treatmentof superficial thrombophlebitisrdquo Journal of Thrombosis andHaemostasis vol 10 no 5 pp 833ndash839 2012

[60] J P Titon D Auger P Grange et al ldquoTherapeutic managementof superficial venous thrombosis with calcium nadroparinDosage testing and comparison with a non-steroidal anti-inflammatory agentrdquo Annales de Cardiologie et d Angeiologievol 43 no 3 pp 160ndash166 1994

[61] H Uncu ldquoA comparison of low-molecular-weight heparin andcombined therapy of low-molecular-weight heparin with ananti-inflammatory agent in the treatment of superficial veinthrombosisrdquo Phlebology vol 24 no 2 pp 56ndash60 2009

[62] J A Sjoslashland R S Pedersen J Jespersen and J GramldquoIntraperitoneal heparin ameliorates the systemic inflamma-tory response in PD patientsrdquo NephronmdashClinical Practice vol100 no 4 pp c105ndashc110 2005

[63] N L Fine C Shim and M H Williams Jr ldquoObjectiveevaluation of heparin in the treatment of asthmardquo AmericanReview of Respiratory Disease vol 98 no 5 pp 886ndash887 1968

14 Advances in Pharmacological Sciences

[64] ZDiamantM C Timmers H van derVeen C P Page F J vander Meer and P J Sterk ldquoEffect of inhaled heparin on allergen-induced early and late asthmatic responses in patients withatopic asthmardquo American Journal of Respiratory and CriticalCare Medicine vol 153 no 6 I pp 1790ndash1795 1996

[65] C M E Tranfa A Vatrella R Parrella G Pelaia F Bariffiand S A Marsico ldquoEffect of inhaled heparin on water-inducedbronchoconstriction in allergic asthmaticsrdquoEuropean Journal ofClinical Pharmacology vol 57 no 1 pp 5ndash9 2001

[66] I Stelmach J Jerzynska A Brzozowska and P Kuna ldquoTheeffect of inhaled heparin on postleukotriene bronchoconstric-tion in children with asthmardquo Polski Merkuriusz Lekarski vol12 no 68 pp 95ndash98 2002

[67] R Polosa S Magrı C Vancheri et al ldquoTime course of changesin adenosine 51015840-monophosphate airway responsiveness withinhaled heparin in allergic asthmardquo Journal of Allergy andClinical Immunology vol 99 no 3 pp 338ndash342 1997

[68] J Butler GM Rocker and SWestaby ldquoInflammatory responseto cardiopulmonary bypassrdquo The Annals of Thoracic Surgeryvol 55 no 2 pp 552ndash559 1993

[69] J M Redmond A M Gillinov R S Stuart et al ldquoHeparin-coated bypass circuits reduce pulmonary injuryrdquoThe Annals ofThoracic Surgery vol 56 no 3 pp 474ndash479 1993

[70] S Svenmarker E Sandstrom T Karlsson et al ldquoClinical effectsof the heparin coated surface in cardiopulmonary bypassrdquoEuropean Journal of Cardio-Thoracic Surgery vol 11 no 5 pp957ndash964 1997

[71] Y J Gu W van Oeveren C Akkerman P W Boonstra RJ Huyzen and C R H Wildevuur ldquoHeparin-coated circuitsreduce the inflammatory response to cardiopulmonary bypassrdquoThe Annals of Thoracic Surgery vol 55 no 4 pp 917ndash922 1993

[72] D Paparella O O Al Radi Q H Meng T Venner K Teohand E Young ldquoThe effects of high-dose heparin on inflamma-tory and coagulation parameters following cardiopulmonarybypassrdquo Blood Coagulation and Fibrinolysis vol 16 no 5 pp323ndash328 2005

[73] S Danese A Papa S Saibeni A Repici A Malesci andM Vecchi ldquoInflammation and coagulation in inflammatorybowel disease the clot thickensrdquo The American Journal ofGastroenterology vol 102 no 1 pp 174ndash186 2007

[74] S Bloom S Kiilerich M R Lassen et al ldquoLow molecularweight heparin (tinzaparin) vs placebo in the treatment of mildto moderately active ulcerative colitisrdquo Alimentary Pharmacol-ogy ampTherapeutics vol 19 no 8 pp 871ndash878 2004

[75] P Libby ldquoCoronary artery injury and the biology of atheroscle-rosis inflammation thrombosis and stabilizationrdquo AmericanJournal of Cardiology vol 86 no 8 2000

[76] N T Mulvihill and J B Foley ldquoInflammation in acute coronarysyndromesrdquo Heart vol 87 no 3 pp 201ndash204 2002

[77] N A JamesonW V Good and C S Hoyt ldquoInflammation aftercataract surgery in childrenrdquoOphthalmic Surgery vol 23 no 2pp 99ndash102 1992

[78] R M Sinskey P A Amin and R Lingua ldquoCataract extractionand intraocular lens implantation in an infant with amonocularcongenital cataractrdquo Journal of Cataract amp Refractive Surgeryvol 20 no 6 pp 647ndash651 1994

[79] A van Ophoven A Heinecke and L Hertle ldquoSafety andefficacy of concurrent application of oral pentosan polysulfateand subcutaneous low-dose heparin for patients with interstitialcystitisrdquo Urology vol 66 no 4 pp 707ndash711 2005

Submit your manuscripts athttpwwwhindawicom

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Page 4: Review Article Anti-Inflammatory Effects of Heparin and Its …downloads.hindawi.com/journals/aps/2015/507151.pdf · 2019. 7. 31. · Review Article Anti-Inflammatory Effects of Heparin

4 Advances in Pharmacological Sciences

Table1Con

tinued

Clinicalsetting

Heparin

preparation

Mod

eof

administratio

nCom

parator

Num

bero

fpatie

nts

Clinicalou

tcom

eLabo

ratory

outcom

eStud

ydesig

n

IBD[18]

UFH

SCmdash

17

Histologyim

proved

significantly

inulcerativ

ecolitispatie

nts(UFH

iseffectiv

einulcerativ

ecolitis

butn

otCr

ohndisease)

CRP(11987500119

)and

ESR

(11987500096)

significantly

redu

cedin

ulcerativ

ecolitis

butn

otCr

ohndisease

Quasi-experim

ental

(pretest-

posttestd

esign)

IBD[19

]UFH

IVMethylpredn

isolone

25(13in

control

grou

p)

Noeffecto

fheparinalso

increasedbleeding

Nochange

inCR

PRa

ndom

izeddou

ble-blind

parallel-g

roup

trial

IBD[20]

Enoxaparin

+sta

ndard

treatment

SCAminosalicylate+

corticosteroid

34(18in

control

grou

p)

Sign

ificant

improvem

entin

diseases

everity

inbo

thgrou

ps(1198750001)

NodifferenceE

SRC

RPandfib

rinogen

and

coagulation

Rand

omized

controlled

trial

IBD[21]

Nadroparin

SCmdash

25

Endo

scop

icand

histo

logicalsignof

inflammationsig

nificantly

improved

mdashQuasi-experim

ental

(Non

-rando

mized

clinical

trial)

Cataractsurgery

[22]

UFH

Intraocular

lens

(IOL)

Polymethylm

ethacrylate

524

mdash

Heparin

surfa

cemod

ificatio

nredu

cedthe

cellu

lard

epositcompared

tocontrolgroup

Rand

omizeddou

ble-blind

parallelgroup

clinicaltria

l

Cataractsurgery

[23]

UFH

Intraocular

lens

(IOL)

Polymethylm

ethacrylate

58(31in

control

grou

p)

Posto

perativ

einfl

ammation

decreasedsig

nificantly

inheparin

grou

p(119875002)

Giant

cellandcelldepo

sitdecreasedsig

nificantly

(119875lt005)

Rand

omizeddou

ble-blind

clinicaltria

l

Cataractsurgery

(pediatric)[24]

UFH

Irrig

ation

Balanced

saltsolutio

n33

(19in

control

grou

p)

Heparin

irrigationredu

ced

numbero

fpostoperativ

einflammatoryrelated

complication

Anteriorc

hamberreaction

inclu

ding

fibrin

form

ation

was

lower

inheparin

grou

p

Rand

omized

prospective

doub

le-blin

dtrial

Cataractsurgery

(pediatrics)[25]

Enoxaparin

Irrig

ation

Notre

atment

40(20in

each

grou

p)

Increase

offlare

andcell

depo

sitaft

ersurgery(1and

3mon

ths)(119875099)

Increase

inlargec

ell

depo

sits

Rand

omizeddou

ble-blind

controlledtrial

Cataractsurgery

[26]

UFH

Irrig

ation

Regu

larirrigation

solutio

n72

Sign

ificant

redu

ctionof

inflammationin

thee

arly

(days1ndash3)p

ostoperativ

eperio

d(119875lt001)

mdashRa

ndom

ized

controlled

trial

Cardiopu

lmon

ary

bypass(pediatric)

[27]

Heparin-

coated

circuit

(119899=11)

mdashNon

-heparin-coated

circuit(119899=10)

21

Decreaseo

fsystemic

inflammatoryrespon

sewith

theu

seof

heparin

-bon

ded

oxygenators

Sign

ificantlydecreased

levelsof

IL-6IL-8term

inal

complem

entcom

plex

neutroph

ilsand

elastase

inheparin

coated

circuit

Rand

omized

controlled

trial

Cardiopu

lmon

ary

bypass[28]

Heparin-

coated

circuit

plusmnaprotin

inmdash

Uncoatedcircuitplusmn

aprotin

in200(4

grou

ps)

Aprotin

inandheparin

had

noeffecto

ncytokine

release

TNF-120572IL-6andIL-8

and

myeloperoxidase

didno

tchange

Rand

omizeddou

ble-blind

clinicaltria

l

Advances in Pharmacological Sciences 5

Table1Con

tinued

Clinicalsetting

Heparin

preparation

Mod

eof

administratio

nCom

parator

Num

bero

fpatie

nts

Clinicalou

tcom

eLabo

ratory

outcom

eStud

ydesig

n

Cardiopu

lmon

ary

bypass[29]

UFH

mdashUncoatedcircuit

51(26in

each

grou

p)

Decreased

pulm

onary

vascular

resistanceind

exandpu

lmon

aryshun

tfractio

nandincreased

PaO2FIO2ratio

Lower

levelsof

phosph

olipaseA

2and

complem

entactivation(119875

0001)

Rand

omizeddou

ble-blind

clinicaltria

l

Cardiopu

lmon

ary

bypass[30]

Heparin-

coated

circuit

mdashNon

-heparin-coated

circuit

16(9

incontrol

grou

p)mdash

Nosig

nificantd

ifference

betweengrou

psregarding

granulocytee

lasta

seIL-6

IL-8

Quasi-experim

ental

(pretest-

posttestd

esign)

Cardiopu

lmon

ary

bypass[31]

Heparin

concentration-

based

syste

m

mdashAc

tivated

clotting

time-based

managem

ent

200(100

incontrol

grou

p)

Noeffecto

npo

stoperativ

ebloo

dloss

Sign

ificant

redu

ctionof

neutroph

ilactiv

ationand

fibrin

olysisandthrombin

generatio

n(119875lt005)

Rand

omized

controlled

trial

Cardiopu

lmon

ary

bypass(pediatric)

[32]

Heparin-

coated

circuit

mdashNon

-heparin-coated

circuit

19(10in

control

grou

p)

Improvem

ento

fthe

biocom

patib

ilityof

CPB

durin

gheartsurgery

Levelsof

complem

ent

factor

C3a(119875lt0001)a

ndIL-6

(1198750005)significantly

redu

cedin

heparin

-coated

circuit

Rand

omized

controlled

trial

Cardiopu

lmon

ary

bypass(pediatric)

[33]

Heparin-

coated

circuit

mdashNon

-heparin-coated

circuit

34(12in

control

grou

p)

Nodifferences

indu

ratio

nof

intubatio

nintensivec

are

unitor

hospita

lstayor

posto

perativ

eblood

loss

IL-6IL-8andTN

F-120572we

resig

nificantly

lower

inheparin

grou

p(119875lt001

119875lt001and119875lt005

resp)

Rand

omized

controlled

trial

Cardiopu

lmon

ary

bypass[34]

Heparin-

coated

circuit

(heparin

+aprotin

in)

mdashNon

-heparin-coated

circuit(heparin

+aprotin

in)

30(15in

each

grou

p)

Nosig

nificantd

ifferences

betweenthetwogrou

psin

term

sofb

leedingand

transfu

sionalrequirements

thetim

espent

ona

ventilatoror

indu

ratio

nof

stayin

theintensiv

ecare

unit(ICU

)

Levelsof

IL-6C

RPand

neutroph

ilcoun

tdid

not

change

byheparin

-coated

circuitMon

ocytec

ount

increasedin

heparin

-coatedcircuit

Rand

omized

controlled

trial

Coron

aryartery

bypassgraft

ing

(CABG

)[35]

Heparin-

coated

circuit

mdashNon

-heparin-coated

circuit

18(9

ineach

grou

p)mdash

Redu

ctionof

levelsof

IL-8

andTN

F-120572andincrease

ofneutroph

ilelastase

Rand

omized

controlled

trial

CRP

C-Re

activ

eProteinC

PBC

ardioPu

lmon

aryB

ypassEC

PEo

sinop

hilC

ationicP

roteinE

SRE

rythrocyteSedimentatio

nICUIntensiv

eCareU

nitILinterleuk

inIV

intravenou

sSC

sub

cutaneou

sSG

AW

SpecificA

irway

Con

ductanceT

NFTu

mor

Necrosis

Factorand

UFH

unfractionatedheparin

6 Advances in Pharmacological Sciences

Table2Summaryandfin

ding

sofo

ther

studied

diseases

Clinicalsetting

Heparin

preparation

Mod

eof

administratio

nCom

parator

Num

bero

fpatie

nts

Clinicalou

tcom

eLabo

ratory

outcom

eStud

ydesig

n

Pancreatitisa

fter

ERCP

[36]

UFH

SCSalin

esolution

105(54in

control

grou

p)

Rateof

posto

perativ

epancreatitisw

asno

tsig

nificantb

etweenbo

thgrou

ps

mdashRa

ndom

ized

placebo-controlledclinical

trial

Acutec

oron

ary

synd

rome(AC

S)[37]

UFH

SCEn

oxaparin

201

mdashNosig

nificantd

ifference

betweenCD

4ligandand

PAI-1inbo

thgrou

ps

Openlabelrand

omized

clinicaltria

l

Skin

orpu

lmon

ary

allergy[38]

UFH

IVnebulizer

Normalsalin

eplacebo

25Sign

ificant

inhibitio

nof

mastcell-m

ediatedallergic

inflammation(119875004)

mdashDou

ble-blind

placebo-controlled

crossoverc

linicaltrial

COPD

[39]

UFH

IVmdash

37(18in

control

grou

p)

Sign

ificant

improvem

entin

bron

chospasm

and

bron

chialsecretio

ns(58

respon

serate)

mdashRa

ndom

ized

placebo-controlledclinical

trial

COPD

[40]

Nadroparin

SCCon

ventionaltreatment

66(33in

each

grou

p)

Decreaseo

fdurationof

mechanicalventilationand

leng

thof

hospita

land

ICU

stay(119875lt001)

Sign

ificant

decrease

inlevelsof

CRPIL-6and

fibrin

ogen

Rand

omized

controlled

trial

Ischem

icstroke

[41]

UFH

IVAs

pirin

167(97in

control

grou

p)

Early

onsetinitia

tionof

heparin

might

improve

recovery

after

stroke

Rise

ofsV

CAM-1at48

hwas

significantly

lower

inpatie

ntstreated

with

UFH

(119875lt001)

Quasi-experim

ental

(con

trolledob

servational

study)

Lign

eous

conjun

ctivitis[42]

UFH

Topical

Alpha

chym

otrypsin

orste

roid

17(12in

control

grou

p)

Intensivea

ndearly

useo

ftopicalh

eparin

may

improvetherapy

results

indisease

mdashQuasi-experim

ental

(non

rand

omized

Clinical

trial)

Endo

toxemia

(indu

cedby

lipop

olysaccharide

inhealthysubjects)

[43]

UFH

IVLM

WHor

placebo

30(10in

each

grou

p)mdash

Noeffecto

nTN

F-120572IL-6

and8CR

PandE-selectin

Rand

omized

doub

le-blin

ded

placebo-controlledparallel

grou

ptrial

Mechanical

ventilatio

n[44]

UFH

Nebulizer

Normalsalin

e(placebo)

50(25in

each

grou

p)

Fewer

days

onmechanical

ventilatio

nbette

rPao2Fio2ratio

mdashDou

ble-blindrand

omized

placebo-controlledtrial

Percutaneous

coronary

interventio

n[45]

Bivalirud

inIV

UFH

+eptifi

batid

e63

(29in

control

grou

p)mdash

Increase

inIL-6

andCR

Paft

er1d

ayD

ecreaseinCR

Pin

bivalirud

ingrou

paft

er30

days

(1198750002)

Rand

omized

controlled

trial

Cysticfib

rosis

(adu

lts)[46

]UFH

Inhaler

mdash12

(6in

control

grou

p)Spiro

metry

parametersd

idno

tchang

eIL-6

redu

cedaft

ertre

atment

Quasi-experim

ental

(pretest-

posttestd

esign)

Advances in Pharmacological Sciences 7Ta

ble2Con

tinued

Clinicalsetting

Heparin

preparation

Mod

eof

administratio

nCom

parator

Num

bero

fpatie

nts

Clinicalou

tcom

eLabo

ratory

outcom

eStud

ydesig

n

Cysticfib

rosis

(adu

lts)[47]

UFH

Inhaler

Placebo

14Noeffecto

nFE

V1

Noeffecto

nsputum

inflammatorymarkers

Rand

omizeddou

ble-blind

placebo-controlled

crossovertria

l

Hem

odialysis

patie

nts[48]

UFH

IVSC

LMWHandno

drug

33

LMWHdecreased

oxidatives

tressand

inflammationwhereas

heparin

increasedthem

CRPTN

F-120572sup

eroxide

dism

utaseMDAincreased

inheparin

grou

pbu

tcomparabletoLM

WH

grou

p

Quasi-experim

ental

(pretest-

posttestd

esign)

Stableangina

[49]

Heparin

+Aspirin

(119899=15)

mdashArgatroban+As

pirin

(119899=12)2

7

Nodifferencein

inflammatoryrespon

seaft

erangiop

lasty

Fibrinogen

decreased

significantly

inargatro

ban

grou

pNodifferenceinvon

Willberand

factor

between

both

grou

psPAI-1

increasedin

argatro

ban

grou

p

Rand

omized

controlled

trial

Phacoemulsifi

catio

n[50]

Heparin

Coatedlenses

Polymethylm

ethacrylate

lenses

367

Heparin

coated

lenses

redu

cedsig

nificantly

inflammationearly

posto

peratio

n(119875005)

mdashRa

ndom

izeddou

ble-blind

multic

enterparallelgroup

trial

Allergicrhinitis[51]

UFH

Intranasal

mdash10

mdashRe

ductionof

eosin

ophil

catio

nicp

rotein

inthen

asal

wash

Quasi-experim

ental

(pretest-

posttestd

esign)

Phacom

orph

icglaucoma[

52]

Dalteparin

Irrig

ation

Balanced

saltsolutio

n46

(23in

each

grou

p)

Sign

ificant

decrease

ofpo

stoperativ

einfl

ammation

indalteparin

grou

pmdash

Rand

omizeddou

ble-blind

clinicaltria

l

Burn

[53]

Dalteparin

SCNotre

atment

24mdash

Decreaseo

fnitricoxide

synthetase

activ

itysig

nificantly

Quasi-experim

ental

(non

rand

omized

clinical

trial)

Unstablec

oron

ary

artery

disease[54]

Enoxaparin

(119899=46)

Dalteparin

(119899=48)

SCUFH

(119899=47)

68

VonWillberand

factor

may

have

progno

sticv

aluebut

otherb

iologicalvariables

didno

tpredictou

tcom

e

CRPfib

rinogenV

onWillberand

factor

increased

over

first2days

despite

medicaltre

atment

Enoxaparin

(13

)and

dalteparin

(19)reduced

releaseo

fVon

Willberand

factor

Openlabelrand

omized

clinicaltria

l

ST-Elevated

Myocardial

Infarctio

n(STE

MI)

[55]

Enoxaparin

SCUFH

34(17in

each

grou

p)

Both

heparin

and

enoxaparin

show

anti-inflammatoryeffects

inST

EMIp

atients

Serum

AmyloidA(119875002)

CRP(119875002)and

ferritin

(119875001)redu

cedin

heparin

grou

pIL-6

(1198750002)SA

A(1198750009)CR

P(119875001)

weres

ignificantly

decreased

inenoxaparin

grou

pTh

eoveralld

ifference

between

grou

pswas

notsignificant

Openlabelrand

omized

clinicaltria

l

8 Advances in Pharmacological Sciences

Table2Con

tinued

Clinicalsetting

Heparin

preparation

Mod

eof

administratio

nCom

parator

Num

bero

fpatie

nts

Clinicalou

tcom

eLabo

ratory

outcom

eStud

ydesig

n

Coron

aryartery

disease[56]

Dalteparin

SCPlacebo

555(285

incontrolgroup

)

Dalteparin

redu

ced

coagulationandso

MyocardialInfarctionbu

thasn

otinflammatory

activ

ity

Noeffectson

IL-6

C-reactiv

eprotein

and

fibrin

ogen

Rand

omizeddou

ble-blind

parallel-g

roup

multic

entre

trial

Stablecoronary

artery

disease[57]

Enoxaparin

SCSo

dium

chlorid

e62

(31ineach

grou

p)

Bymob

ilizing

vesselbo

und

MPO

eno

xaparin

improves

endo

thelialfun

ction

Sign

ificant

increase

ofMPO

levels

Rand

omizeddou

ble-blind

placebo-controlledtrial

Acutec

oron

ary

synd

romea

ndPC

I[58]

Tirofib

an(highdo

se)+

enoxaparin

Tirofib

an(highdo

se)+

UFH

60(30in

each

grou

p)

Thec

ombinatio

nof

tirofi

ban(highdo

se)+

enoxaparin

redu

ced

inflammationaft

erPC

I

Vonwillberand

CRP

D-dim

erand

prothrom

bin

fragmentw

eres

ignificantly

lower

inenoxaparin

grou

pthan

UFH

Openlabelrando

mized

controlledtrial

Superficialveno

usthrombo

phleb

itis

[59]

Dalteparin

SCIbup

rofen

72(37in

dalteparin

grou

p)

Sign

ificant

redu

ctionof

pain

form

baselin

etoday14

offollo

w-upNodifference

onthrombo

sisprogression

after

3mon

ths

mdashRa

ndom

izeddou

ble-blind

controlledtrial

Superficialveno

usthrombo

sis[60]

Nadroparin

SCNaproxen

117(39in

control

grou

p)

Nadroparin

redu

ced

symptom

andsig

nsof

thrombo

sedsuperficial

vein

bette

rthannaproxen

(1198750007)

mdashRa

ndom

izedopenlabel

clinicaltria

l

Superficialveno

usthrombo

sis[61]

Nadroparin

SCNadroparin

+acem

etacin

50

Sign

ificant

symptom

improvem

entinbo

thgrou

ps(1198750001)Th

ecombinatio

ngrou

pwas

bette

r

mdashRa

ndom

ized

controlled

trial

Periton

eald

ialysis

patie

nts[62]

Tinzaparin

Intraperito

neal

Isoton

icsalin

e21

Redu

ctionof

localand

syste

micinflammationin

periton

eald

ialysis

patie

nts

Redu

cedlevelsof

CRP(119875

0032)

andfib

rinogen

(119875

004

2)andIL-6

(1198750007)

indialysate

Rand

omizeddou

ble-blind

placebo-controlled

crossovertria

l

COPD

Chron

icObstructiv

ePu

lmon

aryDise

aseCR

PC-

Reactiv

eProtein

CPB

Cardio

Pulm

onaryBy

passE

CPE

osinop

hilC

ationicProtein

ERCP

End

oscopicRe

trogradeCh

olangiop

ancreatographyE

SR

ErythrocyteSedimentatio

nICUIntensiv

eCa

reUnitILinterleuk

inIV

intravenou

sLM

WHlow

molecular

weighth

eparinM

DAm

alon

dialdehydePAIPlasminogen

Activ

ator

InhibitorSC

sub

cutaneou

ssV

CAMSolub

leVa

scular

CellA

dhesionMoleculeTN

FTu

mor

Necrosis

Factorand

UFH

unfractionatedheparin

Advances in Pharmacological Sciences 9

Table 3 Summary of numbers and percentages of adequatelyreported items in each trial according to CONSORT checklist andJadad score

Trials Jadadscore

Adequately reporteditems (119899119873)

Percentage()

Abdollahi et al [52] 4 2974 392Ahmed et al [9] 3 2074 27Ang et al [17] 2 2474 324Ashraf et al [27] 2 2274 297Becker et al [37] 3 2874 378de Vroege et al [29] 3 2674 351Defraigne et al [28] 4 2874 378Derhaschnig et al [43] 3 3274 432Dixon et al [44] 4 5074 675Duong et al [11] 3 3074 405Gu et al [71] 2 1674 216Jerzynska et al [13] 3 2074 27Keating et al [45] 2 2174 284Koster et al [31] 2 2674 351Montalescot et al [54] 3 3574 473Nasiripour et al [55] 2 3474 46Oldgren et al [56] 3 2774 365Olsson et al [32] 2 2574 338van Ophoven et al [79] 2 2774 365Ozawa et al [33] 2 2774 365Ozkurt et al [24] 3 1874 243Paparella et al [72] 2 2274 297Polosa et al [67] 3 2374 311Rathbun et al [59] 5 4474 595Rudolph et al [57] 3 3174 412Serisier et al [47] 5 4574 608Stelmach et al [16] 3 3174 412Suzuki et al [49] 2 2374 31Vancheri et al [51] 4 2274 297Vasavada et al [25] 5 5274 702Walters et al [58] 3 3274 432Zezos et al [20] 3 3774 50

thrombophlebitis and hemodialysis Unfractionated heparin(UFH) was used in forty studies as subcutaneous intra-venous inhaler or heparin-coated circuits while others usedenoxaparin (119899 = 3) dalteparin (119899 = 4) nadroparin (119899 = 4)and tinzaparin (119899 = 1)

Table 3 provides information on the adequately reporteditems according to Jadad score andCONSORT items Amongthese 32 papers 11 (354) scored 2 and the remaining studiesscored 3 or higher according to Jadad score and just threestudies fulfill the criteria of Jadad score Calculated qualityscores according to CONSORT checklist range from 21 to70 in our object studies with twelve studies scoring greaterthan 40 The following characteristics were not exactlyreported in more than half of the trials identification as

a randomized trial in the title information about the settingand location of studies determination of sample size alloca-tion and implementation of randomization participant flowrecruitment and follow-up subgroup analysis limitations ofstudy harms registration number access to full trial protocoland funding source

4 Discussion

We discuss evidence from clinical studies supporting an anti-inflammatory role for heparin and heparin-related deriva-tives

41 Asthma Asthma is a chronic inflammatory disorderof airways characterized by bronchial hyperresponsivenessresulting in episodic bronchospasm Several studies in 1960sdescribed subjective improvement of symptoms in asthmaticpatients using intravenous heparin for the first time [3963] Inhaled heparin or its derivatives have been shown topossess antiasthmatic properties in various clinical modelsallergen induced [38 64] exercise [9] adenosine [6] anddistilled water challenge models [65] Seven randomizedcontrolled crossover trials studied anti-inflammatory effectsof heparin in exercise-induced or allergen-induced asthmahaving sample size range from 8 to 25 in 5 trials

Heparin inhalation reduced bronchial hyperreactivity ina single-blind randomized crossover trial (119899 = 12) byAhmed et al [9] Heparin inhalation (1000 120583kg) preventsexercise-induced asthma (119875 lt 005) without preventionof histamine-induced bronchoconstriction Stelmach et al[66] provoke challenge tests with histamine or leukotrieneD4 before and after inhalation of heparin showed that hep-arin (5000 Iu) decreases histamine and leukotriene-inducedbronchial hyperreactivity compared to placebo significantly(119875 0043 and 0005) but changes in Forced Expiratory Vol-ume (FEV 1) were not significant (119875 0064) The inhibitoryeffects of inhaled heparin in the airways in the absence ofbronchodilation might be related to suppressive action onmast cell degranulation A randomized double-blind studyin 10 subjects with asthma showed that heparin inhalationattenuates airway response to adenosine 51015840-monophosphate(AMP) but not to methacholine (119875 lt 001) suggestingthe theory that heparin acts more likely in association tomodulation of mediator release compared to a direct effecton smooth muscle [67]

Our results showed that inhaled enoxaparin was usedjust in a pre-post study of 24 asthmatic patients measur-ing inflammatory biomarkers and showed a reduction ineosinophil (119875 0006) and lymphocytes of bronchoalveolarlavage without any significant change in IL-5 or EosinophilCationic Protein (ECP) concentrations [12] Therefore itseems that enoxaparin could be a valuable add on treatmentin asthma like UFH Duong et al [11] evaluated IVX-0142nebulizer a heparin-derived hypersulfated disaccharide inasthma and showed nonsignificant decrease in early and lateasthmatic response

Performed studies did not show any adverse events orharms with heparin or related compounds except increase in

10 Advances in Pharmacological Sciences

the plasma partial thromboplastin time reported by Ahmedet al [9]

All in one considering the results of these studies wecan conclude that heparin and its derivatives could have anti-inflammatory effects and could be considered along withother treatments in asthma

42 Cardiopulmonary Bypass Contact and interaction ofblood with foreign surfaces during cardiopulmonary bypass(CPB) cause systemic inflammatory response syndrome(SIRS) through activation of several humoral cascadesincluding cytokines such as IL-6 IL-8 and Tumor NecrosisFactor-120572 (TNF-120572) [68] The inflammatory response can beattenuated by promoting the biocompatibility of the CPBcircuit Use of heparin-treated surfaces in CPB circuits hasbeen shown to decrease activation of leukocytes and thecomplement cascades [5] As a result need to inotropicsupport postoperative time of mechanical ventilation andrate of acute lung injury decrease and patients durationof hospital stay shortens which reflects the positive effectof heparin in CPB circuits [69 70] Twelve studies whoseendpoints were the effects of heparin-bonded circuits oninflammatory markers were included in our analysis and inthe majority of these trials [27 29 32ndash35 71] heparin-coatedcircuit significantly decreased the level of cytokines such asIL-6 IL-8 TNF-120572 complement complex neutrophils andelastase compared to non-heparin-coated circuit

Defraigne et al [28] randomized 200 patients in 4 groupsheparin-coated circuit with or without aprotinin administra-tion and uncoated circuit with or without aprotinin adminis-tration They measured IL-6 IL-8 TNF-120572 myeloperoxidase(MPO) and elastase level and concluded that cytokine releaseand neutrophil activation were not attenuated by heparin-coated circuit or by the administration of aprotinin Misawaet al [30] evaluated cytokines level under normothermicCPB in a small observational controlled study (119899 = 19 9 incontrol group) Levels of IL-6 IL-8 and ICAM-1 (indicatorof endothelial damage) were not different between study andcontrol group However as mentioned before most studiesindicate the favorable effect of heparin-coated circuit oninflammatory responses in CPB

Paparella et al [72] compared two doses of heparin and300 Iukg and 600 Iukg in 40 patients undergoing CPB in anRCT and showed that IL-6 and TNF-120572 plasma levels were inassociation to heparin dose It seems that lower heparin dosehad small influence on proinflammatory cytokines releasehowever higher doses make a better regulatory effect oncoagulation system

The side effects of heparin-coated circuits were notreported In these studies just a number of included studiesreported a decrease in platelet levels in both groups (coatedand noncoated circuit) No major events including hemor-rhage were reported

43 Inflammatory Bowel Diseases (IBD) Hypercoagulablestate may be an important contributing factor in the patho-genesis of IBD especially ulcerative colitis (UC) [73] A num-ber of studies evaluate the effects of heparin administrationon UC but the results obtained are controversial [17 19]

Bloom et al [74] did not find any favorable effect of LMWHtinzaparin over placebo in the treatment of active UC ina double-blind randomized placebo controlled multicentertrial (119899 = 100) evaluating mean change in colitis activity asthe primary endpoint Ang et al [17] compared heparin tohydrocortisone plus prednisolone in 20 patients (UC 119899 = 17Crohnrsquos colitis 119899 = 3) in open-label randomized crossovertrial whichmeasured endpoints clinical disease activity stoolfrequency and 120572

1acid glycoprotein and endoscopic and

histopathological grading indicate the efficacy and safety ofheparin compared to corticosteroids (119875 gt 005) in contrastthe study by Panes et al [19] did not show the efficacy ofheparin in UC compared to methylprednisolone

Zezos et al [20] compared enoxaparin with standardtreatment (aminosalicylate + corticosteroids) in 34 patientswith active UC The inflammatory biomarkers includingC-Reactive Protein (CRP) Erythrocyte Sedimentation Rate(ESR) and fibrinogen did not show any difference in studygroup compared to control and both groups showed similarrate of disease improvement (119875 gt 005) furthermorecoagulation factors did not change from one to anotherAuthors concluded that enoxaparin is a safe adjuvant but hasno additive benefit over standard treatment of UC

Generally the studies show conflicting results The hep-arin and LMWHs showed efficacy in regard of disease activityand also well tolerated but inflammatory markers did notchange significantly Therefore the improvement in diseaseactivity might be the result of heparinrsquos anticoagulant effects

44 Acute Coronary Syndrome (ACS) Inflammation has akey role in the pathogenesis of coronary artery plaquedestabilization and rupture leading to acute coronary syn-dromes (ACS) [75] Leukocyte activation monocyte andneutrophil infiltration result in local and systemic inflam-matory responses [76] Heparin and LMWHs are commonlyused in ACS to prevent clot formation they also seem tohave desirable effects on inflammatory markers level basedon sparse data

We found 8 studies about heparin and LMWHs in CADsevaluating anti-inflammatory effects as their endpoints Old-gren et al [56] found that dalteparin administration inpatients with unstable CAD (119899 = 555) did not affect IL-6C-Reactive Protein (CRP) and fibrinogen levels although itreduced coagulation activity and mortality rate in long termso it is concluded that these effects are not related to its anti-inflammatory properties Walters et al [58] compared highdose of tirofibanenoxaparin (119899 = 30) with tirofibanheparin(119899 = 30) in an open-label randomized controlled trial in highrisk percutaneous interventionThey found that combinationof high dose of tirofiban with enoxaparin significantly atten-uate inflammatory process (decreased levels of CRP and vonWillebrand factor) compared to tirofiban and heparin

The ARMADA study [54] evaluated anti-inflammatoryeffects of heparin and enoxaparin in Non-ST-ElevatedMyocardial Infarction (Non-STEMI) and reported thatinflammatory markers (CRP and von Willebrand factor)are affected more by LMWH compared to UFH Howeverbecause of the small sample size of the study (119899 = 68)

Advances in Pharmacological Sciences 11

it did not acquire sufficient statistical power to prove anyeffects on defined outcomes Nasiripour et al [55] found thatboth enoxaparin and heparin reduce inflammatory markersin STEMI patients at the same level however this study hadthe same limitations of sample size (119899 = 34) and power too

In summary considering heparins as the main stay treat-ment of ACS its effects are more pronounced as anticoagu-lating than as an anti-inflammatory agent in this pathologicalcondition

45 Cataract Surgery Postoperative inflammation isobserved in cataract surgery especially in children Newertechniques as lensectomy and phacoemulsification cause lesscomplication but still pose potential risks [77 78] It hasbeen suggested that a heparin surface-modified intraocularlens (IOL) or augmenting the irrigating solution withheparin during cataract surgery may reduce the incidence ofpostoperative inflammation Borgioli et al [22] confirm thishypothesis that heparin surface-modified IOL will reducethe inflammatory response compared to conventional IOLat least in short term period (3 months) in a large (524patients) double-blind multicenter trial A similar study byColin et al [23] (119899 = 58) confirms their results howeverthe power of Borgioli et al study was higher Heparinizedlenses showed also more anti-inflammatory effects duringlong term follow-up (1 year) Heparinized irrigating solutionwas used during cataract surgery in two different studies andinflammation decrease observed in the early postoperativeperiod of both studies (Kohnen et al [26] and Ozkurt et al[24]) Therefore it seems that heparin in both forms haveanti-inflammatory effects in cataract surgery

Vasavada et al [25] used enoxaparin irrigation solutionin 20 children undergoing bilateral cataract surgery butthey did not find any beneficial effect in early postoperativeinflammation This study acquired the highest quality in thestudy quality assessment process based on Jadad score andCONSORT items (5274 702) It is worth noticing that themajority of itemsmentioned in the CONSORT checklist wereadequately reported and covered in this paper

Potential mechanisms of anti-inflammatory effects ofheparin have been discussed completely in a review by Young[6] Binding of heparin to different mediators involved inthe immune system response (cytokines and chemokines)acute phase proteins and complement complex proteinsmay contribute to the anti-inflammatory activity of heparinNeutralizing of cytokines at the inflammation site is anotherpossible mechanism In most of the studies level of cytokinessuch as IL-6 IL-8 TNF-120572 and CRP was decreased afterheparin administration which can confirm this mechanismalso heparin and LMWHs inhibit adhesion of leukocytesand neutrophils to endothelial cells by binding to p-selectinand consequently prevent release of oxygen radicals andproteolytic enzymes Other possible mechanisms are as fol-lows inhibition of nuclear factor 120581B (NF-120581B) and inductionof apoptosis by modulation of activity of TNF-120572 and NF-120581B In a double-blind placebo-controlled trial (119899 = 62)in patients with stable coronary artery disease followingadministration of 1mgkg subcutaneous enoxaparin plasmalevels of myeloperoxidase (MPO) increased significantly

(119875 lt 0001) and subsequently endothelial function improved(119903 = 067 119875 lt 0001) through MPO binding to endotheliumand depleting vascular nitric oxide [57] This study confirmsanother possible mechanism of heparins anti-inflammatoryeffects

5 Conclusion

As we discussed heparins potential effects as anti-inflamma-tory agents supported by several clinical trials in varioussetting Heparin and its related derivatives have been shownto benefit patients with asthma and patients undergoingcardiopulmonary bypass and cataract surgery In otherinflammatory diseases such as IBD (ulcerative colitis) thestudies are heterogeneous and incongruent Most studies didnot report any unwanted event with heparins when they usedthem as anti-inflammatory agents whether through systemicor through local (as inhaler or irrigation or heparin-coatedcircuit) administration However because the majority ofthese trials did not pose optimal quality scores we cannotdraw a definite conclusion on the efficacy of heparin and itsderivatives as anti-inflammatory agents

The present review included studies which measuredinflammatory markers as their endpoints and in most ofthem these markers were decreased though not significantlyTo come to a definite conclusion further double-blindrandomized placebo-controlled clinical trials with a largersample size are needed However because the inflammationatherogenesis thrombogenesis and cell proliferation areassociated with each other the pleiotropic effects of heparinand related compounds may have greater therapeutic effectthan compounds that are directed against a single target

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

[1] B Casu ldquoHeparin structurerdquo Pathophysiology of Haemostasisand Thrombosis vol 20 supplement 1 pp 62ndash73 1990

[2] J Hirsh R Raschke T EWarkentin J E Dalen DDeykin andL Poller ldquoHeparin mechanism of action pharmacokineticsdosing considerations monitoring efficacy and safetyrdquo Chestvol 108 no 4 supplement pp 258Sndash275S 1995

[3] J Fareed D A Hoppensteadt and R L Bick ldquoAn update onheparins at the beginning of the new millenniumrdquo Seminars inThrombosis and Hemostasis vol 26 no 3 pp 5ndash21 2000

[4] J Hirsh ldquoDrug therapy heparinrdquo The New England Journal ofMedicine vol 324 no 22 pp 1565ndash1574 1991

[5] R J Ludwig ldquoTherapeutic use of heparin beyond anticoagu-lationrdquo Current Drug Discovery Technologies vol 6 no 4 pp281ndash289 2009

[6] E Young ldquoThe anti-inflammatory effects of heparin and relatedcompoundsrdquo Thrombosis Research vol 122 no 6 pp 743ndash7522008

12 Advances in Pharmacological Sciences

[7] A R Jadad R A Moore D Carroll et al ldquoAssessing the qualityof reports of randomized clinical trials is blinding necessaryrdquoControlled Clinical Trials vol 17 no 1 pp 1ndash12 1996

[8] K F Schulz D G Altman and D Moher ldquoCONSORT 2010statement updated guidelines for reporting parallel grouprandomised trialsrdquo International Journal of Surgery vol 9 no8 pp 672ndash677 2011

[9] T Ahmed J Garrigo and I Danta ldquoPreventing bronchocon-striction in exercise-induced asthma with inhaled heparinrdquoTheNewEngland Journal ofMedicine vol 329 no 2 pp 90ndash95 1993

[10] Z Diamant M C Timmers H Van Der Veen C P PageF J Van Der Meer and P J Sterk ldquoEffect of inhaled heparinon allergen-induced early and late asthmatic responses inpatients with atopic asthmardquo American Journal of Respiratoryand Critical Care Medicine vol 153 no 6 pp 1790ndash1795 1996

[11] M Duong D Cockcroft L-P Boulet et al ldquoThe effect ofIVX-0142 a heparin-derived hypersulfated disaccharide on theallergic airway responses in asthmardquo Allergy vol 63 no 9 pp1195ndash1201 2008

[12] A M Fal M Kraus-Filarska J Miecielica and J MalolepszyldquoMechanisms of action of nebulized low-molecular-weightheparin in patients with bronchial asthmardquo The Journal ofAllergy and Clinical Immunology vol 113 no 2 supplement pS36 2004

[13] J Jerzynska I Stelmach P Majak and P Kuna ldquoThe effectof inhaled heparin on airway responsiveness to histamine andmetacholine in asthmatic childrenrdquo Journal of Allergy andClinical Immunology vol 109 no 1 supplement 1 p S39 2002

[14] A F Kalpaklioglu Y S Demirel S Saryal and Z MisirligilldquoEffect of pretreatment with heparin on pulmonary and cuta-neous responserdquo Journal of Asthma vol 34 no 4 pp 337ndash3431997

[15] I Stelmach J Jerzynska A Brzozowska and P Kuna ldquoTheeffect of inhaled heparin on postleukotriene bronchoconstric-tion in children with asthmardquo Journal of Allergy and ClinicalImmunology vol 109 no 1 supplement 1 p S39 2002

[16] I Stelmach J Jerzynska W Stelmach et al ldquoThe effect ofinhaled heparin on airway responsiveness to histamine andleukotriene D4rdquo Allergy and Asthma Proceedings vol 24 no 1pp 59ndash65 2003

[17] Y S Ang N Mahmud B White et al ldquoRandomized compar-ison of unfractionated heparin with corticosteroids in severeactive inflammatory bowel diseaserdquo Alimentary PharmacologyandTherapeutics vol 14 no 8 pp 1015ndash1022 2000

[18] C Folwaczny B Wiebecke and K Loeschke ldquoUnfractionedheparin in the therapy of patients with highly active inflamma-tory bowel diseaserdquo The American Journal of Gastroenterologyvol 94 no 6 pp 1551ndash1555 1999

[19] J Panes M Esteve E Cabre et al ldquoComparison of heparinand steroids in the treatment of moderate and severe ulcerativecolitisrdquo Gastroenterology vol 119 no 4 pp 903ndash908 2000

[20] P Zezos G Papaioannou N Nikolaidis et al ldquoLow-molecular-weight heparin (enoxaparin) as adjuvant therapy in the treat-ment of active ulcerative colitis a randomized controlledcomparative studyrdquoAlimentary Pharmacology andTherapeuticsvol 23 no 10 pp 1443ndash1453 2006

[21] A A Vrij J M Jansen E J Schoon H C Hemker and RW Stockbrugger ldquoLow molecular weight heparin treatmentin steroid refractory ulcerative colitis clinical outcome andinfluence on mucosal capillary thrombirdquo Scandinavian Journalof Gastroenterology Supplement vol 36 no 234 pp 41ndash47 2001

[22] D M Borgioli D J Coster R F T Fan et al ldquoEffect of heparinsurface modification of polymethylmethacrylate intraocularlenses on signs of postoperative inflammation after extracap-sular cataract extraction one-year results of a double-maskedmulticenter studyrdquoOphthalmology vol 99 no 8 pp 1248ndash12551992

[23] J Colin S Roncin and M Wenzel ldquoEfficacy of heparinsurface-modified IOLs in reducing postoperative inflammatoryreactions in patients with exfoliation syndromemdasha double-blind comparative studyrdquo European Journal of Implant andRefractive Surgery vol 7 no 5 pp 266ndash270 1995

[24] Y B Ozkurt A Taskiran N Erdogan B Kandemir and OK Dogan ldquoEffect of heparin in the intraocular irrigating solu-tion on postoperative inflammation in the pediatric cataractsurgeryrdquoClinical Ophthalmology vol 3 no 1 pp 363ndash365 2009

[25] V A Vasavada M R Praveen S K Shah R H Trivedi andA R Vasavada ldquoAnti-inflammatory effect of low-molecular-weight heparin in pediatric cataract surgery a randomizedclinical trialrdquoThe American Journal of Ophthalmology vol 154no 2 pp 252ndash258 2012

[26] T Kohnen B Dick V Hessemer D D Koch and K WJacobi ldquoEffect of heparin in irrigating solution on inflammationfollowing small incision cataract surgeryrdquo Journal of Cataract ampRefractive Surgery vol 24 no 2 pp 237ndash243 1998

[27] S Ashraf Y Tian D Cowan A Entress P G Martin andK G Watterson ldquoRelease of proinflammatory cytokines dur-ing pediatric cardiopulmonary bypass heparin-bonded versusnonbonded oxygenatorsrdquo Annals of Thoracic Surgery vol 64no 6 pp 1790ndash1794 1997

[28] J-O Defraigne J Pincemail R Larbuisson F Blaffart andR Limet ldquoCytokine release and neutrophil activation are notprevented by heparin- coated circuits and aprotinin administra-tionrdquo Annals of Thoracic Surgery vol 69 no 4 pp 1084ndash10912000

[29] R de Vroege W van Oeveren J van Klarenbosch et al ldquoTheimpact of heparin-coated cardiopulmonary bypass circuits onpulmonary function and the release of inflammatory media-torsrdquo Anesthesia and Analgesia vol 98 no 6 pp 1586ndash15942004

[30] Y Misawa K Kawahito H Konishi and K Fuse ldquoCytokinemediated endothelial activation during and after normothermiccardiopulmonary bypass Heparin-bonded versus non heparin-bonded circuitsrdquo ASAIO Journal vol 46 no 6 pp 740ndash7432000

[31] A Koster T Fischer M Praus et al ldquoHemostatic activationand inflammatory response during cardiopulmonary bypassimpact of heparin managementrdquo Anesthesiology vol 97 no 4pp 837ndash841 2002

[32] C Olsson A Siegbahn A Henze et al ldquoHeparin-coatedcardiopulmonary bypass circuits reduce circulating comple-ment factors and interleukin-6 in paediatric heart surgeryrdquoScandinavian Cardiovascular Journal vol 34 no 1 pp 33ndash402000

[33] T Ozawa K Yoshihara N Koyama Y Watanabe N Shionoand Y Takanashi ldquoClinical efficacy of heparin-bonded bypasscircuits related to cytokine responses in childrenrdquo The Annalsof Thoracic Surgery vol 69 no 2 pp 584ndash590 2000

[34] A Parolari F Alamanni T Gherli et al ldquolsquoHigh dosersquo aprotininand heparin-coated circuits Clinical efficacy and inflammatoryresponserdquo Cardiovascular Surgery vol 7 no 1 pp 117ndash127 1999

[35] H Yamada I Kudoh Y Hirose M Toyoshima H Abe andK Kurahashi ldquoHeparin-coated circuits reduce the formation of

Advances in Pharmacological Sciences 13

TNF120572 during cardiopulmonary bypassrdquo Acta AnaesthesiologicaScandinavica vol 40 no 3 pp 311ndash317 1996

[36] O Barkay E Niv E Santo R Bruck A Hallak and F MKonikoff ldquoLow-dose heparin for the prevention of post-ERCPpancreatitis a randomized placebo-controlled trialrdquo SurgicalEndoscopy and Other Interventional Techniques vol 22 no 9pp 1971ndash1976 2008

[37] R C Becker K W Mahaffey H Yang et al ldquoHeparin-associated anti-Xa activity and platelet-derived prothromboticand proinflammatory biomarkers in moderate to high-riskpatients with acute coronary syndromerdquo Journal of Thrombosisand Thrombolysis vol 31 no 2 pp 146ndash153 2011

[38] S D Bowler S M Smith and P S Lavercombe ldquoHeparininhibits the immediate response to antigen in the skin and lungsof allergic subjectsrdquo American Review of Respiratory Diseasevol 147 no 1 pp 160ndash163 1993

[39] J P Boyle R H Smart and J K Shirey ldquoHeparin in thetreatment of chronic obstructive bronchopulmonary diseaserdquoThe American Journal of Cardiology vol 14 no 1 pp 25ndash281964

[40] Y Qian H Xie R Tian K Yu and R Wang ldquoEfficacy of lowmolecular weight heparin in patients with acute exacerbationof chronic obstructive pulmonary disease receiving ventilatorysupportrdquo COPD Journal of Chronic Obstructive PulmonaryDisease vol 11 no 2 pp 171ndash176 2014

[41] A Chamorro A Cervera J Castillo A Davalos J J Aponteand A M Planas ldquoUnfractionated heparin is associated with alower rise of serum vascular cell adhesion molecule-1 in acuteischemic stroke patientsrdquo Neuroscience Letters vol 328 no 3pp 229ndash232 2002

[42] R de Cock L A Ficker J G Dart A Garner and P WrightldquoTopical heparin in the treatment of ligneous conjunctivitisrdquoOphthalmology vol 102 no 11 pp 1654ndash1659 1995

[43] U Derhaschnig T Pernerstorfer M Knechtelsdorfer U Hol-lenstein S Panzer and B Jilma ldquoEvaluation of antiinflamma-tory and antiadhesive effects of heparins in human endotox-emiardquo Critical Care Medicine vol 31 no 4 pp 1108ndash1112 2003

[44] B DixonM J Schultz R Smith J B Fink J D Santamaria andD J Campbell ldquoNebulized heparin is associatedwith fewer daysof mechanical ventilation in critically ill patients a randomizedcontrolled trialrdquo Critical Care vol 14 no 5 article R180 2010

[45] F K Keating H L Dauerman D A Whitaker B E Sobeland D J Schneider ldquoThe effects of bivalirudin compared withthose of unfractionated heparin plus eptifibatide on inflam-mation and thrombin generation and activity during coronaryinterventionrdquo Coronary Artery Disease vol 16 no 6 pp 401ndash405 2005

[46] M Ledson M Gallagher C A Hart and M Walshaw ldquoNeb-ulized heparin in Burkholderia cepacia colonized adult cysticfibrosis patientsrdquo European Respiratory Journal vol 17 no 1 pp36ndash38 2001

[47] D J Serisier J K Shute P M Hockey B Higgins J Conwayand M P Carroll ldquoInhaled heparin in cystic fibrosisrdquo EuropeanRespiratory Journal vol 27 no 2 pp 354ndash358 2006

[48] O K Poyrazoglu A Dogukan M Yalniz D Seckin andA L Gunal ldquoAcute effect of standard heparin versus lowmolecular weight heparin on oxidative stress and inflammationin hemodialysis patientsrdquo Renal Failure vol 28 no 8 pp 723ndash727 2006

[49] S Suzuki T Matsuo H Kobayashi et al ldquoAntithrombotictreatment (argatroban vs heparin) in coronary angioplastyin angina pectoris effects on inflammatory hemostatic and

endothelium-derived parametersrdquoThrombosis Research vol 98no 4 pp 269ndash279 2000

[50] S D Trocme and H-I Li ldquoEffect of heparin-surface-modifiedintraocular lenses on postoperative inflammation after pha-coemulsification a randomized trial in a United States patientpopulationrdquo Ophthalmology vol 107 no 6 pp 1031ndash1037 2000

[51] C Vancheri C Mastruzzo F Armato et al ldquoIntranasal heparinreduces eosinophil recruitment after nasal allergen challenge inpatients with allergic rhinitisrdquo Journal of Allergy and ClinicalImmunology vol 108 no 5 pp 703ndash708 2001

[52] A Abdollahi M-T Naini H Shams and R Zarei ldquoEffect oflow-molecular-weight heparin on postoperative inflammationin phacomorphic glaucomardquo Archives of Iranian Medicine vol5 no 4 pp 225ndash229 2002

[53] R T S Lakshmi T Priyanka J Meenakshi K R MathangiV Jeyaraman and M Babu ldquoLow molecular weight heparinmediated regulation of nitric oxide synthase during burnwound healingrdquo Annals of Burns and Fire Disasters vol 24 no1 pp 24ndash29 2011

[54] G Montalescot C Bal-dit-Sollier D Chibedi et al ldquoCompar-ison of effects on markers of blood cell activation of enoxa-parin dalteparin and unfractionated heparin in patients withunstable angina pectoris or non-ST-segment elevation acutemyocardial infarction (the ARMADA study)rdquo The AmericanJournal of Cardiology vol 91 no 8 pp 925ndash930 2003

[55] S Nasiripour K Gholami SMousavi et al ldquoComparison of theeffects of enoxaparin and heparin on inflammatory biomarkersin patients with ST-segment elevated myocardial infarction aprospective open label pilot clinical trialrdquo Iranian Journal ofPharmaceutical Research vol 13 no 2 pp 583ndash590 2014

[56] J Oldgren C Fellenius K Boman et al ldquoInfluence of prolongeddalteparin treatment on coagulation fibrinolysis and inflam-mation in unstable coronary artery diseaserdquo Journal of InternalMedicine vol 258 no 5 pp 420ndash427 2005

[57] T K Rudolph V Rudolph A Witte et al ldquoLiberation of vesseladherent myeloperoxidase by enoxaparin improves endothelialfunctionrdquo International Journal of Cardiology vol 140 no 1 pp42ndash47 2010

[58] D L Walters M J Ray P Wood E J Perrin J H N Bettand C N Aroney ldquoHigh-dose tirofiban with enoxaparin andinflammatory markers in high-risk percutaneous interventionrdquoEuropean Journal of Clinical Investigation vol 40 no 2 pp 139ndash147 2010

[59] S W Rathbun C E Aston and T L Whitsett ldquoA randomizedtrial of dalteparin compared with ibuprofen for the treatmentof superficial thrombophlebitisrdquo Journal of Thrombosis andHaemostasis vol 10 no 5 pp 833ndash839 2012

[60] J P Titon D Auger P Grange et al ldquoTherapeutic managementof superficial venous thrombosis with calcium nadroparinDosage testing and comparison with a non-steroidal anti-inflammatory agentrdquo Annales de Cardiologie et d Angeiologievol 43 no 3 pp 160ndash166 1994

[61] H Uncu ldquoA comparison of low-molecular-weight heparin andcombined therapy of low-molecular-weight heparin with ananti-inflammatory agent in the treatment of superficial veinthrombosisrdquo Phlebology vol 24 no 2 pp 56ndash60 2009

[62] J A Sjoslashland R S Pedersen J Jespersen and J GramldquoIntraperitoneal heparin ameliorates the systemic inflamma-tory response in PD patientsrdquo NephronmdashClinical Practice vol100 no 4 pp c105ndashc110 2005

[63] N L Fine C Shim and M H Williams Jr ldquoObjectiveevaluation of heparin in the treatment of asthmardquo AmericanReview of Respiratory Disease vol 98 no 5 pp 886ndash887 1968

14 Advances in Pharmacological Sciences

[64] ZDiamantM C Timmers H van derVeen C P Page F J vander Meer and P J Sterk ldquoEffect of inhaled heparin on allergen-induced early and late asthmatic responses in patients withatopic asthmardquo American Journal of Respiratory and CriticalCare Medicine vol 153 no 6 I pp 1790ndash1795 1996

[65] C M E Tranfa A Vatrella R Parrella G Pelaia F Bariffiand S A Marsico ldquoEffect of inhaled heparin on water-inducedbronchoconstriction in allergic asthmaticsrdquoEuropean Journal ofClinical Pharmacology vol 57 no 1 pp 5ndash9 2001

[66] I Stelmach J Jerzynska A Brzozowska and P Kuna ldquoTheeffect of inhaled heparin on postleukotriene bronchoconstric-tion in children with asthmardquo Polski Merkuriusz Lekarski vol12 no 68 pp 95ndash98 2002

[67] R Polosa S Magrı C Vancheri et al ldquoTime course of changesin adenosine 51015840-monophosphate airway responsiveness withinhaled heparin in allergic asthmardquo Journal of Allergy andClinical Immunology vol 99 no 3 pp 338ndash342 1997

[68] J Butler GM Rocker and SWestaby ldquoInflammatory responseto cardiopulmonary bypassrdquo The Annals of Thoracic Surgeryvol 55 no 2 pp 552ndash559 1993

[69] J M Redmond A M Gillinov R S Stuart et al ldquoHeparin-coated bypass circuits reduce pulmonary injuryrdquoThe Annals ofThoracic Surgery vol 56 no 3 pp 474ndash479 1993

[70] S Svenmarker E Sandstrom T Karlsson et al ldquoClinical effectsof the heparin coated surface in cardiopulmonary bypassrdquoEuropean Journal of Cardio-Thoracic Surgery vol 11 no 5 pp957ndash964 1997

[71] Y J Gu W van Oeveren C Akkerman P W Boonstra RJ Huyzen and C R H Wildevuur ldquoHeparin-coated circuitsreduce the inflammatory response to cardiopulmonary bypassrdquoThe Annals of Thoracic Surgery vol 55 no 4 pp 917ndash922 1993

[72] D Paparella O O Al Radi Q H Meng T Venner K Teohand E Young ldquoThe effects of high-dose heparin on inflamma-tory and coagulation parameters following cardiopulmonarybypassrdquo Blood Coagulation and Fibrinolysis vol 16 no 5 pp323ndash328 2005

[73] S Danese A Papa S Saibeni A Repici A Malesci andM Vecchi ldquoInflammation and coagulation in inflammatorybowel disease the clot thickensrdquo The American Journal ofGastroenterology vol 102 no 1 pp 174ndash186 2007

[74] S Bloom S Kiilerich M R Lassen et al ldquoLow molecularweight heparin (tinzaparin) vs placebo in the treatment of mildto moderately active ulcerative colitisrdquo Alimentary Pharmacol-ogy ampTherapeutics vol 19 no 8 pp 871ndash878 2004

[75] P Libby ldquoCoronary artery injury and the biology of atheroscle-rosis inflammation thrombosis and stabilizationrdquo AmericanJournal of Cardiology vol 86 no 8 2000

[76] N T Mulvihill and J B Foley ldquoInflammation in acute coronarysyndromesrdquo Heart vol 87 no 3 pp 201ndash204 2002

[77] N A JamesonW V Good and C S Hoyt ldquoInflammation aftercataract surgery in childrenrdquoOphthalmic Surgery vol 23 no 2pp 99ndash102 1992

[78] R M Sinskey P A Amin and R Lingua ldquoCataract extractionand intraocular lens implantation in an infant with amonocularcongenital cataractrdquo Journal of Cataract amp Refractive Surgeryvol 20 no 6 pp 647ndash651 1994

[79] A van Ophoven A Heinecke and L Hertle ldquoSafety andefficacy of concurrent application of oral pentosan polysulfateand subcutaneous low-dose heparin for patients with interstitialcystitisrdquo Urology vol 66 no 4 pp 707ndash711 2005

Submit your manuscripts athttpwwwhindawicom

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Page 5: Review Article Anti-Inflammatory Effects of Heparin and Its …downloads.hindawi.com/journals/aps/2015/507151.pdf · 2019. 7. 31. · Review Article Anti-Inflammatory Effects of Heparin

Advances in Pharmacological Sciences 5

Table1Con

tinued

Clinicalsetting

Heparin

preparation

Mod

eof

administratio

nCom

parator

Num

bero

fpatie

nts

Clinicalou

tcom

eLabo

ratory

outcom

eStud

ydesig

n

Cardiopu

lmon

ary

bypass[29]

UFH

mdashUncoatedcircuit

51(26in

each

grou

p)

Decreased

pulm

onary

vascular

resistanceind

exandpu

lmon

aryshun

tfractio

nandincreased

PaO2FIO2ratio

Lower

levelsof

phosph

olipaseA

2and

complem

entactivation(119875

0001)

Rand

omizeddou

ble-blind

clinicaltria

l

Cardiopu

lmon

ary

bypass[30]

Heparin-

coated

circuit

mdashNon

-heparin-coated

circuit

16(9

incontrol

grou

p)mdash

Nosig

nificantd

ifference

betweengrou

psregarding

granulocytee

lasta

seIL-6

IL-8

Quasi-experim

ental

(pretest-

posttestd

esign)

Cardiopu

lmon

ary

bypass[31]

Heparin

concentration-

based

syste

m

mdashAc

tivated

clotting

time-based

managem

ent

200(100

incontrol

grou

p)

Noeffecto

npo

stoperativ

ebloo

dloss

Sign

ificant

redu

ctionof

neutroph

ilactiv

ationand

fibrin

olysisandthrombin

generatio

n(119875lt005)

Rand

omized

controlled

trial

Cardiopu

lmon

ary

bypass(pediatric)

[32]

Heparin-

coated

circuit

mdashNon

-heparin-coated

circuit

19(10in

control

grou

p)

Improvem

ento

fthe

biocom

patib

ilityof

CPB

durin

gheartsurgery

Levelsof

complem

ent

factor

C3a(119875lt0001)a

ndIL-6

(1198750005)significantly

redu

cedin

heparin

-coated

circuit

Rand

omized

controlled

trial

Cardiopu

lmon

ary

bypass(pediatric)

[33]

Heparin-

coated

circuit

mdashNon

-heparin-coated

circuit

34(12in

control

grou

p)

Nodifferences

indu

ratio

nof

intubatio

nintensivec

are

unitor

hospita

lstayor

posto

perativ

eblood

loss

IL-6IL-8andTN

F-120572we

resig

nificantly

lower

inheparin

grou

p(119875lt001

119875lt001and119875lt005

resp)

Rand

omized

controlled

trial

Cardiopu

lmon

ary

bypass[34]

Heparin-

coated

circuit

(heparin

+aprotin

in)

mdashNon

-heparin-coated

circuit(heparin

+aprotin

in)

30(15in

each

grou

p)

Nosig

nificantd

ifferences

betweenthetwogrou

psin

term

sofb

leedingand

transfu

sionalrequirements

thetim

espent

ona

ventilatoror

indu

ratio

nof

stayin

theintensiv

ecare

unit(ICU

)

Levelsof

IL-6C

RPand

neutroph

ilcoun

tdid

not

change

byheparin

-coated

circuitMon

ocytec

ount

increasedin

heparin

-coatedcircuit

Rand

omized

controlled

trial

Coron

aryartery

bypassgraft

ing

(CABG

)[35]

Heparin-

coated

circuit

mdashNon

-heparin-coated

circuit

18(9

ineach

grou

p)mdash

Redu

ctionof

levelsof

IL-8

andTN

F-120572andincrease

ofneutroph

ilelastase

Rand

omized

controlled

trial

CRP

C-Re

activ

eProteinC

PBC

ardioPu

lmon

aryB

ypassEC

PEo

sinop

hilC

ationicP

roteinE

SRE

rythrocyteSedimentatio

nICUIntensiv

eCareU

nitILinterleuk

inIV

intravenou

sSC

sub

cutaneou

sSG

AW

SpecificA

irway

Con

ductanceT

NFTu

mor

Necrosis

Factorand

UFH

unfractionatedheparin

6 Advances in Pharmacological Sciences

Table2Summaryandfin

ding

sofo

ther

studied

diseases

Clinicalsetting

Heparin

preparation

Mod

eof

administratio

nCom

parator

Num

bero

fpatie

nts

Clinicalou

tcom

eLabo

ratory

outcom

eStud

ydesig

n

Pancreatitisa

fter

ERCP

[36]

UFH

SCSalin

esolution

105(54in

control

grou

p)

Rateof

posto

perativ

epancreatitisw

asno

tsig

nificantb

etweenbo

thgrou

ps

mdashRa

ndom

ized

placebo-controlledclinical

trial

Acutec

oron

ary

synd

rome(AC

S)[37]

UFH

SCEn

oxaparin

201

mdashNosig

nificantd

ifference

betweenCD

4ligandand

PAI-1inbo

thgrou

ps

Openlabelrand

omized

clinicaltria

l

Skin

orpu

lmon

ary

allergy[38]

UFH

IVnebulizer

Normalsalin

eplacebo

25Sign

ificant

inhibitio

nof

mastcell-m

ediatedallergic

inflammation(119875004)

mdashDou

ble-blind

placebo-controlled

crossoverc

linicaltrial

COPD

[39]

UFH

IVmdash

37(18in

control

grou

p)

Sign

ificant

improvem

entin

bron

chospasm

and

bron

chialsecretio

ns(58

respon

serate)

mdashRa

ndom

ized

placebo-controlledclinical

trial

COPD

[40]

Nadroparin

SCCon

ventionaltreatment

66(33in

each

grou

p)

Decreaseo

fdurationof

mechanicalventilationand

leng

thof

hospita

land

ICU

stay(119875lt001)

Sign

ificant

decrease

inlevelsof

CRPIL-6and

fibrin

ogen

Rand

omized

controlled

trial

Ischem

icstroke

[41]

UFH

IVAs

pirin

167(97in

control

grou

p)

Early

onsetinitia

tionof

heparin

might

improve

recovery

after

stroke

Rise

ofsV

CAM-1at48

hwas

significantly

lower

inpatie

ntstreated

with

UFH

(119875lt001)

Quasi-experim

ental

(con

trolledob

servational

study)

Lign

eous

conjun

ctivitis[42]

UFH

Topical

Alpha

chym

otrypsin

orste

roid

17(12in

control

grou

p)

Intensivea

ndearly

useo

ftopicalh

eparin

may

improvetherapy

results

indisease

mdashQuasi-experim

ental

(non

rand

omized

Clinical

trial)

Endo

toxemia

(indu

cedby

lipop

olysaccharide

inhealthysubjects)

[43]

UFH

IVLM

WHor

placebo

30(10in

each

grou

p)mdash

Noeffecto

nTN

F-120572IL-6

and8CR

PandE-selectin

Rand

omized

doub

le-blin

ded

placebo-controlledparallel

grou

ptrial

Mechanical

ventilatio

n[44]

UFH

Nebulizer

Normalsalin

e(placebo)

50(25in

each

grou

p)

Fewer

days

onmechanical

ventilatio

nbette

rPao2Fio2ratio

mdashDou

ble-blindrand

omized

placebo-controlledtrial

Percutaneous

coronary

interventio

n[45]

Bivalirud

inIV

UFH

+eptifi

batid

e63

(29in

control

grou

p)mdash

Increase

inIL-6

andCR

Paft

er1d

ayD

ecreaseinCR

Pin

bivalirud

ingrou

paft

er30

days

(1198750002)

Rand

omized

controlled

trial

Cysticfib

rosis

(adu

lts)[46

]UFH

Inhaler

mdash12

(6in

control

grou

p)Spiro

metry

parametersd

idno

tchang

eIL-6

redu

cedaft

ertre

atment

Quasi-experim

ental

(pretest-

posttestd

esign)

Advances in Pharmacological Sciences 7Ta

ble2Con

tinued

Clinicalsetting

Heparin

preparation

Mod

eof

administratio

nCom

parator

Num

bero

fpatie

nts

Clinicalou

tcom

eLabo

ratory

outcom

eStud

ydesig

n

Cysticfib

rosis

(adu

lts)[47]

UFH

Inhaler

Placebo

14Noeffecto

nFE

V1

Noeffecto

nsputum

inflammatorymarkers

Rand

omizeddou

ble-blind

placebo-controlled

crossovertria

l

Hem

odialysis

patie

nts[48]

UFH

IVSC

LMWHandno

drug

33

LMWHdecreased

oxidatives

tressand

inflammationwhereas

heparin

increasedthem

CRPTN

F-120572sup

eroxide

dism

utaseMDAincreased

inheparin

grou

pbu

tcomparabletoLM

WH

grou

p

Quasi-experim

ental

(pretest-

posttestd

esign)

Stableangina

[49]

Heparin

+Aspirin

(119899=15)

mdashArgatroban+As

pirin

(119899=12)2

7

Nodifferencein

inflammatoryrespon

seaft

erangiop

lasty

Fibrinogen

decreased

significantly

inargatro

ban

grou

pNodifferenceinvon

Willberand

factor

between

both

grou

psPAI-1

increasedin

argatro

ban

grou

p

Rand

omized

controlled

trial

Phacoemulsifi

catio

n[50]

Heparin

Coatedlenses

Polymethylm

ethacrylate

lenses

367

Heparin

coated

lenses

redu

cedsig

nificantly

inflammationearly

posto

peratio

n(119875005)

mdashRa

ndom

izeddou

ble-blind

multic

enterparallelgroup

trial

Allergicrhinitis[51]

UFH

Intranasal

mdash10

mdashRe

ductionof

eosin

ophil

catio

nicp

rotein

inthen

asal

wash

Quasi-experim

ental

(pretest-

posttestd

esign)

Phacom

orph

icglaucoma[

52]

Dalteparin

Irrig

ation

Balanced

saltsolutio

n46

(23in

each

grou

p)

Sign

ificant

decrease

ofpo

stoperativ

einfl

ammation

indalteparin

grou

pmdash

Rand

omizeddou

ble-blind

clinicaltria

l

Burn

[53]

Dalteparin

SCNotre

atment

24mdash

Decreaseo

fnitricoxide

synthetase

activ

itysig

nificantly

Quasi-experim

ental

(non

rand

omized

clinical

trial)

Unstablec

oron

ary

artery

disease[54]

Enoxaparin

(119899=46)

Dalteparin

(119899=48)

SCUFH

(119899=47)

68

VonWillberand

factor

may

have

progno

sticv

aluebut

otherb

iologicalvariables

didno

tpredictou

tcom

e

CRPfib

rinogenV

onWillberand

factor

increased

over

first2days

despite

medicaltre

atment

Enoxaparin

(13

)and

dalteparin

(19)reduced

releaseo

fVon

Willberand

factor

Openlabelrand

omized

clinicaltria

l

ST-Elevated

Myocardial

Infarctio

n(STE

MI)

[55]

Enoxaparin

SCUFH

34(17in

each

grou

p)

Both

heparin

and

enoxaparin

show

anti-inflammatoryeffects

inST

EMIp

atients

Serum

AmyloidA(119875002)

CRP(119875002)and

ferritin

(119875001)redu

cedin

heparin

grou

pIL-6

(1198750002)SA

A(1198750009)CR

P(119875001)

weres

ignificantly

decreased

inenoxaparin

grou

pTh

eoveralld

ifference

between

grou

pswas

notsignificant

Openlabelrand

omized

clinicaltria

l

8 Advances in Pharmacological Sciences

Table2Con

tinued

Clinicalsetting

Heparin

preparation

Mod

eof

administratio

nCom

parator

Num

bero

fpatie

nts

Clinicalou

tcom

eLabo

ratory

outcom

eStud

ydesig

n

Coron

aryartery

disease[56]

Dalteparin

SCPlacebo

555(285

incontrolgroup

)

Dalteparin

redu

ced

coagulationandso

MyocardialInfarctionbu

thasn

otinflammatory

activ

ity

Noeffectson

IL-6

C-reactiv

eprotein

and

fibrin

ogen

Rand

omizeddou

ble-blind

parallel-g

roup

multic

entre

trial

Stablecoronary

artery

disease[57]

Enoxaparin

SCSo

dium

chlorid

e62

(31ineach

grou

p)

Bymob

ilizing

vesselbo

und

MPO

eno

xaparin

improves

endo

thelialfun

ction

Sign

ificant

increase

ofMPO

levels

Rand

omizeddou

ble-blind

placebo-controlledtrial

Acutec

oron

ary

synd

romea

ndPC

I[58]

Tirofib

an(highdo

se)+

enoxaparin

Tirofib

an(highdo

se)+

UFH

60(30in

each

grou

p)

Thec

ombinatio

nof

tirofi

ban(highdo

se)+

enoxaparin

redu

ced

inflammationaft

erPC

I

Vonwillberand

CRP

D-dim

erand

prothrom

bin

fragmentw

eres

ignificantly

lower

inenoxaparin

grou

pthan

UFH

Openlabelrando

mized

controlledtrial

Superficialveno

usthrombo

phleb

itis

[59]

Dalteparin

SCIbup

rofen

72(37in

dalteparin

grou

p)

Sign

ificant

redu

ctionof

pain

form

baselin

etoday14

offollo

w-upNodifference

onthrombo

sisprogression

after

3mon

ths

mdashRa

ndom

izeddou

ble-blind

controlledtrial

Superficialveno

usthrombo

sis[60]

Nadroparin

SCNaproxen

117(39in

control

grou

p)

Nadroparin

redu

ced

symptom

andsig

nsof

thrombo

sedsuperficial

vein

bette

rthannaproxen

(1198750007)

mdashRa

ndom

izedopenlabel

clinicaltria

l

Superficialveno

usthrombo

sis[61]

Nadroparin

SCNadroparin

+acem

etacin

50

Sign

ificant

symptom

improvem

entinbo

thgrou

ps(1198750001)Th

ecombinatio

ngrou

pwas

bette

r

mdashRa

ndom

ized

controlled

trial

Periton

eald

ialysis

patie

nts[62]

Tinzaparin

Intraperito

neal

Isoton

icsalin

e21

Redu

ctionof

localand

syste

micinflammationin

periton

eald

ialysis

patie

nts

Redu

cedlevelsof

CRP(119875

0032)

andfib

rinogen

(119875

004

2)andIL-6

(1198750007)

indialysate

Rand

omizeddou

ble-blind

placebo-controlled

crossovertria

l

COPD

Chron

icObstructiv

ePu

lmon

aryDise

aseCR

PC-

Reactiv

eProtein

CPB

Cardio

Pulm

onaryBy

passE

CPE

osinop

hilC

ationicProtein

ERCP

End

oscopicRe

trogradeCh

olangiop

ancreatographyE

SR

ErythrocyteSedimentatio

nICUIntensiv

eCa

reUnitILinterleuk

inIV

intravenou

sLM

WHlow

molecular

weighth

eparinM

DAm

alon

dialdehydePAIPlasminogen

Activ

ator

InhibitorSC

sub

cutaneou

ssV

CAMSolub

leVa

scular

CellA

dhesionMoleculeTN

FTu

mor

Necrosis

Factorand

UFH

unfractionatedheparin

Advances in Pharmacological Sciences 9

Table 3 Summary of numbers and percentages of adequatelyreported items in each trial according to CONSORT checklist andJadad score

Trials Jadadscore

Adequately reporteditems (119899119873)

Percentage()

Abdollahi et al [52] 4 2974 392Ahmed et al [9] 3 2074 27Ang et al [17] 2 2474 324Ashraf et al [27] 2 2274 297Becker et al [37] 3 2874 378de Vroege et al [29] 3 2674 351Defraigne et al [28] 4 2874 378Derhaschnig et al [43] 3 3274 432Dixon et al [44] 4 5074 675Duong et al [11] 3 3074 405Gu et al [71] 2 1674 216Jerzynska et al [13] 3 2074 27Keating et al [45] 2 2174 284Koster et al [31] 2 2674 351Montalescot et al [54] 3 3574 473Nasiripour et al [55] 2 3474 46Oldgren et al [56] 3 2774 365Olsson et al [32] 2 2574 338van Ophoven et al [79] 2 2774 365Ozawa et al [33] 2 2774 365Ozkurt et al [24] 3 1874 243Paparella et al [72] 2 2274 297Polosa et al [67] 3 2374 311Rathbun et al [59] 5 4474 595Rudolph et al [57] 3 3174 412Serisier et al [47] 5 4574 608Stelmach et al [16] 3 3174 412Suzuki et al [49] 2 2374 31Vancheri et al [51] 4 2274 297Vasavada et al [25] 5 5274 702Walters et al [58] 3 3274 432Zezos et al [20] 3 3774 50

thrombophlebitis and hemodialysis Unfractionated heparin(UFH) was used in forty studies as subcutaneous intra-venous inhaler or heparin-coated circuits while others usedenoxaparin (119899 = 3) dalteparin (119899 = 4) nadroparin (119899 = 4)and tinzaparin (119899 = 1)

Table 3 provides information on the adequately reporteditems according to Jadad score andCONSORT items Amongthese 32 papers 11 (354) scored 2 and the remaining studiesscored 3 or higher according to Jadad score and just threestudies fulfill the criteria of Jadad score Calculated qualityscores according to CONSORT checklist range from 21 to70 in our object studies with twelve studies scoring greaterthan 40 The following characteristics were not exactlyreported in more than half of the trials identification as

a randomized trial in the title information about the settingand location of studies determination of sample size alloca-tion and implementation of randomization participant flowrecruitment and follow-up subgroup analysis limitations ofstudy harms registration number access to full trial protocoland funding source

4 Discussion

We discuss evidence from clinical studies supporting an anti-inflammatory role for heparin and heparin-related deriva-tives

41 Asthma Asthma is a chronic inflammatory disorderof airways characterized by bronchial hyperresponsivenessresulting in episodic bronchospasm Several studies in 1960sdescribed subjective improvement of symptoms in asthmaticpatients using intravenous heparin for the first time [3963] Inhaled heparin or its derivatives have been shown topossess antiasthmatic properties in various clinical modelsallergen induced [38 64] exercise [9] adenosine [6] anddistilled water challenge models [65] Seven randomizedcontrolled crossover trials studied anti-inflammatory effectsof heparin in exercise-induced or allergen-induced asthmahaving sample size range from 8 to 25 in 5 trials

Heparin inhalation reduced bronchial hyperreactivity ina single-blind randomized crossover trial (119899 = 12) byAhmed et al [9] Heparin inhalation (1000 120583kg) preventsexercise-induced asthma (119875 lt 005) without preventionof histamine-induced bronchoconstriction Stelmach et al[66] provoke challenge tests with histamine or leukotrieneD4 before and after inhalation of heparin showed that hep-arin (5000 Iu) decreases histamine and leukotriene-inducedbronchial hyperreactivity compared to placebo significantly(119875 0043 and 0005) but changes in Forced Expiratory Vol-ume (FEV 1) were not significant (119875 0064) The inhibitoryeffects of inhaled heparin in the airways in the absence ofbronchodilation might be related to suppressive action onmast cell degranulation A randomized double-blind studyin 10 subjects with asthma showed that heparin inhalationattenuates airway response to adenosine 51015840-monophosphate(AMP) but not to methacholine (119875 lt 001) suggestingthe theory that heparin acts more likely in association tomodulation of mediator release compared to a direct effecton smooth muscle [67]

Our results showed that inhaled enoxaparin was usedjust in a pre-post study of 24 asthmatic patients measur-ing inflammatory biomarkers and showed a reduction ineosinophil (119875 0006) and lymphocytes of bronchoalveolarlavage without any significant change in IL-5 or EosinophilCationic Protein (ECP) concentrations [12] Therefore itseems that enoxaparin could be a valuable add on treatmentin asthma like UFH Duong et al [11] evaluated IVX-0142nebulizer a heparin-derived hypersulfated disaccharide inasthma and showed nonsignificant decrease in early and lateasthmatic response

Performed studies did not show any adverse events orharms with heparin or related compounds except increase in

10 Advances in Pharmacological Sciences

the plasma partial thromboplastin time reported by Ahmedet al [9]

All in one considering the results of these studies wecan conclude that heparin and its derivatives could have anti-inflammatory effects and could be considered along withother treatments in asthma

42 Cardiopulmonary Bypass Contact and interaction ofblood with foreign surfaces during cardiopulmonary bypass(CPB) cause systemic inflammatory response syndrome(SIRS) through activation of several humoral cascadesincluding cytokines such as IL-6 IL-8 and Tumor NecrosisFactor-120572 (TNF-120572) [68] The inflammatory response can beattenuated by promoting the biocompatibility of the CPBcircuit Use of heparin-treated surfaces in CPB circuits hasbeen shown to decrease activation of leukocytes and thecomplement cascades [5] As a result need to inotropicsupport postoperative time of mechanical ventilation andrate of acute lung injury decrease and patients durationof hospital stay shortens which reflects the positive effectof heparin in CPB circuits [69 70] Twelve studies whoseendpoints were the effects of heparin-bonded circuits oninflammatory markers were included in our analysis and inthe majority of these trials [27 29 32ndash35 71] heparin-coatedcircuit significantly decreased the level of cytokines such asIL-6 IL-8 TNF-120572 complement complex neutrophils andelastase compared to non-heparin-coated circuit

Defraigne et al [28] randomized 200 patients in 4 groupsheparin-coated circuit with or without aprotinin administra-tion and uncoated circuit with or without aprotinin adminis-tration They measured IL-6 IL-8 TNF-120572 myeloperoxidase(MPO) and elastase level and concluded that cytokine releaseand neutrophil activation were not attenuated by heparin-coated circuit or by the administration of aprotinin Misawaet al [30] evaluated cytokines level under normothermicCPB in a small observational controlled study (119899 = 19 9 incontrol group) Levels of IL-6 IL-8 and ICAM-1 (indicatorof endothelial damage) were not different between study andcontrol group However as mentioned before most studiesindicate the favorable effect of heparin-coated circuit oninflammatory responses in CPB

Paparella et al [72] compared two doses of heparin and300 Iukg and 600 Iukg in 40 patients undergoing CPB in anRCT and showed that IL-6 and TNF-120572 plasma levels were inassociation to heparin dose It seems that lower heparin dosehad small influence on proinflammatory cytokines releasehowever higher doses make a better regulatory effect oncoagulation system

The side effects of heparin-coated circuits were notreported In these studies just a number of included studiesreported a decrease in platelet levels in both groups (coatedand noncoated circuit) No major events including hemor-rhage were reported

43 Inflammatory Bowel Diseases (IBD) Hypercoagulablestate may be an important contributing factor in the patho-genesis of IBD especially ulcerative colitis (UC) [73] A num-ber of studies evaluate the effects of heparin administrationon UC but the results obtained are controversial [17 19]

Bloom et al [74] did not find any favorable effect of LMWHtinzaparin over placebo in the treatment of active UC ina double-blind randomized placebo controlled multicentertrial (119899 = 100) evaluating mean change in colitis activity asthe primary endpoint Ang et al [17] compared heparin tohydrocortisone plus prednisolone in 20 patients (UC 119899 = 17Crohnrsquos colitis 119899 = 3) in open-label randomized crossovertrial whichmeasured endpoints clinical disease activity stoolfrequency and 120572

1acid glycoprotein and endoscopic and

histopathological grading indicate the efficacy and safety ofheparin compared to corticosteroids (119875 gt 005) in contrastthe study by Panes et al [19] did not show the efficacy ofheparin in UC compared to methylprednisolone

Zezos et al [20] compared enoxaparin with standardtreatment (aminosalicylate + corticosteroids) in 34 patientswith active UC The inflammatory biomarkers includingC-Reactive Protein (CRP) Erythrocyte Sedimentation Rate(ESR) and fibrinogen did not show any difference in studygroup compared to control and both groups showed similarrate of disease improvement (119875 gt 005) furthermorecoagulation factors did not change from one to anotherAuthors concluded that enoxaparin is a safe adjuvant but hasno additive benefit over standard treatment of UC

Generally the studies show conflicting results The hep-arin and LMWHs showed efficacy in regard of disease activityand also well tolerated but inflammatory markers did notchange significantly Therefore the improvement in diseaseactivity might be the result of heparinrsquos anticoagulant effects

44 Acute Coronary Syndrome (ACS) Inflammation has akey role in the pathogenesis of coronary artery plaquedestabilization and rupture leading to acute coronary syn-dromes (ACS) [75] Leukocyte activation monocyte andneutrophil infiltration result in local and systemic inflam-matory responses [76] Heparin and LMWHs are commonlyused in ACS to prevent clot formation they also seem tohave desirable effects on inflammatory markers level basedon sparse data

We found 8 studies about heparin and LMWHs in CADsevaluating anti-inflammatory effects as their endpoints Old-gren et al [56] found that dalteparin administration inpatients with unstable CAD (119899 = 555) did not affect IL-6C-Reactive Protein (CRP) and fibrinogen levels although itreduced coagulation activity and mortality rate in long termso it is concluded that these effects are not related to its anti-inflammatory properties Walters et al [58] compared highdose of tirofibanenoxaparin (119899 = 30) with tirofibanheparin(119899 = 30) in an open-label randomized controlled trial in highrisk percutaneous interventionThey found that combinationof high dose of tirofiban with enoxaparin significantly atten-uate inflammatory process (decreased levels of CRP and vonWillebrand factor) compared to tirofiban and heparin

The ARMADA study [54] evaluated anti-inflammatoryeffects of heparin and enoxaparin in Non-ST-ElevatedMyocardial Infarction (Non-STEMI) and reported thatinflammatory markers (CRP and von Willebrand factor)are affected more by LMWH compared to UFH Howeverbecause of the small sample size of the study (119899 = 68)

Advances in Pharmacological Sciences 11

it did not acquire sufficient statistical power to prove anyeffects on defined outcomes Nasiripour et al [55] found thatboth enoxaparin and heparin reduce inflammatory markersin STEMI patients at the same level however this study hadthe same limitations of sample size (119899 = 34) and power too

In summary considering heparins as the main stay treat-ment of ACS its effects are more pronounced as anticoagu-lating than as an anti-inflammatory agent in this pathologicalcondition

45 Cataract Surgery Postoperative inflammation isobserved in cataract surgery especially in children Newertechniques as lensectomy and phacoemulsification cause lesscomplication but still pose potential risks [77 78] It hasbeen suggested that a heparin surface-modified intraocularlens (IOL) or augmenting the irrigating solution withheparin during cataract surgery may reduce the incidence ofpostoperative inflammation Borgioli et al [22] confirm thishypothesis that heparin surface-modified IOL will reducethe inflammatory response compared to conventional IOLat least in short term period (3 months) in a large (524patients) double-blind multicenter trial A similar study byColin et al [23] (119899 = 58) confirms their results howeverthe power of Borgioli et al study was higher Heparinizedlenses showed also more anti-inflammatory effects duringlong term follow-up (1 year) Heparinized irrigating solutionwas used during cataract surgery in two different studies andinflammation decrease observed in the early postoperativeperiod of both studies (Kohnen et al [26] and Ozkurt et al[24]) Therefore it seems that heparin in both forms haveanti-inflammatory effects in cataract surgery

Vasavada et al [25] used enoxaparin irrigation solutionin 20 children undergoing bilateral cataract surgery butthey did not find any beneficial effect in early postoperativeinflammation This study acquired the highest quality in thestudy quality assessment process based on Jadad score andCONSORT items (5274 702) It is worth noticing that themajority of itemsmentioned in the CONSORT checklist wereadequately reported and covered in this paper

Potential mechanisms of anti-inflammatory effects ofheparin have been discussed completely in a review by Young[6] Binding of heparin to different mediators involved inthe immune system response (cytokines and chemokines)acute phase proteins and complement complex proteinsmay contribute to the anti-inflammatory activity of heparinNeutralizing of cytokines at the inflammation site is anotherpossible mechanism In most of the studies level of cytokinessuch as IL-6 IL-8 TNF-120572 and CRP was decreased afterheparin administration which can confirm this mechanismalso heparin and LMWHs inhibit adhesion of leukocytesand neutrophils to endothelial cells by binding to p-selectinand consequently prevent release of oxygen radicals andproteolytic enzymes Other possible mechanisms are as fol-lows inhibition of nuclear factor 120581B (NF-120581B) and inductionof apoptosis by modulation of activity of TNF-120572 and NF-120581B In a double-blind placebo-controlled trial (119899 = 62)in patients with stable coronary artery disease followingadministration of 1mgkg subcutaneous enoxaparin plasmalevels of myeloperoxidase (MPO) increased significantly

(119875 lt 0001) and subsequently endothelial function improved(119903 = 067 119875 lt 0001) through MPO binding to endotheliumand depleting vascular nitric oxide [57] This study confirmsanother possible mechanism of heparins anti-inflammatoryeffects

5 Conclusion

As we discussed heparins potential effects as anti-inflamma-tory agents supported by several clinical trials in varioussetting Heparin and its related derivatives have been shownto benefit patients with asthma and patients undergoingcardiopulmonary bypass and cataract surgery In otherinflammatory diseases such as IBD (ulcerative colitis) thestudies are heterogeneous and incongruent Most studies didnot report any unwanted event with heparins when they usedthem as anti-inflammatory agents whether through systemicor through local (as inhaler or irrigation or heparin-coatedcircuit) administration However because the majority ofthese trials did not pose optimal quality scores we cannotdraw a definite conclusion on the efficacy of heparin and itsderivatives as anti-inflammatory agents

The present review included studies which measuredinflammatory markers as their endpoints and in most ofthem these markers were decreased though not significantlyTo come to a definite conclusion further double-blindrandomized placebo-controlled clinical trials with a largersample size are needed However because the inflammationatherogenesis thrombogenesis and cell proliferation areassociated with each other the pleiotropic effects of heparinand related compounds may have greater therapeutic effectthan compounds that are directed against a single target

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

[1] B Casu ldquoHeparin structurerdquo Pathophysiology of Haemostasisand Thrombosis vol 20 supplement 1 pp 62ndash73 1990

[2] J Hirsh R Raschke T EWarkentin J E Dalen DDeykin andL Poller ldquoHeparin mechanism of action pharmacokineticsdosing considerations monitoring efficacy and safetyrdquo Chestvol 108 no 4 supplement pp 258Sndash275S 1995

[3] J Fareed D A Hoppensteadt and R L Bick ldquoAn update onheparins at the beginning of the new millenniumrdquo Seminars inThrombosis and Hemostasis vol 26 no 3 pp 5ndash21 2000

[4] J Hirsh ldquoDrug therapy heparinrdquo The New England Journal ofMedicine vol 324 no 22 pp 1565ndash1574 1991

[5] R J Ludwig ldquoTherapeutic use of heparin beyond anticoagu-lationrdquo Current Drug Discovery Technologies vol 6 no 4 pp281ndash289 2009

[6] E Young ldquoThe anti-inflammatory effects of heparin and relatedcompoundsrdquo Thrombosis Research vol 122 no 6 pp 743ndash7522008

12 Advances in Pharmacological Sciences

[7] A R Jadad R A Moore D Carroll et al ldquoAssessing the qualityof reports of randomized clinical trials is blinding necessaryrdquoControlled Clinical Trials vol 17 no 1 pp 1ndash12 1996

[8] K F Schulz D G Altman and D Moher ldquoCONSORT 2010statement updated guidelines for reporting parallel grouprandomised trialsrdquo International Journal of Surgery vol 9 no8 pp 672ndash677 2011

[9] T Ahmed J Garrigo and I Danta ldquoPreventing bronchocon-striction in exercise-induced asthma with inhaled heparinrdquoTheNewEngland Journal ofMedicine vol 329 no 2 pp 90ndash95 1993

[10] Z Diamant M C Timmers H Van Der Veen C P PageF J Van Der Meer and P J Sterk ldquoEffect of inhaled heparinon allergen-induced early and late asthmatic responses inpatients with atopic asthmardquo American Journal of Respiratoryand Critical Care Medicine vol 153 no 6 pp 1790ndash1795 1996

[11] M Duong D Cockcroft L-P Boulet et al ldquoThe effect ofIVX-0142 a heparin-derived hypersulfated disaccharide on theallergic airway responses in asthmardquo Allergy vol 63 no 9 pp1195ndash1201 2008

[12] A M Fal M Kraus-Filarska J Miecielica and J MalolepszyldquoMechanisms of action of nebulized low-molecular-weightheparin in patients with bronchial asthmardquo The Journal ofAllergy and Clinical Immunology vol 113 no 2 supplement pS36 2004

[13] J Jerzynska I Stelmach P Majak and P Kuna ldquoThe effectof inhaled heparin on airway responsiveness to histamine andmetacholine in asthmatic childrenrdquo Journal of Allergy andClinical Immunology vol 109 no 1 supplement 1 p S39 2002

[14] A F Kalpaklioglu Y S Demirel S Saryal and Z MisirligilldquoEffect of pretreatment with heparin on pulmonary and cuta-neous responserdquo Journal of Asthma vol 34 no 4 pp 337ndash3431997

[15] I Stelmach J Jerzynska A Brzozowska and P Kuna ldquoTheeffect of inhaled heparin on postleukotriene bronchoconstric-tion in children with asthmardquo Journal of Allergy and ClinicalImmunology vol 109 no 1 supplement 1 p S39 2002

[16] I Stelmach J Jerzynska W Stelmach et al ldquoThe effect ofinhaled heparin on airway responsiveness to histamine andleukotriene D4rdquo Allergy and Asthma Proceedings vol 24 no 1pp 59ndash65 2003

[17] Y S Ang N Mahmud B White et al ldquoRandomized compar-ison of unfractionated heparin with corticosteroids in severeactive inflammatory bowel diseaserdquo Alimentary PharmacologyandTherapeutics vol 14 no 8 pp 1015ndash1022 2000

[18] C Folwaczny B Wiebecke and K Loeschke ldquoUnfractionedheparin in the therapy of patients with highly active inflamma-tory bowel diseaserdquo The American Journal of Gastroenterologyvol 94 no 6 pp 1551ndash1555 1999

[19] J Panes M Esteve E Cabre et al ldquoComparison of heparinand steroids in the treatment of moderate and severe ulcerativecolitisrdquo Gastroenterology vol 119 no 4 pp 903ndash908 2000

[20] P Zezos G Papaioannou N Nikolaidis et al ldquoLow-molecular-weight heparin (enoxaparin) as adjuvant therapy in the treat-ment of active ulcerative colitis a randomized controlledcomparative studyrdquoAlimentary Pharmacology andTherapeuticsvol 23 no 10 pp 1443ndash1453 2006

[21] A A Vrij J M Jansen E J Schoon H C Hemker and RW Stockbrugger ldquoLow molecular weight heparin treatmentin steroid refractory ulcerative colitis clinical outcome andinfluence on mucosal capillary thrombirdquo Scandinavian Journalof Gastroenterology Supplement vol 36 no 234 pp 41ndash47 2001

[22] D M Borgioli D J Coster R F T Fan et al ldquoEffect of heparinsurface modification of polymethylmethacrylate intraocularlenses on signs of postoperative inflammation after extracap-sular cataract extraction one-year results of a double-maskedmulticenter studyrdquoOphthalmology vol 99 no 8 pp 1248ndash12551992

[23] J Colin S Roncin and M Wenzel ldquoEfficacy of heparinsurface-modified IOLs in reducing postoperative inflammatoryreactions in patients with exfoliation syndromemdasha double-blind comparative studyrdquo European Journal of Implant andRefractive Surgery vol 7 no 5 pp 266ndash270 1995

[24] Y B Ozkurt A Taskiran N Erdogan B Kandemir and OK Dogan ldquoEffect of heparin in the intraocular irrigating solu-tion on postoperative inflammation in the pediatric cataractsurgeryrdquoClinical Ophthalmology vol 3 no 1 pp 363ndash365 2009

[25] V A Vasavada M R Praveen S K Shah R H Trivedi andA R Vasavada ldquoAnti-inflammatory effect of low-molecular-weight heparin in pediatric cataract surgery a randomizedclinical trialrdquoThe American Journal of Ophthalmology vol 154no 2 pp 252ndash258 2012

[26] T Kohnen B Dick V Hessemer D D Koch and K WJacobi ldquoEffect of heparin in irrigating solution on inflammationfollowing small incision cataract surgeryrdquo Journal of Cataract ampRefractive Surgery vol 24 no 2 pp 237ndash243 1998

[27] S Ashraf Y Tian D Cowan A Entress P G Martin andK G Watterson ldquoRelease of proinflammatory cytokines dur-ing pediatric cardiopulmonary bypass heparin-bonded versusnonbonded oxygenatorsrdquo Annals of Thoracic Surgery vol 64no 6 pp 1790ndash1794 1997

[28] J-O Defraigne J Pincemail R Larbuisson F Blaffart andR Limet ldquoCytokine release and neutrophil activation are notprevented by heparin- coated circuits and aprotinin administra-tionrdquo Annals of Thoracic Surgery vol 69 no 4 pp 1084ndash10912000

[29] R de Vroege W van Oeveren J van Klarenbosch et al ldquoTheimpact of heparin-coated cardiopulmonary bypass circuits onpulmonary function and the release of inflammatory media-torsrdquo Anesthesia and Analgesia vol 98 no 6 pp 1586ndash15942004

[30] Y Misawa K Kawahito H Konishi and K Fuse ldquoCytokinemediated endothelial activation during and after normothermiccardiopulmonary bypass Heparin-bonded versus non heparin-bonded circuitsrdquo ASAIO Journal vol 46 no 6 pp 740ndash7432000

[31] A Koster T Fischer M Praus et al ldquoHemostatic activationand inflammatory response during cardiopulmonary bypassimpact of heparin managementrdquo Anesthesiology vol 97 no 4pp 837ndash841 2002

[32] C Olsson A Siegbahn A Henze et al ldquoHeparin-coatedcardiopulmonary bypass circuits reduce circulating comple-ment factors and interleukin-6 in paediatric heart surgeryrdquoScandinavian Cardiovascular Journal vol 34 no 1 pp 33ndash402000

[33] T Ozawa K Yoshihara N Koyama Y Watanabe N Shionoand Y Takanashi ldquoClinical efficacy of heparin-bonded bypasscircuits related to cytokine responses in childrenrdquo The Annalsof Thoracic Surgery vol 69 no 2 pp 584ndash590 2000

[34] A Parolari F Alamanni T Gherli et al ldquolsquoHigh dosersquo aprotininand heparin-coated circuits Clinical efficacy and inflammatoryresponserdquo Cardiovascular Surgery vol 7 no 1 pp 117ndash127 1999

[35] H Yamada I Kudoh Y Hirose M Toyoshima H Abe andK Kurahashi ldquoHeparin-coated circuits reduce the formation of

Advances in Pharmacological Sciences 13

TNF120572 during cardiopulmonary bypassrdquo Acta AnaesthesiologicaScandinavica vol 40 no 3 pp 311ndash317 1996

[36] O Barkay E Niv E Santo R Bruck A Hallak and F MKonikoff ldquoLow-dose heparin for the prevention of post-ERCPpancreatitis a randomized placebo-controlled trialrdquo SurgicalEndoscopy and Other Interventional Techniques vol 22 no 9pp 1971ndash1976 2008

[37] R C Becker K W Mahaffey H Yang et al ldquoHeparin-associated anti-Xa activity and platelet-derived prothromboticand proinflammatory biomarkers in moderate to high-riskpatients with acute coronary syndromerdquo Journal of Thrombosisand Thrombolysis vol 31 no 2 pp 146ndash153 2011

[38] S D Bowler S M Smith and P S Lavercombe ldquoHeparininhibits the immediate response to antigen in the skin and lungsof allergic subjectsrdquo American Review of Respiratory Diseasevol 147 no 1 pp 160ndash163 1993

[39] J P Boyle R H Smart and J K Shirey ldquoHeparin in thetreatment of chronic obstructive bronchopulmonary diseaserdquoThe American Journal of Cardiology vol 14 no 1 pp 25ndash281964

[40] Y Qian H Xie R Tian K Yu and R Wang ldquoEfficacy of lowmolecular weight heparin in patients with acute exacerbationof chronic obstructive pulmonary disease receiving ventilatorysupportrdquo COPD Journal of Chronic Obstructive PulmonaryDisease vol 11 no 2 pp 171ndash176 2014

[41] A Chamorro A Cervera J Castillo A Davalos J J Aponteand A M Planas ldquoUnfractionated heparin is associated with alower rise of serum vascular cell adhesion molecule-1 in acuteischemic stroke patientsrdquo Neuroscience Letters vol 328 no 3pp 229ndash232 2002

[42] R de Cock L A Ficker J G Dart A Garner and P WrightldquoTopical heparin in the treatment of ligneous conjunctivitisrdquoOphthalmology vol 102 no 11 pp 1654ndash1659 1995

[43] U Derhaschnig T Pernerstorfer M Knechtelsdorfer U Hol-lenstein S Panzer and B Jilma ldquoEvaluation of antiinflamma-tory and antiadhesive effects of heparins in human endotox-emiardquo Critical Care Medicine vol 31 no 4 pp 1108ndash1112 2003

[44] B DixonM J Schultz R Smith J B Fink J D Santamaria andD J Campbell ldquoNebulized heparin is associatedwith fewer daysof mechanical ventilation in critically ill patients a randomizedcontrolled trialrdquo Critical Care vol 14 no 5 article R180 2010

[45] F K Keating H L Dauerman D A Whitaker B E Sobeland D J Schneider ldquoThe effects of bivalirudin compared withthose of unfractionated heparin plus eptifibatide on inflam-mation and thrombin generation and activity during coronaryinterventionrdquo Coronary Artery Disease vol 16 no 6 pp 401ndash405 2005

[46] M Ledson M Gallagher C A Hart and M Walshaw ldquoNeb-ulized heparin in Burkholderia cepacia colonized adult cysticfibrosis patientsrdquo European Respiratory Journal vol 17 no 1 pp36ndash38 2001

[47] D J Serisier J K Shute P M Hockey B Higgins J Conwayand M P Carroll ldquoInhaled heparin in cystic fibrosisrdquo EuropeanRespiratory Journal vol 27 no 2 pp 354ndash358 2006

[48] O K Poyrazoglu A Dogukan M Yalniz D Seckin andA L Gunal ldquoAcute effect of standard heparin versus lowmolecular weight heparin on oxidative stress and inflammationin hemodialysis patientsrdquo Renal Failure vol 28 no 8 pp 723ndash727 2006

[49] S Suzuki T Matsuo H Kobayashi et al ldquoAntithrombotictreatment (argatroban vs heparin) in coronary angioplastyin angina pectoris effects on inflammatory hemostatic and

endothelium-derived parametersrdquoThrombosis Research vol 98no 4 pp 269ndash279 2000

[50] S D Trocme and H-I Li ldquoEffect of heparin-surface-modifiedintraocular lenses on postoperative inflammation after pha-coemulsification a randomized trial in a United States patientpopulationrdquo Ophthalmology vol 107 no 6 pp 1031ndash1037 2000

[51] C Vancheri C Mastruzzo F Armato et al ldquoIntranasal heparinreduces eosinophil recruitment after nasal allergen challenge inpatients with allergic rhinitisrdquo Journal of Allergy and ClinicalImmunology vol 108 no 5 pp 703ndash708 2001

[52] A Abdollahi M-T Naini H Shams and R Zarei ldquoEffect oflow-molecular-weight heparin on postoperative inflammationin phacomorphic glaucomardquo Archives of Iranian Medicine vol5 no 4 pp 225ndash229 2002

[53] R T S Lakshmi T Priyanka J Meenakshi K R MathangiV Jeyaraman and M Babu ldquoLow molecular weight heparinmediated regulation of nitric oxide synthase during burnwound healingrdquo Annals of Burns and Fire Disasters vol 24 no1 pp 24ndash29 2011

[54] G Montalescot C Bal-dit-Sollier D Chibedi et al ldquoCompar-ison of effects on markers of blood cell activation of enoxa-parin dalteparin and unfractionated heparin in patients withunstable angina pectoris or non-ST-segment elevation acutemyocardial infarction (the ARMADA study)rdquo The AmericanJournal of Cardiology vol 91 no 8 pp 925ndash930 2003

[55] S Nasiripour K Gholami SMousavi et al ldquoComparison of theeffects of enoxaparin and heparin on inflammatory biomarkersin patients with ST-segment elevated myocardial infarction aprospective open label pilot clinical trialrdquo Iranian Journal ofPharmaceutical Research vol 13 no 2 pp 583ndash590 2014

[56] J Oldgren C Fellenius K Boman et al ldquoInfluence of prolongeddalteparin treatment on coagulation fibrinolysis and inflam-mation in unstable coronary artery diseaserdquo Journal of InternalMedicine vol 258 no 5 pp 420ndash427 2005

[57] T K Rudolph V Rudolph A Witte et al ldquoLiberation of vesseladherent myeloperoxidase by enoxaparin improves endothelialfunctionrdquo International Journal of Cardiology vol 140 no 1 pp42ndash47 2010

[58] D L Walters M J Ray P Wood E J Perrin J H N Bettand C N Aroney ldquoHigh-dose tirofiban with enoxaparin andinflammatory markers in high-risk percutaneous interventionrdquoEuropean Journal of Clinical Investigation vol 40 no 2 pp 139ndash147 2010

[59] S W Rathbun C E Aston and T L Whitsett ldquoA randomizedtrial of dalteparin compared with ibuprofen for the treatmentof superficial thrombophlebitisrdquo Journal of Thrombosis andHaemostasis vol 10 no 5 pp 833ndash839 2012

[60] J P Titon D Auger P Grange et al ldquoTherapeutic managementof superficial venous thrombosis with calcium nadroparinDosage testing and comparison with a non-steroidal anti-inflammatory agentrdquo Annales de Cardiologie et d Angeiologievol 43 no 3 pp 160ndash166 1994

[61] H Uncu ldquoA comparison of low-molecular-weight heparin andcombined therapy of low-molecular-weight heparin with ananti-inflammatory agent in the treatment of superficial veinthrombosisrdquo Phlebology vol 24 no 2 pp 56ndash60 2009

[62] J A Sjoslashland R S Pedersen J Jespersen and J GramldquoIntraperitoneal heparin ameliorates the systemic inflamma-tory response in PD patientsrdquo NephronmdashClinical Practice vol100 no 4 pp c105ndashc110 2005

[63] N L Fine C Shim and M H Williams Jr ldquoObjectiveevaluation of heparin in the treatment of asthmardquo AmericanReview of Respiratory Disease vol 98 no 5 pp 886ndash887 1968

14 Advances in Pharmacological Sciences

[64] ZDiamantM C Timmers H van derVeen C P Page F J vander Meer and P J Sterk ldquoEffect of inhaled heparin on allergen-induced early and late asthmatic responses in patients withatopic asthmardquo American Journal of Respiratory and CriticalCare Medicine vol 153 no 6 I pp 1790ndash1795 1996

[65] C M E Tranfa A Vatrella R Parrella G Pelaia F Bariffiand S A Marsico ldquoEffect of inhaled heparin on water-inducedbronchoconstriction in allergic asthmaticsrdquoEuropean Journal ofClinical Pharmacology vol 57 no 1 pp 5ndash9 2001

[66] I Stelmach J Jerzynska A Brzozowska and P Kuna ldquoTheeffect of inhaled heparin on postleukotriene bronchoconstric-tion in children with asthmardquo Polski Merkuriusz Lekarski vol12 no 68 pp 95ndash98 2002

[67] R Polosa S Magrı C Vancheri et al ldquoTime course of changesin adenosine 51015840-monophosphate airway responsiveness withinhaled heparin in allergic asthmardquo Journal of Allergy andClinical Immunology vol 99 no 3 pp 338ndash342 1997

[68] J Butler GM Rocker and SWestaby ldquoInflammatory responseto cardiopulmonary bypassrdquo The Annals of Thoracic Surgeryvol 55 no 2 pp 552ndash559 1993

[69] J M Redmond A M Gillinov R S Stuart et al ldquoHeparin-coated bypass circuits reduce pulmonary injuryrdquoThe Annals ofThoracic Surgery vol 56 no 3 pp 474ndash479 1993

[70] S Svenmarker E Sandstrom T Karlsson et al ldquoClinical effectsof the heparin coated surface in cardiopulmonary bypassrdquoEuropean Journal of Cardio-Thoracic Surgery vol 11 no 5 pp957ndash964 1997

[71] Y J Gu W van Oeveren C Akkerman P W Boonstra RJ Huyzen and C R H Wildevuur ldquoHeparin-coated circuitsreduce the inflammatory response to cardiopulmonary bypassrdquoThe Annals of Thoracic Surgery vol 55 no 4 pp 917ndash922 1993

[72] D Paparella O O Al Radi Q H Meng T Venner K Teohand E Young ldquoThe effects of high-dose heparin on inflamma-tory and coagulation parameters following cardiopulmonarybypassrdquo Blood Coagulation and Fibrinolysis vol 16 no 5 pp323ndash328 2005

[73] S Danese A Papa S Saibeni A Repici A Malesci andM Vecchi ldquoInflammation and coagulation in inflammatorybowel disease the clot thickensrdquo The American Journal ofGastroenterology vol 102 no 1 pp 174ndash186 2007

[74] S Bloom S Kiilerich M R Lassen et al ldquoLow molecularweight heparin (tinzaparin) vs placebo in the treatment of mildto moderately active ulcerative colitisrdquo Alimentary Pharmacol-ogy ampTherapeutics vol 19 no 8 pp 871ndash878 2004

[75] P Libby ldquoCoronary artery injury and the biology of atheroscle-rosis inflammation thrombosis and stabilizationrdquo AmericanJournal of Cardiology vol 86 no 8 2000

[76] N T Mulvihill and J B Foley ldquoInflammation in acute coronarysyndromesrdquo Heart vol 87 no 3 pp 201ndash204 2002

[77] N A JamesonW V Good and C S Hoyt ldquoInflammation aftercataract surgery in childrenrdquoOphthalmic Surgery vol 23 no 2pp 99ndash102 1992

[78] R M Sinskey P A Amin and R Lingua ldquoCataract extractionand intraocular lens implantation in an infant with amonocularcongenital cataractrdquo Journal of Cataract amp Refractive Surgeryvol 20 no 6 pp 647ndash651 1994

[79] A van Ophoven A Heinecke and L Hertle ldquoSafety andefficacy of concurrent application of oral pentosan polysulfateand subcutaneous low-dose heparin for patients with interstitialcystitisrdquo Urology vol 66 no 4 pp 707ndash711 2005

Submit your manuscripts athttpwwwhindawicom

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ToxinsJournal of

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Page 6: Review Article Anti-Inflammatory Effects of Heparin and Its …downloads.hindawi.com/journals/aps/2015/507151.pdf · 2019. 7. 31. · Review Article Anti-Inflammatory Effects of Heparin

6 Advances in Pharmacological Sciences

Table2Summaryandfin

ding

sofo

ther

studied

diseases

Clinicalsetting

Heparin

preparation

Mod

eof

administratio

nCom

parator

Num

bero

fpatie

nts

Clinicalou

tcom

eLabo

ratory

outcom

eStud

ydesig

n

Pancreatitisa

fter

ERCP

[36]

UFH

SCSalin

esolution

105(54in

control

grou

p)

Rateof

posto

perativ

epancreatitisw

asno

tsig

nificantb

etweenbo

thgrou

ps

mdashRa

ndom

ized

placebo-controlledclinical

trial

Acutec

oron

ary

synd

rome(AC

S)[37]

UFH

SCEn

oxaparin

201

mdashNosig

nificantd

ifference

betweenCD

4ligandand

PAI-1inbo

thgrou

ps

Openlabelrand

omized

clinicaltria

l

Skin

orpu

lmon

ary

allergy[38]

UFH

IVnebulizer

Normalsalin

eplacebo

25Sign

ificant

inhibitio

nof

mastcell-m

ediatedallergic

inflammation(119875004)

mdashDou

ble-blind

placebo-controlled

crossoverc

linicaltrial

COPD

[39]

UFH

IVmdash

37(18in

control

grou

p)

Sign

ificant

improvem

entin

bron

chospasm

and

bron

chialsecretio

ns(58

respon

serate)

mdashRa

ndom

ized

placebo-controlledclinical

trial

COPD

[40]

Nadroparin

SCCon

ventionaltreatment

66(33in

each

grou

p)

Decreaseo

fdurationof

mechanicalventilationand

leng

thof

hospita

land

ICU

stay(119875lt001)

Sign

ificant

decrease

inlevelsof

CRPIL-6and

fibrin

ogen

Rand

omized

controlled

trial

Ischem

icstroke

[41]

UFH

IVAs

pirin

167(97in

control

grou

p)

Early

onsetinitia

tionof

heparin

might

improve

recovery

after

stroke

Rise

ofsV

CAM-1at48

hwas

significantly

lower

inpatie

ntstreated

with

UFH

(119875lt001)

Quasi-experim

ental

(con

trolledob

servational

study)

Lign

eous

conjun

ctivitis[42]

UFH

Topical

Alpha

chym

otrypsin

orste

roid

17(12in

control

grou

p)

Intensivea

ndearly

useo

ftopicalh

eparin

may

improvetherapy

results

indisease

mdashQuasi-experim

ental

(non

rand

omized

Clinical

trial)

Endo

toxemia

(indu

cedby

lipop

olysaccharide

inhealthysubjects)

[43]

UFH

IVLM

WHor

placebo

30(10in

each

grou

p)mdash

Noeffecto

nTN

F-120572IL-6

and8CR

PandE-selectin

Rand

omized

doub

le-blin

ded

placebo-controlledparallel

grou

ptrial

Mechanical

ventilatio

n[44]

UFH

Nebulizer

Normalsalin

e(placebo)

50(25in

each

grou

p)

Fewer

days

onmechanical

ventilatio

nbette

rPao2Fio2ratio

mdashDou

ble-blindrand

omized

placebo-controlledtrial

Percutaneous

coronary

interventio

n[45]

Bivalirud

inIV

UFH

+eptifi

batid

e63

(29in

control

grou

p)mdash

Increase

inIL-6

andCR

Paft

er1d

ayD

ecreaseinCR

Pin

bivalirud

ingrou

paft

er30

days

(1198750002)

Rand

omized

controlled

trial

Cysticfib

rosis

(adu

lts)[46

]UFH

Inhaler

mdash12

(6in

control

grou

p)Spiro

metry

parametersd

idno

tchang

eIL-6

redu

cedaft

ertre

atment

Quasi-experim

ental

(pretest-

posttestd

esign)

Advances in Pharmacological Sciences 7Ta

ble2Con

tinued

Clinicalsetting

Heparin

preparation

Mod

eof

administratio

nCom

parator

Num

bero

fpatie

nts

Clinicalou

tcom

eLabo

ratory

outcom

eStud

ydesig

n

Cysticfib

rosis

(adu

lts)[47]

UFH

Inhaler

Placebo

14Noeffecto

nFE

V1

Noeffecto

nsputum

inflammatorymarkers

Rand

omizeddou

ble-blind

placebo-controlled

crossovertria

l

Hem

odialysis

patie

nts[48]

UFH

IVSC

LMWHandno

drug

33

LMWHdecreased

oxidatives

tressand

inflammationwhereas

heparin

increasedthem

CRPTN

F-120572sup

eroxide

dism

utaseMDAincreased

inheparin

grou

pbu

tcomparabletoLM

WH

grou

p

Quasi-experim

ental

(pretest-

posttestd

esign)

Stableangina

[49]

Heparin

+Aspirin

(119899=15)

mdashArgatroban+As

pirin

(119899=12)2

7

Nodifferencein

inflammatoryrespon

seaft

erangiop

lasty

Fibrinogen

decreased

significantly

inargatro

ban

grou

pNodifferenceinvon

Willberand

factor

between

both

grou

psPAI-1

increasedin

argatro

ban

grou

p

Rand

omized

controlled

trial

Phacoemulsifi

catio

n[50]

Heparin

Coatedlenses

Polymethylm

ethacrylate

lenses

367

Heparin

coated

lenses

redu

cedsig

nificantly

inflammationearly

posto

peratio

n(119875005)

mdashRa

ndom

izeddou

ble-blind

multic

enterparallelgroup

trial

Allergicrhinitis[51]

UFH

Intranasal

mdash10

mdashRe

ductionof

eosin

ophil

catio

nicp

rotein

inthen

asal

wash

Quasi-experim

ental

(pretest-

posttestd

esign)

Phacom

orph

icglaucoma[

52]

Dalteparin

Irrig

ation

Balanced

saltsolutio

n46

(23in

each

grou

p)

Sign

ificant

decrease

ofpo

stoperativ

einfl

ammation

indalteparin

grou

pmdash

Rand

omizeddou

ble-blind

clinicaltria

l

Burn

[53]

Dalteparin

SCNotre

atment

24mdash

Decreaseo

fnitricoxide

synthetase

activ

itysig

nificantly

Quasi-experim

ental

(non

rand

omized

clinical

trial)

Unstablec

oron

ary

artery

disease[54]

Enoxaparin

(119899=46)

Dalteparin

(119899=48)

SCUFH

(119899=47)

68

VonWillberand

factor

may

have

progno

sticv

aluebut

otherb

iologicalvariables

didno

tpredictou

tcom

e

CRPfib

rinogenV

onWillberand

factor

increased

over

first2days

despite

medicaltre

atment

Enoxaparin

(13

)and

dalteparin

(19)reduced

releaseo

fVon

Willberand

factor

Openlabelrand

omized

clinicaltria

l

ST-Elevated

Myocardial

Infarctio

n(STE

MI)

[55]

Enoxaparin

SCUFH

34(17in

each

grou

p)

Both

heparin

and

enoxaparin

show

anti-inflammatoryeffects

inST

EMIp

atients

Serum

AmyloidA(119875002)

CRP(119875002)and

ferritin

(119875001)redu

cedin

heparin

grou

pIL-6

(1198750002)SA

A(1198750009)CR

P(119875001)

weres

ignificantly

decreased

inenoxaparin

grou

pTh

eoveralld

ifference

between

grou

pswas

notsignificant

Openlabelrand

omized

clinicaltria

l

8 Advances in Pharmacological Sciences

Table2Con

tinued

Clinicalsetting

Heparin

preparation

Mod

eof

administratio

nCom

parator

Num

bero

fpatie

nts

Clinicalou

tcom

eLabo

ratory

outcom

eStud

ydesig

n

Coron

aryartery

disease[56]

Dalteparin

SCPlacebo

555(285

incontrolgroup

)

Dalteparin

redu

ced

coagulationandso

MyocardialInfarctionbu

thasn

otinflammatory

activ

ity

Noeffectson

IL-6

C-reactiv

eprotein

and

fibrin

ogen

Rand

omizeddou

ble-blind

parallel-g

roup

multic

entre

trial

Stablecoronary

artery

disease[57]

Enoxaparin

SCSo

dium

chlorid

e62

(31ineach

grou

p)

Bymob

ilizing

vesselbo

und

MPO

eno

xaparin

improves

endo

thelialfun

ction

Sign

ificant

increase

ofMPO

levels

Rand

omizeddou

ble-blind

placebo-controlledtrial

Acutec

oron

ary

synd

romea

ndPC

I[58]

Tirofib

an(highdo

se)+

enoxaparin

Tirofib

an(highdo

se)+

UFH

60(30in

each

grou

p)

Thec

ombinatio

nof

tirofi

ban(highdo

se)+

enoxaparin

redu

ced

inflammationaft

erPC

I

Vonwillberand

CRP

D-dim

erand

prothrom

bin

fragmentw

eres

ignificantly

lower

inenoxaparin

grou

pthan

UFH

Openlabelrando

mized

controlledtrial

Superficialveno

usthrombo

phleb

itis

[59]

Dalteparin

SCIbup

rofen

72(37in

dalteparin

grou

p)

Sign

ificant

redu

ctionof

pain

form

baselin

etoday14

offollo

w-upNodifference

onthrombo

sisprogression

after

3mon

ths

mdashRa

ndom

izeddou

ble-blind

controlledtrial

Superficialveno

usthrombo

sis[60]

Nadroparin

SCNaproxen

117(39in

control

grou

p)

Nadroparin

redu

ced

symptom

andsig

nsof

thrombo

sedsuperficial

vein

bette

rthannaproxen

(1198750007)

mdashRa

ndom

izedopenlabel

clinicaltria

l

Superficialveno

usthrombo

sis[61]

Nadroparin

SCNadroparin

+acem

etacin

50

Sign

ificant

symptom

improvem

entinbo

thgrou

ps(1198750001)Th

ecombinatio

ngrou

pwas

bette

r

mdashRa

ndom

ized

controlled

trial

Periton

eald

ialysis

patie

nts[62]

Tinzaparin

Intraperito

neal

Isoton

icsalin

e21

Redu

ctionof

localand

syste

micinflammationin

periton

eald

ialysis

patie

nts

Redu

cedlevelsof

CRP(119875

0032)

andfib

rinogen

(119875

004

2)andIL-6

(1198750007)

indialysate

Rand

omizeddou

ble-blind

placebo-controlled

crossovertria

l

COPD

Chron

icObstructiv

ePu

lmon

aryDise

aseCR

PC-

Reactiv

eProtein

CPB

Cardio

Pulm

onaryBy

passE

CPE

osinop

hilC

ationicProtein

ERCP

End

oscopicRe

trogradeCh

olangiop

ancreatographyE

SR

ErythrocyteSedimentatio

nICUIntensiv

eCa

reUnitILinterleuk

inIV

intravenou

sLM

WHlow

molecular

weighth

eparinM

DAm

alon

dialdehydePAIPlasminogen

Activ

ator

InhibitorSC

sub

cutaneou

ssV

CAMSolub

leVa

scular

CellA

dhesionMoleculeTN

FTu

mor

Necrosis

Factorand

UFH

unfractionatedheparin

Advances in Pharmacological Sciences 9

Table 3 Summary of numbers and percentages of adequatelyreported items in each trial according to CONSORT checklist andJadad score

Trials Jadadscore

Adequately reporteditems (119899119873)

Percentage()

Abdollahi et al [52] 4 2974 392Ahmed et al [9] 3 2074 27Ang et al [17] 2 2474 324Ashraf et al [27] 2 2274 297Becker et al [37] 3 2874 378de Vroege et al [29] 3 2674 351Defraigne et al [28] 4 2874 378Derhaschnig et al [43] 3 3274 432Dixon et al [44] 4 5074 675Duong et al [11] 3 3074 405Gu et al [71] 2 1674 216Jerzynska et al [13] 3 2074 27Keating et al [45] 2 2174 284Koster et al [31] 2 2674 351Montalescot et al [54] 3 3574 473Nasiripour et al [55] 2 3474 46Oldgren et al [56] 3 2774 365Olsson et al [32] 2 2574 338van Ophoven et al [79] 2 2774 365Ozawa et al [33] 2 2774 365Ozkurt et al [24] 3 1874 243Paparella et al [72] 2 2274 297Polosa et al [67] 3 2374 311Rathbun et al [59] 5 4474 595Rudolph et al [57] 3 3174 412Serisier et al [47] 5 4574 608Stelmach et al [16] 3 3174 412Suzuki et al [49] 2 2374 31Vancheri et al [51] 4 2274 297Vasavada et al [25] 5 5274 702Walters et al [58] 3 3274 432Zezos et al [20] 3 3774 50

thrombophlebitis and hemodialysis Unfractionated heparin(UFH) was used in forty studies as subcutaneous intra-venous inhaler or heparin-coated circuits while others usedenoxaparin (119899 = 3) dalteparin (119899 = 4) nadroparin (119899 = 4)and tinzaparin (119899 = 1)

Table 3 provides information on the adequately reporteditems according to Jadad score andCONSORT items Amongthese 32 papers 11 (354) scored 2 and the remaining studiesscored 3 or higher according to Jadad score and just threestudies fulfill the criteria of Jadad score Calculated qualityscores according to CONSORT checklist range from 21 to70 in our object studies with twelve studies scoring greaterthan 40 The following characteristics were not exactlyreported in more than half of the trials identification as

a randomized trial in the title information about the settingand location of studies determination of sample size alloca-tion and implementation of randomization participant flowrecruitment and follow-up subgroup analysis limitations ofstudy harms registration number access to full trial protocoland funding source

4 Discussion

We discuss evidence from clinical studies supporting an anti-inflammatory role for heparin and heparin-related deriva-tives

41 Asthma Asthma is a chronic inflammatory disorderof airways characterized by bronchial hyperresponsivenessresulting in episodic bronchospasm Several studies in 1960sdescribed subjective improvement of symptoms in asthmaticpatients using intravenous heparin for the first time [3963] Inhaled heparin or its derivatives have been shown topossess antiasthmatic properties in various clinical modelsallergen induced [38 64] exercise [9] adenosine [6] anddistilled water challenge models [65] Seven randomizedcontrolled crossover trials studied anti-inflammatory effectsof heparin in exercise-induced or allergen-induced asthmahaving sample size range from 8 to 25 in 5 trials

Heparin inhalation reduced bronchial hyperreactivity ina single-blind randomized crossover trial (119899 = 12) byAhmed et al [9] Heparin inhalation (1000 120583kg) preventsexercise-induced asthma (119875 lt 005) without preventionof histamine-induced bronchoconstriction Stelmach et al[66] provoke challenge tests with histamine or leukotrieneD4 before and after inhalation of heparin showed that hep-arin (5000 Iu) decreases histamine and leukotriene-inducedbronchial hyperreactivity compared to placebo significantly(119875 0043 and 0005) but changes in Forced Expiratory Vol-ume (FEV 1) were not significant (119875 0064) The inhibitoryeffects of inhaled heparin in the airways in the absence ofbronchodilation might be related to suppressive action onmast cell degranulation A randomized double-blind studyin 10 subjects with asthma showed that heparin inhalationattenuates airway response to adenosine 51015840-monophosphate(AMP) but not to methacholine (119875 lt 001) suggestingthe theory that heparin acts more likely in association tomodulation of mediator release compared to a direct effecton smooth muscle [67]

Our results showed that inhaled enoxaparin was usedjust in a pre-post study of 24 asthmatic patients measur-ing inflammatory biomarkers and showed a reduction ineosinophil (119875 0006) and lymphocytes of bronchoalveolarlavage without any significant change in IL-5 or EosinophilCationic Protein (ECP) concentrations [12] Therefore itseems that enoxaparin could be a valuable add on treatmentin asthma like UFH Duong et al [11] evaluated IVX-0142nebulizer a heparin-derived hypersulfated disaccharide inasthma and showed nonsignificant decrease in early and lateasthmatic response

Performed studies did not show any adverse events orharms with heparin or related compounds except increase in

10 Advances in Pharmacological Sciences

the plasma partial thromboplastin time reported by Ahmedet al [9]

All in one considering the results of these studies wecan conclude that heparin and its derivatives could have anti-inflammatory effects and could be considered along withother treatments in asthma

42 Cardiopulmonary Bypass Contact and interaction ofblood with foreign surfaces during cardiopulmonary bypass(CPB) cause systemic inflammatory response syndrome(SIRS) through activation of several humoral cascadesincluding cytokines such as IL-6 IL-8 and Tumor NecrosisFactor-120572 (TNF-120572) [68] The inflammatory response can beattenuated by promoting the biocompatibility of the CPBcircuit Use of heparin-treated surfaces in CPB circuits hasbeen shown to decrease activation of leukocytes and thecomplement cascades [5] As a result need to inotropicsupport postoperative time of mechanical ventilation andrate of acute lung injury decrease and patients durationof hospital stay shortens which reflects the positive effectof heparin in CPB circuits [69 70] Twelve studies whoseendpoints were the effects of heparin-bonded circuits oninflammatory markers were included in our analysis and inthe majority of these trials [27 29 32ndash35 71] heparin-coatedcircuit significantly decreased the level of cytokines such asIL-6 IL-8 TNF-120572 complement complex neutrophils andelastase compared to non-heparin-coated circuit

Defraigne et al [28] randomized 200 patients in 4 groupsheparin-coated circuit with or without aprotinin administra-tion and uncoated circuit with or without aprotinin adminis-tration They measured IL-6 IL-8 TNF-120572 myeloperoxidase(MPO) and elastase level and concluded that cytokine releaseand neutrophil activation were not attenuated by heparin-coated circuit or by the administration of aprotinin Misawaet al [30] evaluated cytokines level under normothermicCPB in a small observational controlled study (119899 = 19 9 incontrol group) Levels of IL-6 IL-8 and ICAM-1 (indicatorof endothelial damage) were not different between study andcontrol group However as mentioned before most studiesindicate the favorable effect of heparin-coated circuit oninflammatory responses in CPB

Paparella et al [72] compared two doses of heparin and300 Iukg and 600 Iukg in 40 patients undergoing CPB in anRCT and showed that IL-6 and TNF-120572 plasma levels were inassociation to heparin dose It seems that lower heparin dosehad small influence on proinflammatory cytokines releasehowever higher doses make a better regulatory effect oncoagulation system

The side effects of heparin-coated circuits were notreported In these studies just a number of included studiesreported a decrease in platelet levels in both groups (coatedand noncoated circuit) No major events including hemor-rhage were reported

43 Inflammatory Bowel Diseases (IBD) Hypercoagulablestate may be an important contributing factor in the patho-genesis of IBD especially ulcerative colitis (UC) [73] A num-ber of studies evaluate the effects of heparin administrationon UC but the results obtained are controversial [17 19]

Bloom et al [74] did not find any favorable effect of LMWHtinzaparin over placebo in the treatment of active UC ina double-blind randomized placebo controlled multicentertrial (119899 = 100) evaluating mean change in colitis activity asthe primary endpoint Ang et al [17] compared heparin tohydrocortisone plus prednisolone in 20 patients (UC 119899 = 17Crohnrsquos colitis 119899 = 3) in open-label randomized crossovertrial whichmeasured endpoints clinical disease activity stoolfrequency and 120572

1acid glycoprotein and endoscopic and

histopathological grading indicate the efficacy and safety ofheparin compared to corticosteroids (119875 gt 005) in contrastthe study by Panes et al [19] did not show the efficacy ofheparin in UC compared to methylprednisolone

Zezos et al [20] compared enoxaparin with standardtreatment (aminosalicylate + corticosteroids) in 34 patientswith active UC The inflammatory biomarkers includingC-Reactive Protein (CRP) Erythrocyte Sedimentation Rate(ESR) and fibrinogen did not show any difference in studygroup compared to control and both groups showed similarrate of disease improvement (119875 gt 005) furthermorecoagulation factors did not change from one to anotherAuthors concluded that enoxaparin is a safe adjuvant but hasno additive benefit over standard treatment of UC

Generally the studies show conflicting results The hep-arin and LMWHs showed efficacy in regard of disease activityand also well tolerated but inflammatory markers did notchange significantly Therefore the improvement in diseaseactivity might be the result of heparinrsquos anticoagulant effects

44 Acute Coronary Syndrome (ACS) Inflammation has akey role in the pathogenesis of coronary artery plaquedestabilization and rupture leading to acute coronary syn-dromes (ACS) [75] Leukocyte activation monocyte andneutrophil infiltration result in local and systemic inflam-matory responses [76] Heparin and LMWHs are commonlyused in ACS to prevent clot formation they also seem tohave desirable effects on inflammatory markers level basedon sparse data

We found 8 studies about heparin and LMWHs in CADsevaluating anti-inflammatory effects as their endpoints Old-gren et al [56] found that dalteparin administration inpatients with unstable CAD (119899 = 555) did not affect IL-6C-Reactive Protein (CRP) and fibrinogen levels although itreduced coagulation activity and mortality rate in long termso it is concluded that these effects are not related to its anti-inflammatory properties Walters et al [58] compared highdose of tirofibanenoxaparin (119899 = 30) with tirofibanheparin(119899 = 30) in an open-label randomized controlled trial in highrisk percutaneous interventionThey found that combinationof high dose of tirofiban with enoxaparin significantly atten-uate inflammatory process (decreased levels of CRP and vonWillebrand factor) compared to tirofiban and heparin

The ARMADA study [54] evaluated anti-inflammatoryeffects of heparin and enoxaparin in Non-ST-ElevatedMyocardial Infarction (Non-STEMI) and reported thatinflammatory markers (CRP and von Willebrand factor)are affected more by LMWH compared to UFH Howeverbecause of the small sample size of the study (119899 = 68)

Advances in Pharmacological Sciences 11

it did not acquire sufficient statistical power to prove anyeffects on defined outcomes Nasiripour et al [55] found thatboth enoxaparin and heparin reduce inflammatory markersin STEMI patients at the same level however this study hadthe same limitations of sample size (119899 = 34) and power too

In summary considering heparins as the main stay treat-ment of ACS its effects are more pronounced as anticoagu-lating than as an anti-inflammatory agent in this pathologicalcondition

45 Cataract Surgery Postoperative inflammation isobserved in cataract surgery especially in children Newertechniques as lensectomy and phacoemulsification cause lesscomplication but still pose potential risks [77 78] It hasbeen suggested that a heparin surface-modified intraocularlens (IOL) or augmenting the irrigating solution withheparin during cataract surgery may reduce the incidence ofpostoperative inflammation Borgioli et al [22] confirm thishypothesis that heparin surface-modified IOL will reducethe inflammatory response compared to conventional IOLat least in short term period (3 months) in a large (524patients) double-blind multicenter trial A similar study byColin et al [23] (119899 = 58) confirms their results howeverthe power of Borgioli et al study was higher Heparinizedlenses showed also more anti-inflammatory effects duringlong term follow-up (1 year) Heparinized irrigating solutionwas used during cataract surgery in two different studies andinflammation decrease observed in the early postoperativeperiod of both studies (Kohnen et al [26] and Ozkurt et al[24]) Therefore it seems that heparin in both forms haveanti-inflammatory effects in cataract surgery

Vasavada et al [25] used enoxaparin irrigation solutionin 20 children undergoing bilateral cataract surgery butthey did not find any beneficial effect in early postoperativeinflammation This study acquired the highest quality in thestudy quality assessment process based on Jadad score andCONSORT items (5274 702) It is worth noticing that themajority of itemsmentioned in the CONSORT checklist wereadequately reported and covered in this paper

Potential mechanisms of anti-inflammatory effects ofheparin have been discussed completely in a review by Young[6] Binding of heparin to different mediators involved inthe immune system response (cytokines and chemokines)acute phase proteins and complement complex proteinsmay contribute to the anti-inflammatory activity of heparinNeutralizing of cytokines at the inflammation site is anotherpossible mechanism In most of the studies level of cytokinessuch as IL-6 IL-8 TNF-120572 and CRP was decreased afterheparin administration which can confirm this mechanismalso heparin and LMWHs inhibit adhesion of leukocytesand neutrophils to endothelial cells by binding to p-selectinand consequently prevent release of oxygen radicals andproteolytic enzymes Other possible mechanisms are as fol-lows inhibition of nuclear factor 120581B (NF-120581B) and inductionof apoptosis by modulation of activity of TNF-120572 and NF-120581B In a double-blind placebo-controlled trial (119899 = 62)in patients with stable coronary artery disease followingadministration of 1mgkg subcutaneous enoxaparin plasmalevels of myeloperoxidase (MPO) increased significantly

(119875 lt 0001) and subsequently endothelial function improved(119903 = 067 119875 lt 0001) through MPO binding to endotheliumand depleting vascular nitric oxide [57] This study confirmsanother possible mechanism of heparins anti-inflammatoryeffects

5 Conclusion

As we discussed heparins potential effects as anti-inflamma-tory agents supported by several clinical trials in varioussetting Heparin and its related derivatives have been shownto benefit patients with asthma and patients undergoingcardiopulmonary bypass and cataract surgery In otherinflammatory diseases such as IBD (ulcerative colitis) thestudies are heterogeneous and incongruent Most studies didnot report any unwanted event with heparins when they usedthem as anti-inflammatory agents whether through systemicor through local (as inhaler or irrigation or heparin-coatedcircuit) administration However because the majority ofthese trials did not pose optimal quality scores we cannotdraw a definite conclusion on the efficacy of heparin and itsderivatives as anti-inflammatory agents

The present review included studies which measuredinflammatory markers as their endpoints and in most ofthem these markers were decreased though not significantlyTo come to a definite conclusion further double-blindrandomized placebo-controlled clinical trials with a largersample size are needed However because the inflammationatherogenesis thrombogenesis and cell proliferation areassociated with each other the pleiotropic effects of heparinand related compounds may have greater therapeutic effectthan compounds that are directed against a single target

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

[1] B Casu ldquoHeparin structurerdquo Pathophysiology of Haemostasisand Thrombosis vol 20 supplement 1 pp 62ndash73 1990

[2] J Hirsh R Raschke T EWarkentin J E Dalen DDeykin andL Poller ldquoHeparin mechanism of action pharmacokineticsdosing considerations monitoring efficacy and safetyrdquo Chestvol 108 no 4 supplement pp 258Sndash275S 1995

[3] J Fareed D A Hoppensteadt and R L Bick ldquoAn update onheparins at the beginning of the new millenniumrdquo Seminars inThrombosis and Hemostasis vol 26 no 3 pp 5ndash21 2000

[4] J Hirsh ldquoDrug therapy heparinrdquo The New England Journal ofMedicine vol 324 no 22 pp 1565ndash1574 1991

[5] R J Ludwig ldquoTherapeutic use of heparin beyond anticoagu-lationrdquo Current Drug Discovery Technologies vol 6 no 4 pp281ndash289 2009

[6] E Young ldquoThe anti-inflammatory effects of heparin and relatedcompoundsrdquo Thrombosis Research vol 122 no 6 pp 743ndash7522008

12 Advances in Pharmacological Sciences

[7] A R Jadad R A Moore D Carroll et al ldquoAssessing the qualityof reports of randomized clinical trials is blinding necessaryrdquoControlled Clinical Trials vol 17 no 1 pp 1ndash12 1996

[8] K F Schulz D G Altman and D Moher ldquoCONSORT 2010statement updated guidelines for reporting parallel grouprandomised trialsrdquo International Journal of Surgery vol 9 no8 pp 672ndash677 2011

[9] T Ahmed J Garrigo and I Danta ldquoPreventing bronchocon-striction in exercise-induced asthma with inhaled heparinrdquoTheNewEngland Journal ofMedicine vol 329 no 2 pp 90ndash95 1993

[10] Z Diamant M C Timmers H Van Der Veen C P PageF J Van Der Meer and P J Sterk ldquoEffect of inhaled heparinon allergen-induced early and late asthmatic responses inpatients with atopic asthmardquo American Journal of Respiratoryand Critical Care Medicine vol 153 no 6 pp 1790ndash1795 1996

[11] M Duong D Cockcroft L-P Boulet et al ldquoThe effect ofIVX-0142 a heparin-derived hypersulfated disaccharide on theallergic airway responses in asthmardquo Allergy vol 63 no 9 pp1195ndash1201 2008

[12] A M Fal M Kraus-Filarska J Miecielica and J MalolepszyldquoMechanisms of action of nebulized low-molecular-weightheparin in patients with bronchial asthmardquo The Journal ofAllergy and Clinical Immunology vol 113 no 2 supplement pS36 2004

[13] J Jerzynska I Stelmach P Majak and P Kuna ldquoThe effectof inhaled heparin on airway responsiveness to histamine andmetacholine in asthmatic childrenrdquo Journal of Allergy andClinical Immunology vol 109 no 1 supplement 1 p S39 2002

[14] A F Kalpaklioglu Y S Demirel S Saryal and Z MisirligilldquoEffect of pretreatment with heparin on pulmonary and cuta-neous responserdquo Journal of Asthma vol 34 no 4 pp 337ndash3431997

[15] I Stelmach J Jerzynska A Brzozowska and P Kuna ldquoTheeffect of inhaled heparin on postleukotriene bronchoconstric-tion in children with asthmardquo Journal of Allergy and ClinicalImmunology vol 109 no 1 supplement 1 p S39 2002

[16] I Stelmach J Jerzynska W Stelmach et al ldquoThe effect ofinhaled heparin on airway responsiveness to histamine andleukotriene D4rdquo Allergy and Asthma Proceedings vol 24 no 1pp 59ndash65 2003

[17] Y S Ang N Mahmud B White et al ldquoRandomized compar-ison of unfractionated heparin with corticosteroids in severeactive inflammatory bowel diseaserdquo Alimentary PharmacologyandTherapeutics vol 14 no 8 pp 1015ndash1022 2000

[18] C Folwaczny B Wiebecke and K Loeschke ldquoUnfractionedheparin in the therapy of patients with highly active inflamma-tory bowel diseaserdquo The American Journal of Gastroenterologyvol 94 no 6 pp 1551ndash1555 1999

[19] J Panes M Esteve E Cabre et al ldquoComparison of heparinand steroids in the treatment of moderate and severe ulcerativecolitisrdquo Gastroenterology vol 119 no 4 pp 903ndash908 2000

[20] P Zezos G Papaioannou N Nikolaidis et al ldquoLow-molecular-weight heparin (enoxaparin) as adjuvant therapy in the treat-ment of active ulcerative colitis a randomized controlledcomparative studyrdquoAlimentary Pharmacology andTherapeuticsvol 23 no 10 pp 1443ndash1453 2006

[21] A A Vrij J M Jansen E J Schoon H C Hemker and RW Stockbrugger ldquoLow molecular weight heparin treatmentin steroid refractory ulcerative colitis clinical outcome andinfluence on mucosal capillary thrombirdquo Scandinavian Journalof Gastroenterology Supplement vol 36 no 234 pp 41ndash47 2001

[22] D M Borgioli D J Coster R F T Fan et al ldquoEffect of heparinsurface modification of polymethylmethacrylate intraocularlenses on signs of postoperative inflammation after extracap-sular cataract extraction one-year results of a double-maskedmulticenter studyrdquoOphthalmology vol 99 no 8 pp 1248ndash12551992

[23] J Colin S Roncin and M Wenzel ldquoEfficacy of heparinsurface-modified IOLs in reducing postoperative inflammatoryreactions in patients with exfoliation syndromemdasha double-blind comparative studyrdquo European Journal of Implant andRefractive Surgery vol 7 no 5 pp 266ndash270 1995

[24] Y B Ozkurt A Taskiran N Erdogan B Kandemir and OK Dogan ldquoEffect of heparin in the intraocular irrigating solu-tion on postoperative inflammation in the pediatric cataractsurgeryrdquoClinical Ophthalmology vol 3 no 1 pp 363ndash365 2009

[25] V A Vasavada M R Praveen S K Shah R H Trivedi andA R Vasavada ldquoAnti-inflammatory effect of low-molecular-weight heparin in pediatric cataract surgery a randomizedclinical trialrdquoThe American Journal of Ophthalmology vol 154no 2 pp 252ndash258 2012

[26] T Kohnen B Dick V Hessemer D D Koch and K WJacobi ldquoEffect of heparin in irrigating solution on inflammationfollowing small incision cataract surgeryrdquo Journal of Cataract ampRefractive Surgery vol 24 no 2 pp 237ndash243 1998

[27] S Ashraf Y Tian D Cowan A Entress P G Martin andK G Watterson ldquoRelease of proinflammatory cytokines dur-ing pediatric cardiopulmonary bypass heparin-bonded versusnonbonded oxygenatorsrdquo Annals of Thoracic Surgery vol 64no 6 pp 1790ndash1794 1997

[28] J-O Defraigne J Pincemail R Larbuisson F Blaffart andR Limet ldquoCytokine release and neutrophil activation are notprevented by heparin- coated circuits and aprotinin administra-tionrdquo Annals of Thoracic Surgery vol 69 no 4 pp 1084ndash10912000

[29] R de Vroege W van Oeveren J van Klarenbosch et al ldquoTheimpact of heparin-coated cardiopulmonary bypass circuits onpulmonary function and the release of inflammatory media-torsrdquo Anesthesia and Analgesia vol 98 no 6 pp 1586ndash15942004

[30] Y Misawa K Kawahito H Konishi and K Fuse ldquoCytokinemediated endothelial activation during and after normothermiccardiopulmonary bypass Heparin-bonded versus non heparin-bonded circuitsrdquo ASAIO Journal vol 46 no 6 pp 740ndash7432000

[31] A Koster T Fischer M Praus et al ldquoHemostatic activationand inflammatory response during cardiopulmonary bypassimpact of heparin managementrdquo Anesthesiology vol 97 no 4pp 837ndash841 2002

[32] C Olsson A Siegbahn A Henze et al ldquoHeparin-coatedcardiopulmonary bypass circuits reduce circulating comple-ment factors and interleukin-6 in paediatric heart surgeryrdquoScandinavian Cardiovascular Journal vol 34 no 1 pp 33ndash402000

[33] T Ozawa K Yoshihara N Koyama Y Watanabe N Shionoand Y Takanashi ldquoClinical efficacy of heparin-bonded bypasscircuits related to cytokine responses in childrenrdquo The Annalsof Thoracic Surgery vol 69 no 2 pp 584ndash590 2000

[34] A Parolari F Alamanni T Gherli et al ldquolsquoHigh dosersquo aprotininand heparin-coated circuits Clinical efficacy and inflammatoryresponserdquo Cardiovascular Surgery vol 7 no 1 pp 117ndash127 1999

[35] H Yamada I Kudoh Y Hirose M Toyoshima H Abe andK Kurahashi ldquoHeparin-coated circuits reduce the formation of

Advances in Pharmacological Sciences 13

TNF120572 during cardiopulmonary bypassrdquo Acta AnaesthesiologicaScandinavica vol 40 no 3 pp 311ndash317 1996

[36] O Barkay E Niv E Santo R Bruck A Hallak and F MKonikoff ldquoLow-dose heparin for the prevention of post-ERCPpancreatitis a randomized placebo-controlled trialrdquo SurgicalEndoscopy and Other Interventional Techniques vol 22 no 9pp 1971ndash1976 2008

[37] R C Becker K W Mahaffey H Yang et al ldquoHeparin-associated anti-Xa activity and platelet-derived prothromboticand proinflammatory biomarkers in moderate to high-riskpatients with acute coronary syndromerdquo Journal of Thrombosisand Thrombolysis vol 31 no 2 pp 146ndash153 2011

[38] S D Bowler S M Smith and P S Lavercombe ldquoHeparininhibits the immediate response to antigen in the skin and lungsof allergic subjectsrdquo American Review of Respiratory Diseasevol 147 no 1 pp 160ndash163 1993

[39] J P Boyle R H Smart and J K Shirey ldquoHeparin in thetreatment of chronic obstructive bronchopulmonary diseaserdquoThe American Journal of Cardiology vol 14 no 1 pp 25ndash281964

[40] Y Qian H Xie R Tian K Yu and R Wang ldquoEfficacy of lowmolecular weight heparin in patients with acute exacerbationof chronic obstructive pulmonary disease receiving ventilatorysupportrdquo COPD Journal of Chronic Obstructive PulmonaryDisease vol 11 no 2 pp 171ndash176 2014

[41] A Chamorro A Cervera J Castillo A Davalos J J Aponteand A M Planas ldquoUnfractionated heparin is associated with alower rise of serum vascular cell adhesion molecule-1 in acuteischemic stroke patientsrdquo Neuroscience Letters vol 328 no 3pp 229ndash232 2002

[42] R de Cock L A Ficker J G Dart A Garner and P WrightldquoTopical heparin in the treatment of ligneous conjunctivitisrdquoOphthalmology vol 102 no 11 pp 1654ndash1659 1995

[43] U Derhaschnig T Pernerstorfer M Knechtelsdorfer U Hol-lenstein S Panzer and B Jilma ldquoEvaluation of antiinflamma-tory and antiadhesive effects of heparins in human endotox-emiardquo Critical Care Medicine vol 31 no 4 pp 1108ndash1112 2003

[44] B DixonM J Schultz R Smith J B Fink J D Santamaria andD J Campbell ldquoNebulized heparin is associatedwith fewer daysof mechanical ventilation in critically ill patients a randomizedcontrolled trialrdquo Critical Care vol 14 no 5 article R180 2010

[45] F K Keating H L Dauerman D A Whitaker B E Sobeland D J Schneider ldquoThe effects of bivalirudin compared withthose of unfractionated heparin plus eptifibatide on inflam-mation and thrombin generation and activity during coronaryinterventionrdquo Coronary Artery Disease vol 16 no 6 pp 401ndash405 2005

[46] M Ledson M Gallagher C A Hart and M Walshaw ldquoNeb-ulized heparin in Burkholderia cepacia colonized adult cysticfibrosis patientsrdquo European Respiratory Journal vol 17 no 1 pp36ndash38 2001

[47] D J Serisier J K Shute P M Hockey B Higgins J Conwayand M P Carroll ldquoInhaled heparin in cystic fibrosisrdquo EuropeanRespiratory Journal vol 27 no 2 pp 354ndash358 2006

[48] O K Poyrazoglu A Dogukan M Yalniz D Seckin andA L Gunal ldquoAcute effect of standard heparin versus lowmolecular weight heparin on oxidative stress and inflammationin hemodialysis patientsrdquo Renal Failure vol 28 no 8 pp 723ndash727 2006

[49] S Suzuki T Matsuo H Kobayashi et al ldquoAntithrombotictreatment (argatroban vs heparin) in coronary angioplastyin angina pectoris effects on inflammatory hemostatic and

endothelium-derived parametersrdquoThrombosis Research vol 98no 4 pp 269ndash279 2000

[50] S D Trocme and H-I Li ldquoEffect of heparin-surface-modifiedintraocular lenses on postoperative inflammation after pha-coemulsification a randomized trial in a United States patientpopulationrdquo Ophthalmology vol 107 no 6 pp 1031ndash1037 2000

[51] C Vancheri C Mastruzzo F Armato et al ldquoIntranasal heparinreduces eosinophil recruitment after nasal allergen challenge inpatients with allergic rhinitisrdquo Journal of Allergy and ClinicalImmunology vol 108 no 5 pp 703ndash708 2001

[52] A Abdollahi M-T Naini H Shams and R Zarei ldquoEffect oflow-molecular-weight heparin on postoperative inflammationin phacomorphic glaucomardquo Archives of Iranian Medicine vol5 no 4 pp 225ndash229 2002

[53] R T S Lakshmi T Priyanka J Meenakshi K R MathangiV Jeyaraman and M Babu ldquoLow molecular weight heparinmediated regulation of nitric oxide synthase during burnwound healingrdquo Annals of Burns and Fire Disasters vol 24 no1 pp 24ndash29 2011

[54] G Montalescot C Bal-dit-Sollier D Chibedi et al ldquoCompar-ison of effects on markers of blood cell activation of enoxa-parin dalteparin and unfractionated heparin in patients withunstable angina pectoris or non-ST-segment elevation acutemyocardial infarction (the ARMADA study)rdquo The AmericanJournal of Cardiology vol 91 no 8 pp 925ndash930 2003

[55] S Nasiripour K Gholami SMousavi et al ldquoComparison of theeffects of enoxaparin and heparin on inflammatory biomarkersin patients with ST-segment elevated myocardial infarction aprospective open label pilot clinical trialrdquo Iranian Journal ofPharmaceutical Research vol 13 no 2 pp 583ndash590 2014

[56] J Oldgren C Fellenius K Boman et al ldquoInfluence of prolongeddalteparin treatment on coagulation fibrinolysis and inflam-mation in unstable coronary artery diseaserdquo Journal of InternalMedicine vol 258 no 5 pp 420ndash427 2005

[57] T K Rudolph V Rudolph A Witte et al ldquoLiberation of vesseladherent myeloperoxidase by enoxaparin improves endothelialfunctionrdquo International Journal of Cardiology vol 140 no 1 pp42ndash47 2010

[58] D L Walters M J Ray P Wood E J Perrin J H N Bettand C N Aroney ldquoHigh-dose tirofiban with enoxaparin andinflammatory markers in high-risk percutaneous interventionrdquoEuropean Journal of Clinical Investigation vol 40 no 2 pp 139ndash147 2010

[59] S W Rathbun C E Aston and T L Whitsett ldquoA randomizedtrial of dalteparin compared with ibuprofen for the treatmentof superficial thrombophlebitisrdquo Journal of Thrombosis andHaemostasis vol 10 no 5 pp 833ndash839 2012

[60] J P Titon D Auger P Grange et al ldquoTherapeutic managementof superficial venous thrombosis with calcium nadroparinDosage testing and comparison with a non-steroidal anti-inflammatory agentrdquo Annales de Cardiologie et d Angeiologievol 43 no 3 pp 160ndash166 1994

[61] H Uncu ldquoA comparison of low-molecular-weight heparin andcombined therapy of low-molecular-weight heparin with ananti-inflammatory agent in the treatment of superficial veinthrombosisrdquo Phlebology vol 24 no 2 pp 56ndash60 2009

[62] J A Sjoslashland R S Pedersen J Jespersen and J GramldquoIntraperitoneal heparin ameliorates the systemic inflamma-tory response in PD patientsrdquo NephronmdashClinical Practice vol100 no 4 pp c105ndashc110 2005

[63] N L Fine C Shim and M H Williams Jr ldquoObjectiveevaluation of heparin in the treatment of asthmardquo AmericanReview of Respiratory Disease vol 98 no 5 pp 886ndash887 1968

14 Advances in Pharmacological Sciences

[64] ZDiamantM C Timmers H van derVeen C P Page F J vander Meer and P J Sterk ldquoEffect of inhaled heparin on allergen-induced early and late asthmatic responses in patients withatopic asthmardquo American Journal of Respiratory and CriticalCare Medicine vol 153 no 6 I pp 1790ndash1795 1996

[65] C M E Tranfa A Vatrella R Parrella G Pelaia F Bariffiand S A Marsico ldquoEffect of inhaled heparin on water-inducedbronchoconstriction in allergic asthmaticsrdquoEuropean Journal ofClinical Pharmacology vol 57 no 1 pp 5ndash9 2001

[66] I Stelmach J Jerzynska A Brzozowska and P Kuna ldquoTheeffect of inhaled heparin on postleukotriene bronchoconstric-tion in children with asthmardquo Polski Merkuriusz Lekarski vol12 no 68 pp 95ndash98 2002

[67] R Polosa S Magrı C Vancheri et al ldquoTime course of changesin adenosine 51015840-monophosphate airway responsiveness withinhaled heparin in allergic asthmardquo Journal of Allergy andClinical Immunology vol 99 no 3 pp 338ndash342 1997

[68] J Butler GM Rocker and SWestaby ldquoInflammatory responseto cardiopulmonary bypassrdquo The Annals of Thoracic Surgeryvol 55 no 2 pp 552ndash559 1993

[69] J M Redmond A M Gillinov R S Stuart et al ldquoHeparin-coated bypass circuits reduce pulmonary injuryrdquoThe Annals ofThoracic Surgery vol 56 no 3 pp 474ndash479 1993

[70] S Svenmarker E Sandstrom T Karlsson et al ldquoClinical effectsof the heparin coated surface in cardiopulmonary bypassrdquoEuropean Journal of Cardio-Thoracic Surgery vol 11 no 5 pp957ndash964 1997

[71] Y J Gu W van Oeveren C Akkerman P W Boonstra RJ Huyzen and C R H Wildevuur ldquoHeparin-coated circuitsreduce the inflammatory response to cardiopulmonary bypassrdquoThe Annals of Thoracic Surgery vol 55 no 4 pp 917ndash922 1993

[72] D Paparella O O Al Radi Q H Meng T Venner K Teohand E Young ldquoThe effects of high-dose heparin on inflamma-tory and coagulation parameters following cardiopulmonarybypassrdquo Blood Coagulation and Fibrinolysis vol 16 no 5 pp323ndash328 2005

[73] S Danese A Papa S Saibeni A Repici A Malesci andM Vecchi ldquoInflammation and coagulation in inflammatorybowel disease the clot thickensrdquo The American Journal ofGastroenterology vol 102 no 1 pp 174ndash186 2007

[74] S Bloom S Kiilerich M R Lassen et al ldquoLow molecularweight heparin (tinzaparin) vs placebo in the treatment of mildto moderately active ulcerative colitisrdquo Alimentary Pharmacol-ogy ampTherapeutics vol 19 no 8 pp 871ndash878 2004

[75] P Libby ldquoCoronary artery injury and the biology of atheroscle-rosis inflammation thrombosis and stabilizationrdquo AmericanJournal of Cardiology vol 86 no 8 2000

[76] N T Mulvihill and J B Foley ldquoInflammation in acute coronarysyndromesrdquo Heart vol 87 no 3 pp 201ndash204 2002

[77] N A JamesonW V Good and C S Hoyt ldquoInflammation aftercataract surgery in childrenrdquoOphthalmic Surgery vol 23 no 2pp 99ndash102 1992

[78] R M Sinskey P A Amin and R Lingua ldquoCataract extractionand intraocular lens implantation in an infant with amonocularcongenital cataractrdquo Journal of Cataract amp Refractive Surgeryvol 20 no 6 pp 647ndash651 1994

[79] A van Ophoven A Heinecke and L Hertle ldquoSafety andefficacy of concurrent application of oral pentosan polysulfateand subcutaneous low-dose heparin for patients with interstitialcystitisrdquo Urology vol 66 no 4 pp 707ndash711 2005

Submit your manuscripts athttpwwwhindawicom

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ToxinsJournal of

VaccinesJournal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

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AntibioticsInternational Journal of

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StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Drug DeliveryJournal of

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in Pharmacological Sciences

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Autoimmune Diseases

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Page 7: Review Article Anti-Inflammatory Effects of Heparin and Its …downloads.hindawi.com/journals/aps/2015/507151.pdf · 2019. 7. 31. · Review Article Anti-Inflammatory Effects of Heparin

Advances in Pharmacological Sciences 7Ta

ble2Con

tinued

Clinicalsetting

Heparin

preparation

Mod

eof

administratio

nCom

parator

Num

bero

fpatie

nts

Clinicalou

tcom

eLabo

ratory

outcom

eStud

ydesig

n

Cysticfib

rosis

(adu

lts)[47]

UFH

Inhaler

Placebo

14Noeffecto

nFE

V1

Noeffecto

nsputum

inflammatorymarkers

Rand

omizeddou

ble-blind

placebo-controlled

crossovertria

l

Hem

odialysis

patie

nts[48]

UFH

IVSC

LMWHandno

drug

33

LMWHdecreased

oxidatives

tressand

inflammationwhereas

heparin

increasedthem

CRPTN

F-120572sup

eroxide

dism

utaseMDAincreased

inheparin

grou

pbu

tcomparabletoLM

WH

grou

p

Quasi-experim

ental

(pretest-

posttestd

esign)

Stableangina

[49]

Heparin

+Aspirin

(119899=15)

mdashArgatroban+As

pirin

(119899=12)2

7

Nodifferencein

inflammatoryrespon

seaft

erangiop

lasty

Fibrinogen

decreased

significantly

inargatro

ban

grou

pNodifferenceinvon

Willberand

factor

between

both

grou

psPAI-1

increasedin

argatro

ban

grou

p

Rand

omized

controlled

trial

Phacoemulsifi

catio

n[50]

Heparin

Coatedlenses

Polymethylm

ethacrylate

lenses

367

Heparin

coated

lenses

redu

cedsig

nificantly

inflammationearly

posto

peratio

n(119875005)

mdashRa

ndom

izeddou

ble-blind

multic

enterparallelgroup

trial

Allergicrhinitis[51]

UFH

Intranasal

mdash10

mdashRe

ductionof

eosin

ophil

catio

nicp

rotein

inthen

asal

wash

Quasi-experim

ental

(pretest-

posttestd

esign)

Phacom

orph

icglaucoma[

52]

Dalteparin

Irrig

ation

Balanced

saltsolutio

n46

(23in

each

grou

p)

Sign

ificant

decrease

ofpo

stoperativ

einfl

ammation

indalteparin

grou

pmdash

Rand

omizeddou

ble-blind

clinicaltria

l

Burn

[53]

Dalteparin

SCNotre

atment

24mdash

Decreaseo

fnitricoxide

synthetase

activ

itysig

nificantly

Quasi-experim

ental

(non

rand

omized

clinical

trial)

Unstablec

oron

ary

artery

disease[54]

Enoxaparin

(119899=46)

Dalteparin

(119899=48)

SCUFH

(119899=47)

68

VonWillberand

factor

may

have

progno

sticv

aluebut

otherb

iologicalvariables

didno

tpredictou

tcom

e

CRPfib

rinogenV

onWillberand

factor

increased

over

first2days

despite

medicaltre

atment

Enoxaparin

(13

)and

dalteparin

(19)reduced

releaseo

fVon

Willberand

factor

Openlabelrand

omized

clinicaltria

l

ST-Elevated

Myocardial

Infarctio

n(STE

MI)

[55]

Enoxaparin

SCUFH

34(17in

each

grou

p)

Both

heparin

and

enoxaparin

show

anti-inflammatoryeffects

inST

EMIp

atients

Serum

AmyloidA(119875002)

CRP(119875002)and

ferritin

(119875001)redu

cedin

heparin

grou

pIL-6

(1198750002)SA

A(1198750009)CR

P(119875001)

weres

ignificantly

decreased

inenoxaparin

grou

pTh

eoveralld

ifference

between

grou

pswas

notsignificant

Openlabelrand

omized

clinicaltria

l

8 Advances in Pharmacological Sciences

Table2Con

tinued

Clinicalsetting

Heparin

preparation

Mod

eof

administratio

nCom

parator

Num

bero

fpatie

nts

Clinicalou

tcom

eLabo

ratory

outcom

eStud

ydesig

n

Coron

aryartery

disease[56]

Dalteparin

SCPlacebo

555(285

incontrolgroup

)

Dalteparin

redu

ced

coagulationandso

MyocardialInfarctionbu

thasn

otinflammatory

activ

ity

Noeffectson

IL-6

C-reactiv

eprotein

and

fibrin

ogen

Rand

omizeddou

ble-blind

parallel-g

roup

multic

entre

trial

Stablecoronary

artery

disease[57]

Enoxaparin

SCSo

dium

chlorid

e62

(31ineach

grou

p)

Bymob

ilizing

vesselbo

und

MPO

eno

xaparin

improves

endo

thelialfun

ction

Sign

ificant

increase

ofMPO

levels

Rand

omizeddou

ble-blind

placebo-controlledtrial

Acutec

oron

ary

synd

romea

ndPC

I[58]

Tirofib

an(highdo

se)+

enoxaparin

Tirofib

an(highdo

se)+

UFH

60(30in

each

grou

p)

Thec

ombinatio

nof

tirofi

ban(highdo

se)+

enoxaparin

redu

ced

inflammationaft

erPC

I

Vonwillberand

CRP

D-dim

erand

prothrom

bin

fragmentw

eres

ignificantly

lower

inenoxaparin

grou

pthan

UFH

Openlabelrando

mized

controlledtrial

Superficialveno

usthrombo

phleb

itis

[59]

Dalteparin

SCIbup

rofen

72(37in

dalteparin

grou

p)

Sign

ificant

redu

ctionof

pain

form

baselin

etoday14

offollo

w-upNodifference

onthrombo

sisprogression

after

3mon

ths

mdashRa

ndom

izeddou

ble-blind

controlledtrial

Superficialveno

usthrombo

sis[60]

Nadroparin

SCNaproxen

117(39in

control

grou

p)

Nadroparin

redu

ced

symptom

andsig

nsof

thrombo

sedsuperficial

vein

bette

rthannaproxen

(1198750007)

mdashRa

ndom

izedopenlabel

clinicaltria

l

Superficialveno

usthrombo

sis[61]

Nadroparin

SCNadroparin

+acem

etacin

50

Sign

ificant

symptom

improvem

entinbo

thgrou

ps(1198750001)Th

ecombinatio

ngrou

pwas

bette

r

mdashRa

ndom

ized

controlled

trial

Periton

eald

ialysis

patie

nts[62]

Tinzaparin

Intraperito

neal

Isoton

icsalin

e21

Redu

ctionof

localand

syste

micinflammationin

periton

eald

ialysis

patie

nts

Redu

cedlevelsof

CRP(119875

0032)

andfib

rinogen

(119875

004

2)andIL-6

(1198750007)

indialysate

Rand

omizeddou

ble-blind

placebo-controlled

crossovertria

l

COPD

Chron

icObstructiv

ePu

lmon

aryDise

aseCR

PC-

Reactiv

eProtein

CPB

Cardio

Pulm

onaryBy

passE

CPE

osinop

hilC

ationicProtein

ERCP

End

oscopicRe

trogradeCh

olangiop

ancreatographyE

SR

ErythrocyteSedimentatio

nICUIntensiv

eCa

reUnitILinterleuk

inIV

intravenou

sLM

WHlow

molecular

weighth

eparinM

DAm

alon

dialdehydePAIPlasminogen

Activ

ator

InhibitorSC

sub

cutaneou

ssV

CAMSolub

leVa

scular

CellA

dhesionMoleculeTN

FTu

mor

Necrosis

Factorand

UFH

unfractionatedheparin

Advances in Pharmacological Sciences 9

Table 3 Summary of numbers and percentages of adequatelyreported items in each trial according to CONSORT checklist andJadad score

Trials Jadadscore

Adequately reporteditems (119899119873)

Percentage()

Abdollahi et al [52] 4 2974 392Ahmed et al [9] 3 2074 27Ang et al [17] 2 2474 324Ashraf et al [27] 2 2274 297Becker et al [37] 3 2874 378de Vroege et al [29] 3 2674 351Defraigne et al [28] 4 2874 378Derhaschnig et al [43] 3 3274 432Dixon et al [44] 4 5074 675Duong et al [11] 3 3074 405Gu et al [71] 2 1674 216Jerzynska et al [13] 3 2074 27Keating et al [45] 2 2174 284Koster et al [31] 2 2674 351Montalescot et al [54] 3 3574 473Nasiripour et al [55] 2 3474 46Oldgren et al [56] 3 2774 365Olsson et al [32] 2 2574 338van Ophoven et al [79] 2 2774 365Ozawa et al [33] 2 2774 365Ozkurt et al [24] 3 1874 243Paparella et al [72] 2 2274 297Polosa et al [67] 3 2374 311Rathbun et al [59] 5 4474 595Rudolph et al [57] 3 3174 412Serisier et al [47] 5 4574 608Stelmach et al [16] 3 3174 412Suzuki et al [49] 2 2374 31Vancheri et al [51] 4 2274 297Vasavada et al [25] 5 5274 702Walters et al [58] 3 3274 432Zezos et al [20] 3 3774 50

thrombophlebitis and hemodialysis Unfractionated heparin(UFH) was used in forty studies as subcutaneous intra-venous inhaler or heparin-coated circuits while others usedenoxaparin (119899 = 3) dalteparin (119899 = 4) nadroparin (119899 = 4)and tinzaparin (119899 = 1)

Table 3 provides information on the adequately reporteditems according to Jadad score andCONSORT items Amongthese 32 papers 11 (354) scored 2 and the remaining studiesscored 3 or higher according to Jadad score and just threestudies fulfill the criteria of Jadad score Calculated qualityscores according to CONSORT checklist range from 21 to70 in our object studies with twelve studies scoring greaterthan 40 The following characteristics were not exactlyreported in more than half of the trials identification as

a randomized trial in the title information about the settingand location of studies determination of sample size alloca-tion and implementation of randomization participant flowrecruitment and follow-up subgroup analysis limitations ofstudy harms registration number access to full trial protocoland funding source

4 Discussion

We discuss evidence from clinical studies supporting an anti-inflammatory role for heparin and heparin-related deriva-tives

41 Asthma Asthma is a chronic inflammatory disorderof airways characterized by bronchial hyperresponsivenessresulting in episodic bronchospasm Several studies in 1960sdescribed subjective improvement of symptoms in asthmaticpatients using intravenous heparin for the first time [3963] Inhaled heparin or its derivatives have been shown topossess antiasthmatic properties in various clinical modelsallergen induced [38 64] exercise [9] adenosine [6] anddistilled water challenge models [65] Seven randomizedcontrolled crossover trials studied anti-inflammatory effectsof heparin in exercise-induced or allergen-induced asthmahaving sample size range from 8 to 25 in 5 trials

Heparin inhalation reduced bronchial hyperreactivity ina single-blind randomized crossover trial (119899 = 12) byAhmed et al [9] Heparin inhalation (1000 120583kg) preventsexercise-induced asthma (119875 lt 005) without preventionof histamine-induced bronchoconstriction Stelmach et al[66] provoke challenge tests with histamine or leukotrieneD4 before and after inhalation of heparin showed that hep-arin (5000 Iu) decreases histamine and leukotriene-inducedbronchial hyperreactivity compared to placebo significantly(119875 0043 and 0005) but changes in Forced Expiratory Vol-ume (FEV 1) were not significant (119875 0064) The inhibitoryeffects of inhaled heparin in the airways in the absence ofbronchodilation might be related to suppressive action onmast cell degranulation A randomized double-blind studyin 10 subjects with asthma showed that heparin inhalationattenuates airway response to adenosine 51015840-monophosphate(AMP) but not to methacholine (119875 lt 001) suggestingthe theory that heparin acts more likely in association tomodulation of mediator release compared to a direct effecton smooth muscle [67]

Our results showed that inhaled enoxaparin was usedjust in a pre-post study of 24 asthmatic patients measur-ing inflammatory biomarkers and showed a reduction ineosinophil (119875 0006) and lymphocytes of bronchoalveolarlavage without any significant change in IL-5 or EosinophilCationic Protein (ECP) concentrations [12] Therefore itseems that enoxaparin could be a valuable add on treatmentin asthma like UFH Duong et al [11] evaluated IVX-0142nebulizer a heparin-derived hypersulfated disaccharide inasthma and showed nonsignificant decrease in early and lateasthmatic response

Performed studies did not show any adverse events orharms with heparin or related compounds except increase in

10 Advances in Pharmacological Sciences

the plasma partial thromboplastin time reported by Ahmedet al [9]

All in one considering the results of these studies wecan conclude that heparin and its derivatives could have anti-inflammatory effects and could be considered along withother treatments in asthma

42 Cardiopulmonary Bypass Contact and interaction ofblood with foreign surfaces during cardiopulmonary bypass(CPB) cause systemic inflammatory response syndrome(SIRS) through activation of several humoral cascadesincluding cytokines such as IL-6 IL-8 and Tumor NecrosisFactor-120572 (TNF-120572) [68] The inflammatory response can beattenuated by promoting the biocompatibility of the CPBcircuit Use of heparin-treated surfaces in CPB circuits hasbeen shown to decrease activation of leukocytes and thecomplement cascades [5] As a result need to inotropicsupport postoperative time of mechanical ventilation andrate of acute lung injury decrease and patients durationof hospital stay shortens which reflects the positive effectof heparin in CPB circuits [69 70] Twelve studies whoseendpoints were the effects of heparin-bonded circuits oninflammatory markers were included in our analysis and inthe majority of these trials [27 29 32ndash35 71] heparin-coatedcircuit significantly decreased the level of cytokines such asIL-6 IL-8 TNF-120572 complement complex neutrophils andelastase compared to non-heparin-coated circuit

Defraigne et al [28] randomized 200 patients in 4 groupsheparin-coated circuit with or without aprotinin administra-tion and uncoated circuit with or without aprotinin adminis-tration They measured IL-6 IL-8 TNF-120572 myeloperoxidase(MPO) and elastase level and concluded that cytokine releaseand neutrophil activation were not attenuated by heparin-coated circuit or by the administration of aprotinin Misawaet al [30] evaluated cytokines level under normothermicCPB in a small observational controlled study (119899 = 19 9 incontrol group) Levels of IL-6 IL-8 and ICAM-1 (indicatorof endothelial damage) were not different between study andcontrol group However as mentioned before most studiesindicate the favorable effect of heparin-coated circuit oninflammatory responses in CPB

Paparella et al [72] compared two doses of heparin and300 Iukg and 600 Iukg in 40 patients undergoing CPB in anRCT and showed that IL-6 and TNF-120572 plasma levels were inassociation to heparin dose It seems that lower heparin dosehad small influence on proinflammatory cytokines releasehowever higher doses make a better regulatory effect oncoagulation system

The side effects of heparin-coated circuits were notreported In these studies just a number of included studiesreported a decrease in platelet levels in both groups (coatedand noncoated circuit) No major events including hemor-rhage were reported

43 Inflammatory Bowel Diseases (IBD) Hypercoagulablestate may be an important contributing factor in the patho-genesis of IBD especially ulcerative colitis (UC) [73] A num-ber of studies evaluate the effects of heparin administrationon UC but the results obtained are controversial [17 19]

Bloom et al [74] did not find any favorable effect of LMWHtinzaparin over placebo in the treatment of active UC ina double-blind randomized placebo controlled multicentertrial (119899 = 100) evaluating mean change in colitis activity asthe primary endpoint Ang et al [17] compared heparin tohydrocortisone plus prednisolone in 20 patients (UC 119899 = 17Crohnrsquos colitis 119899 = 3) in open-label randomized crossovertrial whichmeasured endpoints clinical disease activity stoolfrequency and 120572

1acid glycoprotein and endoscopic and

histopathological grading indicate the efficacy and safety ofheparin compared to corticosteroids (119875 gt 005) in contrastthe study by Panes et al [19] did not show the efficacy ofheparin in UC compared to methylprednisolone

Zezos et al [20] compared enoxaparin with standardtreatment (aminosalicylate + corticosteroids) in 34 patientswith active UC The inflammatory biomarkers includingC-Reactive Protein (CRP) Erythrocyte Sedimentation Rate(ESR) and fibrinogen did not show any difference in studygroup compared to control and both groups showed similarrate of disease improvement (119875 gt 005) furthermorecoagulation factors did not change from one to anotherAuthors concluded that enoxaparin is a safe adjuvant but hasno additive benefit over standard treatment of UC

Generally the studies show conflicting results The hep-arin and LMWHs showed efficacy in regard of disease activityand also well tolerated but inflammatory markers did notchange significantly Therefore the improvement in diseaseactivity might be the result of heparinrsquos anticoagulant effects

44 Acute Coronary Syndrome (ACS) Inflammation has akey role in the pathogenesis of coronary artery plaquedestabilization and rupture leading to acute coronary syn-dromes (ACS) [75] Leukocyte activation monocyte andneutrophil infiltration result in local and systemic inflam-matory responses [76] Heparin and LMWHs are commonlyused in ACS to prevent clot formation they also seem tohave desirable effects on inflammatory markers level basedon sparse data

We found 8 studies about heparin and LMWHs in CADsevaluating anti-inflammatory effects as their endpoints Old-gren et al [56] found that dalteparin administration inpatients with unstable CAD (119899 = 555) did not affect IL-6C-Reactive Protein (CRP) and fibrinogen levels although itreduced coagulation activity and mortality rate in long termso it is concluded that these effects are not related to its anti-inflammatory properties Walters et al [58] compared highdose of tirofibanenoxaparin (119899 = 30) with tirofibanheparin(119899 = 30) in an open-label randomized controlled trial in highrisk percutaneous interventionThey found that combinationof high dose of tirofiban with enoxaparin significantly atten-uate inflammatory process (decreased levels of CRP and vonWillebrand factor) compared to tirofiban and heparin

The ARMADA study [54] evaluated anti-inflammatoryeffects of heparin and enoxaparin in Non-ST-ElevatedMyocardial Infarction (Non-STEMI) and reported thatinflammatory markers (CRP and von Willebrand factor)are affected more by LMWH compared to UFH Howeverbecause of the small sample size of the study (119899 = 68)

Advances in Pharmacological Sciences 11

it did not acquire sufficient statistical power to prove anyeffects on defined outcomes Nasiripour et al [55] found thatboth enoxaparin and heparin reduce inflammatory markersin STEMI patients at the same level however this study hadthe same limitations of sample size (119899 = 34) and power too

In summary considering heparins as the main stay treat-ment of ACS its effects are more pronounced as anticoagu-lating than as an anti-inflammatory agent in this pathologicalcondition

45 Cataract Surgery Postoperative inflammation isobserved in cataract surgery especially in children Newertechniques as lensectomy and phacoemulsification cause lesscomplication but still pose potential risks [77 78] It hasbeen suggested that a heparin surface-modified intraocularlens (IOL) or augmenting the irrigating solution withheparin during cataract surgery may reduce the incidence ofpostoperative inflammation Borgioli et al [22] confirm thishypothesis that heparin surface-modified IOL will reducethe inflammatory response compared to conventional IOLat least in short term period (3 months) in a large (524patients) double-blind multicenter trial A similar study byColin et al [23] (119899 = 58) confirms their results howeverthe power of Borgioli et al study was higher Heparinizedlenses showed also more anti-inflammatory effects duringlong term follow-up (1 year) Heparinized irrigating solutionwas used during cataract surgery in two different studies andinflammation decrease observed in the early postoperativeperiod of both studies (Kohnen et al [26] and Ozkurt et al[24]) Therefore it seems that heparin in both forms haveanti-inflammatory effects in cataract surgery

Vasavada et al [25] used enoxaparin irrigation solutionin 20 children undergoing bilateral cataract surgery butthey did not find any beneficial effect in early postoperativeinflammation This study acquired the highest quality in thestudy quality assessment process based on Jadad score andCONSORT items (5274 702) It is worth noticing that themajority of itemsmentioned in the CONSORT checklist wereadequately reported and covered in this paper

Potential mechanisms of anti-inflammatory effects ofheparin have been discussed completely in a review by Young[6] Binding of heparin to different mediators involved inthe immune system response (cytokines and chemokines)acute phase proteins and complement complex proteinsmay contribute to the anti-inflammatory activity of heparinNeutralizing of cytokines at the inflammation site is anotherpossible mechanism In most of the studies level of cytokinessuch as IL-6 IL-8 TNF-120572 and CRP was decreased afterheparin administration which can confirm this mechanismalso heparin and LMWHs inhibit adhesion of leukocytesand neutrophils to endothelial cells by binding to p-selectinand consequently prevent release of oxygen radicals andproteolytic enzymes Other possible mechanisms are as fol-lows inhibition of nuclear factor 120581B (NF-120581B) and inductionof apoptosis by modulation of activity of TNF-120572 and NF-120581B In a double-blind placebo-controlled trial (119899 = 62)in patients with stable coronary artery disease followingadministration of 1mgkg subcutaneous enoxaparin plasmalevels of myeloperoxidase (MPO) increased significantly

(119875 lt 0001) and subsequently endothelial function improved(119903 = 067 119875 lt 0001) through MPO binding to endotheliumand depleting vascular nitric oxide [57] This study confirmsanother possible mechanism of heparins anti-inflammatoryeffects

5 Conclusion

As we discussed heparins potential effects as anti-inflamma-tory agents supported by several clinical trials in varioussetting Heparin and its related derivatives have been shownto benefit patients with asthma and patients undergoingcardiopulmonary bypass and cataract surgery In otherinflammatory diseases such as IBD (ulcerative colitis) thestudies are heterogeneous and incongruent Most studies didnot report any unwanted event with heparins when they usedthem as anti-inflammatory agents whether through systemicor through local (as inhaler or irrigation or heparin-coatedcircuit) administration However because the majority ofthese trials did not pose optimal quality scores we cannotdraw a definite conclusion on the efficacy of heparin and itsderivatives as anti-inflammatory agents

The present review included studies which measuredinflammatory markers as their endpoints and in most ofthem these markers were decreased though not significantlyTo come to a definite conclusion further double-blindrandomized placebo-controlled clinical trials with a largersample size are needed However because the inflammationatherogenesis thrombogenesis and cell proliferation areassociated with each other the pleiotropic effects of heparinand related compounds may have greater therapeutic effectthan compounds that are directed against a single target

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

[1] B Casu ldquoHeparin structurerdquo Pathophysiology of Haemostasisand Thrombosis vol 20 supplement 1 pp 62ndash73 1990

[2] J Hirsh R Raschke T EWarkentin J E Dalen DDeykin andL Poller ldquoHeparin mechanism of action pharmacokineticsdosing considerations monitoring efficacy and safetyrdquo Chestvol 108 no 4 supplement pp 258Sndash275S 1995

[3] J Fareed D A Hoppensteadt and R L Bick ldquoAn update onheparins at the beginning of the new millenniumrdquo Seminars inThrombosis and Hemostasis vol 26 no 3 pp 5ndash21 2000

[4] J Hirsh ldquoDrug therapy heparinrdquo The New England Journal ofMedicine vol 324 no 22 pp 1565ndash1574 1991

[5] R J Ludwig ldquoTherapeutic use of heparin beyond anticoagu-lationrdquo Current Drug Discovery Technologies vol 6 no 4 pp281ndash289 2009

[6] E Young ldquoThe anti-inflammatory effects of heparin and relatedcompoundsrdquo Thrombosis Research vol 122 no 6 pp 743ndash7522008

12 Advances in Pharmacological Sciences

[7] A R Jadad R A Moore D Carroll et al ldquoAssessing the qualityof reports of randomized clinical trials is blinding necessaryrdquoControlled Clinical Trials vol 17 no 1 pp 1ndash12 1996

[8] K F Schulz D G Altman and D Moher ldquoCONSORT 2010statement updated guidelines for reporting parallel grouprandomised trialsrdquo International Journal of Surgery vol 9 no8 pp 672ndash677 2011

[9] T Ahmed J Garrigo and I Danta ldquoPreventing bronchocon-striction in exercise-induced asthma with inhaled heparinrdquoTheNewEngland Journal ofMedicine vol 329 no 2 pp 90ndash95 1993

[10] Z Diamant M C Timmers H Van Der Veen C P PageF J Van Der Meer and P J Sterk ldquoEffect of inhaled heparinon allergen-induced early and late asthmatic responses inpatients with atopic asthmardquo American Journal of Respiratoryand Critical Care Medicine vol 153 no 6 pp 1790ndash1795 1996

[11] M Duong D Cockcroft L-P Boulet et al ldquoThe effect ofIVX-0142 a heparin-derived hypersulfated disaccharide on theallergic airway responses in asthmardquo Allergy vol 63 no 9 pp1195ndash1201 2008

[12] A M Fal M Kraus-Filarska J Miecielica and J MalolepszyldquoMechanisms of action of nebulized low-molecular-weightheparin in patients with bronchial asthmardquo The Journal ofAllergy and Clinical Immunology vol 113 no 2 supplement pS36 2004

[13] J Jerzynska I Stelmach P Majak and P Kuna ldquoThe effectof inhaled heparin on airway responsiveness to histamine andmetacholine in asthmatic childrenrdquo Journal of Allergy andClinical Immunology vol 109 no 1 supplement 1 p S39 2002

[14] A F Kalpaklioglu Y S Demirel S Saryal and Z MisirligilldquoEffect of pretreatment with heparin on pulmonary and cuta-neous responserdquo Journal of Asthma vol 34 no 4 pp 337ndash3431997

[15] I Stelmach J Jerzynska A Brzozowska and P Kuna ldquoTheeffect of inhaled heparin on postleukotriene bronchoconstric-tion in children with asthmardquo Journal of Allergy and ClinicalImmunology vol 109 no 1 supplement 1 p S39 2002

[16] I Stelmach J Jerzynska W Stelmach et al ldquoThe effect ofinhaled heparin on airway responsiveness to histamine andleukotriene D4rdquo Allergy and Asthma Proceedings vol 24 no 1pp 59ndash65 2003

[17] Y S Ang N Mahmud B White et al ldquoRandomized compar-ison of unfractionated heparin with corticosteroids in severeactive inflammatory bowel diseaserdquo Alimentary PharmacologyandTherapeutics vol 14 no 8 pp 1015ndash1022 2000

[18] C Folwaczny B Wiebecke and K Loeschke ldquoUnfractionedheparin in the therapy of patients with highly active inflamma-tory bowel diseaserdquo The American Journal of Gastroenterologyvol 94 no 6 pp 1551ndash1555 1999

[19] J Panes M Esteve E Cabre et al ldquoComparison of heparinand steroids in the treatment of moderate and severe ulcerativecolitisrdquo Gastroenterology vol 119 no 4 pp 903ndash908 2000

[20] P Zezos G Papaioannou N Nikolaidis et al ldquoLow-molecular-weight heparin (enoxaparin) as adjuvant therapy in the treat-ment of active ulcerative colitis a randomized controlledcomparative studyrdquoAlimentary Pharmacology andTherapeuticsvol 23 no 10 pp 1443ndash1453 2006

[21] A A Vrij J M Jansen E J Schoon H C Hemker and RW Stockbrugger ldquoLow molecular weight heparin treatmentin steroid refractory ulcerative colitis clinical outcome andinfluence on mucosal capillary thrombirdquo Scandinavian Journalof Gastroenterology Supplement vol 36 no 234 pp 41ndash47 2001

[22] D M Borgioli D J Coster R F T Fan et al ldquoEffect of heparinsurface modification of polymethylmethacrylate intraocularlenses on signs of postoperative inflammation after extracap-sular cataract extraction one-year results of a double-maskedmulticenter studyrdquoOphthalmology vol 99 no 8 pp 1248ndash12551992

[23] J Colin S Roncin and M Wenzel ldquoEfficacy of heparinsurface-modified IOLs in reducing postoperative inflammatoryreactions in patients with exfoliation syndromemdasha double-blind comparative studyrdquo European Journal of Implant andRefractive Surgery vol 7 no 5 pp 266ndash270 1995

[24] Y B Ozkurt A Taskiran N Erdogan B Kandemir and OK Dogan ldquoEffect of heparin in the intraocular irrigating solu-tion on postoperative inflammation in the pediatric cataractsurgeryrdquoClinical Ophthalmology vol 3 no 1 pp 363ndash365 2009

[25] V A Vasavada M R Praveen S K Shah R H Trivedi andA R Vasavada ldquoAnti-inflammatory effect of low-molecular-weight heparin in pediatric cataract surgery a randomizedclinical trialrdquoThe American Journal of Ophthalmology vol 154no 2 pp 252ndash258 2012

[26] T Kohnen B Dick V Hessemer D D Koch and K WJacobi ldquoEffect of heparin in irrigating solution on inflammationfollowing small incision cataract surgeryrdquo Journal of Cataract ampRefractive Surgery vol 24 no 2 pp 237ndash243 1998

[27] S Ashraf Y Tian D Cowan A Entress P G Martin andK G Watterson ldquoRelease of proinflammatory cytokines dur-ing pediatric cardiopulmonary bypass heparin-bonded versusnonbonded oxygenatorsrdquo Annals of Thoracic Surgery vol 64no 6 pp 1790ndash1794 1997

[28] J-O Defraigne J Pincemail R Larbuisson F Blaffart andR Limet ldquoCytokine release and neutrophil activation are notprevented by heparin- coated circuits and aprotinin administra-tionrdquo Annals of Thoracic Surgery vol 69 no 4 pp 1084ndash10912000

[29] R de Vroege W van Oeveren J van Klarenbosch et al ldquoTheimpact of heparin-coated cardiopulmonary bypass circuits onpulmonary function and the release of inflammatory media-torsrdquo Anesthesia and Analgesia vol 98 no 6 pp 1586ndash15942004

[30] Y Misawa K Kawahito H Konishi and K Fuse ldquoCytokinemediated endothelial activation during and after normothermiccardiopulmonary bypass Heparin-bonded versus non heparin-bonded circuitsrdquo ASAIO Journal vol 46 no 6 pp 740ndash7432000

[31] A Koster T Fischer M Praus et al ldquoHemostatic activationand inflammatory response during cardiopulmonary bypassimpact of heparin managementrdquo Anesthesiology vol 97 no 4pp 837ndash841 2002

[32] C Olsson A Siegbahn A Henze et al ldquoHeparin-coatedcardiopulmonary bypass circuits reduce circulating comple-ment factors and interleukin-6 in paediatric heart surgeryrdquoScandinavian Cardiovascular Journal vol 34 no 1 pp 33ndash402000

[33] T Ozawa K Yoshihara N Koyama Y Watanabe N Shionoand Y Takanashi ldquoClinical efficacy of heparin-bonded bypasscircuits related to cytokine responses in childrenrdquo The Annalsof Thoracic Surgery vol 69 no 2 pp 584ndash590 2000

[34] A Parolari F Alamanni T Gherli et al ldquolsquoHigh dosersquo aprotininand heparin-coated circuits Clinical efficacy and inflammatoryresponserdquo Cardiovascular Surgery vol 7 no 1 pp 117ndash127 1999

[35] H Yamada I Kudoh Y Hirose M Toyoshima H Abe andK Kurahashi ldquoHeparin-coated circuits reduce the formation of

Advances in Pharmacological Sciences 13

TNF120572 during cardiopulmonary bypassrdquo Acta AnaesthesiologicaScandinavica vol 40 no 3 pp 311ndash317 1996

[36] O Barkay E Niv E Santo R Bruck A Hallak and F MKonikoff ldquoLow-dose heparin for the prevention of post-ERCPpancreatitis a randomized placebo-controlled trialrdquo SurgicalEndoscopy and Other Interventional Techniques vol 22 no 9pp 1971ndash1976 2008

[37] R C Becker K W Mahaffey H Yang et al ldquoHeparin-associated anti-Xa activity and platelet-derived prothromboticand proinflammatory biomarkers in moderate to high-riskpatients with acute coronary syndromerdquo Journal of Thrombosisand Thrombolysis vol 31 no 2 pp 146ndash153 2011

[38] S D Bowler S M Smith and P S Lavercombe ldquoHeparininhibits the immediate response to antigen in the skin and lungsof allergic subjectsrdquo American Review of Respiratory Diseasevol 147 no 1 pp 160ndash163 1993

[39] J P Boyle R H Smart and J K Shirey ldquoHeparin in thetreatment of chronic obstructive bronchopulmonary diseaserdquoThe American Journal of Cardiology vol 14 no 1 pp 25ndash281964

[40] Y Qian H Xie R Tian K Yu and R Wang ldquoEfficacy of lowmolecular weight heparin in patients with acute exacerbationof chronic obstructive pulmonary disease receiving ventilatorysupportrdquo COPD Journal of Chronic Obstructive PulmonaryDisease vol 11 no 2 pp 171ndash176 2014

[41] A Chamorro A Cervera J Castillo A Davalos J J Aponteand A M Planas ldquoUnfractionated heparin is associated with alower rise of serum vascular cell adhesion molecule-1 in acuteischemic stroke patientsrdquo Neuroscience Letters vol 328 no 3pp 229ndash232 2002

[42] R de Cock L A Ficker J G Dart A Garner and P WrightldquoTopical heparin in the treatment of ligneous conjunctivitisrdquoOphthalmology vol 102 no 11 pp 1654ndash1659 1995

[43] U Derhaschnig T Pernerstorfer M Knechtelsdorfer U Hol-lenstein S Panzer and B Jilma ldquoEvaluation of antiinflamma-tory and antiadhesive effects of heparins in human endotox-emiardquo Critical Care Medicine vol 31 no 4 pp 1108ndash1112 2003

[44] B DixonM J Schultz R Smith J B Fink J D Santamaria andD J Campbell ldquoNebulized heparin is associatedwith fewer daysof mechanical ventilation in critically ill patients a randomizedcontrolled trialrdquo Critical Care vol 14 no 5 article R180 2010

[45] F K Keating H L Dauerman D A Whitaker B E Sobeland D J Schneider ldquoThe effects of bivalirudin compared withthose of unfractionated heparin plus eptifibatide on inflam-mation and thrombin generation and activity during coronaryinterventionrdquo Coronary Artery Disease vol 16 no 6 pp 401ndash405 2005

[46] M Ledson M Gallagher C A Hart and M Walshaw ldquoNeb-ulized heparin in Burkholderia cepacia colonized adult cysticfibrosis patientsrdquo European Respiratory Journal vol 17 no 1 pp36ndash38 2001

[47] D J Serisier J K Shute P M Hockey B Higgins J Conwayand M P Carroll ldquoInhaled heparin in cystic fibrosisrdquo EuropeanRespiratory Journal vol 27 no 2 pp 354ndash358 2006

[48] O K Poyrazoglu A Dogukan M Yalniz D Seckin andA L Gunal ldquoAcute effect of standard heparin versus lowmolecular weight heparin on oxidative stress and inflammationin hemodialysis patientsrdquo Renal Failure vol 28 no 8 pp 723ndash727 2006

[49] S Suzuki T Matsuo H Kobayashi et al ldquoAntithrombotictreatment (argatroban vs heparin) in coronary angioplastyin angina pectoris effects on inflammatory hemostatic and

endothelium-derived parametersrdquoThrombosis Research vol 98no 4 pp 269ndash279 2000

[50] S D Trocme and H-I Li ldquoEffect of heparin-surface-modifiedintraocular lenses on postoperative inflammation after pha-coemulsification a randomized trial in a United States patientpopulationrdquo Ophthalmology vol 107 no 6 pp 1031ndash1037 2000

[51] C Vancheri C Mastruzzo F Armato et al ldquoIntranasal heparinreduces eosinophil recruitment after nasal allergen challenge inpatients with allergic rhinitisrdquo Journal of Allergy and ClinicalImmunology vol 108 no 5 pp 703ndash708 2001

[52] A Abdollahi M-T Naini H Shams and R Zarei ldquoEffect oflow-molecular-weight heparin on postoperative inflammationin phacomorphic glaucomardquo Archives of Iranian Medicine vol5 no 4 pp 225ndash229 2002

[53] R T S Lakshmi T Priyanka J Meenakshi K R MathangiV Jeyaraman and M Babu ldquoLow molecular weight heparinmediated regulation of nitric oxide synthase during burnwound healingrdquo Annals of Burns and Fire Disasters vol 24 no1 pp 24ndash29 2011

[54] G Montalescot C Bal-dit-Sollier D Chibedi et al ldquoCompar-ison of effects on markers of blood cell activation of enoxa-parin dalteparin and unfractionated heparin in patients withunstable angina pectoris or non-ST-segment elevation acutemyocardial infarction (the ARMADA study)rdquo The AmericanJournal of Cardiology vol 91 no 8 pp 925ndash930 2003

[55] S Nasiripour K Gholami SMousavi et al ldquoComparison of theeffects of enoxaparin and heparin on inflammatory biomarkersin patients with ST-segment elevated myocardial infarction aprospective open label pilot clinical trialrdquo Iranian Journal ofPharmaceutical Research vol 13 no 2 pp 583ndash590 2014

[56] J Oldgren C Fellenius K Boman et al ldquoInfluence of prolongeddalteparin treatment on coagulation fibrinolysis and inflam-mation in unstable coronary artery diseaserdquo Journal of InternalMedicine vol 258 no 5 pp 420ndash427 2005

[57] T K Rudolph V Rudolph A Witte et al ldquoLiberation of vesseladherent myeloperoxidase by enoxaparin improves endothelialfunctionrdquo International Journal of Cardiology vol 140 no 1 pp42ndash47 2010

[58] D L Walters M J Ray P Wood E J Perrin J H N Bettand C N Aroney ldquoHigh-dose tirofiban with enoxaparin andinflammatory markers in high-risk percutaneous interventionrdquoEuropean Journal of Clinical Investigation vol 40 no 2 pp 139ndash147 2010

[59] S W Rathbun C E Aston and T L Whitsett ldquoA randomizedtrial of dalteparin compared with ibuprofen for the treatmentof superficial thrombophlebitisrdquo Journal of Thrombosis andHaemostasis vol 10 no 5 pp 833ndash839 2012

[60] J P Titon D Auger P Grange et al ldquoTherapeutic managementof superficial venous thrombosis with calcium nadroparinDosage testing and comparison with a non-steroidal anti-inflammatory agentrdquo Annales de Cardiologie et d Angeiologievol 43 no 3 pp 160ndash166 1994

[61] H Uncu ldquoA comparison of low-molecular-weight heparin andcombined therapy of low-molecular-weight heparin with ananti-inflammatory agent in the treatment of superficial veinthrombosisrdquo Phlebology vol 24 no 2 pp 56ndash60 2009

[62] J A Sjoslashland R S Pedersen J Jespersen and J GramldquoIntraperitoneal heparin ameliorates the systemic inflamma-tory response in PD patientsrdquo NephronmdashClinical Practice vol100 no 4 pp c105ndashc110 2005

[63] N L Fine C Shim and M H Williams Jr ldquoObjectiveevaluation of heparin in the treatment of asthmardquo AmericanReview of Respiratory Disease vol 98 no 5 pp 886ndash887 1968

14 Advances in Pharmacological Sciences

[64] ZDiamantM C Timmers H van derVeen C P Page F J vander Meer and P J Sterk ldquoEffect of inhaled heparin on allergen-induced early and late asthmatic responses in patients withatopic asthmardquo American Journal of Respiratory and CriticalCare Medicine vol 153 no 6 I pp 1790ndash1795 1996

[65] C M E Tranfa A Vatrella R Parrella G Pelaia F Bariffiand S A Marsico ldquoEffect of inhaled heparin on water-inducedbronchoconstriction in allergic asthmaticsrdquoEuropean Journal ofClinical Pharmacology vol 57 no 1 pp 5ndash9 2001

[66] I Stelmach J Jerzynska A Brzozowska and P Kuna ldquoTheeffect of inhaled heparin on postleukotriene bronchoconstric-tion in children with asthmardquo Polski Merkuriusz Lekarski vol12 no 68 pp 95ndash98 2002

[67] R Polosa S Magrı C Vancheri et al ldquoTime course of changesin adenosine 51015840-monophosphate airway responsiveness withinhaled heparin in allergic asthmardquo Journal of Allergy andClinical Immunology vol 99 no 3 pp 338ndash342 1997

[68] J Butler GM Rocker and SWestaby ldquoInflammatory responseto cardiopulmonary bypassrdquo The Annals of Thoracic Surgeryvol 55 no 2 pp 552ndash559 1993

[69] J M Redmond A M Gillinov R S Stuart et al ldquoHeparin-coated bypass circuits reduce pulmonary injuryrdquoThe Annals ofThoracic Surgery vol 56 no 3 pp 474ndash479 1993

[70] S Svenmarker E Sandstrom T Karlsson et al ldquoClinical effectsof the heparin coated surface in cardiopulmonary bypassrdquoEuropean Journal of Cardio-Thoracic Surgery vol 11 no 5 pp957ndash964 1997

[71] Y J Gu W van Oeveren C Akkerman P W Boonstra RJ Huyzen and C R H Wildevuur ldquoHeparin-coated circuitsreduce the inflammatory response to cardiopulmonary bypassrdquoThe Annals of Thoracic Surgery vol 55 no 4 pp 917ndash922 1993

[72] D Paparella O O Al Radi Q H Meng T Venner K Teohand E Young ldquoThe effects of high-dose heparin on inflamma-tory and coagulation parameters following cardiopulmonarybypassrdquo Blood Coagulation and Fibrinolysis vol 16 no 5 pp323ndash328 2005

[73] S Danese A Papa S Saibeni A Repici A Malesci andM Vecchi ldquoInflammation and coagulation in inflammatorybowel disease the clot thickensrdquo The American Journal ofGastroenterology vol 102 no 1 pp 174ndash186 2007

[74] S Bloom S Kiilerich M R Lassen et al ldquoLow molecularweight heparin (tinzaparin) vs placebo in the treatment of mildto moderately active ulcerative colitisrdquo Alimentary Pharmacol-ogy ampTherapeutics vol 19 no 8 pp 871ndash878 2004

[75] P Libby ldquoCoronary artery injury and the biology of atheroscle-rosis inflammation thrombosis and stabilizationrdquo AmericanJournal of Cardiology vol 86 no 8 2000

[76] N T Mulvihill and J B Foley ldquoInflammation in acute coronarysyndromesrdquo Heart vol 87 no 3 pp 201ndash204 2002

[77] N A JamesonW V Good and C S Hoyt ldquoInflammation aftercataract surgery in childrenrdquoOphthalmic Surgery vol 23 no 2pp 99ndash102 1992

[78] R M Sinskey P A Amin and R Lingua ldquoCataract extractionand intraocular lens implantation in an infant with amonocularcongenital cataractrdquo Journal of Cataract amp Refractive Surgeryvol 20 no 6 pp 647ndash651 1994

[79] A van Ophoven A Heinecke and L Hertle ldquoSafety andefficacy of concurrent application of oral pentosan polysulfateand subcutaneous low-dose heparin for patients with interstitialcystitisrdquo Urology vol 66 no 4 pp 707ndash711 2005

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Page 8: Review Article Anti-Inflammatory Effects of Heparin and Its …downloads.hindawi.com/journals/aps/2015/507151.pdf · 2019. 7. 31. · Review Article Anti-Inflammatory Effects of Heparin

8 Advances in Pharmacological Sciences

Table2Con

tinued

Clinicalsetting

Heparin

preparation

Mod

eof

administratio

nCom

parator

Num

bero

fpatie

nts

Clinicalou

tcom

eLabo

ratory

outcom

eStud

ydesig

n

Coron

aryartery

disease[56]

Dalteparin

SCPlacebo

555(285

incontrolgroup

)

Dalteparin

redu

ced

coagulationandso

MyocardialInfarctionbu

thasn

otinflammatory

activ

ity

Noeffectson

IL-6

C-reactiv

eprotein

and

fibrin

ogen

Rand

omizeddou

ble-blind

parallel-g

roup

multic

entre

trial

Stablecoronary

artery

disease[57]

Enoxaparin

SCSo

dium

chlorid

e62

(31ineach

grou

p)

Bymob

ilizing

vesselbo

und

MPO

eno

xaparin

improves

endo

thelialfun

ction

Sign

ificant

increase

ofMPO

levels

Rand

omizeddou

ble-blind

placebo-controlledtrial

Acutec

oron

ary

synd

romea

ndPC

I[58]

Tirofib

an(highdo

se)+

enoxaparin

Tirofib

an(highdo

se)+

UFH

60(30in

each

grou

p)

Thec

ombinatio

nof

tirofi

ban(highdo

se)+

enoxaparin

redu

ced

inflammationaft

erPC

I

Vonwillberand

CRP

D-dim

erand

prothrom

bin

fragmentw

eres

ignificantly

lower

inenoxaparin

grou

pthan

UFH

Openlabelrando

mized

controlledtrial

Superficialveno

usthrombo

phleb

itis

[59]

Dalteparin

SCIbup

rofen

72(37in

dalteparin

grou

p)

Sign

ificant

redu

ctionof

pain

form

baselin

etoday14

offollo

w-upNodifference

onthrombo

sisprogression

after

3mon

ths

mdashRa

ndom

izeddou

ble-blind

controlledtrial

Superficialveno

usthrombo

sis[60]

Nadroparin

SCNaproxen

117(39in

control

grou

p)

Nadroparin

redu

ced

symptom

andsig

nsof

thrombo

sedsuperficial

vein

bette

rthannaproxen

(1198750007)

mdashRa

ndom

izedopenlabel

clinicaltria

l

Superficialveno

usthrombo

sis[61]

Nadroparin

SCNadroparin

+acem

etacin

50

Sign

ificant

symptom

improvem

entinbo

thgrou

ps(1198750001)Th

ecombinatio

ngrou

pwas

bette

r

mdashRa

ndom

ized

controlled

trial

Periton

eald

ialysis

patie

nts[62]

Tinzaparin

Intraperito

neal

Isoton

icsalin

e21

Redu

ctionof

localand

syste

micinflammationin

periton

eald

ialysis

patie

nts

Redu

cedlevelsof

CRP(119875

0032)

andfib

rinogen

(119875

004

2)andIL-6

(1198750007)

indialysate

Rand

omizeddou

ble-blind

placebo-controlled

crossovertria

l

COPD

Chron

icObstructiv

ePu

lmon

aryDise

aseCR

PC-

Reactiv

eProtein

CPB

Cardio

Pulm

onaryBy

passE

CPE

osinop

hilC

ationicProtein

ERCP

End

oscopicRe

trogradeCh

olangiop

ancreatographyE

SR

ErythrocyteSedimentatio

nICUIntensiv

eCa

reUnitILinterleuk

inIV

intravenou

sLM

WHlow

molecular

weighth

eparinM

DAm

alon

dialdehydePAIPlasminogen

Activ

ator

InhibitorSC

sub

cutaneou

ssV

CAMSolub

leVa

scular

CellA

dhesionMoleculeTN

FTu

mor

Necrosis

Factorand

UFH

unfractionatedheparin

Advances in Pharmacological Sciences 9

Table 3 Summary of numbers and percentages of adequatelyreported items in each trial according to CONSORT checklist andJadad score

Trials Jadadscore

Adequately reporteditems (119899119873)

Percentage()

Abdollahi et al [52] 4 2974 392Ahmed et al [9] 3 2074 27Ang et al [17] 2 2474 324Ashraf et al [27] 2 2274 297Becker et al [37] 3 2874 378de Vroege et al [29] 3 2674 351Defraigne et al [28] 4 2874 378Derhaschnig et al [43] 3 3274 432Dixon et al [44] 4 5074 675Duong et al [11] 3 3074 405Gu et al [71] 2 1674 216Jerzynska et al [13] 3 2074 27Keating et al [45] 2 2174 284Koster et al [31] 2 2674 351Montalescot et al [54] 3 3574 473Nasiripour et al [55] 2 3474 46Oldgren et al [56] 3 2774 365Olsson et al [32] 2 2574 338van Ophoven et al [79] 2 2774 365Ozawa et al [33] 2 2774 365Ozkurt et al [24] 3 1874 243Paparella et al [72] 2 2274 297Polosa et al [67] 3 2374 311Rathbun et al [59] 5 4474 595Rudolph et al [57] 3 3174 412Serisier et al [47] 5 4574 608Stelmach et al [16] 3 3174 412Suzuki et al [49] 2 2374 31Vancheri et al [51] 4 2274 297Vasavada et al [25] 5 5274 702Walters et al [58] 3 3274 432Zezos et al [20] 3 3774 50

thrombophlebitis and hemodialysis Unfractionated heparin(UFH) was used in forty studies as subcutaneous intra-venous inhaler or heparin-coated circuits while others usedenoxaparin (119899 = 3) dalteparin (119899 = 4) nadroparin (119899 = 4)and tinzaparin (119899 = 1)

Table 3 provides information on the adequately reporteditems according to Jadad score andCONSORT items Amongthese 32 papers 11 (354) scored 2 and the remaining studiesscored 3 or higher according to Jadad score and just threestudies fulfill the criteria of Jadad score Calculated qualityscores according to CONSORT checklist range from 21 to70 in our object studies with twelve studies scoring greaterthan 40 The following characteristics were not exactlyreported in more than half of the trials identification as

a randomized trial in the title information about the settingand location of studies determination of sample size alloca-tion and implementation of randomization participant flowrecruitment and follow-up subgroup analysis limitations ofstudy harms registration number access to full trial protocoland funding source

4 Discussion

We discuss evidence from clinical studies supporting an anti-inflammatory role for heparin and heparin-related deriva-tives

41 Asthma Asthma is a chronic inflammatory disorderof airways characterized by bronchial hyperresponsivenessresulting in episodic bronchospasm Several studies in 1960sdescribed subjective improvement of symptoms in asthmaticpatients using intravenous heparin for the first time [3963] Inhaled heparin or its derivatives have been shown topossess antiasthmatic properties in various clinical modelsallergen induced [38 64] exercise [9] adenosine [6] anddistilled water challenge models [65] Seven randomizedcontrolled crossover trials studied anti-inflammatory effectsof heparin in exercise-induced or allergen-induced asthmahaving sample size range from 8 to 25 in 5 trials

Heparin inhalation reduced bronchial hyperreactivity ina single-blind randomized crossover trial (119899 = 12) byAhmed et al [9] Heparin inhalation (1000 120583kg) preventsexercise-induced asthma (119875 lt 005) without preventionof histamine-induced bronchoconstriction Stelmach et al[66] provoke challenge tests with histamine or leukotrieneD4 before and after inhalation of heparin showed that hep-arin (5000 Iu) decreases histamine and leukotriene-inducedbronchial hyperreactivity compared to placebo significantly(119875 0043 and 0005) but changes in Forced Expiratory Vol-ume (FEV 1) were not significant (119875 0064) The inhibitoryeffects of inhaled heparin in the airways in the absence ofbronchodilation might be related to suppressive action onmast cell degranulation A randomized double-blind studyin 10 subjects with asthma showed that heparin inhalationattenuates airway response to adenosine 51015840-monophosphate(AMP) but not to methacholine (119875 lt 001) suggestingthe theory that heparin acts more likely in association tomodulation of mediator release compared to a direct effecton smooth muscle [67]

Our results showed that inhaled enoxaparin was usedjust in a pre-post study of 24 asthmatic patients measur-ing inflammatory biomarkers and showed a reduction ineosinophil (119875 0006) and lymphocytes of bronchoalveolarlavage without any significant change in IL-5 or EosinophilCationic Protein (ECP) concentrations [12] Therefore itseems that enoxaparin could be a valuable add on treatmentin asthma like UFH Duong et al [11] evaluated IVX-0142nebulizer a heparin-derived hypersulfated disaccharide inasthma and showed nonsignificant decrease in early and lateasthmatic response

Performed studies did not show any adverse events orharms with heparin or related compounds except increase in

10 Advances in Pharmacological Sciences

the plasma partial thromboplastin time reported by Ahmedet al [9]

All in one considering the results of these studies wecan conclude that heparin and its derivatives could have anti-inflammatory effects and could be considered along withother treatments in asthma

42 Cardiopulmonary Bypass Contact and interaction ofblood with foreign surfaces during cardiopulmonary bypass(CPB) cause systemic inflammatory response syndrome(SIRS) through activation of several humoral cascadesincluding cytokines such as IL-6 IL-8 and Tumor NecrosisFactor-120572 (TNF-120572) [68] The inflammatory response can beattenuated by promoting the biocompatibility of the CPBcircuit Use of heparin-treated surfaces in CPB circuits hasbeen shown to decrease activation of leukocytes and thecomplement cascades [5] As a result need to inotropicsupport postoperative time of mechanical ventilation andrate of acute lung injury decrease and patients durationof hospital stay shortens which reflects the positive effectof heparin in CPB circuits [69 70] Twelve studies whoseendpoints were the effects of heparin-bonded circuits oninflammatory markers were included in our analysis and inthe majority of these trials [27 29 32ndash35 71] heparin-coatedcircuit significantly decreased the level of cytokines such asIL-6 IL-8 TNF-120572 complement complex neutrophils andelastase compared to non-heparin-coated circuit

Defraigne et al [28] randomized 200 patients in 4 groupsheparin-coated circuit with or without aprotinin administra-tion and uncoated circuit with or without aprotinin adminis-tration They measured IL-6 IL-8 TNF-120572 myeloperoxidase(MPO) and elastase level and concluded that cytokine releaseand neutrophil activation were not attenuated by heparin-coated circuit or by the administration of aprotinin Misawaet al [30] evaluated cytokines level under normothermicCPB in a small observational controlled study (119899 = 19 9 incontrol group) Levels of IL-6 IL-8 and ICAM-1 (indicatorof endothelial damage) were not different between study andcontrol group However as mentioned before most studiesindicate the favorable effect of heparin-coated circuit oninflammatory responses in CPB

Paparella et al [72] compared two doses of heparin and300 Iukg and 600 Iukg in 40 patients undergoing CPB in anRCT and showed that IL-6 and TNF-120572 plasma levels were inassociation to heparin dose It seems that lower heparin dosehad small influence on proinflammatory cytokines releasehowever higher doses make a better regulatory effect oncoagulation system

The side effects of heparin-coated circuits were notreported In these studies just a number of included studiesreported a decrease in platelet levels in both groups (coatedand noncoated circuit) No major events including hemor-rhage were reported

43 Inflammatory Bowel Diseases (IBD) Hypercoagulablestate may be an important contributing factor in the patho-genesis of IBD especially ulcerative colitis (UC) [73] A num-ber of studies evaluate the effects of heparin administrationon UC but the results obtained are controversial [17 19]

Bloom et al [74] did not find any favorable effect of LMWHtinzaparin over placebo in the treatment of active UC ina double-blind randomized placebo controlled multicentertrial (119899 = 100) evaluating mean change in colitis activity asthe primary endpoint Ang et al [17] compared heparin tohydrocortisone plus prednisolone in 20 patients (UC 119899 = 17Crohnrsquos colitis 119899 = 3) in open-label randomized crossovertrial whichmeasured endpoints clinical disease activity stoolfrequency and 120572

1acid glycoprotein and endoscopic and

histopathological grading indicate the efficacy and safety ofheparin compared to corticosteroids (119875 gt 005) in contrastthe study by Panes et al [19] did not show the efficacy ofheparin in UC compared to methylprednisolone

Zezos et al [20] compared enoxaparin with standardtreatment (aminosalicylate + corticosteroids) in 34 patientswith active UC The inflammatory biomarkers includingC-Reactive Protein (CRP) Erythrocyte Sedimentation Rate(ESR) and fibrinogen did not show any difference in studygroup compared to control and both groups showed similarrate of disease improvement (119875 gt 005) furthermorecoagulation factors did not change from one to anotherAuthors concluded that enoxaparin is a safe adjuvant but hasno additive benefit over standard treatment of UC

Generally the studies show conflicting results The hep-arin and LMWHs showed efficacy in regard of disease activityand also well tolerated but inflammatory markers did notchange significantly Therefore the improvement in diseaseactivity might be the result of heparinrsquos anticoagulant effects

44 Acute Coronary Syndrome (ACS) Inflammation has akey role in the pathogenesis of coronary artery plaquedestabilization and rupture leading to acute coronary syn-dromes (ACS) [75] Leukocyte activation monocyte andneutrophil infiltration result in local and systemic inflam-matory responses [76] Heparin and LMWHs are commonlyused in ACS to prevent clot formation they also seem tohave desirable effects on inflammatory markers level basedon sparse data

We found 8 studies about heparin and LMWHs in CADsevaluating anti-inflammatory effects as their endpoints Old-gren et al [56] found that dalteparin administration inpatients with unstable CAD (119899 = 555) did not affect IL-6C-Reactive Protein (CRP) and fibrinogen levels although itreduced coagulation activity and mortality rate in long termso it is concluded that these effects are not related to its anti-inflammatory properties Walters et al [58] compared highdose of tirofibanenoxaparin (119899 = 30) with tirofibanheparin(119899 = 30) in an open-label randomized controlled trial in highrisk percutaneous interventionThey found that combinationof high dose of tirofiban with enoxaparin significantly atten-uate inflammatory process (decreased levels of CRP and vonWillebrand factor) compared to tirofiban and heparin

The ARMADA study [54] evaluated anti-inflammatoryeffects of heparin and enoxaparin in Non-ST-ElevatedMyocardial Infarction (Non-STEMI) and reported thatinflammatory markers (CRP and von Willebrand factor)are affected more by LMWH compared to UFH Howeverbecause of the small sample size of the study (119899 = 68)

Advances in Pharmacological Sciences 11

it did not acquire sufficient statistical power to prove anyeffects on defined outcomes Nasiripour et al [55] found thatboth enoxaparin and heparin reduce inflammatory markersin STEMI patients at the same level however this study hadthe same limitations of sample size (119899 = 34) and power too

In summary considering heparins as the main stay treat-ment of ACS its effects are more pronounced as anticoagu-lating than as an anti-inflammatory agent in this pathologicalcondition

45 Cataract Surgery Postoperative inflammation isobserved in cataract surgery especially in children Newertechniques as lensectomy and phacoemulsification cause lesscomplication but still pose potential risks [77 78] It hasbeen suggested that a heparin surface-modified intraocularlens (IOL) or augmenting the irrigating solution withheparin during cataract surgery may reduce the incidence ofpostoperative inflammation Borgioli et al [22] confirm thishypothesis that heparin surface-modified IOL will reducethe inflammatory response compared to conventional IOLat least in short term period (3 months) in a large (524patients) double-blind multicenter trial A similar study byColin et al [23] (119899 = 58) confirms their results howeverthe power of Borgioli et al study was higher Heparinizedlenses showed also more anti-inflammatory effects duringlong term follow-up (1 year) Heparinized irrigating solutionwas used during cataract surgery in two different studies andinflammation decrease observed in the early postoperativeperiod of both studies (Kohnen et al [26] and Ozkurt et al[24]) Therefore it seems that heparin in both forms haveanti-inflammatory effects in cataract surgery

Vasavada et al [25] used enoxaparin irrigation solutionin 20 children undergoing bilateral cataract surgery butthey did not find any beneficial effect in early postoperativeinflammation This study acquired the highest quality in thestudy quality assessment process based on Jadad score andCONSORT items (5274 702) It is worth noticing that themajority of itemsmentioned in the CONSORT checklist wereadequately reported and covered in this paper

Potential mechanisms of anti-inflammatory effects ofheparin have been discussed completely in a review by Young[6] Binding of heparin to different mediators involved inthe immune system response (cytokines and chemokines)acute phase proteins and complement complex proteinsmay contribute to the anti-inflammatory activity of heparinNeutralizing of cytokines at the inflammation site is anotherpossible mechanism In most of the studies level of cytokinessuch as IL-6 IL-8 TNF-120572 and CRP was decreased afterheparin administration which can confirm this mechanismalso heparin and LMWHs inhibit adhesion of leukocytesand neutrophils to endothelial cells by binding to p-selectinand consequently prevent release of oxygen radicals andproteolytic enzymes Other possible mechanisms are as fol-lows inhibition of nuclear factor 120581B (NF-120581B) and inductionof apoptosis by modulation of activity of TNF-120572 and NF-120581B In a double-blind placebo-controlled trial (119899 = 62)in patients with stable coronary artery disease followingadministration of 1mgkg subcutaneous enoxaparin plasmalevels of myeloperoxidase (MPO) increased significantly

(119875 lt 0001) and subsequently endothelial function improved(119903 = 067 119875 lt 0001) through MPO binding to endotheliumand depleting vascular nitric oxide [57] This study confirmsanother possible mechanism of heparins anti-inflammatoryeffects

5 Conclusion

As we discussed heparins potential effects as anti-inflamma-tory agents supported by several clinical trials in varioussetting Heparin and its related derivatives have been shownto benefit patients with asthma and patients undergoingcardiopulmonary bypass and cataract surgery In otherinflammatory diseases such as IBD (ulcerative colitis) thestudies are heterogeneous and incongruent Most studies didnot report any unwanted event with heparins when they usedthem as anti-inflammatory agents whether through systemicor through local (as inhaler or irrigation or heparin-coatedcircuit) administration However because the majority ofthese trials did not pose optimal quality scores we cannotdraw a definite conclusion on the efficacy of heparin and itsderivatives as anti-inflammatory agents

The present review included studies which measuredinflammatory markers as their endpoints and in most ofthem these markers were decreased though not significantlyTo come to a definite conclusion further double-blindrandomized placebo-controlled clinical trials with a largersample size are needed However because the inflammationatherogenesis thrombogenesis and cell proliferation areassociated with each other the pleiotropic effects of heparinand related compounds may have greater therapeutic effectthan compounds that are directed against a single target

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

[1] B Casu ldquoHeparin structurerdquo Pathophysiology of Haemostasisand Thrombosis vol 20 supplement 1 pp 62ndash73 1990

[2] J Hirsh R Raschke T EWarkentin J E Dalen DDeykin andL Poller ldquoHeparin mechanism of action pharmacokineticsdosing considerations monitoring efficacy and safetyrdquo Chestvol 108 no 4 supplement pp 258Sndash275S 1995

[3] J Fareed D A Hoppensteadt and R L Bick ldquoAn update onheparins at the beginning of the new millenniumrdquo Seminars inThrombosis and Hemostasis vol 26 no 3 pp 5ndash21 2000

[4] J Hirsh ldquoDrug therapy heparinrdquo The New England Journal ofMedicine vol 324 no 22 pp 1565ndash1574 1991

[5] R J Ludwig ldquoTherapeutic use of heparin beyond anticoagu-lationrdquo Current Drug Discovery Technologies vol 6 no 4 pp281ndash289 2009

[6] E Young ldquoThe anti-inflammatory effects of heparin and relatedcompoundsrdquo Thrombosis Research vol 122 no 6 pp 743ndash7522008

12 Advances in Pharmacological Sciences

[7] A R Jadad R A Moore D Carroll et al ldquoAssessing the qualityof reports of randomized clinical trials is blinding necessaryrdquoControlled Clinical Trials vol 17 no 1 pp 1ndash12 1996

[8] K F Schulz D G Altman and D Moher ldquoCONSORT 2010statement updated guidelines for reporting parallel grouprandomised trialsrdquo International Journal of Surgery vol 9 no8 pp 672ndash677 2011

[9] T Ahmed J Garrigo and I Danta ldquoPreventing bronchocon-striction in exercise-induced asthma with inhaled heparinrdquoTheNewEngland Journal ofMedicine vol 329 no 2 pp 90ndash95 1993

[10] Z Diamant M C Timmers H Van Der Veen C P PageF J Van Der Meer and P J Sterk ldquoEffect of inhaled heparinon allergen-induced early and late asthmatic responses inpatients with atopic asthmardquo American Journal of Respiratoryand Critical Care Medicine vol 153 no 6 pp 1790ndash1795 1996

[11] M Duong D Cockcroft L-P Boulet et al ldquoThe effect ofIVX-0142 a heparin-derived hypersulfated disaccharide on theallergic airway responses in asthmardquo Allergy vol 63 no 9 pp1195ndash1201 2008

[12] A M Fal M Kraus-Filarska J Miecielica and J MalolepszyldquoMechanisms of action of nebulized low-molecular-weightheparin in patients with bronchial asthmardquo The Journal ofAllergy and Clinical Immunology vol 113 no 2 supplement pS36 2004

[13] J Jerzynska I Stelmach P Majak and P Kuna ldquoThe effectof inhaled heparin on airway responsiveness to histamine andmetacholine in asthmatic childrenrdquo Journal of Allergy andClinical Immunology vol 109 no 1 supplement 1 p S39 2002

[14] A F Kalpaklioglu Y S Demirel S Saryal and Z MisirligilldquoEffect of pretreatment with heparin on pulmonary and cuta-neous responserdquo Journal of Asthma vol 34 no 4 pp 337ndash3431997

[15] I Stelmach J Jerzynska A Brzozowska and P Kuna ldquoTheeffect of inhaled heparin on postleukotriene bronchoconstric-tion in children with asthmardquo Journal of Allergy and ClinicalImmunology vol 109 no 1 supplement 1 p S39 2002

[16] I Stelmach J Jerzynska W Stelmach et al ldquoThe effect ofinhaled heparin on airway responsiveness to histamine andleukotriene D4rdquo Allergy and Asthma Proceedings vol 24 no 1pp 59ndash65 2003

[17] Y S Ang N Mahmud B White et al ldquoRandomized compar-ison of unfractionated heparin with corticosteroids in severeactive inflammatory bowel diseaserdquo Alimentary PharmacologyandTherapeutics vol 14 no 8 pp 1015ndash1022 2000

[18] C Folwaczny B Wiebecke and K Loeschke ldquoUnfractionedheparin in the therapy of patients with highly active inflamma-tory bowel diseaserdquo The American Journal of Gastroenterologyvol 94 no 6 pp 1551ndash1555 1999

[19] J Panes M Esteve E Cabre et al ldquoComparison of heparinand steroids in the treatment of moderate and severe ulcerativecolitisrdquo Gastroenterology vol 119 no 4 pp 903ndash908 2000

[20] P Zezos G Papaioannou N Nikolaidis et al ldquoLow-molecular-weight heparin (enoxaparin) as adjuvant therapy in the treat-ment of active ulcerative colitis a randomized controlledcomparative studyrdquoAlimentary Pharmacology andTherapeuticsvol 23 no 10 pp 1443ndash1453 2006

[21] A A Vrij J M Jansen E J Schoon H C Hemker and RW Stockbrugger ldquoLow molecular weight heparin treatmentin steroid refractory ulcerative colitis clinical outcome andinfluence on mucosal capillary thrombirdquo Scandinavian Journalof Gastroenterology Supplement vol 36 no 234 pp 41ndash47 2001

[22] D M Borgioli D J Coster R F T Fan et al ldquoEffect of heparinsurface modification of polymethylmethacrylate intraocularlenses on signs of postoperative inflammation after extracap-sular cataract extraction one-year results of a double-maskedmulticenter studyrdquoOphthalmology vol 99 no 8 pp 1248ndash12551992

[23] J Colin S Roncin and M Wenzel ldquoEfficacy of heparinsurface-modified IOLs in reducing postoperative inflammatoryreactions in patients with exfoliation syndromemdasha double-blind comparative studyrdquo European Journal of Implant andRefractive Surgery vol 7 no 5 pp 266ndash270 1995

[24] Y B Ozkurt A Taskiran N Erdogan B Kandemir and OK Dogan ldquoEffect of heparin in the intraocular irrigating solu-tion on postoperative inflammation in the pediatric cataractsurgeryrdquoClinical Ophthalmology vol 3 no 1 pp 363ndash365 2009

[25] V A Vasavada M R Praveen S K Shah R H Trivedi andA R Vasavada ldquoAnti-inflammatory effect of low-molecular-weight heparin in pediatric cataract surgery a randomizedclinical trialrdquoThe American Journal of Ophthalmology vol 154no 2 pp 252ndash258 2012

[26] T Kohnen B Dick V Hessemer D D Koch and K WJacobi ldquoEffect of heparin in irrigating solution on inflammationfollowing small incision cataract surgeryrdquo Journal of Cataract ampRefractive Surgery vol 24 no 2 pp 237ndash243 1998

[27] S Ashraf Y Tian D Cowan A Entress P G Martin andK G Watterson ldquoRelease of proinflammatory cytokines dur-ing pediatric cardiopulmonary bypass heparin-bonded versusnonbonded oxygenatorsrdquo Annals of Thoracic Surgery vol 64no 6 pp 1790ndash1794 1997

[28] J-O Defraigne J Pincemail R Larbuisson F Blaffart andR Limet ldquoCytokine release and neutrophil activation are notprevented by heparin- coated circuits and aprotinin administra-tionrdquo Annals of Thoracic Surgery vol 69 no 4 pp 1084ndash10912000

[29] R de Vroege W van Oeveren J van Klarenbosch et al ldquoTheimpact of heparin-coated cardiopulmonary bypass circuits onpulmonary function and the release of inflammatory media-torsrdquo Anesthesia and Analgesia vol 98 no 6 pp 1586ndash15942004

[30] Y Misawa K Kawahito H Konishi and K Fuse ldquoCytokinemediated endothelial activation during and after normothermiccardiopulmonary bypass Heparin-bonded versus non heparin-bonded circuitsrdquo ASAIO Journal vol 46 no 6 pp 740ndash7432000

[31] A Koster T Fischer M Praus et al ldquoHemostatic activationand inflammatory response during cardiopulmonary bypassimpact of heparin managementrdquo Anesthesiology vol 97 no 4pp 837ndash841 2002

[32] C Olsson A Siegbahn A Henze et al ldquoHeparin-coatedcardiopulmonary bypass circuits reduce circulating comple-ment factors and interleukin-6 in paediatric heart surgeryrdquoScandinavian Cardiovascular Journal vol 34 no 1 pp 33ndash402000

[33] T Ozawa K Yoshihara N Koyama Y Watanabe N Shionoand Y Takanashi ldquoClinical efficacy of heparin-bonded bypasscircuits related to cytokine responses in childrenrdquo The Annalsof Thoracic Surgery vol 69 no 2 pp 584ndash590 2000

[34] A Parolari F Alamanni T Gherli et al ldquolsquoHigh dosersquo aprotininand heparin-coated circuits Clinical efficacy and inflammatoryresponserdquo Cardiovascular Surgery vol 7 no 1 pp 117ndash127 1999

[35] H Yamada I Kudoh Y Hirose M Toyoshima H Abe andK Kurahashi ldquoHeparin-coated circuits reduce the formation of

Advances in Pharmacological Sciences 13

TNF120572 during cardiopulmonary bypassrdquo Acta AnaesthesiologicaScandinavica vol 40 no 3 pp 311ndash317 1996

[36] O Barkay E Niv E Santo R Bruck A Hallak and F MKonikoff ldquoLow-dose heparin for the prevention of post-ERCPpancreatitis a randomized placebo-controlled trialrdquo SurgicalEndoscopy and Other Interventional Techniques vol 22 no 9pp 1971ndash1976 2008

[37] R C Becker K W Mahaffey H Yang et al ldquoHeparin-associated anti-Xa activity and platelet-derived prothromboticand proinflammatory biomarkers in moderate to high-riskpatients with acute coronary syndromerdquo Journal of Thrombosisand Thrombolysis vol 31 no 2 pp 146ndash153 2011

[38] S D Bowler S M Smith and P S Lavercombe ldquoHeparininhibits the immediate response to antigen in the skin and lungsof allergic subjectsrdquo American Review of Respiratory Diseasevol 147 no 1 pp 160ndash163 1993

[39] J P Boyle R H Smart and J K Shirey ldquoHeparin in thetreatment of chronic obstructive bronchopulmonary diseaserdquoThe American Journal of Cardiology vol 14 no 1 pp 25ndash281964

[40] Y Qian H Xie R Tian K Yu and R Wang ldquoEfficacy of lowmolecular weight heparin in patients with acute exacerbationof chronic obstructive pulmonary disease receiving ventilatorysupportrdquo COPD Journal of Chronic Obstructive PulmonaryDisease vol 11 no 2 pp 171ndash176 2014

[41] A Chamorro A Cervera J Castillo A Davalos J J Aponteand A M Planas ldquoUnfractionated heparin is associated with alower rise of serum vascular cell adhesion molecule-1 in acuteischemic stroke patientsrdquo Neuroscience Letters vol 328 no 3pp 229ndash232 2002

[42] R de Cock L A Ficker J G Dart A Garner and P WrightldquoTopical heparin in the treatment of ligneous conjunctivitisrdquoOphthalmology vol 102 no 11 pp 1654ndash1659 1995

[43] U Derhaschnig T Pernerstorfer M Knechtelsdorfer U Hol-lenstein S Panzer and B Jilma ldquoEvaluation of antiinflamma-tory and antiadhesive effects of heparins in human endotox-emiardquo Critical Care Medicine vol 31 no 4 pp 1108ndash1112 2003

[44] B DixonM J Schultz R Smith J B Fink J D Santamaria andD J Campbell ldquoNebulized heparin is associatedwith fewer daysof mechanical ventilation in critically ill patients a randomizedcontrolled trialrdquo Critical Care vol 14 no 5 article R180 2010

[45] F K Keating H L Dauerman D A Whitaker B E Sobeland D J Schneider ldquoThe effects of bivalirudin compared withthose of unfractionated heparin plus eptifibatide on inflam-mation and thrombin generation and activity during coronaryinterventionrdquo Coronary Artery Disease vol 16 no 6 pp 401ndash405 2005

[46] M Ledson M Gallagher C A Hart and M Walshaw ldquoNeb-ulized heparin in Burkholderia cepacia colonized adult cysticfibrosis patientsrdquo European Respiratory Journal vol 17 no 1 pp36ndash38 2001

[47] D J Serisier J K Shute P M Hockey B Higgins J Conwayand M P Carroll ldquoInhaled heparin in cystic fibrosisrdquo EuropeanRespiratory Journal vol 27 no 2 pp 354ndash358 2006

[48] O K Poyrazoglu A Dogukan M Yalniz D Seckin andA L Gunal ldquoAcute effect of standard heparin versus lowmolecular weight heparin on oxidative stress and inflammationin hemodialysis patientsrdquo Renal Failure vol 28 no 8 pp 723ndash727 2006

[49] S Suzuki T Matsuo H Kobayashi et al ldquoAntithrombotictreatment (argatroban vs heparin) in coronary angioplastyin angina pectoris effects on inflammatory hemostatic and

endothelium-derived parametersrdquoThrombosis Research vol 98no 4 pp 269ndash279 2000

[50] S D Trocme and H-I Li ldquoEffect of heparin-surface-modifiedintraocular lenses on postoperative inflammation after pha-coemulsification a randomized trial in a United States patientpopulationrdquo Ophthalmology vol 107 no 6 pp 1031ndash1037 2000

[51] C Vancheri C Mastruzzo F Armato et al ldquoIntranasal heparinreduces eosinophil recruitment after nasal allergen challenge inpatients with allergic rhinitisrdquo Journal of Allergy and ClinicalImmunology vol 108 no 5 pp 703ndash708 2001

[52] A Abdollahi M-T Naini H Shams and R Zarei ldquoEffect oflow-molecular-weight heparin on postoperative inflammationin phacomorphic glaucomardquo Archives of Iranian Medicine vol5 no 4 pp 225ndash229 2002

[53] R T S Lakshmi T Priyanka J Meenakshi K R MathangiV Jeyaraman and M Babu ldquoLow molecular weight heparinmediated regulation of nitric oxide synthase during burnwound healingrdquo Annals of Burns and Fire Disasters vol 24 no1 pp 24ndash29 2011

[54] G Montalescot C Bal-dit-Sollier D Chibedi et al ldquoCompar-ison of effects on markers of blood cell activation of enoxa-parin dalteparin and unfractionated heparin in patients withunstable angina pectoris or non-ST-segment elevation acutemyocardial infarction (the ARMADA study)rdquo The AmericanJournal of Cardiology vol 91 no 8 pp 925ndash930 2003

[55] S Nasiripour K Gholami SMousavi et al ldquoComparison of theeffects of enoxaparin and heparin on inflammatory biomarkersin patients with ST-segment elevated myocardial infarction aprospective open label pilot clinical trialrdquo Iranian Journal ofPharmaceutical Research vol 13 no 2 pp 583ndash590 2014

[56] J Oldgren C Fellenius K Boman et al ldquoInfluence of prolongeddalteparin treatment on coagulation fibrinolysis and inflam-mation in unstable coronary artery diseaserdquo Journal of InternalMedicine vol 258 no 5 pp 420ndash427 2005

[57] T K Rudolph V Rudolph A Witte et al ldquoLiberation of vesseladherent myeloperoxidase by enoxaparin improves endothelialfunctionrdquo International Journal of Cardiology vol 140 no 1 pp42ndash47 2010

[58] D L Walters M J Ray P Wood E J Perrin J H N Bettand C N Aroney ldquoHigh-dose tirofiban with enoxaparin andinflammatory markers in high-risk percutaneous interventionrdquoEuropean Journal of Clinical Investigation vol 40 no 2 pp 139ndash147 2010

[59] S W Rathbun C E Aston and T L Whitsett ldquoA randomizedtrial of dalteparin compared with ibuprofen for the treatmentof superficial thrombophlebitisrdquo Journal of Thrombosis andHaemostasis vol 10 no 5 pp 833ndash839 2012

[60] J P Titon D Auger P Grange et al ldquoTherapeutic managementof superficial venous thrombosis with calcium nadroparinDosage testing and comparison with a non-steroidal anti-inflammatory agentrdquo Annales de Cardiologie et d Angeiologievol 43 no 3 pp 160ndash166 1994

[61] H Uncu ldquoA comparison of low-molecular-weight heparin andcombined therapy of low-molecular-weight heparin with ananti-inflammatory agent in the treatment of superficial veinthrombosisrdquo Phlebology vol 24 no 2 pp 56ndash60 2009

[62] J A Sjoslashland R S Pedersen J Jespersen and J GramldquoIntraperitoneal heparin ameliorates the systemic inflamma-tory response in PD patientsrdquo NephronmdashClinical Practice vol100 no 4 pp c105ndashc110 2005

[63] N L Fine C Shim and M H Williams Jr ldquoObjectiveevaluation of heparin in the treatment of asthmardquo AmericanReview of Respiratory Disease vol 98 no 5 pp 886ndash887 1968

14 Advances in Pharmacological Sciences

[64] ZDiamantM C Timmers H van derVeen C P Page F J vander Meer and P J Sterk ldquoEffect of inhaled heparin on allergen-induced early and late asthmatic responses in patients withatopic asthmardquo American Journal of Respiratory and CriticalCare Medicine vol 153 no 6 I pp 1790ndash1795 1996

[65] C M E Tranfa A Vatrella R Parrella G Pelaia F Bariffiand S A Marsico ldquoEffect of inhaled heparin on water-inducedbronchoconstriction in allergic asthmaticsrdquoEuropean Journal ofClinical Pharmacology vol 57 no 1 pp 5ndash9 2001

[66] I Stelmach J Jerzynska A Brzozowska and P Kuna ldquoTheeffect of inhaled heparin on postleukotriene bronchoconstric-tion in children with asthmardquo Polski Merkuriusz Lekarski vol12 no 68 pp 95ndash98 2002

[67] R Polosa S Magrı C Vancheri et al ldquoTime course of changesin adenosine 51015840-monophosphate airway responsiveness withinhaled heparin in allergic asthmardquo Journal of Allergy andClinical Immunology vol 99 no 3 pp 338ndash342 1997

[68] J Butler GM Rocker and SWestaby ldquoInflammatory responseto cardiopulmonary bypassrdquo The Annals of Thoracic Surgeryvol 55 no 2 pp 552ndash559 1993

[69] J M Redmond A M Gillinov R S Stuart et al ldquoHeparin-coated bypass circuits reduce pulmonary injuryrdquoThe Annals ofThoracic Surgery vol 56 no 3 pp 474ndash479 1993

[70] S Svenmarker E Sandstrom T Karlsson et al ldquoClinical effectsof the heparin coated surface in cardiopulmonary bypassrdquoEuropean Journal of Cardio-Thoracic Surgery vol 11 no 5 pp957ndash964 1997

[71] Y J Gu W van Oeveren C Akkerman P W Boonstra RJ Huyzen and C R H Wildevuur ldquoHeparin-coated circuitsreduce the inflammatory response to cardiopulmonary bypassrdquoThe Annals of Thoracic Surgery vol 55 no 4 pp 917ndash922 1993

[72] D Paparella O O Al Radi Q H Meng T Venner K Teohand E Young ldquoThe effects of high-dose heparin on inflamma-tory and coagulation parameters following cardiopulmonarybypassrdquo Blood Coagulation and Fibrinolysis vol 16 no 5 pp323ndash328 2005

[73] S Danese A Papa S Saibeni A Repici A Malesci andM Vecchi ldquoInflammation and coagulation in inflammatorybowel disease the clot thickensrdquo The American Journal ofGastroenterology vol 102 no 1 pp 174ndash186 2007

[74] S Bloom S Kiilerich M R Lassen et al ldquoLow molecularweight heparin (tinzaparin) vs placebo in the treatment of mildto moderately active ulcerative colitisrdquo Alimentary Pharmacol-ogy ampTherapeutics vol 19 no 8 pp 871ndash878 2004

[75] P Libby ldquoCoronary artery injury and the biology of atheroscle-rosis inflammation thrombosis and stabilizationrdquo AmericanJournal of Cardiology vol 86 no 8 2000

[76] N T Mulvihill and J B Foley ldquoInflammation in acute coronarysyndromesrdquo Heart vol 87 no 3 pp 201ndash204 2002

[77] N A JamesonW V Good and C S Hoyt ldquoInflammation aftercataract surgery in childrenrdquoOphthalmic Surgery vol 23 no 2pp 99ndash102 1992

[78] R M Sinskey P A Amin and R Lingua ldquoCataract extractionand intraocular lens implantation in an infant with amonocularcongenital cataractrdquo Journal of Cataract amp Refractive Surgeryvol 20 no 6 pp 647ndash651 1994

[79] A van Ophoven A Heinecke and L Hertle ldquoSafety andefficacy of concurrent application of oral pentosan polysulfateand subcutaneous low-dose heparin for patients with interstitialcystitisrdquo Urology vol 66 no 4 pp 707ndash711 2005

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Page 9: Review Article Anti-Inflammatory Effects of Heparin and Its …downloads.hindawi.com/journals/aps/2015/507151.pdf · 2019. 7. 31. · Review Article Anti-Inflammatory Effects of Heparin

Advances in Pharmacological Sciences 9

Table 3 Summary of numbers and percentages of adequatelyreported items in each trial according to CONSORT checklist andJadad score

Trials Jadadscore

Adequately reporteditems (119899119873)

Percentage()

Abdollahi et al [52] 4 2974 392Ahmed et al [9] 3 2074 27Ang et al [17] 2 2474 324Ashraf et al [27] 2 2274 297Becker et al [37] 3 2874 378de Vroege et al [29] 3 2674 351Defraigne et al [28] 4 2874 378Derhaschnig et al [43] 3 3274 432Dixon et al [44] 4 5074 675Duong et al [11] 3 3074 405Gu et al [71] 2 1674 216Jerzynska et al [13] 3 2074 27Keating et al [45] 2 2174 284Koster et al [31] 2 2674 351Montalescot et al [54] 3 3574 473Nasiripour et al [55] 2 3474 46Oldgren et al [56] 3 2774 365Olsson et al [32] 2 2574 338van Ophoven et al [79] 2 2774 365Ozawa et al [33] 2 2774 365Ozkurt et al [24] 3 1874 243Paparella et al [72] 2 2274 297Polosa et al [67] 3 2374 311Rathbun et al [59] 5 4474 595Rudolph et al [57] 3 3174 412Serisier et al [47] 5 4574 608Stelmach et al [16] 3 3174 412Suzuki et al [49] 2 2374 31Vancheri et al [51] 4 2274 297Vasavada et al [25] 5 5274 702Walters et al [58] 3 3274 432Zezos et al [20] 3 3774 50

thrombophlebitis and hemodialysis Unfractionated heparin(UFH) was used in forty studies as subcutaneous intra-venous inhaler or heparin-coated circuits while others usedenoxaparin (119899 = 3) dalteparin (119899 = 4) nadroparin (119899 = 4)and tinzaparin (119899 = 1)

Table 3 provides information on the adequately reporteditems according to Jadad score andCONSORT items Amongthese 32 papers 11 (354) scored 2 and the remaining studiesscored 3 or higher according to Jadad score and just threestudies fulfill the criteria of Jadad score Calculated qualityscores according to CONSORT checklist range from 21 to70 in our object studies with twelve studies scoring greaterthan 40 The following characteristics were not exactlyreported in more than half of the trials identification as

a randomized trial in the title information about the settingand location of studies determination of sample size alloca-tion and implementation of randomization participant flowrecruitment and follow-up subgroup analysis limitations ofstudy harms registration number access to full trial protocoland funding source

4 Discussion

We discuss evidence from clinical studies supporting an anti-inflammatory role for heparin and heparin-related deriva-tives

41 Asthma Asthma is a chronic inflammatory disorderof airways characterized by bronchial hyperresponsivenessresulting in episodic bronchospasm Several studies in 1960sdescribed subjective improvement of symptoms in asthmaticpatients using intravenous heparin for the first time [3963] Inhaled heparin or its derivatives have been shown topossess antiasthmatic properties in various clinical modelsallergen induced [38 64] exercise [9] adenosine [6] anddistilled water challenge models [65] Seven randomizedcontrolled crossover trials studied anti-inflammatory effectsof heparin in exercise-induced or allergen-induced asthmahaving sample size range from 8 to 25 in 5 trials

Heparin inhalation reduced bronchial hyperreactivity ina single-blind randomized crossover trial (119899 = 12) byAhmed et al [9] Heparin inhalation (1000 120583kg) preventsexercise-induced asthma (119875 lt 005) without preventionof histamine-induced bronchoconstriction Stelmach et al[66] provoke challenge tests with histamine or leukotrieneD4 before and after inhalation of heparin showed that hep-arin (5000 Iu) decreases histamine and leukotriene-inducedbronchial hyperreactivity compared to placebo significantly(119875 0043 and 0005) but changes in Forced Expiratory Vol-ume (FEV 1) were not significant (119875 0064) The inhibitoryeffects of inhaled heparin in the airways in the absence ofbronchodilation might be related to suppressive action onmast cell degranulation A randomized double-blind studyin 10 subjects with asthma showed that heparin inhalationattenuates airway response to adenosine 51015840-monophosphate(AMP) but not to methacholine (119875 lt 001) suggestingthe theory that heparin acts more likely in association tomodulation of mediator release compared to a direct effecton smooth muscle [67]

Our results showed that inhaled enoxaparin was usedjust in a pre-post study of 24 asthmatic patients measur-ing inflammatory biomarkers and showed a reduction ineosinophil (119875 0006) and lymphocytes of bronchoalveolarlavage without any significant change in IL-5 or EosinophilCationic Protein (ECP) concentrations [12] Therefore itseems that enoxaparin could be a valuable add on treatmentin asthma like UFH Duong et al [11] evaluated IVX-0142nebulizer a heparin-derived hypersulfated disaccharide inasthma and showed nonsignificant decrease in early and lateasthmatic response

Performed studies did not show any adverse events orharms with heparin or related compounds except increase in

10 Advances in Pharmacological Sciences

the plasma partial thromboplastin time reported by Ahmedet al [9]

All in one considering the results of these studies wecan conclude that heparin and its derivatives could have anti-inflammatory effects and could be considered along withother treatments in asthma

42 Cardiopulmonary Bypass Contact and interaction ofblood with foreign surfaces during cardiopulmonary bypass(CPB) cause systemic inflammatory response syndrome(SIRS) through activation of several humoral cascadesincluding cytokines such as IL-6 IL-8 and Tumor NecrosisFactor-120572 (TNF-120572) [68] The inflammatory response can beattenuated by promoting the biocompatibility of the CPBcircuit Use of heparin-treated surfaces in CPB circuits hasbeen shown to decrease activation of leukocytes and thecomplement cascades [5] As a result need to inotropicsupport postoperative time of mechanical ventilation andrate of acute lung injury decrease and patients durationof hospital stay shortens which reflects the positive effectof heparin in CPB circuits [69 70] Twelve studies whoseendpoints were the effects of heparin-bonded circuits oninflammatory markers were included in our analysis and inthe majority of these trials [27 29 32ndash35 71] heparin-coatedcircuit significantly decreased the level of cytokines such asIL-6 IL-8 TNF-120572 complement complex neutrophils andelastase compared to non-heparin-coated circuit

Defraigne et al [28] randomized 200 patients in 4 groupsheparin-coated circuit with or without aprotinin administra-tion and uncoated circuit with or without aprotinin adminis-tration They measured IL-6 IL-8 TNF-120572 myeloperoxidase(MPO) and elastase level and concluded that cytokine releaseand neutrophil activation were not attenuated by heparin-coated circuit or by the administration of aprotinin Misawaet al [30] evaluated cytokines level under normothermicCPB in a small observational controlled study (119899 = 19 9 incontrol group) Levels of IL-6 IL-8 and ICAM-1 (indicatorof endothelial damage) were not different between study andcontrol group However as mentioned before most studiesindicate the favorable effect of heparin-coated circuit oninflammatory responses in CPB

Paparella et al [72] compared two doses of heparin and300 Iukg and 600 Iukg in 40 patients undergoing CPB in anRCT and showed that IL-6 and TNF-120572 plasma levels were inassociation to heparin dose It seems that lower heparin dosehad small influence on proinflammatory cytokines releasehowever higher doses make a better regulatory effect oncoagulation system

The side effects of heparin-coated circuits were notreported In these studies just a number of included studiesreported a decrease in platelet levels in both groups (coatedand noncoated circuit) No major events including hemor-rhage were reported

43 Inflammatory Bowel Diseases (IBD) Hypercoagulablestate may be an important contributing factor in the patho-genesis of IBD especially ulcerative colitis (UC) [73] A num-ber of studies evaluate the effects of heparin administrationon UC but the results obtained are controversial [17 19]

Bloom et al [74] did not find any favorable effect of LMWHtinzaparin over placebo in the treatment of active UC ina double-blind randomized placebo controlled multicentertrial (119899 = 100) evaluating mean change in colitis activity asthe primary endpoint Ang et al [17] compared heparin tohydrocortisone plus prednisolone in 20 patients (UC 119899 = 17Crohnrsquos colitis 119899 = 3) in open-label randomized crossovertrial whichmeasured endpoints clinical disease activity stoolfrequency and 120572

1acid glycoprotein and endoscopic and

histopathological grading indicate the efficacy and safety ofheparin compared to corticosteroids (119875 gt 005) in contrastthe study by Panes et al [19] did not show the efficacy ofheparin in UC compared to methylprednisolone

Zezos et al [20] compared enoxaparin with standardtreatment (aminosalicylate + corticosteroids) in 34 patientswith active UC The inflammatory biomarkers includingC-Reactive Protein (CRP) Erythrocyte Sedimentation Rate(ESR) and fibrinogen did not show any difference in studygroup compared to control and both groups showed similarrate of disease improvement (119875 gt 005) furthermorecoagulation factors did not change from one to anotherAuthors concluded that enoxaparin is a safe adjuvant but hasno additive benefit over standard treatment of UC

Generally the studies show conflicting results The hep-arin and LMWHs showed efficacy in regard of disease activityand also well tolerated but inflammatory markers did notchange significantly Therefore the improvement in diseaseactivity might be the result of heparinrsquos anticoagulant effects

44 Acute Coronary Syndrome (ACS) Inflammation has akey role in the pathogenesis of coronary artery plaquedestabilization and rupture leading to acute coronary syn-dromes (ACS) [75] Leukocyte activation monocyte andneutrophil infiltration result in local and systemic inflam-matory responses [76] Heparin and LMWHs are commonlyused in ACS to prevent clot formation they also seem tohave desirable effects on inflammatory markers level basedon sparse data

We found 8 studies about heparin and LMWHs in CADsevaluating anti-inflammatory effects as their endpoints Old-gren et al [56] found that dalteparin administration inpatients with unstable CAD (119899 = 555) did not affect IL-6C-Reactive Protein (CRP) and fibrinogen levels although itreduced coagulation activity and mortality rate in long termso it is concluded that these effects are not related to its anti-inflammatory properties Walters et al [58] compared highdose of tirofibanenoxaparin (119899 = 30) with tirofibanheparin(119899 = 30) in an open-label randomized controlled trial in highrisk percutaneous interventionThey found that combinationof high dose of tirofiban with enoxaparin significantly atten-uate inflammatory process (decreased levels of CRP and vonWillebrand factor) compared to tirofiban and heparin

The ARMADA study [54] evaluated anti-inflammatoryeffects of heparin and enoxaparin in Non-ST-ElevatedMyocardial Infarction (Non-STEMI) and reported thatinflammatory markers (CRP and von Willebrand factor)are affected more by LMWH compared to UFH Howeverbecause of the small sample size of the study (119899 = 68)

Advances in Pharmacological Sciences 11

it did not acquire sufficient statistical power to prove anyeffects on defined outcomes Nasiripour et al [55] found thatboth enoxaparin and heparin reduce inflammatory markersin STEMI patients at the same level however this study hadthe same limitations of sample size (119899 = 34) and power too

In summary considering heparins as the main stay treat-ment of ACS its effects are more pronounced as anticoagu-lating than as an anti-inflammatory agent in this pathologicalcondition

45 Cataract Surgery Postoperative inflammation isobserved in cataract surgery especially in children Newertechniques as lensectomy and phacoemulsification cause lesscomplication but still pose potential risks [77 78] It hasbeen suggested that a heparin surface-modified intraocularlens (IOL) or augmenting the irrigating solution withheparin during cataract surgery may reduce the incidence ofpostoperative inflammation Borgioli et al [22] confirm thishypothesis that heparin surface-modified IOL will reducethe inflammatory response compared to conventional IOLat least in short term period (3 months) in a large (524patients) double-blind multicenter trial A similar study byColin et al [23] (119899 = 58) confirms their results howeverthe power of Borgioli et al study was higher Heparinizedlenses showed also more anti-inflammatory effects duringlong term follow-up (1 year) Heparinized irrigating solutionwas used during cataract surgery in two different studies andinflammation decrease observed in the early postoperativeperiod of both studies (Kohnen et al [26] and Ozkurt et al[24]) Therefore it seems that heparin in both forms haveanti-inflammatory effects in cataract surgery

Vasavada et al [25] used enoxaparin irrigation solutionin 20 children undergoing bilateral cataract surgery butthey did not find any beneficial effect in early postoperativeinflammation This study acquired the highest quality in thestudy quality assessment process based on Jadad score andCONSORT items (5274 702) It is worth noticing that themajority of itemsmentioned in the CONSORT checklist wereadequately reported and covered in this paper

Potential mechanisms of anti-inflammatory effects ofheparin have been discussed completely in a review by Young[6] Binding of heparin to different mediators involved inthe immune system response (cytokines and chemokines)acute phase proteins and complement complex proteinsmay contribute to the anti-inflammatory activity of heparinNeutralizing of cytokines at the inflammation site is anotherpossible mechanism In most of the studies level of cytokinessuch as IL-6 IL-8 TNF-120572 and CRP was decreased afterheparin administration which can confirm this mechanismalso heparin and LMWHs inhibit adhesion of leukocytesand neutrophils to endothelial cells by binding to p-selectinand consequently prevent release of oxygen radicals andproteolytic enzymes Other possible mechanisms are as fol-lows inhibition of nuclear factor 120581B (NF-120581B) and inductionof apoptosis by modulation of activity of TNF-120572 and NF-120581B In a double-blind placebo-controlled trial (119899 = 62)in patients with stable coronary artery disease followingadministration of 1mgkg subcutaneous enoxaparin plasmalevels of myeloperoxidase (MPO) increased significantly

(119875 lt 0001) and subsequently endothelial function improved(119903 = 067 119875 lt 0001) through MPO binding to endotheliumand depleting vascular nitric oxide [57] This study confirmsanother possible mechanism of heparins anti-inflammatoryeffects

5 Conclusion

As we discussed heparins potential effects as anti-inflamma-tory agents supported by several clinical trials in varioussetting Heparin and its related derivatives have been shownto benefit patients with asthma and patients undergoingcardiopulmonary bypass and cataract surgery In otherinflammatory diseases such as IBD (ulcerative colitis) thestudies are heterogeneous and incongruent Most studies didnot report any unwanted event with heparins when they usedthem as anti-inflammatory agents whether through systemicor through local (as inhaler or irrigation or heparin-coatedcircuit) administration However because the majority ofthese trials did not pose optimal quality scores we cannotdraw a definite conclusion on the efficacy of heparin and itsderivatives as anti-inflammatory agents

The present review included studies which measuredinflammatory markers as their endpoints and in most ofthem these markers were decreased though not significantlyTo come to a definite conclusion further double-blindrandomized placebo-controlled clinical trials with a largersample size are needed However because the inflammationatherogenesis thrombogenesis and cell proliferation areassociated with each other the pleiotropic effects of heparinand related compounds may have greater therapeutic effectthan compounds that are directed against a single target

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

[1] B Casu ldquoHeparin structurerdquo Pathophysiology of Haemostasisand Thrombosis vol 20 supplement 1 pp 62ndash73 1990

[2] J Hirsh R Raschke T EWarkentin J E Dalen DDeykin andL Poller ldquoHeparin mechanism of action pharmacokineticsdosing considerations monitoring efficacy and safetyrdquo Chestvol 108 no 4 supplement pp 258Sndash275S 1995

[3] J Fareed D A Hoppensteadt and R L Bick ldquoAn update onheparins at the beginning of the new millenniumrdquo Seminars inThrombosis and Hemostasis vol 26 no 3 pp 5ndash21 2000

[4] J Hirsh ldquoDrug therapy heparinrdquo The New England Journal ofMedicine vol 324 no 22 pp 1565ndash1574 1991

[5] R J Ludwig ldquoTherapeutic use of heparin beyond anticoagu-lationrdquo Current Drug Discovery Technologies vol 6 no 4 pp281ndash289 2009

[6] E Young ldquoThe anti-inflammatory effects of heparin and relatedcompoundsrdquo Thrombosis Research vol 122 no 6 pp 743ndash7522008

12 Advances in Pharmacological Sciences

[7] A R Jadad R A Moore D Carroll et al ldquoAssessing the qualityof reports of randomized clinical trials is blinding necessaryrdquoControlled Clinical Trials vol 17 no 1 pp 1ndash12 1996

[8] K F Schulz D G Altman and D Moher ldquoCONSORT 2010statement updated guidelines for reporting parallel grouprandomised trialsrdquo International Journal of Surgery vol 9 no8 pp 672ndash677 2011

[9] T Ahmed J Garrigo and I Danta ldquoPreventing bronchocon-striction in exercise-induced asthma with inhaled heparinrdquoTheNewEngland Journal ofMedicine vol 329 no 2 pp 90ndash95 1993

[10] Z Diamant M C Timmers H Van Der Veen C P PageF J Van Der Meer and P J Sterk ldquoEffect of inhaled heparinon allergen-induced early and late asthmatic responses inpatients with atopic asthmardquo American Journal of Respiratoryand Critical Care Medicine vol 153 no 6 pp 1790ndash1795 1996

[11] M Duong D Cockcroft L-P Boulet et al ldquoThe effect ofIVX-0142 a heparin-derived hypersulfated disaccharide on theallergic airway responses in asthmardquo Allergy vol 63 no 9 pp1195ndash1201 2008

[12] A M Fal M Kraus-Filarska J Miecielica and J MalolepszyldquoMechanisms of action of nebulized low-molecular-weightheparin in patients with bronchial asthmardquo The Journal ofAllergy and Clinical Immunology vol 113 no 2 supplement pS36 2004

[13] J Jerzynska I Stelmach P Majak and P Kuna ldquoThe effectof inhaled heparin on airway responsiveness to histamine andmetacholine in asthmatic childrenrdquo Journal of Allergy andClinical Immunology vol 109 no 1 supplement 1 p S39 2002

[14] A F Kalpaklioglu Y S Demirel S Saryal and Z MisirligilldquoEffect of pretreatment with heparin on pulmonary and cuta-neous responserdquo Journal of Asthma vol 34 no 4 pp 337ndash3431997

[15] I Stelmach J Jerzynska A Brzozowska and P Kuna ldquoTheeffect of inhaled heparin on postleukotriene bronchoconstric-tion in children with asthmardquo Journal of Allergy and ClinicalImmunology vol 109 no 1 supplement 1 p S39 2002

[16] I Stelmach J Jerzynska W Stelmach et al ldquoThe effect ofinhaled heparin on airway responsiveness to histamine andleukotriene D4rdquo Allergy and Asthma Proceedings vol 24 no 1pp 59ndash65 2003

[17] Y S Ang N Mahmud B White et al ldquoRandomized compar-ison of unfractionated heparin with corticosteroids in severeactive inflammatory bowel diseaserdquo Alimentary PharmacologyandTherapeutics vol 14 no 8 pp 1015ndash1022 2000

[18] C Folwaczny B Wiebecke and K Loeschke ldquoUnfractionedheparin in the therapy of patients with highly active inflamma-tory bowel diseaserdquo The American Journal of Gastroenterologyvol 94 no 6 pp 1551ndash1555 1999

[19] J Panes M Esteve E Cabre et al ldquoComparison of heparinand steroids in the treatment of moderate and severe ulcerativecolitisrdquo Gastroenterology vol 119 no 4 pp 903ndash908 2000

[20] P Zezos G Papaioannou N Nikolaidis et al ldquoLow-molecular-weight heparin (enoxaparin) as adjuvant therapy in the treat-ment of active ulcerative colitis a randomized controlledcomparative studyrdquoAlimentary Pharmacology andTherapeuticsvol 23 no 10 pp 1443ndash1453 2006

[21] A A Vrij J M Jansen E J Schoon H C Hemker and RW Stockbrugger ldquoLow molecular weight heparin treatmentin steroid refractory ulcerative colitis clinical outcome andinfluence on mucosal capillary thrombirdquo Scandinavian Journalof Gastroenterology Supplement vol 36 no 234 pp 41ndash47 2001

[22] D M Borgioli D J Coster R F T Fan et al ldquoEffect of heparinsurface modification of polymethylmethacrylate intraocularlenses on signs of postoperative inflammation after extracap-sular cataract extraction one-year results of a double-maskedmulticenter studyrdquoOphthalmology vol 99 no 8 pp 1248ndash12551992

[23] J Colin S Roncin and M Wenzel ldquoEfficacy of heparinsurface-modified IOLs in reducing postoperative inflammatoryreactions in patients with exfoliation syndromemdasha double-blind comparative studyrdquo European Journal of Implant andRefractive Surgery vol 7 no 5 pp 266ndash270 1995

[24] Y B Ozkurt A Taskiran N Erdogan B Kandemir and OK Dogan ldquoEffect of heparin in the intraocular irrigating solu-tion on postoperative inflammation in the pediatric cataractsurgeryrdquoClinical Ophthalmology vol 3 no 1 pp 363ndash365 2009

[25] V A Vasavada M R Praveen S K Shah R H Trivedi andA R Vasavada ldquoAnti-inflammatory effect of low-molecular-weight heparin in pediatric cataract surgery a randomizedclinical trialrdquoThe American Journal of Ophthalmology vol 154no 2 pp 252ndash258 2012

[26] T Kohnen B Dick V Hessemer D D Koch and K WJacobi ldquoEffect of heparin in irrigating solution on inflammationfollowing small incision cataract surgeryrdquo Journal of Cataract ampRefractive Surgery vol 24 no 2 pp 237ndash243 1998

[27] S Ashraf Y Tian D Cowan A Entress P G Martin andK G Watterson ldquoRelease of proinflammatory cytokines dur-ing pediatric cardiopulmonary bypass heparin-bonded versusnonbonded oxygenatorsrdquo Annals of Thoracic Surgery vol 64no 6 pp 1790ndash1794 1997

[28] J-O Defraigne J Pincemail R Larbuisson F Blaffart andR Limet ldquoCytokine release and neutrophil activation are notprevented by heparin- coated circuits and aprotinin administra-tionrdquo Annals of Thoracic Surgery vol 69 no 4 pp 1084ndash10912000

[29] R de Vroege W van Oeveren J van Klarenbosch et al ldquoTheimpact of heparin-coated cardiopulmonary bypass circuits onpulmonary function and the release of inflammatory media-torsrdquo Anesthesia and Analgesia vol 98 no 6 pp 1586ndash15942004

[30] Y Misawa K Kawahito H Konishi and K Fuse ldquoCytokinemediated endothelial activation during and after normothermiccardiopulmonary bypass Heparin-bonded versus non heparin-bonded circuitsrdquo ASAIO Journal vol 46 no 6 pp 740ndash7432000

[31] A Koster T Fischer M Praus et al ldquoHemostatic activationand inflammatory response during cardiopulmonary bypassimpact of heparin managementrdquo Anesthesiology vol 97 no 4pp 837ndash841 2002

[32] C Olsson A Siegbahn A Henze et al ldquoHeparin-coatedcardiopulmonary bypass circuits reduce circulating comple-ment factors and interleukin-6 in paediatric heart surgeryrdquoScandinavian Cardiovascular Journal vol 34 no 1 pp 33ndash402000

[33] T Ozawa K Yoshihara N Koyama Y Watanabe N Shionoand Y Takanashi ldquoClinical efficacy of heparin-bonded bypasscircuits related to cytokine responses in childrenrdquo The Annalsof Thoracic Surgery vol 69 no 2 pp 584ndash590 2000

[34] A Parolari F Alamanni T Gherli et al ldquolsquoHigh dosersquo aprotininand heparin-coated circuits Clinical efficacy and inflammatoryresponserdquo Cardiovascular Surgery vol 7 no 1 pp 117ndash127 1999

[35] H Yamada I Kudoh Y Hirose M Toyoshima H Abe andK Kurahashi ldquoHeparin-coated circuits reduce the formation of

Advances in Pharmacological Sciences 13

TNF120572 during cardiopulmonary bypassrdquo Acta AnaesthesiologicaScandinavica vol 40 no 3 pp 311ndash317 1996

[36] O Barkay E Niv E Santo R Bruck A Hallak and F MKonikoff ldquoLow-dose heparin for the prevention of post-ERCPpancreatitis a randomized placebo-controlled trialrdquo SurgicalEndoscopy and Other Interventional Techniques vol 22 no 9pp 1971ndash1976 2008

[37] R C Becker K W Mahaffey H Yang et al ldquoHeparin-associated anti-Xa activity and platelet-derived prothromboticand proinflammatory biomarkers in moderate to high-riskpatients with acute coronary syndromerdquo Journal of Thrombosisand Thrombolysis vol 31 no 2 pp 146ndash153 2011

[38] S D Bowler S M Smith and P S Lavercombe ldquoHeparininhibits the immediate response to antigen in the skin and lungsof allergic subjectsrdquo American Review of Respiratory Diseasevol 147 no 1 pp 160ndash163 1993

[39] J P Boyle R H Smart and J K Shirey ldquoHeparin in thetreatment of chronic obstructive bronchopulmonary diseaserdquoThe American Journal of Cardiology vol 14 no 1 pp 25ndash281964

[40] Y Qian H Xie R Tian K Yu and R Wang ldquoEfficacy of lowmolecular weight heparin in patients with acute exacerbationof chronic obstructive pulmonary disease receiving ventilatorysupportrdquo COPD Journal of Chronic Obstructive PulmonaryDisease vol 11 no 2 pp 171ndash176 2014

[41] A Chamorro A Cervera J Castillo A Davalos J J Aponteand A M Planas ldquoUnfractionated heparin is associated with alower rise of serum vascular cell adhesion molecule-1 in acuteischemic stroke patientsrdquo Neuroscience Letters vol 328 no 3pp 229ndash232 2002

[42] R de Cock L A Ficker J G Dart A Garner and P WrightldquoTopical heparin in the treatment of ligneous conjunctivitisrdquoOphthalmology vol 102 no 11 pp 1654ndash1659 1995

[43] U Derhaschnig T Pernerstorfer M Knechtelsdorfer U Hol-lenstein S Panzer and B Jilma ldquoEvaluation of antiinflamma-tory and antiadhesive effects of heparins in human endotox-emiardquo Critical Care Medicine vol 31 no 4 pp 1108ndash1112 2003

[44] B DixonM J Schultz R Smith J B Fink J D Santamaria andD J Campbell ldquoNebulized heparin is associatedwith fewer daysof mechanical ventilation in critically ill patients a randomizedcontrolled trialrdquo Critical Care vol 14 no 5 article R180 2010

[45] F K Keating H L Dauerman D A Whitaker B E Sobeland D J Schneider ldquoThe effects of bivalirudin compared withthose of unfractionated heparin plus eptifibatide on inflam-mation and thrombin generation and activity during coronaryinterventionrdquo Coronary Artery Disease vol 16 no 6 pp 401ndash405 2005

[46] M Ledson M Gallagher C A Hart and M Walshaw ldquoNeb-ulized heparin in Burkholderia cepacia colonized adult cysticfibrosis patientsrdquo European Respiratory Journal vol 17 no 1 pp36ndash38 2001

[47] D J Serisier J K Shute P M Hockey B Higgins J Conwayand M P Carroll ldquoInhaled heparin in cystic fibrosisrdquo EuropeanRespiratory Journal vol 27 no 2 pp 354ndash358 2006

[48] O K Poyrazoglu A Dogukan M Yalniz D Seckin andA L Gunal ldquoAcute effect of standard heparin versus lowmolecular weight heparin on oxidative stress and inflammationin hemodialysis patientsrdquo Renal Failure vol 28 no 8 pp 723ndash727 2006

[49] S Suzuki T Matsuo H Kobayashi et al ldquoAntithrombotictreatment (argatroban vs heparin) in coronary angioplastyin angina pectoris effects on inflammatory hemostatic and

endothelium-derived parametersrdquoThrombosis Research vol 98no 4 pp 269ndash279 2000

[50] S D Trocme and H-I Li ldquoEffect of heparin-surface-modifiedintraocular lenses on postoperative inflammation after pha-coemulsification a randomized trial in a United States patientpopulationrdquo Ophthalmology vol 107 no 6 pp 1031ndash1037 2000

[51] C Vancheri C Mastruzzo F Armato et al ldquoIntranasal heparinreduces eosinophil recruitment after nasal allergen challenge inpatients with allergic rhinitisrdquo Journal of Allergy and ClinicalImmunology vol 108 no 5 pp 703ndash708 2001

[52] A Abdollahi M-T Naini H Shams and R Zarei ldquoEffect oflow-molecular-weight heparin on postoperative inflammationin phacomorphic glaucomardquo Archives of Iranian Medicine vol5 no 4 pp 225ndash229 2002

[53] R T S Lakshmi T Priyanka J Meenakshi K R MathangiV Jeyaraman and M Babu ldquoLow molecular weight heparinmediated regulation of nitric oxide synthase during burnwound healingrdquo Annals of Burns and Fire Disasters vol 24 no1 pp 24ndash29 2011

[54] G Montalescot C Bal-dit-Sollier D Chibedi et al ldquoCompar-ison of effects on markers of blood cell activation of enoxa-parin dalteparin and unfractionated heparin in patients withunstable angina pectoris or non-ST-segment elevation acutemyocardial infarction (the ARMADA study)rdquo The AmericanJournal of Cardiology vol 91 no 8 pp 925ndash930 2003

[55] S Nasiripour K Gholami SMousavi et al ldquoComparison of theeffects of enoxaparin and heparin on inflammatory biomarkersin patients with ST-segment elevated myocardial infarction aprospective open label pilot clinical trialrdquo Iranian Journal ofPharmaceutical Research vol 13 no 2 pp 583ndash590 2014

[56] J Oldgren C Fellenius K Boman et al ldquoInfluence of prolongeddalteparin treatment on coagulation fibrinolysis and inflam-mation in unstable coronary artery diseaserdquo Journal of InternalMedicine vol 258 no 5 pp 420ndash427 2005

[57] T K Rudolph V Rudolph A Witte et al ldquoLiberation of vesseladherent myeloperoxidase by enoxaparin improves endothelialfunctionrdquo International Journal of Cardiology vol 140 no 1 pp42ndash47 2010

[58] D L Walters M J Ray P Wood E J Perrin J H N Bettand C N Aroney ldquoHigh-dose tirofiban with enoxaparin andinflammatory markers in high-risk percutaneous interventionrdquoEuropean Journal of Clinical Investigation vol 40 no 2 pp 139ndash147 2010

[59] S W Rathbun C E Aston and T L Whitsett ldquoA randomizedtrial of dalteparin compared with ibuprofen for the treatmentof superficial thrombophlebitisrdquo Journal of Thrombosis andHaemostasis vol 10 no 5 pp 833ndash839 2012

[60] J P Titon D Auger P Grange et al ldquoTherapeutic managementof superficial venous thrombosis with calcium nadroparinDosage testing and comparison with a non-steroidal anti-inflammatory agentrdquo Annales de Cardiologie et d Angeiologievol 43 no 3 pp 160ndash166 1994

[61] H Uncu ldquoA comparison of low-molecular-weight heparin andcombined therapy of low-molecular-weight heparin with ananti-inflammatory agent in the treatment of superficial veinthrombosisrdquo Phlebology vol 24 no 2 pp 56ndash60 2009

[62] J A Sjoslashland R S Pedersen J Jespersen and J GramldquoIntraperitoneal heparin ameliorates the systemic inflamma-tory response in PD patientsrdquo NephronmdashClinical Practice vol100 no 4 pp c105ndashc110 2005

[63] N L Fine C Shim and M H Williams Jr ldquoObjectiveevaluation of heparin in the treatment of asthmardquo AmericanReview of Respiratory Disease vol 98 no 5 pp 886ndash887 1968

14 Advances in Pharmacological Sciences

[64] ZDiamantM C Timmers H van derVeen C P Page F J vander Meer and P J Sterk ldquoEffect of inhaled heparin on allergen-induced early and late asthmatic responses in patients withatopic asthmardquo American Journal of Respiratory and CriticalCare Medicine vol 153 no 6 I pp 1790ndash1795 1996

[65] C M E Tranfa A Vatrella R Parrella G Pelaia F Bariffiand S A Marsico ldquoEffect of inhaled heparin on water-inducedbronchoconstriction in allergic asthmaticsrdquoEuropean Journal ofClinical Pharmacology vol 57 no 1 pp 5ndash9 2001

[66] I Stelmach J Jerzynska A Brzozowska and P Kuna ldquoTheeffect of inhaled heparin on postleukotriene bronchoconstric-tion in children with asthmardquo Polski Merkuriusz Lekarski vol12 no 68 pp 95ndash98 2002

[67] R Polosa S Magrı C Vancheri et al ldquoTime course of changesin adenosine 51015840-monophosphate airway responsiveness withinhaled heparin in allergic asthmardquo Journal of Allergy andClinical Immunology vol 99 no 3 pp 338ndash342 1997

[68] J Butler GM Rocker and SWestaby ldquoInflammatory responseto cardiopulmonary bypassrdquo The Annals of Thoracic Surgeryvol 55 no 2 pp 552ndash559 1993

[69] J M Redmond A M Gillinov R S Stuart et al ldquoHeparin-coated bypass circuits reduce pulmonary injuryrdquoThe Annals ofThoracic Surgery vol 56 no 3 pp 474ndash479 1993

[70] S Svenmarker E Sandstrom T Karlsson et al ldquoClinical effectsof the heparin coated surface in cardiopulmonary bypassrdquoEuropean Journal of Cardio-Thoracic Surgery vol 11 no 5 pp957ndash964 1997

[71] Y J Gu W van Oeveren C Akkerman P W Boonstra RJ Huyzen and C R H Wildevuur ldquoHeparin-coated circuitsreduce the inflammatory response to cardiopulmonary bypassrdquoThe Annals of Thoracic Surgery vol 55 no 4 pp 917ndash922 1993

[72] D Paparella O O Al Radi Q H Meng T Venner K Teohand E Young ldquoThe effects of high-dose heparin on inflamma-tory and coagulation parameters following cardiopulmonarybypassrdquo Blood Coagulation and Fibrinolysis vol 16 no 5 pp323ndash328 2005

[73] S Danese A Papa S Saibeni A Repici A Malesci andM Vecchi ldquoInflammation and coagulation in inflammatorybowel disease the clot thickensrdquo The American Journal ofGastroenterology vol 102 no 1 pp 174ndash186 2007

[74] S Bloom S Kiilerich M R Lassen et al ldquoLow molecularweight heparin (tinzaparin) vs placebo in the treatment of mildto moderately active ulcerative colitisrdquo Alimentary Pharmacol-ogy ampTherapeutics vol 19 no 8 pp 871ndash878 2004

[75] P Libby ldquoCoronary artery injury and the biology of atheroscle-rosis inflammation thrombosis and stabilizationrdquo AmericanJournal of Cardiology vol 86 no 8 2000

[76] N T Mulvihill and J B Foley ldquoInflammation in acute coronarysyndromesrdquo Heart vol 87 no 3 pp 201ndash204 2002

[77] N A JamesonW V Good and C S Hoyt ldquoInflammation aftercataract surgery in childrenrdquoOphthalmic Surgery vol 23 no 2pp 99ndash102 1992

[78] R M Sinskey P A Amin and R Lingua ldquoCataract extractionand intraocular lens implantation in an infant with amonocularcongenital cataractrdquo Journal of Cataract amp Refractive Surgeryvol 20 no 6 pp 647ndash651 1994

[79] A van Ophoven A Heinecke and L Hertle ldquoSafety andefficacy of concurrent application of oral pentosan polysulfateand subcutaneous low-dose heparin for patients with interstitialcystitisrdquo Urology vol 66 no 4 pp 707ndash711 2005

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Page 10: Review Article Anti-Inflammatory Effects of Heparin and Its …downloads.hindawi.com/journals/aps/2015/507151.pdf · 2019. 7. 31. · Review Article Anti-Inflammatory Effects of Heparin

10 Advances in Pharmacological Sciences

the plasma partial thromboplastin time reported by Ahmedet al [9]

All in one considering the results of these studies wecan conclude that heparin and its derivatives could have anti-inflammatory effects and could be considered along withother treatments in asthma

42 Cardiopulmonary Bypass Contact and interaction ofblood with foreign surfaces during cardiopulmonary bypass(CPB) cause systemic inflammatory response syndrome(SIRS) through activation of several humoral cascadesincluding cytokines such as IL-6 IL-8 and Tumor NecrosisFactor-120572 (TNF-120572) [68] The inflammatory response can beattenuated by promoting the biocompatibility of the CPBcircuit Use of heparin-treated surfaces in CPB circuits hasbeen shown to decrease activation of leukocytes and thecomplement cascades [5] As a result need to inotropicsupport postoperative time of mechanical ventilation andrate of acute lung injury decrease and patients durationof hospital stay shortens which reflects the positive effectof heparin in CPB circuits [69 70] Twelve studies whoseendpoints were the effects of heparin-bonded circuits oninflammatory markers were included in our analysis and inthe majority of these trials [27 29 32ndash35 71] heparin-coatedcircuit significantly decreased the level of cytokines such asIL-6 IL-8 TNF-120572 complement complex neutrophils andelastase compared to non-heparin-coated circuit

Defraigne et al [28] randomized 200 patients in 4 groupsheparin-coated circuit with or without aprotinin administra-tion and uncoated circuit with or without aprotinin adminis-tration They measured IL-6 IL-8 TNF-120572 myeloperoxidase(MPO) and elastase level and concluded that cytokine releaseand neutrophil activation were not attenuated by heparin-coated circuit or by the administration of aprotinin Misawaet al [30] evaluated cytokines level under normothermicCPB in a small observational controlled study (119899 = 19 9 incontrol group) Levels of IL-6 IL-8 and ICAM-1 (indicatorof endothelial damage) were not different between study andcontrol group However as mentioned before most studiesindicate the favorable effect of heparin-coated circuit oninflammatory responses in CPB

Paparella et al [72] compared two doses of heparin and300 Iukg and 600 Iukg in 40 patients undergoing CPB in anRCT and showed that IL-6 and TNF-120572 plasma levels were inassociation to heparin dose It seems that lower heparin dosehad small influence on proinflammatory cytokines releasehowever higher doses make a better regulatory effect oncoagulation system

The side effects of heparin-coated circuits were notreported In these studies just a number of included studiesreported a decrease in platelet levels in both groups (coatedand noncoated circuit) No major events including hemor-rhage were reported

43 Inflammatory Bowel Diseases (IBD) Hypercoagulablestate may be an important contributing factor in the patho-genesis of IBD especially ulcerative colitis (UC) [73] A num-ber of studies evaluate the effects of heparin administrationon UC but the results obtained are controversial [17 19]

Bloom et al [74] did not find any favorable effect of LMWHtinzaparin over placebo in the treatment of active UC ina double-blind randomized placebo controlled multicentertrial (119899 = 100) evaluating mean change in colitis activity asthe primary endpoint Ang et al [17] compared heparin tohydrocortisone plus prednisolone in 20 patients (UC 119899 = 17Crohnrsquos colitis 119899 = 3) in open-label randomized crossovertrial whichmeasured endpoints clinical disease activity stoolfrequency and 120572

1acid glycoprotein and endoscopic and

histopathological grading indicate the efficacy and safety ofheparin compared to corticosteroids (119875 gt 005) in contrastthe study by Panes et al [19] did not show the efficacy ofheparin in UC compared to methylprednisolone

Zezos et al [20] compared enoxaparin with standardtreatment (aminosalicylate + corticosteroids) in 34 patientswith active UC The inflammatory biomarkers includingC-Reactive Protein (CRP) Erythrocyte Sedimentation Rate(ESR) and fibrinogen did not show any difference in studygroup compared to control and both groups showed similarrate of disease improvement (119875 gt 005) furthermorecoagulation factors did not change from one to anotherAuthors concluded that enoxaparin is a safe adjuvant but hasno additive benefit over standard treatment of UC

Generally the studies show conflicting results The hep-arin and LMWHs showed efficacy in regard of disease activityand also well tolerated but inflammatory markers did notchange significantly Therefore the improvement in diseaseactivity might be the result of heparinrsquos anticoagulant effects

44 Acute Coronary Syndrome (ACS) Inflammation has akey role in the pathogenesis of coronary artery plaquedestabilization and rupture leading to acute coronary syn-dromes (ACS) [75] Leukocyte activation monocyte andneutrophil infiltration result in local and systemic inflam-matory responses [76] Heparin and LMWHs are commonlyused in ACS to prevent clot formation they also seem tohave desirable effects on inflammatory markers level basedon sparse data

We found 8 studies about heparin and LMWHs in CADsevaluating anti-inflammatory effects as their endpoints Old-gren et al [56] found that dalteparin administration inpatients with unstable CAD (119899 = 555) did not affect IL-6C-Reactive Protein (CRP) and fibrinogen levels although itreduced coagulation activity and mortality rate in long termso it is concluded that these effects are not related to its anti-inflammatory properties Walters et al [58] compared highdose of tirofibanenoxaparin (119899 = 30) with tirofibanheparin(119899 = 30) in an open-label randomized controlled trial in highrisk percutaneous interventionThey found that combinationof high dose of tirofiban with enoxaparin significantly atten-uate inflammatory process (decreased levels of CRP and vonWillebrand factor) compared to tirofiban and heparin

The ARMADA study [54] evaluated anti-inflammatoryeffects of heparin and enoxaparin in Non-ST-ElevatedMyocardial Infarction (Non-STEMI) and reported thatinflammatory markers (CRP and von Willebrand factor)are affected more by LMWH compared to UFH Howeverbecause of the small sample size of the study (119899 = 68)

Advances in Pharmacological Sciences 11

it did not acquire sufficient statistical power to prove anyeffects on defined outcomes Nasiripour et al [55] found thatboth enoxaparin and heparin reduce inflammatory markersin STEMI patients at the same level however this study hadthe same limitations of sample size (119899 = 34) and power too

In summary considering heparins as the main stay treat-ment of ACS its effects are more pronounced as anticoagu-lating than as an anti-inflammatory agent in this pathologicalcondition

45 Cataract Surgery Postoperative inflammation isobserved in cataract surgery especially in children Newertechniques as lensectomy and phacoemulsification cause lesscomplication but still pose potential risks [77 78] It hasbeen suggested that a heparin surface-modified intraocularlens (IOL) or augmenting the irrigating solution withheparin during cataract surgery may reduce the incidence ofpostoperative inflammation Borgioli et al [22] confirm thishypothesis that heparin surface-modified IOL will reducethe inflammatory response compared to conventional IOLat least in short term period (3 months) in a large (524patients) double-blind multicenter trial A similar study byColin et al [23] (119899 = 58) confirms their results howeverthe power of Borgioli et al study was higher Heparinizedlenses showed also more anti-inflammatory effects duringlong term follow-up (1 year) Heparinized irrigating solutionwas used during cataract surgery in two different studies andinflammation decrease observed in the early postoperativeperiod of both studies (Kohnen et al [26] and Ozkurt et al[24]) Therefore it seems that heparin in both forms haveanti-inflammatory effects in cataract surgery

Vasavada et al [25] used enoxaparin irrigation solutionin 20 children undergoing bilateral cataract surgery butthey did not find any beneficial effect in early postoperativeinflammation This study acquired the highest quality in thestudy quality assessment process based on Jadad score andCONSORT items (5274 702) It is worth noticing that themajority of itemsmentioned in the CONSORT checklist wereadequately reported and covered in this paper

Potential mechanisms of anti-inflammatory effects ofheparin have been discussed completely in a review by Young[6] Binding of heparin to different mediators involved inthe immune system response (cytokines and chemokines)acute phase proteins and complement complex proteinsmay contribute to the anti-inflammatory activity of heparinNeutralizing of cytokines at the inflammation site is anotherpossible mechanism In most of the studies level of cytokinessuch as IL-6 IL-8 TNF-120572 and CRP was decreased afterheparin administration which can confirm this mechanismalso heparin and LMWHs inhibit adhesion of leukocytesand neutrophils to endothelial cells by binding to p-selectinand consequently prevent release of oxygen radicals andproteolytic enzymes Other possible mechanisms are as fol-lows inhibition of nuclear factor 120581B (NF-120581B) and inductionof apoptosis by modulation of activity of TNF-120572 and NF-120581B In a double-blind placebo-controlled trial (119899 = 62)in patients with stable coronary artery disease followingadministration of 1mgkg subcutaneous enoxaparin plasmalevels of myeloperoxidase (MPO) increased significantly

(119875 lt 0001) and subsequently endothelial function improved(119903 = 067 119875 lt 0001) through MPO binding to endotheliumand depleting vascular nitric oxide [57] This study confirmsanother possible mechanism of heparins anti-inflammatoryeffects

5 Conclusion

As we discussed heparins potential effects as anti-inflamma-tory agents supported by several clinical trials in varioussetting Heparin and its related derivatives have been shownto benefit patients with asthma and patients undergoingcardiopulmonary bypass and cataract surgery In otherinflammatory diseases such as IBD (ulcerative colitis) thestudies are heterogeneous and incongruent Most studies didnot report any unwanted event with heparins when they usedthem as anti-inflammatory agents whether through systemicor through local (as inhaler or irrigation or heparin-coatedcircuit) administration However because the majority ofthese trials did not pose optimal quality scores we cannotdraw a definite conclusion on the efficacy of heparin and itsderivatives as anti-inflammatory agents

The present review included studies which measuredinflammatory markers as their endpoints and in most ofthem these markers were decreased though not significantlyTo come to a definite conclusion further double-blindrandomized placebo-controlled clinical trials with a largersample size are needed However because the inflammationatherogenesis thrombogenesis and cell proliferation areassociated with each other the pleiotropic effects of heparinand related compounds may have greater therapeutic effectthan compounds that are directed against a single target

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

[1] B Casu ldquoHeparin structurerdquo Pathophysiology of Haemostasisand Thrombosis vol 20 supplement 1 pp 62ndash73 1990

[2] J Hirsh R Raschke T EWarkentin J E Dalen DDeykin andL Poller ldquoHeparin mechanism of action pharmacokineticsdosing considerations monitoring efficacy and safetyrdquo Chestvol 108 no 4 supplement pp 258Sndash275S 1995

[3] J Fareed D A Hoppensteadt and R L Bick ldquoAn update onheparins at the beginning of the new millenniumrdquo Seminars inThrombosis and Hemostasis vol 26 no 3 pp 5ndash21 2000

[4] J Hirsh ldquoDrug therapy heparinrdquo The New England Journal ofMedicine vol 324 no 22 pp 1565ndash1574 1991

[5] R J Ludwig ldquoTherapeutic use of heparin beyond anticoagu-lationrdquo Current Drug Discovery Technologies vol 6 no 4 pp281ndash289 2009

[6] E Young ldquoThe anti-inflammatory effects of heparin and relatedcompoundsrdquo Thrombosis Research vol 122 no 6 pp 743ndash7522008

12 Advances in Pharmacological Sciences

[7] A R Jadad R A Moore D Carroll et al ldquoAssessing the qualityof reports of randomized clinical trials is blinding necessaryrdquoControlled Clinical Trials vol 17 no 1 pp 1ndash12 1996

[8] K F Schulz D G Altman and D Moher ldquoCONSORT 2010statement updated guidelines for reporting parallel grouprandomised trialsrdquo International Journal of Surgery vol 9 no8 pp 672ndash677 2011

[9] T Ahmed J Garrigo and I Danta ldquoPreventing bronchocon-striction in exercise-induced asthma with inhaled heparinrdquoTheNewEngland Journal ofMedicine vol 329 no 2 pp 90ndash95 1993

[10] Z Diamant M C Timmers H Van Der Veen C P PageF J Van Der Meer and P J Sterk ldquoEffect of inhaled heparinon allergen-induced early and late asthmatic responses inpatients with atopic asthmardquo American Journal of Respiratoryand Critical Care Medicine vol 153 no 6 pp 1790ndash1795 1996

[11] M Duong D Cockcroft L-P Boulet et al ldquoThe effect ofIVX-0142 a heparin-derived hypersulfated disaccharide on theallergic airway responses in asthmardquo Allergy vol 63 no 9 pp1195ndash1201 2008

[12] A M Fal M Kraus-Filarska J Miecielica and J MalolepszyldquoMechanisms of action of nebulized low-molecular-weightheparin in patients with bronchial asthmardquo The Journal ofAllergy and Clinical Immunology vol 113 no 2 supplement pS36 2004

[13] J Jerzynska I Stelmach P Majak and P Kuna ldquoThe effectof inhaled heparin on airway responsiveness to histamine andmetacholine in asthmatic childrenrdquo Journal of Allergy andClinical Immunology vol 109 no 1 supplement 1 p S39 2002

[14] A F Kalpaklioglu Y S Demirel S Saryal and Z MisirligilldquoEffect of pretreatment with heparin on pulmonary and cuta-neous responserdquo Journal of Asthma vol 34 no 4 pp 337ndash3431997

[15] I Stelmach J Jerzynska A Brzozowska and P Kuna ldquoTheeffect of inhaled heparin on postleukotriene bronchoconstric-tion in children with asthmardquo Journal of Allergy and ClinicalImmunology vol 109 no 1 supplement 1 p S39 2002

[16] I Stelmach J Jerzynska W Stelmach et al ldquoThe effect ofinhaled heparin on airway responsiveness to histamine andleukotriene D4rdquo Allergy and Asthma Proceedings vol 24 no 1pp 59ndash65 2003

[17] Y S Ang N Mahmud B White et al ldquoRandomized compar-ison of unfractionated heparin with corticosteroids in severeactive inflammatory bowel diseaserdquo Alimentary PharmacologyandTherapeutics vol 14 no 8 pp 1015ndash1022 2000

[18] C Folwaczny B Wiebecke and K Loeschke ldquoUnfractionedheparin in the therapy of patients with highly active inflamma-tory bowel diseaserdquo The American Journal of Gastroenterologyvol 94 no 6 pp 1551ndash1555 1999

[19] J Panes M Esteve E Cabre et al ldquoComparison of heparinand steroids in the treatment of moderate and severe ulcerativecolitisrdquo Gastroenterology vol 119 no 4 pp 903ndash908 2000

[20] P Zezos G Papaioannou N Nikolaidis et al ldquoLow-molecular-weight heparin (enoxaparin) as adjuvant therapy in the treat-ment of active ulcerative colitis a randomized controlledcomparative studyrdquoAlimentary Pharmacology andTherapeuticsvol 23 no 10 pp 1443ndash1453 2006

[21] A A Vrij J M Jansen E J Schoon H C Hemker and RW Stockbrugger ldquoLow molecular weight heparin treatmentin steroid refractory ulcerative colitis clinical outcome andinfluence on mucosal capillary thrombirdquo Scandinavian Journalof Gastroenterology Supplement vol 36 no 234 pp 41ndash47 2001

[22] D M Borgioli D J Coster R F T Fan et al ldquoEffect of heparinsurface modification of polymethylmethacrylate intraocularlenses on signs of postoperative inflammation after extracap-sular cataract extraction one-year results of a double-maskedmulticenter studyrdquoOphthalmology vol 99 no 8 pp 1248ndash12551992

[23] J Colin S Roncin and M Wenzel ldquoEfficacy of heparinsurface-modified IOLs in reducing postoperative inflammatoryreactions in patients with exfoliation syndromemdasha double-blind comparative studyrdquo European Journal of Implant andRefractive Surgery vol 7 no 5 pp 266ndash270 1995

[24] Y B Ozkurt A Taskiran N Erdogan B Kandemir and OK Dogan ldquoEffect of heparin in the intraocular irrigating solu-tion on postoperative inflammation in the pediatric cataractsurgeryrdquoClinical Ophthalmology vol 3 no 1 pp 363ndash365 2009

[25] V A Vasavada M R Praveen S K Shah R H Trivedi andA R Vasavada ldquoAnti-inflammatory effect of low-molecular-weight heparin in pediatric cataract surgery a randomizedclinical trialrdquoThe American Journal of Ophthalmology vol 154no 2 pp 252ndash258 2012

[26] T Kohnen B Dick V Hessemer D D Koch and K WJacobi ldquoEffect of heparin in irrigating solution on inflammationfollowing small incision cataract surgeryrdquo Journal of Cataract ampRefractive Surgery vol 24 no 2 pp 237ndash243 1998

[27] S Ashraf Y Tian D Cowan A Entress P G Martin andK G Watterson ldquoRelease of proinflammatory cytokines dur-ing pediatric cardiopulmonary bypass heparin-bonded versusnonbonded oxygenatorsrdquo Annals of Thoracic Surgery vol 64no 6 pp 1790ndash1794 1997

[28] J-O Defraigne J Pincemail R Larbuisson F Blaffart andR Limet ldquoCytokine release and neutrophil activation are notprevented by heparin- coated circuits and aprotinin administra-tionrdquo Annals of Thoracic Surgery vol 69 no 4 pp 1084ndash10912000

[29] R de Vroege W van Oeveren J van Klarenbosch et al ldquoTheimpact of heparin-coated cardiopulmonary bypass circuits onpulmonary function and the release of inflammatory media-torsrdquo Anesthesia and Analgesia vol 98 no 6 pp 1586ndash15942004

[30] Y Misawa K Kawahito H Konishi and K Fuse ldquoCytokinemediated endothelial activation during and after normothermiccardiopulmonary bypass Heparin-bonded versus non heparin-bonded circuitsrdquo ASAIO Journal vol 46 no 6 pp 740ndash7432000

[31] A Koster T Fischer M Praus et al ldquoHemostatic activationand inflammatory response during cardiopulmonary bypassimpact of heparin managementrdquo Anesthesiology vol 97 no 4pp 837ndash841 2002

[32] C Olsson A Siegbahn A Henze et al ldquoHeparin-coatedcardiopulmonary bypass circuits reduce circulating comple-ment factors and interleukin-6 in paediatric heart surgeryrdquoScandinavian Cardiovascular Journal vol 34 no 1 pp 33ndash402000

[33] T Ozawa K Yoshihara N Koyama Y Watanabe N Shionoand Y Takanashi ldquoClinical efficacy of heparin-bonded bypasscircuits related to cytokine responses in childrenrdquo The Annalsof Thoracic Surgery vol 69 no 2 pp 584ndash590 2000

[34] A Parolari F Alamanni T Gherli et al ldquolsquoHigh dosersquo aprotininand heparin-coated circuits Clinical efficacy and inflammatoryresponserdquo Cardiovascular Surgery vol 7 no 1 pp 117ndash127 1999

[35] H Yamada I Kudoh Y Hirose M Toyoshima H Abe andK Kurahashi ldquoHeparin-coated circuits reduce the formation of

Advances in Pharmacological Sciences 13

TNF120572 during cardiopulmonary bypassrdquo Acta AnaesthesiologicaScandinavica vol 40 no 3 pp 311ndash317 1996

[36] O Barkay E Niv E Santo R Bruck A Hallak and F MKonikoff ldquoLow-dose heparin for the prevention of post-ERCPpancreatitis a randomized placebo-controlled trialrdquo SurgicalEndoscopy and Other Interventional Techniques vol 22 no 9pp 1971ndash1976 2008

[37] R C Becker K W Mahaffey H Yang et al ldquoHeparin-associated anti-Xa activity and platelet-derived prothromboticand proinflammatory biomarkers in moderate to high-riskpatients with acute coronary syndromerdquo Journal of Thrombosisand Thrombolysis vol 31 no 2 pp 146ndash153 2011

[38] S D Bowler S M Smith and P S Lavercombe ldquoHeparininhibits the immediate response to antigen in the skin and lungsof allergic subjectsrdquo American Review of Respiratory Diseasevol 147 no 1 pp 160ndash163 1993

[39] J P Boyle R H Smart and J K Shirey ldquoHeparin in thetreatment of chronic obstructive bronchopulmonary diseaserdquoThe American Journal of Cardiology vol 14 no 1 pp 25ndash281964

[40] Y Qian H Xie R Tian K Yu and R Wang ldquoEfficacy of lowmolecular weight heparin in patients with acute exacerbationof chronic obstructive pulmonary disease receiving ventilatorysupportrdquo COPD Journal of Chronic Obstructive PulmonaryDisease vol 11 no 2 pp 171ndash176 2014

[41] A Chamorro A Cervera J Castillo A Davalos J J Aponteand A M Planas ldquoUnfractionated heparin is associated with alower rise of serum vascular cell adhesion molecule-1 in acuteischemic stroke patientsrdquo Neuroscience Letters vol 328 no 3pp 229ndash232 2002

[42] R de Cock L A Ficker J G Dart A Garner and P WrightldquoTopical heparin in the treatment of ligneous conjunctivitisrdquoOphthalmology vol 102 no 11 pp 1654ndash1659 1995

[43] U Derhaschnig T Pernerstorfer M Knechtelsdorfer U Hol-lenstein S Panzer and B Jilma ldquoEvaluation of antiinflamma-tory and antiadhesive effects of heparins in human endotox-emiardquo Critical Care Medicine vol 31 no 4 pp 1108ndash1112 2003

[44] B DixonM J Schultz R Smith J B Fink J D Santamaria andD J Campbell ldquoNebulized heparin is associatedwith fewer daysof mechanical ventilation in critically ill patients a randomizedcontrolled trialrdquo Critical Care vol 14 no 5 article R180 2010

[45] F K Keating H L Dauerman D A Whitaker B E Sobeland D J Schneider ldquoThe effects of bivalirudin compared withthose of unfractionated heparin plus eptifibatide on inflam-mation and thrombin generation and activity during coronaryinterventionrdquo Coronary Artery Disease vol 16 no 6 pp 401ndash405 2005

[46] M Ledson M Gallagher C A Hart and M Walshaw ldquoNeb-ulized heparin in Burkholderia cepacia colonized adult cysticfibrosis patientsrdquo European Respiratory Journal vol 17 no 1 pp36ndash38 2001

[47] D J Serisier J K Shute P M Hockey B Higgins J Conwayand M P Carroll ldquoInhaled heparin in cystic fibrosisrdquo EuropeanRespiratory Journal vol 27 no 2 pp 354ndash358 2006

[48] O K Poyrazoglu A Dogukan M Yalniz D Seckin andA L Gunal ldquoAcute effect of standard heparin versus lowmolecular weight heparin on oxidative stress and inflammationin hemodialysis patientsrdquo Renal Failure vol 28 no 8 pp 723ndash727 2006

[49] S Suzuki T Matsuo H Kobayashi et al ldquoAntithrombotictreatment (argatroban vs heparin) in coronary angioplastyin angina pectoris effects on inflammatory hemostatic and

endothelium-derived parametersrdquoThrombosis Research vol 98no 4 pp 269ndash279 2000

[50] S D Trocme and H-I Li ldquoEffect of heparin-surface-modifiedintraocular lenses on postoperative inflammation after pha-coemulsification a randomized trial in a United States patientpopulationrdquo Ophthalmology vol 107 no 6 pp 1031ndash1037 2000

[51] C Vancheri C Mastruzzo F Armato et al ldquoIntranasal heparinreduces eosinophil recruitment after nasal allergen challenge inpatients with allergic rhinitisrdquo Journal of Allergy and ClinicalImmunology vol 108 no 5 pp 703ndash708 2001

[52] A Abdollahi M-T Naini H Shams and R Zarei ldquoEffect oflow-molecular-weight heparin on postoperative inflammationin phacomorphic glaucomardquo Archives of Iranian Medicine vol5 no 4 pp 225ndash229 2002

[53] R T S Lakshmi T Priyanka J Meenakshi K R MathangiV Jeyaraman and M Babu ldquoLow molecular weight heparinmediated regulation of nitric oxide synthase during burnwound healingrdquo Annals of Burns and Fire Disasters vol 24 no1 pp 24ndash29 2011

[54] G Montalescot C Bal-dit-Sollier D Chibedi et al ldquoCompar-ison of effects on markers of blood cell activation of enoxa-parin dalteparin and unfractionated heparin in patients withunstable angina pectoris or non-ST-segment elevation acutemyocardial infarction (the ARMADA study)rdquo The AmericanJournal of Cardiology vol 91 no 8 pp 925ndash930 2003

[55] S Nasiripour K Gholami SMousavi et al ldquoComparison of theeffects of enoxaparin and heparin on inflammatory biomarkersin patients with ST-segment elevated myocardial infarction aprospective open label pilot clinical trialrdquo Iranian Journal ofPharmaceutical Research vol 13 no 2 pp 583ndash590 2014

[56] J Oldgren C Fellenius K Boman et al ldquoInfluence of prolongeddalteparin treatment on coagulation fibrinolysis and inflam-mation in unstable coronary artery diseaserdquo Journal of InternalMedicine vol 258 no 5 pp 420ndash427 2005

[57] T K Rudolph V Rudolph A Witte et al ldquoLiberation of vesseladherent myeloperoxidase by enoxaparin improves endothelialfunctionrdquo International Journal of Cardiology vol 140 no 1 pp42ndash47 2010

[58] D L Walters M J Ray P Wood E J Perrin J H N Bettand C N Aroney ldquoHigh-dose tirofiban with enoxaparin andinflammatory markers in high-risk percutaneous interventionrdquoEuropean Journal of Clinical Investigation vol 40 no 2 pp 139ndash147 2010

[59] S W Rathbun C E Aston and T L Whitsett ldquoA randomizedtrial of dalteparin compared with ibuprofen for the treatmentof superficial thrombophlebitisrdquo Journal of Thrombosis andHaemostasis vol 10 no 5 pp 833ndash839 2012

[60] J P Titon D Auger P Grange et al ldquoTherapeutic managementof superficial venous thrombosis with calcium nadroparinDosage testing and comparison with a non-steroidal anti-inflammatory agentrdquo Annales de Cardiologie et d Angeiologievol 43 no 3 pp 160ndash166 1994

[61] H Uncu ldquoA comparison of low-molecular-weight heparin andcombined therapy of low-molecular-weight heparin with ananti-inflammatory agent in the treatment of superficial veinthrombosisrdquo Phlebology vol 24 no 2 pp 56ndash60 2009

[62] J A Sjoslashland R S Pedersen J Jespersen and J GramldquoIntraperitoneal heparin ameliorates the systemic inflamma-tory response in PD patientsrdquo NephronmdashClinical Practice vol100 no 4 pp c105ndashc110 2005

[63] N L Fine C Shim and M H Williams Jr ldquoObjectiveevaluation of heparin in the treatment of asthmardquo AmericanReview of Respiratory Disease vol 98 no 5 pp 886ndash887 1968

14 Advances in Pharmacological Sciences

[64] ZDiamantM C Timmers H van derVeen C P Page F J vander Meer and P J Sterk ldquoEffect of inhaled heparin on allergen-induced early and late asthmatic responses in patients withatopic asthmardquo American Journal of Respiratory and CriticalCare Medicine vol 153 no 6 I pp 1790ndash1795 1996

[65] C M E Tranfa A Vatrella R Parrella G Pelaia F Bariffiand S A Marsico ldquoEffect of inhaled heparin on water-inducedbronchoconstriction in allergic asthmaticsrdquoEuropean Journal ofClinical Pharmacology vol 57 no 1 pp 5ndash9 2001

[66] I Stelmach J Jerzynska A Brzozowska and P Kuna ldquoTheeffect of inhaled heparin on postleukotriene bronchoconstric-tion in children with asthmardquo Polski Merkuriusz Lekarski vol12 no 68 pp 95ndash98 2002

[67] R Polosa S Magrı C Vancheri et al ldquoTime course of changesin adenosine 51015840-monophosphate airway responsiveness withinhaled heparin in allergic asthmardquo Journal of Allergy andClinical Immunology vol 99 no 3 pp 338ndash342 1997

[68] J Butler GM Rocker and SWestaby ldquoInflammatory responseto cardiopulmonary bypassrdquo The Annals of Thoracic Surgeryvol 55 no 2 pp 552ndash559 1993

[69] J M Redmond A M Gillinov R S Stuart et al ldquoHeparin-coated bypass circuits reduce pulmonary injuryrdquoThe Annals ofThoracic Surgery vol 56 no 3 pp 474ndash479 1993

[70] S Svenmarker E Sandstrom T Karlsson et al ldquoClinical effectsof the heparin coated surface in cardiopulmonary bypassrdquoEuropean Journal of Cardio-Thoracic Surgery vol 11 no 5 pp957ndash964 1997

[71] Y J Gu W van Oeveren C Akkerman P W Boonstra RJ Huyzen and C R H Wildevuur ldquoHeparin-coated circuitsreduce the inflammatory response to cardiopulmonary bypassrdquoThe Annals of Thoracic Surgery vol 55 no 4 pp 917ndash922 1993

[72] D Paparella O O Al Radi Q H Meng T Venner K Teohand E Young ldquoThe effects of high-dose heparin on inflamma-tory and coagulation parameters following cardiopulmonarybypassrdquo Blood Coagulation and Fibrinolysis vol 16 no 5 pp323ndash328 2005

[73] S Danese A Papa S Saibeni A Repici A Malesci andM Vecchi ldquoInflammation and coagulation in inflammatorybowel disease the clot thickensrdquo The American Journal ofGastroenterology vol 102 no 1 pp 174ndash186 2007

[74] S Bloom S Kiilerich M R Lassen et al ldquoLow molecularweight heparin (tinzaparin) vs placebo in the treatment of mildto moderately active ulcerative colitisrdquo Alimentary Pharmacol-ogy ampTherapeutics vol 19 no 8 pp 871ndash878 2004

[75] P Libby ldquoCoronary artery injury and the biology of atheroscle-rosis inflammation thrombosis and stabilizationrdquo AmericanJournal of Cardiology vol 86 no 8 2000

[76] N T Mulvihill and J B Foley ldquoInflammation in acute coronarysyndromesrdquo Heart vol 87 no 3 pp 201ndash204 2002

[77] N A JamesonW V Good and C S Hoyt ldquoInflammation aftercataract surgery in childrenrdquoOphthalmic Surgery vol 23 no 2pp 99ndash102 1992

[78] R M Sinskey P A Amin and R Lingua ldquoCataract extractionand intraocular lens implantation in an infant with amonocularcongenital cataractrdquo Journal of Cataract amp Refractive Surgeryvol 20 no 6 pp 647ndash651 1994

[79] A van Ophoven A Heinecke and L Hertle ldquoSafety andefficacy of concurrent application of oral pentosan polysulfateand subcutaneous low-dose heparin for patients with interstitialcystitisrdquo Urology vol 66 no 4 pp 707ndash711 2005

Submit your manuscripts athttpwwwhindawicom

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ToxinsJournal of

VaccinesJournal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

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Advances in Pharmacological Sciences

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Page 11: Review Article Anti-Inflammatory Effects of Heparin and Its …downloads.hindawi.com/journals/aps/2015/507151.pdf · 2019. 7. 31. · Review Article Anti-Inflammatory Effects of Heparin

Advances in Pharmacological Sciences 11

it did not acquire sufficient statistical power to prove anyeffects on defined outcomes Nasiripour et al [55] found thatboth enoxaparin and heparin reduce inflammatory markersin STEMI patients at the same level however this study hadthe same limitations of sample size (119899 = 34) and power too

In summary considering heparins as the main stay treat-ment of ACS its effects are more pronounced as anticoagu-lating than as an anti-inflammatory agent in this pathologicalcondition

45 Cataract Surgery Postoperative inflammation isobserved in cataract surgery especially in children Newertechniques as lensectomy and phacoemulsification cause lesscomplication but still pose potential risks [77 78] It hasbeen suggested that a heparin surface-modified intraocularlens (IOL) or augmenting the irrigating solution withheparin during cataract surgery may reduce the incidence ofpostoperative inflammation Borgioli et al [22] confirm thishypothesis that heparin surface-modified IOL will reducethe inflammatory response compared to conventional IOLat least in short term period (3 months) in a large (524patients) double-blind multicenter trial A similar study byColin et al [23] (119899 = 58) confirms their results howeverthe power of Borgioli et al study was higher Heparinizedlenses showed also more anti-inflammatory effects duringlong term follow-up (1 year) Heparinized irrigating solutionwas used during cataract surgery in two different studies andinflammation decrease observed in the early postoperativeperiod of both studies (Kohnen et al [26] and Ozkurt et al[24]) Therefore it seems that heparin in both forms haveanti-inflammatory effects in cataract surgery

Vasavada et al [25] used enoxaparin irrigation solutionin 20 children undergoing bilateral cataract surgery butthey did not find any beneficial effect in early postoperativeinflammation This study acquired the highest quality in thestudy quality assessment process based on Jadad score andCONSORT items (5274 702) It is worth noticing that themajority of itemsmentioned in the CONSORT checklist wereadequately reported and covered in this paper

Potential mechanisms of anti-inflammatory effects ofheparin have been discussed completely in a review by Young[6] Binding of heparin to different mediators involved inthe immune system response (cytokines and chemokines)acute phase proteins and complement complex proteinsmay contribute to the anti-inflammatory activity of heparinNeutralizing of cytokines at the inflammation site is anotherpossible mechanism In most of the studies level of cytokinessuch as IL-6 IL-8 TNF-120572 and CRP was decreased afterheparin administration which can confirm this mechanismalso heparin and LMWHs inhibit adhesion of leukocytesand neutrophils to endothelial cells by binding to p-selectinand consequently prevent release of oxygen radicals andproteolytic enzymes Other possible mechanisms are as fol-lows inhibition of nuclear factor 120581B (NF-120581B) and inductionof apoptosis by modulation of activity of TNF-120572 and NF-120581B In a double-blind placebo-controlled trial (119899 = 62)in patients with stable coronary artery disease followingadministration of 1mgkg subcutaneous enoxaparin plasmalevels of myeloperoxidase (MPO) increased significantly

(119875 lt 0001) and subsequently endothelial function improved(119903 = 067 119875 lt 0001) through MPO binding to endotheliumand depleting vascular nitric oxide [57] This study confirmsanother possible mechanism of heparins anti-inflammatoryeffects

5 Conclusion

As we discussed heparins potential effects as anti-inflamma-tory agents supported by several clinical trials in varioussetting Heparin and its related derivatives have been shownto benefit patients with asthma and patients undergoingcardiopulmonary bypass and cataract surgery In otherinflammatory diseases such as IBD (ulcerative colitis) thestudies are heterogeneous and incongruent Most studies didnot report any unwanted event with heparins when they usedthem as anti-inflammatory agents whether through systemicor through local (as inhaler or irrigation or heparin-coatedcircuit) administration However because the majority ofthese trials did not pose optimal quality scores we cannotdraw a definite conclusion on the efficacy of heparin and itsderivatives as anti-inflammatory agents

The present review included studies which measuredinflammatory markers as their endpoints and in most ofthem these markers were decreased though not significantlyTo come to a definite conclusion further double-blindrandomized placebo-controlled clinical trials with a largersample size are needed However because the inflammationatherogenesis thrombogenesis and cell proliferation areassociated with each other the pleiotropic effects of heparinand related compounds may have greater therapeutic effectthan compounds that are directed against a single target

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

[1] B Casu ldquoHeparin structurerdquo Pathophysiology of Haemostasisand Thrombosis vol 20 supplement 1 pp 62ndash73 1990

[2] J Hirsh R Raschke T EWarkentin J E Dalen DDeykin andL Poller ldquoHeparin mechanism of action pharmacokineticsdosing considerations monitoring efficacy and safetyrdquo Chestvol 108 no 4 supplement pp 258Sndash275S 1995

[3] J Fareed D A Hoppensteadt and R L Bick ldquoAn update onheparins at the beginning of the new millenniumrdquo Seminars inThrombosis and Hemostasis vol 26 no 3 pp 5ndash21 2000

[4] J Hirsh ldquoDrug therapy heparinrdquo The New England Journal ofMedicine vol 324 no 22 pp 1565ndash1574 1991

[5] R J Ludwig ldquoTherapeutic use of heparin beyond anticoagu-lationrdquo Current Drug Discovery Technologies vol 6 no 4 pp281ndash289 2009

[6] E Young ldquoThe anti-inflammatory effects of heparin and relatedcompoundsrdquo Thrombosis Research vol 122 no 6 pp 743ndash7522008

12 Advances in Pharmacological Sciences

[7] A R Jadad R A Moore D Carroll et al ldquoAssessing the qualityof reports of randomized clinical trials is blinding necessaryrdquoControlled Clinical Trials vol 17 no 1 pp 1ndash12 1996

[8] K F Schulz D G Altman and D Moher ldquoCONSORT 2010statement updated guidelines for reporting parallel grouprandomised trialsrdquo International Journal of Surgery vol 9 no8 pp 672ndash677 2011

[9] T Ahmed J Garrigo and I Danta ldquoPreventing bronchocon-striction in exercise-induced asthma with inhaled heparinrdquoTheNewEngland Journal ofMedicine vol 329 no 2 pp 90ndash95 1993

[10] Z Diamant M C Timmers H Van Der Veen C P PageF J Van Der Meer and P J Sterk ldquoEffect of inhaled heparinon allergen-induced early and late asthmatic responses inpatients with atopic asthmardquo American Journal of Respiratoryand Critical Care Medicine vol 153 no 6 pp 1790ndash1795 1996

[11] M Duong D Cockcroft L-P Boulet et al ldquoThe effect ofIVX-0142 a heparin-derived hypersulfated disaccharide on theallergic airway responses in asthmardquo Allergy vol 63 no 9 pp1195ndash1201 2008

[12] A M Fal M Kraus-Filarska J Miecielica and J MalolepszyldquoMechanisms of action of nebulized low-molecular-weightheparin in patients with bronchial asthmardquo The Journal ofAllergy and Clinical Immunology vol 113 no 2 supplement pS36 2004

[13] J Jerzynska I Stelmach P Majak and P Kuna ldquoThe effectof inhaled heparin on airway responsiveness to histamine andmetacholine in asthmatic childrenrdquo Journal of Allergy andClinical Immunology vol 109 no 1 supplement 1 p S39 2002

[14] A F Kalpaklioglu Y S Demirel S Saryal and Z MisirligilldquoEffect of pretreatment with heparin on pulmonary and cuta-neous responserdquo Journal of Asthma vol 34 no 4 pp 337ndash3431997

[15] I Stelmach J Jerzynska A Brzozowska and P Kuna ldquoTheeffect of inhaled heparin on postleukotriene bronchoconstric-tion in children with asthmardquo Journal of Allergy and ClinicalImmunology vol 109 no 1 supplement 1 p S39 2002

[16] I Stelmach J Jerzynska W Stelmach et al ldquoThe effect ofinhaled heparin on airway responsiveness to histamine andleukotriene D4rdquo Allergy and Asthma Proceedings vol 24 no 1pp 59ndash65 2003

[17] Y S Ang N Mahmud B White et al ldquoRandomized compar-ison of unfractionated heparin with corticosteroids in severeactive inflammatory bowel diseaserdquo Alimentary PharmacologyandTherapeutics vol 14 no 8 pp 1015ndash1022 2000

[18] C Folwaczny B Wiebecke and K Loeschke ldquoUnfractionedheparin in the therapy of patients with highly active inflamma-tory bowel diseaserdquo The American Journal of Gastroenterologyvol 94 no 6 pp 1551ndash1555 1999

[19] J Panes M Esteve E Cabre et al ldquoComparison of heparinand steroids in the treatment of moderate and severe ulcerativecolitisrdquo Gastroenterology vol 119 no 4 pp 903ndash908 2000

[20] P Zezos G Papaioannou N Nikolaidis et al ldquoLow-molecular-weight heparin (enoxaparin) as adjuvant therapy in the treat-ment of active ulcerative colitis a randomized controlledcomparative studyrdquoAlimentary Pharmacology andTherapeuticsvol 23 no 10 pp 1443ndash1453 2006

[21] A A Vrij J M Jansen E J Schoon H C Hemker and RW Stockbrugger ldquoLow molecular weight heparin treatmentin steroid refractory ulcerative colitis clinical outcome andinfluence on mucosal capillary thrombirdquo Scandinavian Journalof Gastroenterology Supplement vol 36 no 234 pp 41ndash47 2001

[22] D M Borgioli D J Coster R F T Fan et al ldquoEffect of heparinsurface modification of polymethylmethacrylate intraocularlenses on signs of postoperative inflammation after extracap-sular cataract extraction one-year results of a double-maskedmulticenter studyrdquoOphthalmology vol 99 no 8 pp 1248ndash12551992

[23] J Colin S Roncin and M Wenzel ldquoEfficacy of heparinsurface-modified IOLs in reducing postoperative inflammatoryreactions in patients with exfoliation syndromemdasha double-blind comparative studyrdquo European Journal of Implant andRefractive Surgery vol 7 no 5 pp 266ndash270 1995

[24] Y B Ozkurt A Taskiran N Erdogan B Kandemir and OK Dogan ldquoEffect of heparin in the intraocular irrigating solu-tion on postoperative inflammation in the pediatric cataractsurgeryrdquoClinical Ophthalmology vol 3 no 1 pp 363ndash365 2009

[25] V A Vasavada M R Praveen S K Shah R H Trivedi andA R Vasavada ldquoAnti-inflammatory effect of low-molecular-weight heparin in pediatric cataract surgery a randomizedclinical trialrdquoThe American Journal of Ophthalmology vol 154no 2 pp 252ndash258 2012

[26] T Kohnen B Dick V Hessemer D D Koch and K WJacobi ldquoEffect of heparin in irrigating solution on inflammationfollowing small incision cataract surgeryrdquo Journal of Cataract ampRefractive Surgery vol 24 no 2 pp 237ndash243 1998

[27] S Ashraf Y Tian D Cowan A Entress P G Martin andK G Watterson ldquoRelease of proinflammatory cytokines dur-ing pediatric cardiopulmonary bypass heparin-bonded versusnonbonded oxygenatorsrdquo Annals of Thoracic Surgery vol 64no 6 pp 1790ndash1794 1997

[28] J-O Defraigne J Pincemail R Larbuisson F Blaffart andR Limet ldquoCytokine release and neutrophil activation are notprevented by heparin- coated circuits and aprotinin administra-tionrdquo Annals of Thoracic Surgery vol 69 no 4 pp 1084ndash10912000

[29] R de Vroege W van Oeveren J van Klarenbosch et al ldquoTheimpact of heparin-coated cardiopulmonary bypass circuits onpulmonary function and the release of inflammatory media-torsrdquo Anesthesia and Analgesia vol 98 no 6 pp 1586ndash15942004

[30] Y Misawa K Kawahito H Konishi and K Fuse ldquoCytokinemediated endothelial activation during and after normothermiccardiopulmonary bypass Heparin-bonded versus non heparin-bonded circuitsrdquo ASAIO Journal vol 46 no 6 pp 740ndash7432000

[31] A Koster T Fischer M Praus et al ldquoHemostatic activationand inflammatory response during cardiopulmonary bypassimpact of heparin managementrdquo Anesthesiology vol 97 no 4pp 837ndash841 2002

[32] C Olsson A Siegbahn A Henze et al ldquoHeparin-coatedcardiopulmonary bypass circuits reduce circulating comple-ment factors and interleukin-6 in paediatric heart surgeryrdquoScandinavian Cardiovascular Journal vol 34 no 1 pp 33ndash402000

[33] T Ozawa K Yoshihara N Koyama Y Watanabe N Shionoand Y Takanashi ldquoClinical efficacy of heparin-bonded bypasscircuits related to cytokine responses in childrenrdquo The Annalsof Thoracic Surgery vol 69 no 2 pp 584ndash590 2000

[34] A Parolari F Alamanni T Gherli et al ldquolsquoHigh dosersquo aprotininand heparin-coated circuits Clinical efficacy and inflammatoryresponserdquo Cardiovascular Surgery vol 7 no 1 pp 117ndash127 1999

[35] H Yamada I Kudoh Y Hirose M Toyoshima H Abe andK Kurahashi ldquoHeparin-coated circuits reduce the formation of

Advances in Pharmacological Sciences 13

TNF120572 during cardiopulmonary bypassrdquo Acta AnaesthesiologicaScandinavica vol 40 no 3 pp 311ndash317 1996

[36] O Barkay E Niv E Santo R Bruck A Hallak and F MKonikoff ldquoLow-dose heparin for the prevention of post-ERCPpancreatitis a randomized placebo-controlled trialrdquo SurgicalEndoscopy and Other Interventional Techniques vol 22 no 9pp 1971ndash1976 2008

[37] R C Becker K W Mahaffey H Yang et al ldquoHeparin-associated anti-Xa activity and platelet-derived prothromboticand proinflammatory biomarkers in moderate to high-riskpatients with acute coronary syndromerdquo Journal of Thrombosisand Thrombolysis vol 31 no 2 pp 146ndash153 2011

[38] S D Bowler S M Smith and P S Lavercombe ldquoHeparininhibits the immediate response to antigen in the skin and lungsof allergic subjectsrdquo American Review of Respiratory Diseasevol 147 no 1 pp 160ndash163 1993

[39] J P Boyle R H Smart and J K Shirey ldquoHeparin in thetreatment of chronic obstructive bronchopulmonary diseaserdquoThe American Journal of Cardiology vol 14 no 1 pp 25ndash281964

[40] Y Qian H Xie R Tian K Yu and R Wang ldquoEfficacy of lowmolecular weight heparin in patients with acute exacerbationof chronic obstructive pulmonary disease receiving ventilatorysupportrdquo COPD Journal of Chronic Obstructive PulmonaryDisease vol 11 no 2 pp 171ndash176 2014

[41] A Chamorro A Cervera J Castillo A Davalos J J Aponteand A M Planas ldquoUnfractionated heparin is associated with alower rise of serum vascular cell adhesion molecule-1 in acuteischemic stroke patientsrdquo Neuroscience Letters vol 328 no 3pp 229ndash232 2002

[42] R de Cock L A Ficker J G Dart A Garner and P WrightldquoTopical heparin in the treatment of ligneous conjunctivitisrdquoOphthalmology vol 102 no 11 pp 1654ndash1659 1995

[43] U Derhaschnig T Pernerstorfer M Knechtelsdorfer U Hol-lenstein S Panzer and B Jilma ldquoEvaluation of antiinflamma-tory and antiadhesive effects of heparins in human endotox-emiardquo Critical Care Medicine vol 31 no 4 pp 1108ndash1112 2003

[44] B DixonM J Schultz R Smith J B Fink J D Santamaria andD J Campbell ldquoNebulized heparin is associatedwith fewer daysof mechanical ventilation in critically ill patients a randomizedcontrolled trialrdquo Critical Care vol 14 no 5 article R180 2010

[45] F K Keating H L Dauerman D A Whitaker B E Sobeland D J Schneider ldquoThe effects of bivalirudin compared withthose of unfractionated heparin plus eptifibatide on inflam-mation and thrombin generation and activity during coronaryinterventionrdquo Coronary Artery Disease vol 16 no 6 pp 401ndash405 2005

[46] M Ledson M Gallagher C A Hart and M Walshaw ldquoNeb-ulized heparin in Burkholderia cepacia colonized adult cysticfibrosis patientsrdquo European Respiratory Journal vol 17 no 1 pp36ndash38 2001

[47] D J Serisier J K Shute P M Hockey B Higgins J Conwayand M P Carroll ldquoInhaled heparin in cystic fibrosisrdquo EuropeanRespiratory Journal vol 27 no 2 pp 354ndash358 2006

[48] O K Poyrazoglu A Dogukan M Yalniz D Seckin andA L Gunal ldquoAcute effect of standard heparin versus lowmolecular weight heparin on oxidative stress and inflammationin hemodialysis patientsrdquo Renal Failure vol 28 no 8 pp 723ndash727 2006

[49] S Suzuki T Matsuo H Kobayashi et al ldquoAntithrombotictreatment (argatroban vs heparin) in coronary angioplastyin angina pectoris effects on inflammatory hemostatic and

endothelium-derived parametersrdquoThrombosis Research vol 98no 4 pp 269ndash279 2000

[50] S D Trocme and H-I Li ldquoEffect of heparin-surface-modifiedintraocular lenses on postoperative inflammation after pha-coemulsification a randomized trial in a United States patientpopulationrdquo Ophthalmology vol 107 no 6 pp 1031ndash1037 2000

[51] C Vancheri C Mastruzzo F Armato et al ldquoIntranasal heparinreduces eosinophil recruitment after nasal allergen challenge inpatients with allergic rhinitisrdquo Journal of Allergy and ClinicalImmunology vol 108 no 5 pp 703ndash708 2001

[52] A Abdollahi M-T Naini H Shams and R Zarei ldquoEffect oflow-molecular-weight heparin on postoperative inflammationin phacomorphic glaucomardquo Archives of Iranian Medicine vol5 no 4 pp 225ndash229 2002

[53] R T S Lakshmi T Priyanka J Meenakshi K R MathangiV Jeyaraman and M Babu ldquoLow molecular weight heparinmediated regulation of nitric oxide synthase during burnwound healingrdquo Annals of Burns and Fire Disasters vol 24 no1 pp 24ndash29 2011

[54] G Montalescot C Bal-dit-Sollier D Chibedi et al ldquoCompar-ison of effects on markers of blood cell activation of enoxa-parin dalteparin and unfractionated heparin in patients withunstable angina pectoris or non-ST-segment elevation acutemyocardial infarction (the ARMADA study)rdquo The AmericanJournal of Cardiology vol 91 no 8 pp 925ndash930 2003

[55] S Nasiripour K Gholami SMousavi et al ldquoComparison of theeffects of enoxaparin and heparin on inflammatory biomarkersin patients with ST-segment elevated myocardial infarction aprospective open label pilot clinical trialrdquo Iranian Journal ofPharmaceutical Research vol 13 no 2 pp 583ndash590 2014

[56] J Oldgren C Fellenius K Boman et al ldquoInfluence of prolongeddalteparin treatment on coagulation fibrinolysis and inflam-mation in unstable coronary artery diseaserdquo Journal of InternalMedicine vol 258 no 5 pp 420ndash427 2005

[57] T K Rudolph V Rudolph A Witte et al ldquoLiberation of vesseladherent myeloperoxidase by enoxaparin improves endothelialfunctionrdquo International Journal of Cardiology vol 140 no 1 pp42ndash47 2010

[58] D L Walters M J Ray P Wood E J Perrin J H N Bettand C N Aroney ldquoHigh-dose tirofiban with enoxaparin andinflammatory markers in high-risk percutaneous interventionrdquoEuropean Journal of Clinical Investigation vol 40 no 2 pp 139ndash147 2010

[59] S W Rathbun C E Aston and T L Whitsett ldquoA randomizedtrial of dalteparin compared with ibuprofen for the treatmentof superficial thrombophlebitisrdquo Journal of Thrombosis andHaemostasis vol 10 no 5 pp 833ndash839 2012

[60] J P Titon D Auger P Grange et al ldquoTherapeutic managementof superficial venous thrombosis with calcium nadroparinDosage testing and comparison with a non-steroidal anti-inflammatory agentrdquo Annales de Cardiologie et d Angeiologievol 43 no 3 pp 160ndash166 1994

[61] H Uncu ldquoA comparison of low-molecular-weight heparin andcombined therapy of low-molecular-weight heparin with ananti-inflammatory agent in the treatment of superficial veinthrombosisrdquo Phlebology vol 24 no 2 pp 56ndash60 2009

[62] J A Sjoslashland R S Pedersen J Jespersen and J GramldquoIntraperitoneal heparin ameliorates the systemic inflamma-tory response in PD patientsrdquo NephronmdashClinical Practice vol100 no 4 pp c105ndashc110 2005

[63] N L Fine C Shim and M H Williams Jr ldquoObjectiveevaluation of heparin in the treatment of asthmardquo AmericanReview of Respiratory Disease vol 98 no 5 pp 886ndash887 1968

14 Advances in Pharmacological Sciences

[64] ZDiamantM C Timmers H van derVeen C P Page F J vander Meer and P J Sterk ldquoEffect of inhaled heparin on allergen-induced early and late asthmatic responses in patients withatopic asthmardquo American Journal of Respiratory and CriticalCare Medicine vol 153 no 6 I pp 1790ndash1795 1996

[65] C M E Tranfa A Vatrella R Parrella G Pelaia F Bariffiand S A Marsico ldquoEffect of inhaled heparin on water-inducedbronchoconstriction in allergic asthmaticsrdquoEuropean Journal ofClinical Pharmacology vol 57 no 1 pp 5ndash9 2001

[66] I Stelmach J Jerzynska A Brzozowska and P Kuna ldquoTheeffect of inhaled heparin on postleukotriene bronchoconstric-tion in children with asthmardquo Polski Merkuriusz Lekarski vol12 no 68 pp 95ndash98 2002

[67] R Polosa S Magrı C Vancheri et al ldquoTime course of changesin adenosine 51015840-monophosphate airway responsiveness withinhaled heparin in allergic asthmardquo Journal of Allergy andClinical Immunology vol 99 no 3 pp 338ndash342 1997

[68] J Butler GM Rocker and SWestaby ldquoInflammatory responseto cardiopulmonary bypassrdquo The Annals of Thoracic Surgeryvol 55 no 2 pp 552ndash559 1993

[69] J M Redmond A M Gillinov R S Stuart et al ldquoHeparin-coated bypass circuits reduce pulmonary injuryrdquoThe Annals ofThoracic Surgery vol 56 no 3 pp 474ndash479 1993

[70] S Svenmarker E Sandstrom T Karlsson et al ldquoClinical effectsof the heparin coated surface in cardiopulmonary bypassrdquoEuropean Journal of Cardio-Thoracic Surgery vol 11 no 5 pp957ndash964 1997

[71] Y J Gu W van Oeveren C Akkerman P W Boonstra RJ Huyzen and C R H Wildevuur ldquoHeparin-coated circuitsreduce the inflammatory response to cardiopulmonary bypassrdquoThe Annals of Thoracic Surgery vol 55 no 4 pp 917ndash922 1993

[72] D Paparella O O Al Radi Q H Meng T Venner K Teohand E Young ldquoThe effects of high-dose heparin on inflamma-tory and coagulation parameters following cardiopulmonarybypassrdquo Blood Coagulation and Fibrinolysis vol 16 no 5 pp323ndash328 2005

[73] S Danese A Papa S Saibeni A Repici A Malesci andM Vecchi ldquoInflammation and coagulation in inflammatorybowel disease the clot thickensrdquo The American Journal ofGastroenterology vol 102 no 1 pp 174ndash186 2007

[74] S Bloom S Kiilerich M R Lassen et al ldquoLow molecularweight heparin (tinzaparin) vs placebo in the treatment of mildto moderately active ulcerative colitisrdquo Alimentary Pharmacol-ogy ampTherapeutics vol 19 no 8 pp 871ndash878 2004

[75] P Libby ldquoCoronary artery injury and the biology of atheroscle-rosis inflammation thrombosis and stabilizationrdquo AmericanJournal of Cardiology vol 86 no 8 2000

[76] N T Mulvihill and J B Foley ldquoInflammation in acute coronarysyndromesrdquo Heart vol 87 no 3 pp 201ndash204 2002

[77] N A JamesonW V Good and C S Hoyt ldquoInflammation aftercataract surgery in childrenrdquoOphthalmic Surgery vol 23 no 2pp 99ndash102 1992

[78] R M Sinskey P A Amin and R Lingua ldquoCataract extractionand intraocular lens implantation in an infant with amonocularcongenital cataractrdquo Journal of Cataract amp Refractive Surgeryvol 20 no 6 pp 647ndash651 1994

[79] A van Ophoven A Heinecke and L Hertle ldquoSafety andefficacy of concurrent application of oral pentosan polysulfateand subcutaneous low-dose heparin for patients with interstitialcystitisrdquo Urology vol 66 no 4 pp 707ndash711 2005

Submit your manuscripts athttpwwwhindawicom

PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom

Volume 2014

ToxinsJournal of

VaccinesJournal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AntibioticsInternational Journal of

ToxicologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Drug DeliveryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in Pharmacological Sciences

Tropical MedicineJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AddictionJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Autoimmune Diseases

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anesthesiology Research and Practice

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Pharmaceutics

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Page 12: Review Article Anti-Inflammatory Effects of Heparin and Its …downloads.hindawi.com/journals/aps/2015/507151.pdf · 2019. 7. 31. · Review Article Anti-Inflammatory Effects of Heparin

12 Advances in Pharmacological Sciences

[7] A R Jadad R A Moore D Carroll et al ldquoAssessing the qualityof reports of randomized clinical trials is blinding necessaryrdquoControlled Clinical Trials vol 17 no 1 pp 1ndash12 1996

[8] K F Schulz D G Altman and D Moher ldquoCONSORT 2010statement updated guidelines for reporting parallel grouprandomised trialsrdquo International Journal of Surgery vol 9 no8 pp 672ndash677 2011

[9] T Ahmed J Garrigo and I Danta ldquoPreventing bronchocon-striction in exercise-induced asthma with inhaled heparinrdquoTheNewEngland Journal ofMedicine vol 329 no 2 pp 90ndash95 1993

[10] Z Diamant M C Timmers H Van Der Veen C P PageF J Van Der Meer and P J Sterk ldquoEffect of inhaled heparinon allergen-induced early and late asthmatic responses inpatients with atopic asthmardquo American Journal of Respiratoryand Critical Care Medicine vol 153 no 6 pp 1790ndash1795 1996

[11] M Duong D Cockcroft L-P Boulet et al ldquoThe effect ofIVX-0142 a heparin-derived hypersulfated disaccharide on theallergic airway responses in asthmardquo Allergy vol 63 no 9 pp1195ndash1201 2008

[12] A M Fal M Kraus-Filarska J Miecielica and J MalolepszyldquoMechanisms of action of nebulized low-molecular-weightheparin in patients with bronchial asthmardquo The Journal ofAllergy and Clinical Immunology vol 113 no 2 supplement pS36 2004

[13] J Jerzynska I Stelmach P Majak and P Kuna ldquoThe effectof inhaled heparin on airway responsiveness to histamine andmetacholine in asthmatic childrenrdquo Journal of Allergy andClinical Immunology vol 109 no 1 supplement 1 p S39 2002

[14] A F Kalpaklioglu Y S Demirel S Saryal and Z MisirligilldquoEffect of pretreatment with heparin on pulmonary and cuta-neous responserdquo Journal of Asthma vol 34 no 4 pp 337ndash3431997

[15] I Stelmach J Jerzynska A Brzozowska and P Kuna ldquoTheeffect of inhaled heparin on postleukotriene bronchoconstric-tion in children with asthmardquo Journal of Allergy and ClinicalImmunology vol 109 no 1 supplement 1 p S39 2002

[16] I Stelmach J Jerzynska W Stelmach et al ldquoThe effect ofinhaled heparin on airway responsiveness to histamine andleukotriene D4rdquo Allergy and Asthma Proceedings vol 24 no 1pp 59ndash65 2003

[17] Y S Ang N Mahmud B White et al ldquoRandomized compar-ison of unfractionated heparin with corticosteroids in severeactive inflammatory bowel diseaserdquo Alimentary PharmacologyandTherapeutics vol 14 no 8 pp 1015ndash1022 2000

[18] C Folwaczny B Wiebecke and K Loeschke ldquoUnfractionedheparin in the therapy of patients with highly active inflamma-tory bowel diseaserdquo The American Journal of Gastroenterologyvol 94 no 6 pp 1551ndash1555 1999

[19] J Panes M Esteve E Cabre et al ldquoComparison of heparinand steroids in the treatment of moderate and severe ulcerativecolitisrdquo Gastroenterology vol 119 no 4 pp 903ndash908 2000

[20] P Zezos G Papaioannou N Nikolaidis et al ldquoLow-molecular-weight heparin (enoxaparin) as adjuvant therapy in the treat-ment of active ulcerative colitis a randomized controlledcomparative studyrdquoAlimentary Pharmacology andTherapeuticsvol 23 no 10 pp 1443ndash1453 2006

[21] A A Vrij J M Jansen E J Schoon H C Hemker and RW Stockbrugger ldquoLow molecular weight heparin treatmentin steroid refractory ulcerative colitis clinical outcome andinfluence on mucosal capillary thrombirdquo Scandinavian Journalof Gastroenterology Supplement vol 36 no 234 pp 41ndash47 2001

[22] D M Borgioli D J Coster R F T Fan et al ldquoEffect of heparinsurface modification of polymethylmethacrylate intraocularlenses on signs of postoperative inflammation after extracap-sular cataract extraction one-year results of a double-maskedmulticenter studyrdquoOphthalmology vol 99 no 8 pp 1248ndash12551992

[23] J Colin S Roncin and M Wenzel ldquoEfficacy of heparinsurface-modified IOLs in reducing postoperative inflammatoryreactions in patients with exfoliation syndromemdasha double-blind comparative studyrdquo European Journal of Implant andRefractive Surgery vol 7 no 5 pp 266ndash270 1995

[24] Y B Ozkurt A Taskiran N Erdogan B Kandemir and OK Dogan ldquoEffect of heparin in the intraocular irrigating solu-tion on postoperative inflammation in the pediatric cataractsurgeryrdquoClinical Ophthalmology vol 3 no 1 pp 363ndash365 2009

[25] V A Vasavada M R Praveen S K Shah R H Trivedi andA R Vasavada ldquoAnti-inflammatory effect of low-molecular-weight heparin in pediatric cataract surgery a randomizedclinical trialrdquoThe American Journal of Ophthalmology vol 154no 2 pp 252ndash258 2012

[26] T Kohnen B Dick V Hessemer D D Koch and K WJacobi ldquoEffect of heparin in irrigating solution on inflammationfollowing small incision cataract surgeryrdquo Journal of Cataract ampRefractive Surgery vol 24 no 2 pp 237ndash243 1998

[27] S Ashraf Y Tian D Cowan A Entress P G Martin andK G Watterson ldquoRelease of proinflammatory cytokines dur-ing pediatric cardiopulmonary bypass heparin-bonded versusnonbonded oxygenatorsrdquo Annals of Thoracic Surgery vol 64no 6 pp 1790ndash1794 1997

[28] J-O Defraigne J Pincemail R Larbuisson F Blaffart andR Limet ldquoCytokine release and neutrophil activation are notprevented by heparin- coated circuits and aprotinin administra-tionrdquo Annals of Thoracic Surgery vol 69 no 4 pp 1084ndash10912000

[29] R de Vroege W van Oeveren J van Klarenbosch et al ldquoTheimpact of heparin-coated cardiopulmonary bypass circuits onpulmonary function and the release of inflammatory media-torsrdquo Anesthesia and Analgesia vol 98 no 6 pp 1586ndash15942004

[30] Y Misawa K Kawahito H Konishi and K Fuse ldquoCytokinemediated endothelial activation during and after normothermiccardiopulmonary bypass Heparin-bonded versus non heparin-bonded circuitsrdquo ASAIO Journal vol 46 no 6 pp 740ndash7432000

[31] A Koster T Fischer M Praus et al ldquoHemostatic activationand inflammatory response during cardiopulmonary bypassimpact of heparin managementrdquo Anesthesiology vol 97 no 4pp 837ndash841 2002

[32] C Olsson A Siegbahn A Henze et al ldquoHeparin-coatedcardiopulmonary bypass circuits reduce circulating comple-ment factors and interleukin-6 in paediatric heart surgeryrdquoScandinavian Cardiovascular Journal vol 34 no 1 pp 33ndash402000

[33] T Ozawa K Yoshihara N Koyama Y Watanabe N Shionoand Y Takanashi ldquoClinical efficacy of heparin-bonded bypasscircuits related to cytokine responses in childrenrdquo The Annalsof Thoracic Surgery vol 69 no 2 pp 584ndash590 2000

[34] A Parolari F Alamanni T Gherli et al ldquolsquoHigh dosersquo aprotininand heparin-coated circuits Clinical efficacy and inflammatoryresponserdquo Cardiovascular Surgery vol 7 no 1 pp 117ndash127 1999

[35] H Yamada I Kudoh Y Hirose M Toyoshima H Abe andK Kurahashi ldquoHeparin-coated circuits reduce the formation of

Advances in Pharmacological Sciences 13

TNF120572 during cardiopulmonary bypassrdquo Acta AnaesthesiologicaScandinavica vol 40 no 3 pp 311ndash317 1996

[36] O Barkay E Niv E Santo R Bruck A Hallak and F MKonikoff ldquoLow-dose heparin for the prevention of post-ERCPpancreatitis a randomized placebo-controlled trialrdquo SurgicalEndoscopy and Other Interventional Techniques vol 22 no 9pp 1971ndash1976 2008

[37] R C Becker K W Mahaffey H Yang et al ldquoHeparin-associated anti-Xa activity and platelet-derived prothromboticand proinflammatory biomarkers in moderate to high-riskpatients with acute coronary syndromerdquo Journal of Thrombosisand Thrombolysis vol 31 no 2 pp 146ndash153 2011

[38] S D Bowler S M Smith and P S Lavercombe ldquoHeparininhibits the immediate response to antigen in the skin and lungsof allergic subjectsrdquo American Review of Respiratory Diseasevol 147 no 1 pp 160ndash163 1993

[39] J P Boyle R H Smart and J K Shirey ldquoHeparin in thetreatment of chronic obstructive bronchopulmonary diseaserdquoThe American Journal of Cardiology vol 14 no 1 pp 25ndash281964

[40] Y Qian H Xie R Tian K Yu and R Wang ldquoEfficacy of lowmolecular weight heparin in patients with acute exacerbationof chronic obstructive pulmonary disease receiving ventilatorysupportrdquo COPD Journal of Chronic Obstructive PulmonaryDisease vol 11 no 2 pp 171ndash176 2014

[41] A Chamorro A Cervera J Castillo A Davalos J J Aponteand A M Planas ldquoUnfractionated heparin is associated with alower rise of serum vascular cell adhesion molecule-1 in acuteischemic stroke patientsrdquo Neuroscience Letters vol 328 no 3pp 229ndash232 2002

[42] R de Cock L A Ficker J G Dart A Garner and P WrightldquoTopical heparin in the treatment of ligneous conjunctivitisrdquoOphthalmology vol 102 no 11 pp 1654ndash1659 1995

[43] U Derhaschnig T Pernerstorfer M Knechtelsdorfer U Hol-lenstein S Panzer and B Jilma ldquoEvaluation of antiinflamma-tory and antiadhesive effects of heparins in human endotox-emiardquo Critical Care Medicine vol 31 no 4 pp 1108ndash1112 2003

[44] B DixonM J Schultz R Smith J B Fink J D Santamaria andD J Campbell ldquoNebulized heparin is associatedwith fewer daysof mechanical ventilation in critically ill patients a randomizedcontrolled trialrdquo Critical Care vol 14 no 5 article R180 2010

[45] F K Keating H L Dauerman D A Whitaker B E Sobeland D J Schneider ldquoThe effects of bivalirudin compared withthose of unfractionated heparin plus eptifibatide on inflam-mation and thrombin generation and activity during coronaryinterventionrdquo Coronary Artery Disease vol 16 no 6 pp 401ndash405 2005

[46] M Ledson M Gallagher C A Hart and M Walshaw ldquoNeb-ulized heparin in Burkholderia cepacia colonized adult cysticfibrosis patientsrdquo European Respiratory Journal vol 17 no 1 pp36ndash38 2001

[47] D J Serisier J K Shute P M Hockey B Higgins J Conwayand M P Carroll ldquoInhaled heparin in cystic fibrosisrdquo EuropeanRespiratory Journal vol 27 no 2 pp 354ndash358 2006

[48] O K Poyrazoglu A Dogukan M Yalniz D Seckin andA L Gunal ldquoAcute effect of standard heparin versus lowmolecular weight heparin on oxidative stress and inflammationin hemodialysis patientsrdquo Renal Failure vol 28 no 8 pp 723ndash727 2006

[49] S Suzuki T Matsuo H Kobayashi et al ldquoAntithrombotictreatment (argatroban vs heparin) in coronary angioplastyin angina pectoris effects on inflammatory hemostatic and

endothelium-derived parametersrdquoThrombosis Research vol 98no 4 pp 269ndash279 2000

[50] S D Trocme and H-I Li ldquoEffect of heparin-surface-modifiedintraocular lenses on postoperative inflammation after pha-coemulsification a randomized trial in a United States patientpopulationrdquo Ophthalmology vol 107 no 6 pp 1031ndash1037 2000

[51] C Vancheri C Mastruzzo F Armato et al ldquoIntranasal heparinreduces eosinophil recruitment after nasal allergen challenge inpatients with allergic rhinitisrdquo Journal of Allergy and ClinicalImmunology vol 108 no 5 pp 703ndash708 2001

[52] A Abdollahi M-T Naini H Shams and R Zarei ldquoEffect oflow-molecular-weight heparin on postoperative inflammationin phacomorphic glaucomardquo Archives of Iranian Medicine vol5 no 4 pp 225ndash229 2002

[53] R T S Lakshmi T Priyanka J Meenakshi K R MathangiV Jeyaraman and M Babu ldquoLow molecular weight heparinmediated regulation of nitric oxide synthase during burnwound healingrdquo Annals of Burns and Fire Disasters vol 24 no1 pp 24ndash29 2011

[54] G Montalescot C Bal-dit-Sollier D Chibedi et al ldquoCompar-ison of effects on markers of blood cell activation of enoxa-parin dalteparin and unfractionated heparin in patients withunstable angina pectoris or non-ST-segment elevation acutemyocardial infarction (the ARMADA study)rdquo The AmericanJournal of Cardiology vol 91 no 8 pp 925ndash930 2003

[55] S Nasiripour K Gholami SMousavi et al ldquoComparison of theeffects of enoxaparin and heparin on inflammatory biomarkersin patients with ST-segment elevated myocardial infarction aprospective open label pilot clinical trialrdquo Iranian Journal ofPharmaceutical Research vol 13 no 2 pp 583ndash590 2014

[56] J Oldgren C Fellenius K Boman et al ldquoInfluence of prolongeddalteparin treatment on coagulation fibrinolysis and inflam-mation in unstable coronary artery diseaserdquo Journal of InternalMedicine vol 258 no 5 pp 420ndash427 2005

[57] T K Rudolph V Rudolph A Witte et al ldquoLiberation of vesseladherent myeloperoxidase by enoxaparin improves endothelialfunctionrdquo International Journal of Cardiology vol 140 no 1 pp42ndash47 2010

[58] D L Walters M J Ray P Wood E J Perrin J H N Bettand C N Aroney ldquoHigh-dose tirofiban with enoxaparin andinflammatory markers in high-risk percutaneous interventionrdquoEuropean Journal of Clinical Investigation vol 40 no 2 pp 139ndash147 2010

[59] S W Rathbun C E Aston and T L Whitsett ldquoA randomizedtrial of dalteparin compared with ibuprofen for the treatmentof superficial thrombophlebitisrdquo Journal of Thrombosis andHaemostasis vol 10 no 5 pp 833ndash839 2012

[60] J P Titon D Auger P Grange et al ldquoTherapeutic managementof superficial venous thrombosis with calcium nadroparinDosage testing and comparison with a non-steroidal anti-inflammatory agentrdquo Annales de Cardiologie et d Angeiologievol 43 no 3 pp 160ndash166 1994

[61] H Uncu ldquoA comparison of low-molecular-weight heparin andcombined therapy of low-molecular-weight heparin with ananti-inflammatory agent in the treatment of superficial veinthrombosisrdquo Phlebology vol 24 no 2 pp 56ndash60 2009

[62] J A Sjoslashland R S Pedersen J Jespersen and J GramldquoIntraperitoneal heparin ameliorates the systemic inflamma-tory response in PD patientsrdquo NephronmdashClinical Practice vol100 no 4 pp c105ndashc110 2005

[63] N L Fine C Shim and M H Williams Jr ldquoObjectiveevaluation of heparin in the treatment of asthmardquo AmericanReview of Respiratory Disease vol 98 no 5 pp 886ndash887 1968

14 Advances in Pharmacological Sciences

[64] ZDiamantM C Timmers H van derVeen C P Page F J vander Meer and P J Sterk ldquoEffect of inhaled heparin on allergen-induced early and late asthmatic responses in patients withatopic asthmardquo American Journal of Respiratory and CriticalCare Medicine vol 153 no 6 I pp 1790ndash1795 1996

[65] C M E Tranfa A Vatrella R Parrella G Pelaia F Bariffiand S A Marsico ldquoEffect of inhaled heparin on water-inducedbronchoconstriction in allergic asthmaticsrdquoEuropean Journal ofClinical Pharmacology vol 57 no 1 pp 5ndash9 2001

[66] I Stelmach J Jerzynska A Brzozowska and P Kuna ldquoTheeffect of inhaled heparin on postleukotriene bronchoconstric-tion in children with asthmardquo Polski Merkuriusz Lekarski vol12 no 68 pp 95ndash98 2002

[67] R Polosa S Magrı C Vancheri et al ldquoTime course of changesin adenosine 51015840-monophosphate airway responsiveness withinhaled heparin in allergic asthmardquo Journal of Allergy andClinical Immunology vol 99 no 3 pp 338ndash342 1997

[68] J Butler GM Rocker and SWestaby ldquoInflammatory responseto cardiopulmonary bypassrdquo The Annals of Thoracic Surgeryvol 55 no 2 pp 552ndash559 1993

[69] J M Redmond A M Gillinov R S Stuart et al ldquoHeparin-coated bypass circuits reduce pulmonary injuryrdquoThe Annals ofThoracic Surgery vol 56 no 3 pp 474ndash479 1993

[70] S Svenmarker E Sandstrom T Karlsson et al ldquoClinical effectsof the heparin coated surface in cardiopulmonary bypassrdquoEuropean Journal of Cardio-Thoracic Surgery vol 11 no 5 pp957ndash964 1997

[71] Y J Gu W van Oeveren C Akkerman P W Boonstra RJ Huyzen and C R H Wildevuur ldquoHeparin-coated circuitsreduce the inflammatory response to cardiopulmonary bypassrdquoThe Annals of Thoracic Surgery vol 55 no 4 pp 917ndash922 1993

[72] D Paparella O O Al Radi Q H Meng T Venner K Teohand E Young ldquoThe effects of high-dose heparin on inflamma-tory and coagulation parameters following cardiopulmonarybypassrdquo Blood Coagulation and Fibrinolysis vol 16 no 5 pp323ndash328 2005

[73] S Danese A Papa S Saibeni A Repici A Malesci andM Vecchi ldquoInflammation and coagulation in inflammatorybowel disease the clot thickensrdquo The American Journal ofGastroenterology vol 102 no 1 pp 174ndash186 2007

[74] S Bloom S Kiilerich M R Lassen et al ldquoLow molecularweight heparin (tinzaparin) vs placebo in the treatment of mildto moderately active ulcerative colitisrdquo Alimentary Pharmacol-ogy ampTherapeutics vol 19 no 8 pp 871ndash878 2004

[75] P Libby ldquoCoronary artery injury and the biology of atheroscle-rosis inflammation thrombosis and stabilizationrdquo AmericanJournal of Cardiology vol 86 no 8 2000

[76] N T Mulvihill and J B Foley ldquoInflammation in acute coronarysyndromesrdquo Heart vol 87 no 3 pp 201ndash204 2002

[77] N A JamesonW V Good and C S Hoyt ldquoInflammation aftercataract surgery in childrenrdquoOphthalmic Surgery vol 23 no 2pp 99ndash102 1992

[78] R M Sinskey P A Amin and R Lingua ldquoCataract extractionand intraocular lens implantation in an infant with amonocularcongenital cataractrdquo Journal of Cataract amp Refractive Surgeryvol 20 no 6 pp 647ndash651 1994

[79] A van Ophoven A Heinecke and L Hertle ldquoSafety andefficacy of concurrent application of oral pentosan polysulfateand subcutaneous low-dose heparin for patients with interstitialcystitisrdquo Urology vol 66 no 4 pp 707ndash711 2005

Submit your manuscripts athttpwwwhindawicom

PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom

Volume 2014

ToxinsJournal of

VaccinesJournal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AntibioticsInternational Journal of

ToxicologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Drug DeliveryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in Pharmacological Sciences

Tropical MedicineJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AddictionJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Autoimmune Diseases

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anesthesiology Research and Practice

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Pharmaceutics

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Page 13: Review Article Anti-Inflammatory Effects of Heparin and Its …downloads.hindawi.com/journals/aps/2015/507151.pdf · 2019. 7. 31. · Review Article Anti-Inflammatory Effects of Heparin

Advances in Pharmacological Sciences 13

TNF120572 during cardiopulmonary bypassrdquo Acta AnaesthesiologicaScandinavica vol 40 no 3 pp 311ndash317 1996

[36] O Barkay E Niv E Santo R Bruck A Hallak and F MKonikoff ldquoLow-dose heparin for the prevention of post-ERCPpancreatitis a randomized placebo-controlled trialrdquo SurgicalEndoscopy and Other Interventional Techniques vol 22 no 9pp 1971ndash1976 2008

[37] R C Becker K W Mahaffey H Yang et al ldquoHeparin-associated anti-Xa activity and platelet-derived prothromboticand proinflammatory biomarkers in moderate to high-riskpatients with acute coronary syndromerdquo Journal of Thrombosisand Thrombolysis vol 31 no 2 pp 146ndash153 2011

[38] S D Bowler S M Smith and P S Lavercombe ldquoHeparininhibits the immediate response to antigen in the skin and lungsof allergic subjectsrdquo American Review of Respiratory Diseasevol 147 no 1 pp 160ndash163 1993

[39] J P Boyle R H Smart and J K Shirey ldquoHeparin in thetreatment of chronic obstructive bronchopulmonary diseaserdquoThe American Journal of Cardiology vol 14 no 1 pp 25ndash281964

[40] Y Qian H Xie R Tian K Yu and R Wang ldquoEfficacy of lowmolecular weight heparin in patients with acute exacerbationof chronic obstructive pulmonary disease receiving ventilatorysupportrdquo COPD Journal of Chronic Obstructive PulmonaryDisease vol 11 no 2 pp 171ndash176 2014

[41] A Chamorro A Cervera J Castillo A Davalos J J Aponteand A M Planas ldquoUnfractionated heparin is associated with alower rise of serum vascular cell adhesion molecule-1 in acuteischemic stroke patientsrdquo Neuroscience Letters vol 328 no 3pp 229ndash232 2002

[42] R de Cock L A Ficker J G Dart A Garner and P WrightldquoTopical heparin in the treatment of ligneous conjunctivitisrdquoOphthalmology vol 102 no 11 pp 1654ndash1659 1995

[43] U Derhaschnig T Pernerstorfer M Knechtelsdorfer U Hol-lenstein S Panzer and B Jilma ldquoEvaluation of antiinflamma-tory and antiadhesive effects of heparins in human endotox-emiardquo Critical Care Medicine vol 31 no 4 pp 1108ndash1112 2003

[44] B DixonM J Schultz R Smith J B Fink J D Santamaria andD J Campbell ldquoNebulized heparin is associatedwith fewer daysof mechanical ventilation in critically ill patients a randomizedcontrolled trialrdquo Critical Care vol 14 no 5 article R180 2010

[45] F K Keating H L Dauerman D A Whitaker B E Sobeland D J Schneider ldquoThe effects of bivalirudin compared withthose of unfractionated heparin plus eptifibatide on inflam-mation and thrombin generation and activity during coronaryinterventionrdquo Coronary Artery Disease vol 16 no 6 pp 401ndash405 2005

[46] M Ledson M Gallagher C A Hart and M Walshaw ldquoNeb-ulized heparin in Burkholderia cepacia colonized adult cysticfibrosis patientsrdquo European Respiratory Journal vol 17 no 1 pp36ndash38 2001

[47] D J Serisier J K Shute P M Hockey B Higgins J Conwayand M P Carroll ldquoInhaled heparin in cystic fibrosisrdquo EuropeanRespiratory Journal vol 27 no 2 pp 354ndash358 2006

[48] O K Poyrazoglu A Dogukan M Yalniz D Seckin andA L Gunal ldquoAcute effect of standard heparin versus lowmolecular weight heparin on oxidative stress and inflammationin hemodialysis patientsrdquo Renal Failure vol 28 no 8 pp 723ndash727 2006

[49] S Suzuki T Matsuo H Kobayashi et al ldquoAntithrombotictreatment (argatroban vs heparin) in coronary angioplastyin angina pectoris effects on inflammatory hemostatic and

endothelium-derived parametersrdquoThrombosis Research vol 98no 4 pp 269ndash279 2000

[50] S D Trocme and H-I Li ldquoEffect of heparin-surface-modifiedintraocular lenses on postoperative inflammation after pha-coemulsification a randomized trial in a United States patientpopulationrdquo Ophthalmology vol 107 no 6 pp 1031ndash1037 2000

[51] C Vancheri C Mastruzzo F Armato et al ldquoIntranasal heparinreduces eosinophil recruitment after nasal allergen challenge inpatients with allergic rhinitisrdquo Journal of Allergy and ClinicalImmunology vol 108 no 5 pp 703ndash708 2001

[52] A Abdollahi M-T Naini H Shams and R Zarei ldquoEffect oflow-molecular-weight heparin on postoperative inflammationin phacomorphic glaucomardquo Archives of Iranian Medicine vol5 no 4 pp 225ndash229 2002

[53] R T S Lakshmi T Priyanka J Meenakshi K R MathangiV Jeyaraman and M Babu ldquoLow molecular weight heparinmediated regulation of nitric oxide synthase during burnwound healingrdquo Annals of Burns and Fire Disasters vol 24 no1 pp 24ndash29 2011

[54] G Montalescot C Bal-dit-Sollier D Chibedi et al ldquoCompar-ison of effects on markers of blood cell activation of enoxa-parin dalteparin and unfractionated heparin in patients withunstable angina pectoris or non-ST-segment elevation acutemyocardial infarction (the ARMADA study)rdquo The AmericanJournal of Cardiology vol 91 no 8 pp 925ndash930 2003

[55] S Nasiripour K Gholami SMousavi et al ldquoComparison of theeffects of enoxaparin and heparin on inflammatory biomarkersin patients with ST-segment elevated myocardial infarction aprospective open label pilot clinical trialrdquo Iranian Journal ofPharmaceutical Research vol 13 no 2 pp 583ndash590 2014

[56] J Oldgren C Fellenius K Boman et al ldquoInfluence of prolongeddalteparin treatment on coagulation fibrinolysis and inflam-mation in unstable coronary artery diseaserdquo Journal of InternalMedicine vol 258 no 5 pp 420ndash427 2005

[57] T K Rudolph V Rudolph A Witte et al ldquoLiberation of vesseladherent myeloperoxidase by enoxaparin improves endothelialfunctionrdquo International Journal of Cardiology vol 140 no 1 pp42ndash47 2010

[58] D L Walters M J Ray P Wood E J Perrin J H N Bettand C N Aroney ldquoHigh-dose tirofiban with enoxaparin andinflammatory markers in high-risk percutaneous interventionrdquoEuropean Journal of Clinical Investigation vol 40 no 2 pp 139ndash147 2010

[59] S W Rathbun C E Aston and T L Whitsett ldquoA randomizedtrial of dalteparin compared with ibuprofen for the treatmentof superficial thrombophlebitisrdquo Journal of Thrombosis andHaemostasis vol 10 no 5 pp 833ndash839 2012

[60] J P Titon D Auger P Grange et al ldquoTherapeutic managementof superficial venous thrombosis with calcium nadroparinDosage testing and comparison with a non-steroidal anti-inflammatory agentrdquo Annales de Cardiologie et d Angeiologievol 43 no 3 pp 160ndash166 1994

[61] H Uncu ldquoA comparison of low-molecular-weight heparin andcombined therapy of low-molecular-weight heparin with ananti-inflammatory agent in the treatment of superficial veinthrombosisrdquo Phlebology vol 24 no 2 pp 56ndash60 2009

[62] J A Sjoslashland R S Pedersen J Jespersen and J GramldquoIntraperitoneal heparin ameliorates the systemic inflamma-tory response in PD patientsrdquo NephronmdashClinical Practice vol100 no 4 pp c105ndashc110 2005

[63] N L Fine C Shim and M H Williams Jr ldquoObjectiveevaluation of heparin in the treatment of asthmardquo AmericanReview of Respiratory Disease vol 98 no 5 pp 886ndash887 1968

14 Advances in Pharmacological Sciences

[64] ZDiamantM C Timmers H van derVeen C P Page F J vander Meer and P J Sterk ldquoEffect of inhaled heparin on allergen-induced early and late asthmatic responses in patients withatopic asthmardquo American Journal of Respiratory and CriticalCare Medicine vol 153 no 6 I pp 1790ndash1795 1996

[65] C M E Tranfa A Vatrella R Parrella G Pelaia F Bariffiand S A Marsico ldquoEffect of inhaled heparin on water-inducedbronchoconstriction in allergic asthmaticsrdquoEuropean Journal ofClinical Pharmacology vol 57 no 1 pp 5ndash9 2001

[66] I Stelmach J Jerzynska A Brzozowska and P Kuna ldquoTheeffect of inhaled heparin on postleukotriene bronchoconstric-tion in children with asthmardquo Polski Merkuriusz Lekarski vol12 no 68 pp 95ndash98 2002

[67] R Polosa S Magrı C Vancheri et al ldquoTime course of changesin adenosine 51015840-monophosphate airway responsiveness withinhaled heparin in allergic asthmardquo Journal of Allergy andClinical Immunology vol 99 no 3 pp 338ndash342 1997

[68] J Butler GM Rocker and SWestaby ldquoInflammatory responseto cardiopulmonary bypassrdquo The Annals of Thoracic Surgeryvol 55 no 2 pp 552ndash559 1993

[69] J M Redmond A M Gillinov R S Stuart et al ldquoHeparin-coated bypass circuits reduce pulmonary injuryrdquoThe Annals ofThoracic Surgery vol 56 no 3 pp 474ndash479 1993

[70] S Svenmarker E Sandstrom T Karlsson et al ldquoClinical effectsof the heparin coated surface in cardiopulmonary bypassrdquoEuropean Journal of Cardio-Thoracic Surgery vol 11 no 5 pp957ndash964 1997

[71] Y J Gu W van Oeveren C Akkerman P W Boonstra RJ Huyzen and C R H Wildevuur ldquoHeparin-coated circuitsreduce the inflammatory response to cardiopulmonary bypassrdquoThe Annals of Thoracic Surgery vol 55 no 4 pp 917ndash922 1993

[72] D Paparella O O Al Radi Q H Meng T Venner K Teohand E Young ldquoThe effects of high-dose heparin on inflamma-tory and coagulation parameters following cardiopulmonarybypassrdquo Blood Coagulation and Fibrinolysis vol 16 no 5 pp323ndash328 2005

[73] S Danese A Papa S Saibeni A Repici A Malesci andM Vecchi ldquoInflammation and coagulation in inflammatorybowel disease the clot thickensrdquo The American Journal ofGastroenterology vol 102 no 1 pp 174ndash186 2007

[74] S Bloom S Kiilerich M R Lassen et al ldquoLow molecularweight heparin (tinzaparin) vs placebo in the treatment of mildto moderately active ulcerative colitisrdquo Alimentary Pharmacol-ogy ampTherapeutics vol 19 no 8 pp 871ndash878 2004

[75] P Libby ldquoCoronary artery injury and the biology of atheroscle-rosis inflammation thrombosis and stabilizationrdquo AmericanJournal of Cardiology vol 86 no 8 2000

[76] N T Mulvihill and J B Foley ldquoInflammation in acute coronarysyndromesrdquo Heart vol 87 no 3 pp 201ndash204 2002

[77] N A JamesonW V Good and C S Hoyt ldquoInflammation aftercataract surgery in childrenrdquoOphthalmic Surgery vol 23 no 2pp 99ndash102 1992

[78] R M Sinskey P A Amin and R Lingua ldquoCataract extractionand intraocular lens implantation in an infant with amonocularcongenital cataractrdquo Journal of Cataract amp Refractive Surgeryvol 20 no 6 pp 647ndash651 1994

[79] A van Ophoven A Heinecke and L Hertle ldquoSafety andefficacy of concurrent application of oral pentosan polysulfateand subcutaneous low-dose heparin for patients with interstitialcystitisrdquo Urology vol 66 no 4 pp 707ndash711 2005

Submit your manuscripts athttpwwwhindawicom

PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom

Volume 2014

ToxinsJournal of

VaccinesJournal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AntibioticsInternational Journal of

ToxicologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Drug DeliveryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in Pharmacological Sciences

Tropical MedicineJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AddictionJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Autoimmune Diseases

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anesthesiology Research and Practice

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Pharmaceutics

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Page 14: Review Article Anti-Inflammatory Effects of Heparin and Its …downloads.hindawi.com/journals/aps/2015/507151.pdf · 2019. 7. 31. · Review Article Anti-Inflammatory Effects of Heparin

14 Advances in Pharmacological Sciences

[64] ZDiamantM C Timmers H van derVeen C P Page F J vander Meer and P J Sterk ldquoEffect of inhaled heparin on allergen-induced early and late asthmatic responses in patients withatopic asthmardquo American Journal of Respiratory and CriticalCare Medicine vol 153 no 6 I pp 1790ndash1795 1996

[65] C M E Tranfa A Vatrella R Parrella G Pelaia F Bariffiand S A Marsico ldquoEffect of inhaled heparin on water-inducedbronchoconstriction in allergic asthmaticsrdquoEuropean Journal ofClinical Pharmacology vol 57 no 1 pp 5ndash9 2001

[66] I Stelmach J Jerzynska A Brzozowska and P Kuna ldquoTheeffect of inhaled heparin on postleukotriene bronchoconstric-tion in children with asthmardquo Polski Merkuriusz Lekarski vol12 no 68 pp 95ndash98 2002

[67] R Polosa S Magrı C Vancheri et al ldquoTime course of changesin adenosine 51015840-monophosphate airway responsiveness withinhaled heparin in allergic asthmardquo Journal of Allergy andClinical Immunology vol 99 no 3 pp 338ndash342 1997

[68] J Butler GM Rocker and SWestaby ldquoInflammatory responseto cardiopulmonary bypassrdquo The Annals of Thoracic Surgeryvol 55 no 2 pp 552ndash559 1993

[69] J M Redmond A M Gillinov R S Stuart et al ldquoHeparin-coated bypass circuits reduce pulmonary injuryrdquoThe Annals ofThoracic Surgery vol 56 no 3 pp 474ndash479 1993

[70] S Svenmarker E Sandstrom T Karlsson et al ldquoClinical effectsof the heparin coated surface in cardiopulmonary bypassrdquoEuropean Journal of Cardio-Thoracic Surgery vol 11 no 5 pp957ndash964 1997

[71] Y J Gu W van Oeveren C Akkerman P W Boonstra RJ Huyzen and C R H Wildevuur ldquoHeparin-coated circuitsreduce the inflammatory response to cardiopulmonary bypassrdquoThe Annals of Thoracic Surgery vol 55 no 4 pp 917ndash922 1993

[72] D Paparella O O Al Radi Q H Meng T Venner K Teohand E Young ldquoThe effects of high-dose heparin on inflamma-tory and coagulation parameters following cardiopulmonarybypassrdquo Blood Coagulation and Fibrinolysis vol 16 no 5 pp323ndash328 2005

[73] S Danese A Papa S Saibeni A Repici A Malesci andM Vecchi ldquoInflammation and coagulation in inflammatorybowel disease the clot thickensrdquo The American Journal ofGastroenterology vol 102 no 1 pp 174ndash186 2007

[74] S Bloom S Kiilerich M R Lassen et al ldquoLow molecularweight heparin (tinzaparin) vs placebo in the treatment of mildto moderately active ulcerative colitisrdquo Alimentary Pharmacol-ogy ampTherapeutics vol 19 no 8 pp 871ndash878 2004

[75] P Libby ldquoCoronary artery injury and the biology of atheroscle-rosis inflammation thrombosis and stabilizationrdquo AmericanJournal of Cardiology vol 86 no 8 2000

[76] N T Mulvihill and J B Foley ldquoInflammation in acute coronarysyndromesrdquo Heart vol 87 no 3 pp 201ndash204 2002

[77] N A JamesonW V Good and C S Hoyt ldquoInflammation aftercataract surgery in childrenrdquoOphthalmic Surgery vol 23 no 2pp 99ndash102 1992

[78] R M Sinskey P A Amin and R Lingua ldquoCataract extractionand intraocular lens implantation in an infant with amonocularcongenital cataractrdquo Journal of Cataract amp Refractive Surgeryvol 20 no 6 pp 647ndash651 1994

[79] A van Ophoven A Heinecke and L Hertle ldquoSafety andefficacy of concurrent application of oral pentosan polysulfateand subcutaneous low-dose heparin for patients with interstitialcystitisrdquo Urology vol 66 no 4 pp 707ndash711 2005

Submit your manuscripts athttpwwwhindawicom

PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom

Volume 2014

ToxinsJournal of

VaccinesJournal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AntibioticsInternational Journal of

ToxicologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Drug DeliveryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in Pharmacological Sciences

Tropical MedicineJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AddictionJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Autoimmune Diseases

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anesthesiology Research and Practice

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Pharmaceutics

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Page 15: Review Article Anti-Inflammatory Effects of Heparin and Its …downloads.hindawi.com/journals/aps/2015/507151.pdf · 2019. 7. 31. · Review Article Anti-Inflammatory Effects of Heparin

Submit your manuscripts athttpwwwhindawicom

PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom

Volume 2014

ToxinsJournal of

VaccinesJournal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AntibioticsInternational Journal of

ToxicologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Drug DeliveryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in Pharmacological Sciences

Tropical MedicineJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AddictionJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Autoimmune Diseases

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anesthesiology Research and Practice

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Pharmaceutics

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of


Nanoparticles as Anti-Microbial, Anti-Inflammatory, and ...

Nanoparticles as Anti-Microbial, Anti-Inflammatory, and ...

Anti Inflammatory Diet

Anti Inflammatory Diet

Anti-Inflammatory Responses

Anti-Inflammatory Responses

Evaluation of Anti-Inflammatory and Anti-Nociceptive ...

Evaluation of Anti-Inflammatory and Anti-Nociceptive ...

The Anti-Inflammatory Lifestyle · The Anti-Inflammatory Lifestyle Anti-Inflammatory Lifestyle 2PATIENT HANDOUT University of Wisconsin Integrative Health

The Anti-Inflammatory Lifestyle · The Anti-Inflammatory Lifestyle Anti-Inflammatory Lifestyle 2PATIENT HANDOUT University of Wisconsin Integrative Health

Synthesis, Anti-Inflammatory and Anti- Nociceptive Activities and …ijbms.mums.ac.ir/article_1982_8f308be02e1569af889ab444f6... · 2020-06-09 · Synthesis, Anti-Inflammatory and

Synthesis, Anti-Inflammatory and Anti- Nociceptive Activities and …ijbms.mums.ac.ir/article_1982_8f308be02e1569af889ab444f6... · 2020-06-09 · Synthesis, Anti-Inflammatory and

Anti Inflammatory

Anti Inflammatory

Beneficial Anti-Platelet and Anti- Inflammatory Properties ...

Beneficial Anti-Platelet and Anti- Inflammatory Properties ...

ANTI-INFLAMMATORY AGENTS

ANTI-INFLAMMATORY AGENTS

Anti-inflammatory, antioxidative and anti-atherogenic ...

Anti-inflammatory, antioxidative and anti-atherogenic ...

Anti inflammatory drugs (2)

Anti inflammatory drugs (2)

Anti-Inflammatory Activity of - Cardiff Universityorca.cf.ac.uk/96567/3/Anti-Inflammatory Activity of...1 Anti-Inflammatory Activity of Punica granatum L. (Pomegranate) Rind Extracts

Anti-Inflammatory Activity of - Cardiff Universityorca.cf.ac.uk/96567/3/Anti-Inflammatory Activity of...1 Anti-Inflammatory Activity of Punica granatum L. (Pomegranate) Rind Extracts

Evaluation of anti-inflammatory and anti-arthritic ...

Evaluation of anti-inflammatory and anti-arthritic ...

Anti inflammatory drugs

Anti inflammatory drugs

Anti-Inflammatory Products

Anti-Inflammatory Products

Anti Inflammatory Agent

Anti Inflammatory Agent

Potential anti-inflammatory, anti-adhesive, anti ...digital.csic.es/bitstream/10261/60383/4/Potential anti-inflammatory... · 1 Potential anti-inflammatory, anti-adhesive, anti/estrogenic,

Potential anti-inflammatory, anti-adhesive, anti ...digital.csic.es/bitstream/10261/60383/4/Potential anti-inflammatory... · 1 Potential anti-inflammatory, anti-adhesive, anti/estrogenic,

Anti-inflammatory Food Charts and Recipe Samplers3.amazonaws.com/drritamarie/materials/painfree.pdf · Anti-inflammatory Food Charts and Recipe Sampler. ... provide anti-inflammatory

Anti-inflammatory Food Charts and Recipe Samplers3.amazonaws.com/drritamarie/materials/painfree.pdf · Anti-inflammatory Food Charts and Recipe Sampler. ... provide anti-inflammatory

Antipyretic, Analgesic, and Anti-inflammatory Drugs (Non-steroidal anti-inflammatory drugs, NSAIDs)

Antipyretic, Analgesic, and Anti-inflammatory Drugs (Non-steroidal anti-inflammatory drugs, NSAIDs)

The Anti-Inflammatory Lifestyle · The Anti-Inflammatory Lifestyle Includes • Eating anti-inflammatory foods • Not smoking • Limiting alcohol intake • Adequate exercise and

The Anti-Inflammatory Lifestyle · The Anti-Inflammatory Lifestyle Includes • Eating anti-inflammatory foods • Not smoking • Limiting alcohol intake • Adequate exercise and