Intravenous and oral anticoagulants

Mechanisms of action

Service d’Hématologie

Biologique Hôpital Tenon,

APHP, Paris, France

Groupe de Thrombose

Equipe de recherche ER2UPMC

Interactions cellulaires tumorales et

leur environnement et réponses

aux agents anticancéreux.

Grigoris T Gerotziafas

+ F

VII

Ia

+ P

hospholipid

s “Intrinsic Tenase”

Thrombin

Prothrombinase Va - Xa

Phospholipids

Platelets

Activation

Fibrinogen

Fibrin

X Xa IX IXa

Tissue Factor

VII VIIa

Vascular lesion Atherosclerotic plaque

Blood borne TF

amplification

FXI

FXIa

Va V

VIII VIIIa

// ASIS-rTFPI

NAPC2

Anti-IXa (aptamers, and others)

//

Anti-IIa Heparins+AT

Bivalirudin Argatroban

Dabigatra Semuloparin

//

// Anti-Xa Pentasaccharide+AT

Heparins + AT Rivaroxaban

Apixaban DX-9065a

Semuloparin …

NAPC2 // ASIS-rTFPI

0

50

100

150

200

thro

mb

in (

nM

)

time (min)

0 10 20

Xa free

Initiation phase

/ FT VIIa

activation of platelets, FVIII and FV First traces of

thrombin

Clot formation

PROTHROMBINASE

TENASE

IXa+VIIIa+ PS

Activation of TAFI* to TAFIa

* Thrombine Activatable Fibrinolysis Inhibitor

The activation of TAFI

to TAFIa increases the

resistance of the clot to

fibrinolysis

Thrombin generation after TF pathway activation in platelet rich plasma

(according to C. Hemker et K. Mann) G.T. Gerotziafas and M.M. Samama

Thrombin FXa

Thrombin FXa

Thrombogenicity of thrombus

thrombin FXa

thrombin FXa

Activation of platelets

Thrombin generation

Re-occlusion

In accelerated lysis

Thrombogenicity of thrombus

Rivaroxaban, dabigatran, bivalirudin :

Inhibition of clot bound FXa or thrombin

0 10 20 time (min)

thro

mbine (nM

)

0

50

100

150

200

250

Profile of thrombin generation

normal

hypocoagulability

Hypercoagulable state

Antithrombotic treatment

HCII-dependent inhibitors

Factor Xa

Direct inhibitors:

Rivaroxaban, apixaban,

edoxaban …

AT-dependent inhibitors:

Pentasaccharide, heparins

Direct inhibitors:

Dabigatran, lepirudin,

bivalirudin…

AT-dependent inhibitors:

Heparins, danaparoid

Simple classification of

anticoagulants

Thrombin

Parenteral Oral

Gerotziafas GT, Samama MM. Current Pharmaceutical Design, 2005,

8

Mechanism of action of UFH and LMWHs

AT IIa AT Xa

Below Critical Length Material

MW<5400 Da

(<18 monosaccharides)

Above Critical Length Material

>5400 Da

(>18 monosaccharides)

Similar mechanism for the inhibition of

FIXa

9

Fondaparinux

Idraparinux

fondaparinux Heparin

antithrombin other plasma proteins

Endothelial cells

Macrophage

Heparin

focus on the active

site showing the key

interaction between

rivaroxaban and

Tyr228 in the S1

pocket

Perzborn et al Arterioscler Thromb Vasc Biol. 2010;30:376-381

Selective binding of rivaroxaban on the

active site of FXa

AT/pentasaccharide

AT/Heparins

(UFH and LMWHs)

Direct inhibitors of FXa

(rivaroxaban, DX9065a,…)

FXa

Fluide phase

FVa Phospholipids prothrombinase

Ca ++ FXa

Effect of FXa inhibitors on free and prothrombinase bound FXa

Barrowcliffe et al Biochem J 1987; 243:31–37.

Pieters et al, J Biol Chem 1988; 263:15313–15318.

Hemker et al, Biochim Biophys Acta 1989;

992:409–411.

Herault et al J Pharmacol Exp Ther 1997; 283:16–22

Rezaie AR. Blood 2001; 97:2308–2313.

Herault et al J Thromb Haemost 2003;1:1959-65

Perzborn et al J Thromb Haemost 2005; 3: 514–21

control

0.1 μg/ml

0.25 μg/ml

10 20 30

time(min)

20

40

60

80

100

120

140

160

180

200

thro

mb

in

(nM

)

10 20 30

time(min)

20

40

60

80

100

120

140

160

180

200

thro

mb

in

(nM

)

10 20 30

time(min)

20

40

60

80

100

120

140

160

180

200

thro

mb

in

(nM

)

1.25 μg/ml

0.5 μg/ml

0.8 μg/ml

Comparison of the effect of enoxaparin and fondaparinux on thrombin generation

Influence of fondaparinux

Gerotziafas et al, Blood Coagul Fibrinolysis 2004;15:149–156 Gerotziafas et al. Journal Thromb Haemost 2007

0

0

PRP and Recombiplastin 1/1000 f.d.

Gerotziafas et al. Journal Thromb Haemost 2007 Gerotziafas et al. Journal Thromb Haemost 2007

Xarelto® : pharmacocinétique

Mueck et al, Thromb Haemost 2008

Durée (h)

0 2 4 6 8 10 12 14 16 18 20 22 24

Co

nc

en

tra

tio

ns

pla

sm

ati

qu

es

Riv

aro

xa

ba

n (

µg

/l)

0

50

100

150

200

250

300 Patient moyen (étude ODIXa-OD.PTH): 65 ans, 75 kg, CLCr 90 ml/min

Intervalle de confiance 95%

Patient de 90 ans

Patient-clairance créatinine de 30 ml/min

Patient de 40 kg

Patient de 90 ans et de 40 kg

80% inhibition oF TG

20% inhibition oF TG

Heterogenity of specific FXa inhibitors

Gerotziafas and Samama MM Curr Pharm Des 2005;11:3855-76

Idraparinux Fondaparinux Rivaroxaban Otamixaban

Mode of action AT-dependent

Kd for AT= 1,4

AT-depentent

Kd for AT= 58 Direct Direct

Administration route s.c. s.c. orall i.v.

Half life >80 h 17 h 4h 30 min

Cmax in plasma 0,3 – 1,5 μg/ml 0,3 – 1,5 μg/ml 500 nM 150 - 735 ng/ml

PT prolongation no no +++ ++

aPTT prolongation no no +++ +++

Inhibition of

prothrombinase

bound FXa

Not assessed no yes Not assessed

Inhibition of fibrin

bound FXa Not assessed no yes Not assessed

Inhibition of FVIIa Not assessed yes Not assessed Not assessed

IIa

Direct inhibition of thrombin

Dabigatran

20

–COOH N

G

D E

E F I P E E

L Y

PRO

PRO

ARG

GLY

Arginine replaces lysine: the Arg-Pro

bond is cleaved by thrombin

D+PHE

GLY

GLY

GLY

The [GLY]4 spacer provides

the minimum distance to

optimize the simultaneous

binding of Angiox to the

catalytic site and to the

binding site

The terminal dodecapeptide is

the same as in hirudin

A non-natural amino

acid initiates the chain

NH2–

1

THROMBIN

exosite 2

Reversible inhibition of thrombin by

bivalirudin

Influence of Rivaroxaban fondaparinux and dabigatran

on TF-triggered whole blood thromboelastometry

Rivaroxaban Fondaparinux

Dabigatran

= fibrin bound thrombin

rHirudin

dabigatran

= free thrombin

AT -heparin

stop

Direct FXa inhibitors

= clot bound FXa

Pernzborn et al, Arterioscler Thromb Vasc Biol 2010

RIVAROXABAN : ABSORPTION, DISTRIBUTION,

MÉTABOLISATION, ELIMINATION

Absorption

Biodisponibilité : 80 - 100 %

Cmax : 2 - 4 h

Distribution

Liaison aux protéines plasmatiques de 92 - 95 %

Volume de distribution modéré

Métabolisation

~ 2/3 métabolisé, pas de métabolite actif circulant majeur

CYP 3A4, CYP 2J2, mécanismes indépendants des CYP

Elimination

~ 1/3 non métabolisé : excrété sous forme active par voie rénale

2/3 métabolisé : 50 % éliminés par voie rénale,

Demi-vie d'élimination : 7 - 11 heures

Xarelto® : pharmacodynamique

Accumulation si : inhibiteur CYP3A4 (CI : ketoconazole, ritonavir…) grand âge insuffisance rénale sévère, atteinte hépatique

Absorption accrue si prise alimentaire concomitante

Pas d’interférence : inhibiteurs anti-acides aspirine et AINS digoxine amiodarone

23

Xarelto® : Impact sur les tests

Kubitza et al., Eur J Clin Pharmacol 2005

r = 0.958

Plasma Concentration of Rivaroxaban (µg/l)

0 100 200 300 400 500 600

Pro

thro

mb

in T

ime

(s)

0

10

20

30

40 Prothrombin time Model

Perzborn et al. J Thromb Haemost 2005; Hillarp et al J Thromb Haemost 2011

10 mg

1,4 x PT

PT x 2 : 0,23 mM ApTT x 2 : 0,69 mM 389±106 to 617±149 ng/mL

Correlation between PT and

Rivaroxaban plasma concentration

Mesure de l’activité anti-Xa :

méthode spécifique de l’anti-Xa direct

MM Samama et al., Thromb Haemost 2010

10 mg/j

Au pic

n=135

Effect of dabigatranon clotting tests in patients

with AF

Van Ryn et al Thromb Haemost 2010

Effect of dabigatran on clotting assays in patients

with AF

Van Ryn et al Thromb Haemost 2010

Pharmacodynamics of dabigatran

following a single dose oral dose

of 200 mg

Distribution of patients according to mean

trough aPTT after oral administration of

dabigatran etexilate twice daily

Messages clés sur les

nouveaux

antithrombotiques • Les inhibiteurs spécifique du FXa ou du FIIa

• sont efficaces

• Dans la prophylaxie de la MTEV

• Le traitement de la MTEV

• Le traitement des SCA

• ont une large fenêtre thérapeutique

• Sont associés à un risque hémorragique négligeable mais prèsent

• Les inhibiteurs spécifiques du FXa ou du FIIa sont des molécules hétérogènes

• Dabigatran (inhibiteur spécifique de la thrombine) est efficace dans la prévention des AVC chez les patients avec ACFA et mieux toléré vs le traitement par AVK

• La multiplication des options thérapeutiques permettra l’optimisation de la stratégie antithrombotique à l’échelle individuelle