Appropriate Component Therapy

Diane K. Eklund, M.D.

Transfusion Medicine Symposium

August 6, 2016

Disclosures

» I have no financial relationships

related to this presentation.

» I will not be speaking about any

specific commercial product,

device, or medication.

» I will not be speaking of any off

label use of medications or

devices

Goals and Objectives• Discuss blood management and the associated decrease in

utilization of blood products

• Discuss the impact of new anticoagulant and antiplatelet drugs

on prevention and treatment of bleeding

• Discuss massive transfusion protocols and their impact on

reducing coagulopathic bleeding

Objectives:

• Demonstrate knowledge of appropriate blood component usage

• Identify the blood component for which transfusion does not

need to be ABO compatible

• List 2 transfusion alternatives for reducing the risk of

transfusion-transmitted CMV infection

2005 by TACTICS (Training And Competency for Trent Intra-operative Cell Salvage)

Essential test only

Multiple tests per sample

Nutritional and/or

Medical Support –

correct anemia prior

to surgery

Hemodilution;

Intraoperative

Salvage/Recovery

Improved surgical

devices or techniques

Volume

expanders

• Two early studies in particular are frequently quoted:– TRICC trial

• Hebert, et al, NEJM, 1999

• Concluded that a restrictive strategy of red cell transfusion is at least as effective as and possibly superior to a liberal transfusion strategy in critically ill patients, with the possible exception of patients with acute MI and unstable angina

– CRIT study• Corwin, et al,

Critical Care Medicine, 2004

• Concluded the increased number of transfused RBC units is an independent predictor of worse clinical outcome

Conclusions

A liberal transfusion

strategy, as compared with

a restrictive strategy, did not

reduce rates of death or

inability to walk

independently on a 60-day

follow-up or reduce in-

hospital morbidity in elderly

patient at high

cardiovascular risk.

Transfusion Strategies for Acute Upper Gastrointestinal Bleeding

Càndid Villanueva, M.D., et al.NEJM, Volume 368(1):11-21January 3, 2013

A randomized clinical trial shows that among patients with upper GI bleeding, withholding transfusion until the hemoglobin level falls below 7 g per deciliter results in better outcomes than using 9 g per deciliter as the trigger for transfusion

Outcomes Using Lower vs Higher Hemoglobin Thresholds for Red Blood Cell TransfusionJAMA. 2013;309(1):83-84.

30-Day mortality was evaluated in 4975 patients included in 11 of 19 trials. Adapted from Analysis 3.2 in Carson JL, Carless PA,

Hebert PC. Transfusion thresholds and other strategies for guiding allogeneic red blood cell transfusion.

Figure Legend:

1. Bernard et al, JAmCollSurg 2009;208

2. Ferraris et al, Arch Surg. 2012;147(1)

3. Napolitano et al, CritCareMed 20099;37(12)

Why give 2,

when 1 will do?Complications are dose dependent!

Peri-operative Management

• Optimize hemoglobin levels prior to surgery – anemia clinics popping up– Treat anemia with supplements or drugs if available

• Give Iron, folate, B12 as needed• Use ESAs in treating anemia, where appropriate and

approved– Limit autologous donations to ideal candidates

• The surgical procedure is known to require transfusions and the use of autologous will likely prevent the need for allogeneic blood

• Post-donation hemoglobin level is sufficiently high to prevent jeopardy during surgery (don’t leave them anemic!)

• There is no medical contraindication to the donation process or to the quality of blood

– Coordinate pre-op lab draws• Order essential tests only• Request multiple tests per sample• Collect smaller volume samples

– Iatrogenic blood loss can be close to 100 mL a day!– Maximize coagulation function

• Stop anti-platelet drugs if possible• Reevaluate coagulation therapies (i.e. coumadin)

Peri-operative Management

Continued…

– Review use of herbal supplements• Anise and Dong Quai potentiate the

effects of other anticoagulants• Omega 3 fatty acids, garlic, ginger,

Ginkgo, Ginseng, and vitamin E have anti-platelet properties

• Ginseng may inhibit the coagulation cascade

• Fucus has heparin-like activity• St. John’s Wort interferes with drug

metabolism including Warfarin

– Prescription or Poison? ; Dasgupta, 2010

Red Blood Cells

Red Blood Cells

• The only proven use for RBCs is to improve oxygenation• The number of units transfused should always be

determined by improvement in the symptoms of the patient• Transfusion “triggers” are no longer useful in appropriate

RBC transfusion protocols – never transfuse because of a number, always because of symptom(s) of inadequate oxygenation or because of evidenced-based literature– Consider the patient’s:

• Age• Sex• Rapidity of onset of anemia• Physiologic adaptation to anemia• Status of cardiopulmonary function• History of ischemic co-morbidities• Signs and symptoms such as pallor, syncope,

dyspnea, orthostatic hypotension, tachycardia, tachypnea, angina, TIA or abnormal arterial oxygenation

Red Blood Cells• It is best to transfuse type-specific RBCs; however, blood

shortages will occasionally dictate the use of other compatible RBCs– Never hesitate to give Rh negative components to Rh

positive patients– Always use O negative products judiciously

• Change to O positive in emergencies if the patient is male or a female of non-childbearing age

• Even in young females, switch to O positive in massive transfusion situations or give type specific

• Crossmatch is required except in an emergency• “Type and Cross” vs. “Type and Screen”

– Always obtain an antibody screen prior to anticipation of need for transfusion; this will significantly shorten the overall time to receiving blood when the need for crossmatch arises; it will also alert the physician to potentially complex crossmatch problems and rare antibodies

– Only crossmatch when there is a reasonable indication that blood will likely be transfused; never tie-up inventory and use technology time with an unnecessary type and cross

Red Blood Cells

• RBC antigen exposure, particularly in the frequently transfused patient, can lead to antibody formation in some patients, further leading to difficult future crossmatches

• Once a clinically significant antibody is formed, the corresponding antigen must be avoided in all future RBC transfusions, even if the strength of the antibody reaches undetectable levels

• Antigen-matching beyond ABO for each transfusion is not cost effective; the chronically transfused patient might benefit from further defining the patient’s extended antigen profile for crossmatching procedures – Sickle cell patients should always receive blood negative

for Ee, Cc, and Kell antigens, even if they don’t make the antibodies)

• Today, many clinicians are considering even more extended matching

– If someone chronically transfused is known to be an “antibody maker”, extended antigen matching should also be considered

Red Blood Cells

• Special RBC products:– Washed (rarely indicated)

• May be needed in patients with hypersensitivity to plasma proteins and severe allergic responses to transfusion

• Absolutely required for patients with IgA deficiency and likely presence of IgA antibodies

• May be needed for neonates, depending on additive solutions or age of product

– Frozen, deglycerolized• May be needed for patients with rare atypical antibodies or

hypersensitivity to plasma proteins– Irradiated

• Required for prevention of transfusion associated Graft vs. Host Disease in the immunocompromised patient

– CMV-negative products (applies to all blood components)• Leukoreduction usually considered equivalent, and possibly

even safer than serologic testing for prevent of CMV transmission

• Studies show that newly infected donors, testing CMV-negative by serology (window period), are much more infectious to the recipient than known CMV-positive donors where CMV resides in the white blood cell and is removed by leukoreduction!

• Statistically, the false negative rate of CMV-negative by serological methods probably equals the residual risk of leukoreduction

Storage Effects Consequences

Decreased 2,3-diphosphoglycerate (2,3 DPG) Increased oxygen affinity and decreased oxygen

unloading by hemoglobin

ATP depletion Erythrocyte shape change

Increased osmotic fragility

Decreased deformability

Microvesiculation and loss of lipid membrane Decreased erythrocyte viability

Lipid peroxidation (degradation of lipids) Cellular injury and death

Bioactive substance generation: histamine,

cytokines, lipids

Febrile transfusion reactions

Neutrophil priming/endothelial activation

Cellular injury

TRALI

Multiple organ failure (?)

Immune modulation(?)

S-nitrosohemoglobin deficiency Impaired vasodilatory response to hypoxia

Fresh RBCs for Adults?

The Red Blood Cell “Storage Lesion”

Fresh Red Blood Cells?

• > 25 major studies addressing fresh vs. non-fresh, showing mixed results– Primarily observational studies– Some show favor for fresh RBCs– Some show no advantage at all– Papers describe the definition of fresh differently

• Published 2012 [the Age of Red Blood Cells in Premature Infants (ARIPI)

trial], found no difference in outcomes among pediatric patients when

comparing older with fresher blood

• Similar results with the TOTAL trial (ASH, 2015)

• Published 2014 [REDS-III RECESS trial(Recipient Epidemiology and Donor Evaluation Study)]– Conclusion: The trial had good compliance with the randomized

storage age assignment with a minimal amount of overlap. RBC storage duration was not significantly associated with 7-day change in multiple organ disfunction syndrome (MODS), serious adverse events, or 28-day mortality

• ABLE (age of blood evaluation) 2015– Transfusion of fresh red cells, as compared with standard-issue red

cells, did not decrease the 90-day mortality among critically ill adults

Red Blood Cells

• Major indications include:– Significant acute bleeding with symptoms of

hypovolemia that no longer respond to crystalloid or colloid infusions

– Symptomatic chronic anemia where other therapies such as iron, folate, and B12 will unlikely correct the anemia

– Anemia with a hemoglobin of <7.0 gm/dL and impending surgery with expected blood loss

– Sickle cell disease patients needing anesthesia, or exchange transfusion (“trigger” for H/H may apply)

• One unit of RBCs, in the ideal adult patient (70Kg, not currently bleeding or hemolyzing) will raise the hemoglobin by 1 gm/dL or hematocrit by 3 percentage points

Components to Stop the Bleeding!

Crystal Therapy

Bloodstone, carnelian, sapphire,

lodestone (magnetite), ruby, red jasper,

or clear quartz may be used to stop

and help prevent bleeding

Tannins have an astringent effect

electro-negatively charged surface

activates clotting process

Plasma

Historic Introduction of Plasma

• Plasma was the first blood product,

born ~75 years ago– Produced for WW II

– Dubbed the “Plasma War”• Should it be a liquid or a dried powder?

– The American National Red Cross

collected more than 13 million units of

blood between 1942 and 1945; more than

12 million were converted into plasma,

with the red blood cells being discarded

Historic Introduction of Plasma

• Liquid vs. Dried Powder– John Elliott chose liquid and is

famous also for developing the vacuum bulb-tube which became the TransfusoVac bottle, replacing the open beaker and the milk bottle in transfusion practice

– Max Strumia chose dried plasma secondarily to his work using plasma as an antimicrobial agent

– Dried was appealing for the war but lost favor with the realization that hepatitis transmission was a major problem

• (This would have been a problem for both liquid and dried, but at the time was attributed to dried)

Clinical Indications for Plasma Products?

• U.S. use of plasma is disproportionately high compared to other countries with similar levels of health care– U.S. use of plasma has doubled since 1979

• Few if any quality studies as to the safety and effectiveness of plasma; little evidence for prophylactic use of plasma; no evidence to justify a certain dose

• 1/3 of all requests for plasma made to correct an elevated INR prior to a procedure

Transfusion Rates of FFPCountry # FFP units / 1000 population

France (1996) 4.0

Denmark (2001) 5.16

Australia (2001) 5.33

New Zealand (2003) 5.5

UK (2001) 6.5

Finland (2004) 8.6

Norway (2003) 8.7 (7.0)

Canada (2005) 8.9

US (2011) 12.0

• In the U.S., 5,700,000 units of plasma were produced

for transfusion in 2009, a 0.3% increase from 2006

and a 23% increase from 2005 – WHY?

• Use is now decreasing due to blood management

initiatives and evidenced-based studies

• Similarly, usage is going down in other countries

• We still use the most overall!

May 1960

Wallis, Transfusion 2004

Palo, Transfusion 2006

Cobain, Transfusion Medicine 2007

Devine, Transfusion 2007

National Blood Collection and Utilization

Report 2011

Each solid circle

represents a unique

hospital, with the

observed transfusion rate

percentages for that

hospital (red blood cells,

fresh-frozen plasma, and

platelets) plotted against

the hospital's 2008 volume

of isolated primary CABG

operations. The solid line

indicates the overall mean

transfusion rate across all

hospitals. The dashed

lines indicate the upper

and lower 99.9%

prediction limits based on

the binomial distribution.

Bennett-Guerrero, E. et al. 2010;304:1568-1575

Variation in Use of Blood Transfusion in Coronary Artery Bypass Graft Surgery

Figure 1. Observed Variation in Hospital-Specific Transfusion Rates for Primary Isolated CABG Surgery With Cardiopulmonary Bypass During 2008 (N = 798 Sites)

INR Thresholds for Prophylactic and

Therapeutic Use of FFP• Transfusion, Nov., 2004, 44(11); 1674-5

– 30% of requests for FFP outside the operating room were for attempted correction of the INR

• Assumptions (none validated, nor with good clinical evidence)– Elevated INR identifies patients at increased risk of bleeding– Pre-procedure plasma will “correct” the abnormality– Risk-benefit or cost-benefit ratios of plasma given before the

procedure is higher than if given after the procedure to individuals who actually bleed

• Several reviews have underscored that the pre-procedure INR does not predict the risk of bleeding at the time of invasive bedside procedures and that 1-4 units of plasma fails to correct mild to moderate prolongation of the INR in nearly all cases– American Journal of Clinical Pathology, July 2006: only 50%

of patients with an INR of 1.7 showed a significant change in INR with plasma transfusion

• Yet, ~30% of plasma transfusions were given to correct INR of 1.5

The INR

• INR (international normalized ratio) was developed

to standardize the prothrombin time across

laboratories

• INR was developed specifically for patients on

warfarin

• INR is a unitless ratio

• INR value accounts for the PT of the patient, the

lab’s reference range and the sensitivity of the

reagents used

• There is NO literature evidence that the INR predicts

bleeding

The INR• INR has been the traditional measure of anticoagulation

reversal

• INR has a non-linear relationship to the level of coagulation

factors in the blood

• INR test is widely misinterpreted:

• INR value is “abnormal” even among patients with levels of

clotting factors that are perfectly adequate for hemostasis

• Physicians who claim that a patient has a “coagulopathy”

as evidenced by an INR of 1.6 are misinformed

• Would be similar to claiming that a platelet count of

140,000 represents clinically important

thrombocytopenia

• FFP has little effect on mildly prolonged INR values

• Very large increases in factor levels, requiring large

volumes of FFP are required if one (incorrectly) wishes to

achieve “normal” INR results

Does an elevated INR need to be

corrected prior to surgery?• The relationship between clotting factors and PT is exponential

• Abnormal test results can occur in people with adequate coag factor concentrations

% Coagulation Factors INR and Coagulation Reserve

100%

50%

30%

PT (sec) 12 13 14 15 16 17 18 19 20 21 22

INR 1.0 1.3 1.7 2.0 2.2 3.0

Zone of Normal Hemostasis

(physiologic reserve)

Zone of

Therapeutic

Anticoagulation

zone of adequate factor levels zone of anticoagulation

1 - 2 FFP

1 - 2 FFP

Diminishing Returns With a Low INR

2 4 6 8 10 12 14

Number of FFP units

Adapted from Holland and Brooks, AJCP 2006

INR3

2.6

2.4

2.0

1.8

1.6

1.4

1.2

1.0

INR of the Products on the Shelf

(from normal donors)

0.9 1.0 1.1 1.2 1.3

INR

Holland, Transfusion 2005

% of

units

70

60

50

40

30

20

10

0

Paucity of studies to support that abnormal

coagulation test results predict bleeding in the setting

of invasive procedures: an evidence-based reviewSegal and Dzik, Transfusion, 9/2005

• Review of 25 studies (with mixed quality of evidence)

• In summary, a systematic review of the published literature provides little evidence that pre-procedure elevation of the INR or PT predicts an increase in bleeding at the time of an invasive diagnostic procedure

Paucity of studies to support that abnormal coag test results predict

bleeding in the setting of invasive procedures: evidence-based reviewSegal and Dzik, Transfusion, 9/2005

• Review of 25 studies (with mixed quality of evidence)

• In summary, a systematic review of the published literature provides little

evidence that pre-procedure elevation of the INR or PT predicts an increase

in bleeding at the time of an invasive diagnostic procedure

Fig. 1 Mostly negligible risk differences (and 95% CIs) between patients with abnormal and normal coagulation test results

Little evidence that plasma is needed

for any of these common procedures:

• Central venous catheters

• Liver biopsies

• Thoracentesis and paracentesis

• Bronchoscopy and transbronchial biopsy

• Renal biopsy

Evidence against prophylactic use of FFP

• NNNI (Northern Neonatal Nursing Initiative Trial; Tin, et al.,

Lancet, 1996):– Randomized 776 neonates and compared FP with volume

expanders in the prevention of intraventricular hemorrhage – no

significant difference in outcomes in 2 groups

• Leese, et al., Ann Royal College Surg Engl, 1991):– 275 patients with acute pancreatitis, randomized to either FP or

colloid solution – no evidence of benefit for plasma

• Peterson, Anesthesiology, 1991:– Consecutive central lines prior to cardiac surgery with no

increase in hemorrhagic complications in heparin-anticoagulated

patients

• Ewe K, Dig Dis Sci, 1981:– Bleeding times after laparoscopic liver biopsy showed no

correlation between bleeding time and coagulation variables; even

patients with INR > 3 and platelets <50K did not bleed more than

patients with better test results

“Can We Predict Bleeding?

• Review article, Seminars in Thrombosis

and Hemostasis, Feb 2008, Authors

Watson and Greaves

• A “Structured Bleeding History” is likely

a more powerful tool for prediction of

bleeding than any of the current available

laboratory approaches

Bleeding History

For each of the following findings, add the indicated number of points:

Epistaxis: infrequent, brief, self-limited episodes 1

Easy bruising with trauma 1

Prolonged bleeding after brushing teeth 1

Dental extraction: prolonged bleeding (> 1 hour) 2

Hemoptysis, Hematemesis 2

Melena 2

Ob/Gyn bleeding (menorrhagia, post-partum) 2

Post-operative bleeding (> 1 hour or delayed) 3

Intracranial hemorrhage 3

Umbilical hemorrhage 4

Positive family history 4

Excessive bleeding following injury to mouth or loss of deciduous teeth 5

Prolonged bleeding (> 1 hour) from minor injuries 5

Epistaxis: frequent, prolonged, or requiring treatment 5

Hematuria 5

Hemarthrosis in absence of major trauma 8

Telangiectasia 8

Petechiae 8

Bleeding History

Likelihood for a coagulopathy:

>10 Highly suspicious

5 – 9 Suspicious

< 5 Not suspicious

Each of the above conditions should have no surgical or

anatomic lesion to account for the bleeding

Is fresh-frozen plasma clinically effective?

An update of a systematic review of randomized controlled trials

Lucy Yang, Simon Stanworth, Sally Hopewell, Carolyn Doree and Mike Murphy

Transfusion, 2012

Background• Use of plasma continues to increase for both

prophylactic and therapeutic settings• In 2004, a paper of similar title was published in the

British Journal of Haematology (authors Stanworth, et al.)– British Committee for Standards in Haematology reviewed

57 trials in the literature– Found that there was little evidence for the effectiveness

of prophylactic use of FFP– Most studies were small and did not provide adequate

information on the ability of the trial to detect meaningful differences in outcomes between 2 patient groups

– No study examined assessed whether or not adverse effects might negate clinical benefits of treatment with FFP

• This paper is an update of the paper from 2004 and includes an examination of all new randomized controlled trials (RCTs) since the prior publication

Additional Background Information

• Recurring theme for transfusion of plasma is that there is a variation in practice and uncertainty around the evidence-based indications for appropriate use

• In the U.S., 5,700,000 units of plasma were produced for transfusion in 2009, a 0.3% increase from 2006 and a 23% increase from 2005

• Two reasons given for transfusion:– Prevent bleeding– Stop bleeding

Is fresh frozen plasma clinically effective? An update of a systematic review of

randomized controlled trialsTransfusion, 2012 Lucy Yang, et al.

Results

• 21 additional publications of RCTs were eligible

for inclusion in this updated review

• 8 ongoing trials and 4 recently completed trials

awaiting publication were also eligible for

inclusion

• Many trials suffered from methodological

limitations (didn’t fulfill all criteria of study

quality)

Results• Liver disease

– When combining the results with the 2004 review, a total of 10 trials enrolling 381 patients, there were no significant benefits across a range of clinical indications and outcomes

• Cardiac Surgery– When combined with the results of the 2004 review, 19 trials

enrolling 948 patients in total showed no consistent clinical benefit

of plasma

• Warfarin reversal– Results indicated more rapid INR correction with coagulation factor

concentrates (prothrombin complex concentrates or PCCs)

compared to plasma and with plasma compared to vitamin K, but

uncertainty regarding the effects on reducing mortality

– When adding to the results of the 2004 review, a total of 5 trials with

227 study participants showed similar results as above

Discussion

• Using data from both the 2004 and the 2012

publication, 80 RCT studies have been

completed and published in the past 50 years

• Of the new studies, 8 evaluated prophylactic

use and 13 evaluated therapeutic use in

patients with bleeding and active disease

• Overall, there was little evidence of any

consistent benefit from using plasma infusion

in either group

INR Action/Recommendation

Greater than therapeutic,

but < 5 and no significant

bleeding

Lower the warfarin dose, or omit a dose and resume

therapy at a lower dose when INR is therapeutic

5 – 9 with no significant

bleeding

Omit 1 or 2 warfarin doses and resume therapy at a lower

dose when INR is therapeutic or omit a dose and give

vitamin K (1-2.5 mg p.o.) if patient is at risk of bleeding

5 – 9 and rapid reversal

required for surgery

Give vitamin K (≤ 5 mg p.o.) with the expectation that INR

will be reduced in 24 hours

> 9 and no significant

bleeding

Omit warfarin and administer vitamin K (2.5-5 mg p.o.) and

monitor INR more frequently, repeating vitamin K dose if

needed

> 9 and serious bleeding Hold Warfarin. Give Vitamin K (10 mg IV) and plasma

infusion or rVIIa

Life-threatening bleeding Hold Warfarin. rFVIIa or plasma infusion supplemented

with vitamin K (10 mg IV)

Guidelines for Administration of Vitamin K –

American College of Chest Physicians

• Correction of excessive microvascular bleeding with known

coagulopathy or when coagulation test results are delayed

• Multiple coagulation factor deficiencies associated with severe

bleeding and/or DIC

– Plasma is not indicated in DIC with no evidence of bleeding; there

is no evidence that prophylactic replacement regimens prevent DIC

or reduce transfusion requirements

• Urgent reversal of Warfarin – PCC might be more appropriate

• contains factors II, VII, IX and X, protein C and protein S

• Plasmapheresis for TTP/HUS to replace enzyme• Single coagulation factor deficiencies for which no virus-safe

fractionated product is available • Currently applies mainly to factor V and antithrombin

deficiencies

• Massive transfusion

Appropriate Clinical Indications for

Plasma Products

• Do not use for prophylactic treatment of mild elevations of

PT (INR <2.0) or aPTT

• Do not use for non-urgent reversal of warfarin

• Do not use for reversal of heparin effect

• Do not use for hypovolemia or augmentation of albumin

concentration

• Do not use for promotion of wound healing or general

well-being

• Do not use for treatment of immunodeficiency states

• Do not use for therapeutic apheresis (except for TTP/HUS

or long term daily procedures)

• Do not use where specific therapy is available (FVIII,

vitamin K)

Plasma Product Contraindications

What happens when…

• Hemoglobin is 11 g/dL (>12.5 g/dL)

– We don’t transfuse RBCs (risk > benefit)

• Platelet count is 105,000 (>150,000)

– We don’t transfuse platelets (risk > benefit)

• Creatinine is 2.1 mg/dL (<1.2 mg/dL)

– We don’t start dialysis

• Why then transfuse FFP for a PT (INR) that is

mildly elevated????

Plasma Products

• Fresh Frozen Plasma (FFP) – Plasma placed in a <-18oC freezer within 8 hours; expiration date 1 year; volume 200-250 mL or 400-500 mL (jumbo)• “normal” levels of coagulation factors• OK to use for 24 hours after thawing

• Frozen Plasma (FP) –As above, but frozen within 24 hours; contains coagulation factors in concentrations similar to that of FFP with variably reduced amounts of Factor VIII and Factor V

• Thawed Plasma – FFP or FP that has been thawed and stored between 1-6o C; expires 5 days after start of thaw• Adequate for virtually all hemostasis, unless used to

replace labile factors (i.e. FVIII); even FVIII is at a hemostatic level of 30-35% (clotting adequate at 25-30%) as is FV (clotting adequate at 15-25%)

Plasma Products Continued

• Cryoprecipitate Reduced Plasma - Deficient in Von Willebrand factor, Factor VIII, Factor XIII, fibrinogen and fibronectin; thought by some to have value in treatment of TTP (but now that we know more about ADAMTS13 deficiency, probably not)

• Liquid Plasma – separated and infused no later than

5 days after the expiration date of whole blood

stored at 1-6o C; source of plasma proteins; variable

coagulation activity; can be used for 26 days

Coagulation factor Day 1 Day 2 Day 3 Day 4 Day 5 Mean Change from

Day 1 to Day 5 (%)

P values

FVIII (%), Blood group A 107

+/- 26

76

+/- 19

66

+/- 18

65

+/- 17

63

+/- 16

41 <0.004*

FVIII (%), Blood group B 103

+/- 44

74

+/- 37

71

+/- 35

67

+/- 36

67

+/- 33

35 <0.02*

FVIII (%), Blood group O 70

+/- 16

51

+/- 10

43

+/- 10

43

+/- 7

41

+/- 8

41 <0.001*

Factor II (%) 81

+/- 9

81

+/- 9

81

+/- 9

80

+/- 10

80

+/- 10

1 NS

Factor V (%) 79

+/- 7

75

+/- 8

71

+/- 9

68

+/- 9

66

+/- 9

16 NS

Factor VII (%) 90

+/- 18

81

+/- 15

76

+/- 15

72

+/- 14

72

+/- 15

20 NS

Factor X (%) 85

+/- 13

84

+/- 13

84

+/- 15

82

+/- 11

80

+/- 11

6 NS

Fibrinogen 225

+/- 12

224

+/- 13

224

+/- 13

224

+/- 17

225

+/- 12

0 NS

*Comparison of FVIII activity at Day 1 and that at Day 3 was statistically significant.

Downes, Katharine A., Wilson, Erica, Yomtovian, Roslyn & Sarode, Ravindra

Serial measurement of clotting factors in thawed plasma stored for 5 days.

Transfusion 41 (4), 570-570, 2001

TABLE 1. Mean coagulation factor levels at 24-hour intervals by blood group

Plasma Products Continued

• Dose to replace factors, 10-20 mL/kg (3-6 units

for an adult)

• Compatibility testing not required, but ABO

compatible plasma must be used

Plasma Dosing

Plasma Dosing

Is there an optimal dose?

• National guidelines generally specify a dose of around

10 to 20 mL/kg

• A study in Transfusion, 2006, Abdel-Wahab, et al.,

prospectively evaluated the effects of FFP on PT/INR

in hospital patients with a pretransfusion PT between

13.1 seconds and 17 seconds (INR equivalent, 1.1-

1.85)

• 324 plasma units evaluated in 121 patients

• <1% of patients had normalization of PT/INR after

transfusion and only 15% demonstrated a correction

of half way to normal

Plasma Dosing• If, and only if, someone requires plasma transfusions, what

is the correct dose?• “Efficacy of standard dose and 30 ml/kg fresh frozen plasma

in correcting laboratory parameters of haemostasis in critically ill patients” British J of Haem, 4/2004– Group 1 (10 patients) received 12.2 ml/kg and group 2 (12

patients) 33.5 ml/kg FFP– PT, aPTT and factors I–XII were measured before and

after FFP infusion– This study assessed the effect of FFP on laboratory

coagulation parameters in patients on the ICU and compared the effect of different doses of FFP.

• The results suggested that in many patients FFP was not indicated (based on coagulation factor levels)

• Coagulation screening tests were poor predictors of significantly low coagulation factor levels

• A standard regimen of 1 L or about 12·5 mL/kg of FFP lead to relatively small and, in most patients, inadequate increments in coagulation factor levels

• 30 ml/kg of FFP adequately corrected all individual coagulation factors

Another Historic Milestone for Plasma

• More than 45 years ago plasma was frozen immediately after collection, thawed rapidly and sent to the bedside with ice crystals still present, in order to preserve Factor VIII

• Clinicians would infuse quickly and any remaining ice crystals would be discarded with the “sludge” that formed in the crystals

• Responding to complaints about the efficacy of the products, Judith Pool, an American scientist, studied the sludge, and discovered cryoprecipitate

• Today we have a finely tuned method to collect and freeze this “sludge”

Cryoprecipitate

Cryoprecipitate• Cryoprecipitate (~15 mL) contains:

– factor VIII (80 to 100 U) – von Willebrand factor – fibrinogen [150 to 300 mg (4.4-8.8 µmol/L)]

• FFP has 500mg– fibronectin (20%-25% total protein) – factor XIII (40 to 60 U) – IgG (5%-8% total protein) – IgM (1%-2% total protein)– albumin (5%-8% total protein) – platelet microparticles

• Cryoprecipitate is a poor source of vitamin K-dependent factors and, therefore, should not be used in this setting

• To infuse: thaw at 30-37C; use single within 6 hours and pooled within 4 hours

• No crossmatch/compatibility required - any blood group is safe to use

Cryoprecipitate Dosing• 1 bag contains ~400 mg fibrinogen

• 4 or 5 bags (1 pool) contains ~2000 mg fibrinogen

• Recovery with transfusion = 75%

• 5 bags (1 pool) cryoprecipitate provides ~1500mg fibrinogen to the patient

Therefore:

• In a 70 kg patient, with a plasma volume of ~3.5 L, 1 pool will raise fibrinogen by ~40-45 mg/dL

• In a 90 kg patient, with a plasma volume of ~4.5 L, 1 pool will raise fibrinogen by ~30-35 mg/dL

• In a 50 kg patient, with a plasma volume of ~2.5 L, 1 pool will raise fibrinogen by ~60 mg/dL

• Fibrinogen replacement: Effect should be monitored by fibrinogen level assay and clinical response

Again, keep in mind that 1 unit of plasma has ~500 mg of fibrinogen

Cryoprecipitate: The Current State of KnowledgeCallum, et al., Transfusion Medicine Reviews 2009

• Review article

– “The role of this complex product in the management

of hemostasis has not been well studied (excluding

patients with factor VIII deficiency)”

– “There are insufficient data to determine the clinical

setting where this product might be clinically

efficacious despite its widespread use in multiple

different clinical scenarios.”

– “There are insufficient data in the literature to

determine the efficacy, safety, and dosage in the

patient population.”

– “Despite 45 years of the use of this product, we still

have a lot to learn regarding the optimal use of

cryoprecipitate.”

Appropriate Use of Cryoprecipitate• There is evidence that the use of cryoprecipitate is rising in

many countries, although the exact reasons remain unclear – A specific purified fibrinogen concentrate is available, and it

may represent a safer concentrate for direct fibrinogen replacement in isolated deficiencies, such as inherited hypofibrinogenemia (although transfusable fibrinogen concentrates are not widely available in the U.S.)

• The value of cryoprecipitate to correct surgical bleeding in the absence of a specific factor VIII, vWF, or fibrinogen deficiency is unclear

• The American Society of Anesthesiologists task force on blood component therapy recommends the perioperative administration of cryoprecipitate in only 3 circumstances: – prophylaxis in nonbleeding perioperative or peripartum

patients with congenital fibrinogen deficiencies or vWD unresponsive to DDAVP

– for bleeding patients with vWD – for the correction of microvascular bleeding in massively

transfused patients (not routine patients) with fibrinogen concentrations less than 80 to 100 mg/dL (0.80-1.00 g/L) or when fibrinogen concentrations cannot be measured in a timely manner

Appropriate Use of Cryoprecipitate (Cryo)

• Frozen plasma will correct low fibrinogen if the volumes for infusion are tolerable

• Cryo should not be considered for transfusion solely as a more concentrated form of FP (for example, where there are concerns about fluid overload), as it only contains significant levels of FVIII, VWF, fibronectin, FXIII and fibrinogen – Cryo is not a source of all coagulation factors and therefore is not

appropriate replacement therapy in patients with global coagulation factor deficiencies, for example, with liver disease

• Cryo use should be reserved for patients with documented isolated hypofibrinogenemia - few prospective trial data to define the optimal use of cryo

• Appropriate indications:

– Hypofibrinogenemia, massive transfusion, TPA-associated

bleeding, as a tissue sealant (fibrinogen)

– Uremic bleeding and von Willebrand Disease (factors VIII and

vWF)

• Inappropriate indications:

– Warfarin reversal

– Surgical hemostasis

– Hepatic coagulopathy

Prothrombin Complex Concentrates

What are PCCs?

• Prothrombin complex concentrates (PCCs) are pooled,

virus-inactivated human plasma products that

conveniently and rapidly provide coagulation factors

• The majority of PCCs contain the vitamin K-dependent

coagulation factors (II [prothrombin], VII, IX and X), as

well as therapeutically effective concentrations of

thromboinhibitors (protein C and S).

• PCCs are most commonly indicated and used in vitamin

K antagonist reversal (oral anticoagulant reversal)

• In Europe they are also indicated for treatment and

perioperative prophylaxis of bleeds in acquired

deficiency of the prothrombin complex coagulation

factors (II, VII, IX and X)

Prothrombin Complex Concentrates• American College of Chest Physicians guidelines suggest

four-factor prothrombin complex concentrates as the first

choice for warfarin reversal in the setting of major bleeding

• Four-factor PCCs contain (relatively new to the U.S.):

• Six vitamin K-dependent factors:

• Factors II, VII, IX, X, proteins C and S

• Three-factor PCCs (available in the U.S.) contain:

• Three therapeutically useful factors:

• Factors II, IX, X

• Given that Factor VII is the most severely depleted in

warfarin-treated patients, these are not effective in

correcting the hemostatic defect!

When clinicians in the U.S. request three-factor PCCs

to correct warfarin effects, educate them as to the

inadequacy of this approach!

Prothrombin Complex Concentrates

Four-factor PCCs

(currently approved in US – KCentra)

FFP

Smaller volume /

Higher concentration of factors

Potential of volume overload

More rapid delivery More time to infuse

May be thrombogenic

Expensive 1/10 the price of PCCs

No strong clinical evidence that PCCs are better than FFP; studies using

corrected INR as an endpoint are misinformed about INR as a surrogate for

clinical effectiveness

Four-factor prothrombin complex concentrate versus

plasma for rapid vitamin K antagonist reversal in patients

needing urgent surgical or invasive interventions: a phase

3b, open-label, non-inferiority, randomised trial

Joshua N Goldstein, DrMD, Majed A Refaai, MD, Truman J Milling, MD, Brandon Lewis, DO, Robert Goldberg-Alberts, MA, Bruce

A Hug, MD, Ravi Sarode, ProfMD

The Lancet

DOI: 10.1016/S0140-6736(14)61685-8

Copyright © 2015 Elsevier Ltd

Figure 1

The Lancet DOI: (10.1016/S0140-6736(14)61685-8)

Copyright © 2015 Elsevier Ltd

Figure 2

The Lancet DOI: (10.1016/S0140-6736(14)61685-8)

Copyright © 2015 Elsevier Ltd

Interpretation

•For the endpoint of rapid INR reduction, the results

demonstrate that 4F-PCC is non-inferior and superior to

plasma for rapid INR reduction in patients on VKA therapy

•Furthermore, 4F-PCC could be given more rapidly than

plasma

•We noted that 4F-PCC was superior to plasma for

haemostatic efficacy

•We did not detect any between-treatment differences for

the occurrence of thromboembolic events or deaths, a

finding in agreement with the existing scientific literature

•Additionally, although these data guide clinicians on how

best to achieve urgent VKA reversal, the scientific literature

concerning which patients should be urgently reversed

before surgical or invasive interventions continues to

evolve

The ASH Choosing Wisely® campaign: five hematologic

tests and treatments to questionLisa K Hicks, Harriet Bering, Kenneth R Carson, Judith Kleinerman, Vishal Kukreti, Alice Ma, Brigitta U Mueller, Sarah H O’Brien, Marcelo

Pasquini, Ravindra Sarode,Lawrence Solberg Jr, Adam E Haynes, Mark A Crowther

1. In situations where transfusion of RBCs is necessary, transfuse the minimum number of units required to relieve symptoms of anemia or to return the patient to a safe hemoglobin range (7-8 g/dL in stable, noncardiac in-patients)2. Do not test for thrombophilia in adult patients with venous thromboembolism occurring in the setting of major transient risk factors (surgery, trauma, or prolonged immobility)3. Do not use inferior vena cava filters routinely in patients with acute venous thromboembolism 4. Do not administer plasma or prothrombin complex concentrates for nonemergent reversal of vitamin K antagonists (ie, outside of the setting of major bleeding, intracranial hemorrhage, or anticipated emergent surgery)5. Limit surveillance CT scans in asymptomatic patients after curative-intent treatment for aggressive lymphoma

Platelets

Platelets• In the 70 kg adult (not septic, bleeding, etc.), one dose of

platelets should raise the platelet count approximately 30-40,000/uL– Rarely happens because the majority of platelet usage is in

patients with complicating factors (counts may rise less than 20,000/uL)

• No crossmatch required; apheresis products are not significantly RBC-contaminated– Crossmatch required for RBC antigens if product

contaminated with RBCs

• ABO-matched platelets have a slightly longer in vivo survival rate– But, supply rarely allows for the ability to match blood types

• A dose is considered to be one apheresis platelet or 4-6 whole blood-derived (aka random-donor) platelets

• Alloimmunization occurs when a patient makes antibodies to donor HLA antigens or to donor platelet specific antigens – Once alloimmunized, platelets lacking the offending antigens

must be used for transfusion. Finding such platelets may be difficult or impossible and transfusion of “unmatched” platelets may result in little to no post-transfusion increment

• Platelet crossmatching • HLA matched products

Dose of Prophylactic Platelet Transfusions and

Prevention of HemorrhageSlichter, et al., NEJM 2010

• Randomly assigned hospitalized cancer patients to a low dose, medium dose or high dose regimen (1.1x1011, 2.2x1011, or 4.4x1011 platelets per square meter of body surface area) when morning platelet counts were 10,000 or lower

• Patients assessed for clinical signs of bleeding daily

• Concluded that low doses of platelets administered as a prophylactic transfusion led to a decreased overall number of platelets transfused per patient but an increased number of transfusions given

• Dose of platelets had no effect on the incidence of bleeding

Platelets

• Causes of low post-transfusion platelet counts include:• Sepsis• Ongoing oozing• Disseminated intravascular coagulopathy (DIC)• Splenomegaly• Hepatomegaly• Drugs

• A corrected count increment (CCI) can help to determine if someone is alloimmunized or truly refractory to platelets:

absolute platelet increment/uL X BSA (m2)____________________________________________________________________________

number of platelets transfused (1011)

Platelets

• CCI example:– Starting platelet count is 10,000/uL– One hour post-transfusion count is 50,000/uL– Number of platelets in the bag is ~3-4 X 1011

– So…..

(50,000-10,000) X 2

3 (X 1011, not used to calculate)

• CCI > 10,000 indicates no refractoriness• CCI < 5,000 indicates likely refractoriness

Platelets

•Causes of low post-transfusion platelet

counts include:•Sepsis

•Ongoing oozing

•Disseminated intravascular coagulopathy (DIC)

•Splenomegaly

•Hepatomegaly

•Drugs

Platelets

•When to transfuse:–Platelet count less than 5,000 –

10,000/uL

–Platelet count less than 50,000 if major

surgery is anticipated or if life-

threatening bleeding is occurring

–Documented or anticipated platelet

dysfunction, regardless of the platelet

count

–Excessive bleeding regardless of

platelet count

–In patients on cardiopulmonary bypass

or on ECMO

Anticoagulants and Antiplatelet Agents

Clotting factors affected by vitamin K:II,VII, IX, X, C, S

Warfarin (Coumadin)

Reversing Warfarin

• Vitamin K: effective, inexpensive, misunderstood

• K used for “Koagulation”

• Vitamin K effectively reverses INR when given IV or orally

• Vitamin K anaphylactoid reactions are very rare

• Plasma

• Used for “emergency” reversal of warfarin

• Very loosely defined, usually not an emergency but

rather a physician wishing to perform an invasive

procedure

• Probably justified for intracranial bleeding

• When plasma is used to reverse warfarin for serious

bleeding, vitamin K must also be given

• Factor VII in FFP has a short half-life and Factor IX

has a large volume of distribution

• If vitamin K is not given, FVII and FIX will decline

Recombinant Factor VIIa and PCCs

• rFVIIa not recommended as a solo agent to reverse

warfarin

• One would not expect a single-factor agent to

restore a hemostatic defect resulting from depletion

of four vitamin K dependent procoagulant factors

• FEIBA contains Factors II and IX, and X, non-activated,

and activated Factor VII

• Activated factors can cause unwanted thrombosis

• Contraindicated for all but those hemophiliacs who

make inhibitors to factor replacements

• K-centra contains non-activated II, VII, IX, X, and anti-

thrombotic proteins C and S

• Can also cause unwanted thrombosis

Reversal of drug-induced anticoagulation:

old solutions and new problems

Walter “Sunny” Dzik

Transfusion May 2012

This Review

• All anticoagulant therapies are

accompanied by bleeding complications

• This review summarizes use of blood

products for urgent reversal of drug-

induced anticoagulation

New Oral Anticoagulants:

Convenient to Use But Not Reversible

• Direct thrombin inhibitors (i.e. Dabigatran) or inhibitors

of Factor Xa (i.e. Rivaroxaban or Apixaban)

• Approved for stroke prevention in A-fib patients

• Widely quoted that these drugs are safer than warfarin

with few bleeding events; however, after being in use for

a while, this is less clearly the case

• No good evidence available on how to successfully

reverse these agents should bleeding occur

• Mixed results using PCCs, rFVIIa, etc

• Dialysis or therapeutic apheresis can be effective

• Local hemostatic agents used as topicals could be

effective

• Conclusion: Be skeptical of upcoming claims

regarding reversal agents

THREE ANTIDOTESNo reversal agent (antidote, neutralizing drug) is presently clinically available if (a) major

bleeding occurs or (b) urgent reversal for emergent surgery is needed in patients on one of

the new oral anticoagulants (apixaban = Eliquis®; dabigatran = Pradaxa®; edoxaban =

Savaysa®; rivaroxaban = Xarelto®).

The following three drugs are in development, but are at least 2 years away from being

clinically available, should they prove to be beneficial:1. ARIPAZINE (PER977; ciraparantag)

What is it? This is a synthetic small molecule (D-arginine compound) which has broad activity

against various old and new oral anticoagulants

What anticoagulant drugs might it reverse? Apixaban, edoxaban, rivaroxaban, dabigatran,

heparin, LMWH.

Clinical trial status: A human volunteer study of 80 individuals receiving aripazine published this

week in the New England Journal of Medicine [ref 1] shows that clotting assays (whole-blood clotting time)

that were prolonged by edoxaban, decreased after the test persons received aripazine. Another healthy

volunteer study is presently ongoing [NCT02207257].

2. ANDEXANET (PRT064445)

What is it? Recombinant, modified factor Xa molecule that is being developed as a direct reversal

agent for patients receiving a Factor-Xa inhibitor who suffer a major bleeding episode or who require

emergency surgery. It sort-of sops up the anti-Xa anticoagulant, making a patient’s own factor Xa available

again to participate in the coagulation process.

What anticoagulant drugs might it reverse? Apixaban, edoxaban, rivaroxaban.

Clinical trial status: Healthy volunteer studies to (a) evaluate the ability of Andexanet to reverse the

effects of several anticoagulant drugs on laboratory tests and (b) reverse apixaban and rivaroxaban are

presently ongoing.

3. IDARUCIZUMAB (BI 655075)

What is it? It is a humanized antibody fragment directed against dabigatran; generated from mouse

monoclonal antibody against dabigatran; humanized and reduced to a FAb fragment.

What anticoagulant drugs might it reverse? Dabigatran.

Approved October 2015

Conclusion

The ultimate goal for society is the

development of an oral anticoagulant that can

be taken once a day, that will effectively reduce

the risk of stroke or thrombosis in patients with

a wide range of thrombophilic disorders, that is

inexpensive and non-toxic, and that can be

promptly reversed should bleeding occur

Sort of sounds like warfarin, doesn’t it?

Antiplatelet Agents

• Millions of patients are prescribed antiplatelet agents (APAs)

for a variety of clinical conditions such as coronary artery

syndrome, stroke, transient ischemic attacks and peripheral

arterial disease

• Millions more self-medicate with aspirin or herbs and

supplements known to affect platelet function

• Older APAs have a low bleeding risk profile; newer APAs

have a higher bleeding risk profile

• When patients on APAs present with bleeding or when they

need urgent surgical intervention, treating physicians and

transfusion medicine specialists are challenged with how to

reverse or counteract effects of APAs

APAs classified into 4 groups• Group 1: COX-1 inhibitors (aspirin and nonsteroidal anti-inflammatory drugs)

• Group 2: ADP receptor (P2Y12) inhibitors [ticlopidine (Ticlid), clopidogrel

(Plavix), prasugrel (Efient)]

• Group 3: GPIIb/IIIa inhibitors (fibrinogen receptor antagonists) including

Abciximab (ReoPro), Eptifibatide (Integrilin), and Tirofiban (Aggrastat)

• Group 4: Miscellaneous• Dipyridamole (Persantin) and cilostazol (Pletal) inhibit the 2,3 phosphodiesterase

enzyme inhibiting aggregation (weak)

• Aggrenox is a combination of ASA and dipyridamole and is very effective against

platelet function

• Fish oil and many herbs can inhibit platelet function

Summary of APAs• APAs are used increasingly in our aging patient population

• With more potent APAs there is an increased risk and extent

of bleeding

• Judicious use of specific tests to assess anti-platelet drug

effect and platelet transfusion therapy can assist clinicians

in the management of patients who present with bleeding

complications or trauma or who require urgent surgery

• Prospective clinical trials to optimize the dose and timing of

platelet transfusion with greatly add to our knowledge of the

efficacy of platelet transfusion

Platelet Function Tests

Comparison of platelet function tests in predicting clinical outcome in

patients undergoing coronary stent implantation

Breet, et al., JAMA 2010 Feb 24;303(8):754-62

•None of the tests identified patients at risk for bleeding

•Conclusions

– Of the platelet function tests assessed, light transmittance

aggregometry, Verify Now, Platelet works, and Innovance , the

predictive accuracy was only modest

– None of the tests provided accurate prognostic information to identify

patients at higher risk of bleeding following stent implantation

•Other described limitations:

– Prolonged (dysfunction) for blood group O samples than for other

blood groups

– Prolonged when platelet count or hematocrit is significantly decreased

(PFA-100 closure times are usually prolonged when platelet count is

<50,000/μl or hematocrit is <25%)

– Clinical performance for platelet dysfunction may be influenced by

other pre-analytical variables

• Age?

• Diurnal variations?

Thromboelastography [TEG] and Rotational

Elastometry [ROTEM]

Not just for platelet function, but also to detect low fibrinogen,

presence of heparin, fibrinolysis…

How do I transfuse platelets to reverse

anti-platelet drug effect?

Ravi Sarode

TransfusionApril 2012

Platelet Transfusion for Reversing Drug

Effects

• Patient is on ASA

• Not considered to be a very potent agent in terms

of increased bleeding risk

• If the patient requires surgery (other than

neurosurgery) and is on a standard dose of ASA

(81-325 mg per day) no prophylactic platelets are

recommended

• If the patient requires neurosurgery, give one dose

of platelets within a few hours prior to surgery

• NSAIDS

• Discontinue drug 12 hours before elective surgery

if possible

• Platelets are not required for urgent surgery

Platelet Transfusion for Reversing Drug

Effects

• Patient is on P2Y12 (ADP receptor) inhibitor

• ticlopidine (Ticlid), clopidogrel (Plavix), prasugrel

(Efient)

• Increased bleeding tendency

• Urgent surgery required? Significant bleeding? Give

one dose of platelets

• Neurosurgery or eye surgery? Give two doses of

platelets (100K functional platelets)

• Patient is on both ASA and P2Y12 inhibitor

• Same as above

• Patient is on Aggrenox (ASA and dipyridamole)

• Urgent surgery other than neurosurgery? No platelets

necessary

• Neurosurgery? One dose of platelets

Platelet Transfusion for Reversing Drug

Effects

• Patient is on GPIIb/IIIa inhibitor

• Fibrinogen receptor antagonists including Abciximab

(ReoPro), Eptifibatide (Integrilin), and Tirofiban

(Aggrastat)

• Coronary intervention, and the patient bleeds

excessively after heparin has been reversed with

protamine, give one dose of platelets

• Patient on miscellaneous Anti-platelet agents

• Dipyridamole (Persantin) and cilostazol (Pletal),

Aggrenox, a combination of ASA and dipyridamole,

and fish oil and other herbs that inhibit platelet

function

• Prophylactic platelet transfusions are not indicated

Alternative to Platelet Transfusion

• Desmopressin (DDAVP)

• Stimulates the release of stored VWF from

the endothelium thereby indirectly improving

platelet function

• Recombinant Factor VIIa

• Increases thrombin generation on the

platelet surface thereby reversing the effect

of anti-platelet drugs

Massive Transfusion Protocols

Massive Transfusion Protocols

Why might a protocol-driven, ratio-

based, massive transfusion

protocol improve trauma patient

outcomes?

Fig. 1. A diagram showing some of the mechanisms leading to coagulopathy in

the injured. Trauma can lead to hemorrhage which can lead to resuscitation,

which in turn leads to dilution and hypothermia causing coagulopathy and

further hemorrhage. This is classic “dilutional coagulopathy”. Hemorrhage can

also cause shock which causes acidosis and hypothermia that in turn lead to

coagulopathy, the “fatal triad”. Trauma and shock can also cause the Acute

Coagulopathy of Trauma-Shock (ACoTS) associated with factor consumption

and fibrinolysis. Coagulopathy is further associated with trauma-induced

inflammation and modified by genetics, medications, and acquired diseases.

Trauma Hemorrhage

The Coagulopathy of Trauma: A Review of MechanismsHess, et al., J Trauma. 2008;65:748 –754

ResuscitationInflammation

Other Diseases

Medications

Genetics

COAGULOPATHY

Dilution

Hypothermia Hypothermia

Acidemia Fibrinolysis

Factor

Consumption

ACoTS

Shock

Risk Factors for Trauma-Induced

Coagulopathy

• Extent of tissue damage

• Shock (3-fold increase)

• Pre-hospital IV fluids > 3000 mL

• Hypothermia (< 35 C)

• Acidosis (3-fold increase)

• Inflammation

• Preexisting coagulopathic comorbidities– Cirrhosis, hemophilia and other bleeding disorders,

anticoagulant or antiplatelet therapy

Wafaisade, A, et al. Emerg Med J. 2010

Kauvar DS, et al. J Trauma, 2006

Massive Transfusion Protocols for Patients With

Substantial HemorrhageYoung, et al, Transfusion Medicine Reviews 10/2011

• Reviewed multiple protocols

• Concluded:– Massive transfusion protocols with higher ratios of

plasma and platelets to red blood cells appear to

be associated with improved survival in patients

with massive hemorrhage

– Further research needed

Table 2. Studies Evaluating the Impact of an MTP on Outcomes in Trauma Patients, Young, et al

Author(s) Design Number of

MT Patients

Ratios used

PRBC/Plasma/PLT

Impact of MTP on Outcomes Limitations and

Comments

Cotton et al

(2008)

Retrospective (before

and after) cohort study,

single civilian center

264 3:2:3 Reduction in 24-hour blood

utilization, 30-day mortality,

multiple-organ failure, and

abdominal compartment

syndrome

Single center,

retrospective, no

standardized activation

criteria

Cotton et al

(2009)

Prospective cohort

study, single civilian

center

125 3:2:3 Poor compliance with MTP

guidelines is associated with worse

outcomes; failure to activate MTP

early and to transfuse predefined

ratios of plasma and PLTs associated

with higher 24-hour and30-day

mortality

Single center, no

standardized activation

criteria. Prospective

examination of protocol

compliance and provider-

related factors and their

impact on patient

outcomes

Dente

et al (2009)

Retrospective (before

and after) cohort study,

single civilian center

157 1:1:1 Reduction in 24-hour mortality and

reduction in 30-daymortality in blunt

trauma

Single center,

retrospective with

historical controls, high

MTP failure rate

Duchesne et al

(2009)

Retrospective registry

review, single civilian

center

435 1:1:1 Reduction in 24-hour and30-day

mortality

Single center,

retrospective but has

standardized activation

criteria

O' Keeffe et al

(2008)

Retrospective (before

and after) cohort study,

single civilian center

132 5:2:3 Reduction in blood and blood

component utilization, time to

delivery of initial products, and

hospital charges

Single center,

retrospective, no

standardized activation

criteria; also used

cryoprecipitate and rFVIIa

Riskin et al

(2009)

Retrospective (before

and after) cohort study,

single civilian center

77 3:2:3 Reduction in time to delivery of initial

products and 30-daymortality

Small study size, single

center, retrospective, no

standard activation

criteria

Management of bleeding and coagulopathy following major

trauma: an updated European guidelineDonat R Spahn, et al.

Current concepts of pathogenesis of coagulopathy following traumatic injury.

Spahn et al. Critical Care 2013 17:R76 doi:10.1186/cc12685

HematocritRecommendation 10

We do not recommend the use of single Hct measurements as an isolated

laboratory marker for bleeding• A major limit of the Hct's diagnostic value is the confounding influence of resuscitative measures

on the Hct due to administration of intravenous fluids and red cell concentrates

• Initial Hct does not accurately reflect blood loss because patients bleed whole blood and

compensatory mechanisms that move fluids from interstitial space require time and are not

reflected in initial Hct measurements

Antifibrinolytic agentsRecommendation 24

•We recommend that tranexamic (TXA) acid be administered as early as

possible to the trauma patient who is bleeding or at risk of significant

hemorrhage

PlasmaRecommendation 26

•We recommend the initial administration of plasma or fibrinogen in patients

with massive bleeding

•If further plasma is administered, we suggest an optimal plasma:red blood

cell ratio of at least 1:2

•We recommend that plasma transfusion be avoided in patients without

substantial bleeding

Fibrinogen and cryoprecipitateRecommendation 27

•We recommend treatment with fibrinogen concentrate or cryoprecipitate in

the continuing management of the patient if significant bleeding is

accompanied by signs of a functional fibrinogen deficit or a plasma

fibrinogen level of less than 1.5 to 2.0 g/l

PlateletsRecommendation 28

•We recommend that platelets be administered to maintain a platelet count

above 50 × 109/l

•We suggest maintenance of a platelet count above 100 × 109/l in patients

with ongoing bleeding and/or TBI

Antiplatelet agentsRecommendation 29

•We suggest administration of platelets in patients with substantial bleeding

or intracranial hemorrhage who have been treated with antiplatelet agents

•We suggest the measurement of platelet function in patients treated or

suspected of being treated with antiplatelet agents; if platelet dysfunction is

documented in a patient with continued microvascular bleeding, we

suggest treatment with platelets

Prothrombin complex concentrateRecommendation 31

•We recommend the early use of prothrombin complex concentrate (PCC)

for the emergency reversal of vitamin K-dependent oral anticoagulants

Recombinant activated coagulation factor VIIRecommendation 33

•We suggest that the use of recombinant activated coagulation factor VII

(rFVIIa) be considered if major bleeding and traumatic coagulopathy

persist despite standard attempts to control bleeding and best-practice

use of conventional haemostatic measures

•We do not suggest the use of rFVIIa in patients with intracerebral

hemorrhage caused by isolated head trauma

Plasma in Massive Transfusions• A cautionary tale:

– Administration of plasma is associated with significant increase in overall complications but without significant differences in mortality

– An increase in lung injury, multiorgan dysfunction and sepsis seen with increased plasma transfusions

– Incremental risk of compatible but ABO non-identical plasma (for patients receiving more than 5 units of plasma), especially for group O patients transfused with group AB plasma• Probably due to antigen complexes formed

from residual antigens remaining in plasma– Most plasma today from men, except for AB

because of shortages• Women are associated with the highest risk

of TRALI

Objectives:

• Demonstrate knowledge of appropriate blood component

usage

• Identify the blood component for which transfusion

does not need to be ABO compatible

• Cryoprecipitate

• Platelets

• List 2 transfusion alternatives for reducing the risk of

transfusion-transmitted CMV infection

• Leukoreduction

• Serologic testing - CMV negative results

Questions?