Peyman Eshghi Prof. of Pediatric Hematology & Oncology Pediatric Congenital Hematologic Disorders Research Center Mofid Children Hospital S.B.M.U 9-9-93

Main topics

Definition of massive transfusion

Consequences and complications of MT

Management: Plasma/platelets/red blood cell ratio

rFVIIa

PCC

Antifibrinolytics

Fibrinogen

Definition of

Massive Transfusion: The replacement of patient’s entire blood volume in a 24-hour period.

The transfusion of more than 20u of whole blood or 40u of PRBC.

The replacement of over 50% of circulating blood volume in 3 hour or less.

transfusion of four or more red cell concentrates within one hour

Loss of blood more than 150ml/min

Coagulopathy : is used interchangeably with the more general term “defective

hemostasis” and encompasses both defects of primary hemostasis (related to platelet function) and coagulopathy (related to alterations of the plasma phase of coagulation).

The incidence of hemostatic defects associated with MT

will vary according to:

the clinical context : (blunt vs penetrating trauma, presence of brain injury, elective surgery)

the definition of coagulopathy :(clinical findings vs laboratory test results)

the administered blood products

Pathophysiology of coagulopathy in MT:

Previous : Hemodilution Hypothermia Blood components and alterations of hemostasis Acidosis DIC

Recent : It is due to not only the above but also-and mainly-the activation of:

Inflammatory: protein C Hemostatic: hypofibrinogenemia Fibrinolytic pathways

cohort of 1088 trauma patients:

24% had a coagulopathy on arrival

higher rate of death with these abnormal laboratory test (46% vs 11%, P < .001)

The incidence of coagulopathy was strongly associated with the injury severity score

Brohi K. et al ,Acute traumatic coagulopathy.J Trauma 2003 ; 54(6) :1127-1130.

A prospective cohort study of 203 major trauma patients :

patients with tissue hypoperfusion and severe injury had activation of protein C, with subsequent inactivation of factor V and VIII and activation of fibrinolysis

Cohen et al. Ann Surg. 2012;255(2): 379-385.

Figure 111-04

Copyright © 2005 Elsevier Inc. (USA) All rights reserved.

The endothelial cell protein C receptor (EPCR) provides cell-specific binding sites for both protein C and APC.

• NL fibrinolysis pathway • Degradation of clot

• Inhibitor of clot formation in nontraumatized areas

Endothelial Cell

Α2-antiplasmin

Plasmin Plasminogen

Va, VIIIa

Vi, VIIIi

FDP Fibrinogen

Fibrin

XIIa

PAI-1

u-PA t-PA

Α2-antiplasmin

XIIIa

The potentially antifibrinolytic effect of thrombin appears to be mediated through its ability to activate TAFI in the presence of

thrombomodulin.

Hypoperfusion :

Increased expression of thrombomodulin on the surface of endothelial cells binds thrombin activates protein C:

proteolytically inactivates factor V and VIII impairment of clot generation

Depletes plasminogen activator inhibitor(PAI-1) unrestrained tissue plasminogen activator plasmin generation:

clot lysis (fibrinolysis).

to degrade fibrinogen (fibrinogenolysis)

depleting the fibrinogen reserves.

Importance of Hypofibrinogenemia

in non-cardiac surgery patients that fibrinogen was the first factor to reach a set “critical level” (< 1.0 g/L) at 142% of total blood volume loss compared with platelets decreasing below a critical level (50 × 109/L) at 230% of total blood volume loss.

HiipalaS.T.etal.,AnesthAnalg(1995)81:360

Importance of Hyperfibrinolysis

Incidence and morbidity : in a cohort of 161 trauma patients, the incidence of

hyperfibrinolysis was only 2.5%, but was associated with a mortality rate of 67%.Caroll. Transl Res. 2009;154(1):34-39.

Similarly, in a study of 334 major trauma patients, hyperfibrinolysis was observed in 6.8% of patients, and the mortality rate was 86%. Tauber. Br J Anaesth. 2011;107(3): 378-387.

Early recognition of this entity,

Early administration of antifibrinolytic drugs

Possibly the use of fibrinogen replacement.

Platelet dysfunction as a previously unrecognized defect in trauma patients

Platelet&Fibrinogen

glycoprotein IIb/IIIa (GPIIb/IIIa, also known as integrin αIIbβ3) is an integrin complex found on platelets.

It is a receptor forfibrinogen and von Willebrand factor and aids in platelet activation.

The complex is formed via calcium-dependent association of gpIIb and gpIIIa, a required step in normal platelet aggregation and endothelial adherence.[

Platelet activation by ADP (blocked by clopidogrel) leads to a conformational change in platelet gpIIb/IIIa receptors that induces binding to fibrinogen.

The gpIIb/IIIa receptor is a target of several Glycoprotein IIb/IIIa inhibitors drugs including abciximab, eptifibatide, tirofiban.

Threshold level at which hypofibrinogenemia contributes to hemorrhage

Current European Guideline on the management of bleeding guidelines: > 1.5 g/L N. RAHE-MEYER and B . SØRENSEN Journal of Thrombosis and Haemostasis, 9: 1–5

Some recommending a cutoff of 1.5-2.0 g/L. Sørensen . Br J Haematol. 2010;149(6):834-843. /

Rossaint R, Crit Care. 2010;14(2):R52.

In the setting of postpartum hemorrhage, a fibrinogen level below 2.0 g/L increased the risk of severe postpartum hemorrhage. Charbit B,. J Thromb

Haemost. 2007;5(2):266-273.

Austrian Society of Anesthesiology, Resuscitation and Intensive Care: 1.5 – 2.0 g/L

A study in patients undergoing cardiac surgery found that a low-normal preoperative baseline fibrinogen, even when within the normal range, increased the risk of postoperative transfusion. Karlsson

Transfusion. 2008;48(10):2152-2158.

Management of coagulopathy in MT

the INR being most common and more consistently useful than the PTT

Once the INR is >1.5 then the level of clotting factors is approaching 20%.

J. Bormanis / Transfusion and Apheresis Science 38 (2008) 57–63

PT& aPTT Clotting factors fibrinogen

1-<1.5× NL 30-50%

1.5- <1.8× NL

15-30% <1 gr/l

>1.8× NL <15%

Transfus Apheresis Sci 2002; 27:83-92

Why TEG standard “rapid hemorrhage panel”(aPTT,PT,INR,CBC,Plt Fibrinogen) :

platelet count provides no information on platelet function( anti platelet medications; role of fibrinogen;..)

both the INR and the partial thromboplastin time are suboptimal measures of thrombin generation and fibrinogen

Measurement of fibrinogen by the Clauss method is usually the last parameter to be reported out by the laboratory

fibrin degradation products and the colloid plasma expanders can produce artificially high results when fibrinogen levels are measured

provide no information regarding fibrinolysis.

Benefits of TEG: Rapid Near-patient test Run on whole blood(no centrifuge) Provide information on coagulation factors, platelet function, fibrinogen level, and fibrinolysis

Blood components and alterations of hemostasis

only marked prolongations of the PT or aPTT (1.5 and 1.8 times higher than control when the fibrinogen level is low and normal respectively) are likely to be significant from a clinical perspective

Cryo:1unit/10kg increases fibrinogen by 50 Platelet TX: Indications:

Dilutional Thrombocytopenia <50,000 (50,000-100,000 relative indication)

Platelet Dysfunction (hypothermia, etc)

Optimal Plasma/platelets/red blood cell ratio in MT

A systematic review including 11 studies (3 prospective, 7 retrospective, and 1 case-control) concluded that there was insufficient evidence to support the use of fixed ratios in massively transfused trauma patients. Rajasekhar et al Crit Care Med. 2011;39(6):1507-

1513.

Two randomized trials are under way to assist with answering this question without survivorship bias : the Trauma Lab vs Formula Pilot Trial (TR-FL)

the Pragmatic Randomized Optimum Platelet and Plasma Ratios (PROPPR) trial : will be the first prospective trial to address the role of early platelet transfusion in the management of massively bleeding trauma patients.

Alternative (and adjunctive) strategies to ratio-based plasma infusions

Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage (CRASH-2):

more than 20 000 patients to either tranexamic acid or placebo

TA reduces the risk of death (odds ratio [OR] 0.91, 95% confidence interval [CI], 0.85-0.97, P < .0035) and death from hemorrhage (OR 0.85, 95% CI, 0.76-0.96, P < .0077) especially if administered within the first hour of injury (OR 0.68, 95% CI, 0.57-0.82, P<.001).

Despite its antifibrinolytic effect, there was no increased risk of thromboembolic complications.

any patient bleeding sufficiently to get RBC and plasma transfusions should receive tranexamic acid, commenced immediately on arrival to hospital (or during transportif possible).

analysis of 896 consecutive United Kingdom and US military trauma admissions and more than 5000 cases in The WOMAN trial confirmed CRASH-2

Dose hemodilution explain all of the changes?

the number of units of blood transfused explained less than 20% of the variance in factors V and VIII and was not related to factor VII, X, XI, XII and fibrinogen levels Observed platelet counts are higher than those predicted by hemodilution alone Clinically-especially in trauma- simple hemodilution has failed to explain several observations. 1- extravasation of tissue factor can rapidly (within one to four hours after injury): especially in brain injury(40%) 2- shock and tissue anoxia and consumptive coagulopathy

Adverse effects of allogeneic RBC, FFP and platelets

TRALI

New ALI : non-cardiogenic (PCWP < 18

mmHg) pulmonary edema (bilateral infiltrates)

Hypoxemia (PaO2/FiO2 < 300 mm Hg)

Onset within 6h after transfusion Symptoms : Dyspnea, fever,

tachycardia, hypotension Silliman C. C. et al. Blood (2005) 105: 2266 Crit Care Med (2006) 5 Suppl

Clinical incidence and relevance

Transfusion of:5044 RBC

2745 FFP

885 Platelet

228 Cryoprecipitate

Incidence of suspected TRALI 1: 1271

Incidence of possible TRALI 1: 534

Incidence of TACO: 1: 356

Mortality: TRALI: 67%, TACO: 20%, Control: 11% Rana R. et al. Transfusion(2006) 46: 1478

Fibrinogen in MT

Current guidelines recommend fibrinogen supplementation in all cases where significant bleeding is accompanied by thrombelastometric signs of a functional fibrinogen deficit or a plasma fibrinogen level of < 1.5–2.0 g L)

the key questions:

“How should we supplement fibrinogen levels?” rather than “Should we supplement fibrinogen levels?”

what is the appropriate level of fibrinogen to trigger treatment, and what is the optimal dose of fibrinogen?

Role of Fibrinogen in major hemorrhage to reduce need for blood products

Fibrinogen in major surgery

69 patients with fibrinogen < 1.0 g/L

Median dose of fibrinogen: 4 g

Median fibrinogen: 0.8 1.9 g/L

Danes A. F. et al. Vox Sanguinis (2008)

FFP=2.5 gr/l Cryo= 1gr/60 cc(4 unit pooled) FC=1 gr/50 cc

N. RAHE-MEYER* and B . SØRENSEN § Journal of Thrombosis and Haemostasis,2010 9: 1–5

• Ninety-one eligible studies (70 FFP and 21 fibrinogen concentrate) reported outcomes of interest. Few were high-quality prospective studies.

• Fibrinogen concentrate was compared directly with FFP in three high-quality studies and was found to be superior for > 50% of outcomes in terms of reducing blood loss, allogeneic transfusion requirements, length of intensive care unit and hospital stay and increasing plasma fibrinogen levels.

• We found no fibrinogen concentrate comparator studies in patients with haemorrhage due to massive trauma, although efficacy across all assessed outcomes was reported in a number of noncomparator trauma studies

• patients were randomized as follows: group A received 4 units FFP and group B received 2 units FFP plus 2 g fibrinogen concentrate

• Partial replacement of transfused FFP by fibrinogen increases fibrin clot formation at the expense of less improved thrombin generation.

• Coagulation factors other than fibrinogen alone are required for full restoration of haemostasis

safety

A 22 year pharmacosurveillance report and review of clinical study data showed no significant safety concerns associated with fibrinogen concentrate used in perioperative bleeding situations, either with regard to thrombogenicity or viral transmission Dickneite G.et al,Blood Coagul Fibrinolysis 2009; 20: 535–40.

Adverse drug reaction

Number of reported cases

Number and causaly of reported cases

Allergic /anaphylactoid reactions

21 4 highly probable 14 possible 3 insufficient data

Thromboembolic event

13 12 possible 1 insufficient data

Suspected transmissin of infectious disease

16 15 unlikely 1insufficient data

Lack of ffect 3 1 unlikely 2 insufficient data

PCC

PCC must be expected if the activity of the procoagulants, and prothrombin especially, is <30%. This generally only occurs with blood losses >150%-200% of the estimated blood volume.

thromboembolic complications in liberal usage

Efficacy in massive bleeding has not been proven in any prospective controlled study

Should be used after Fibrinogen

rFVIIa

Lead to thrombin formation Should be used after:

Correction of acidosis (ph>7.2) Hypofibrinogenemia Thrombocytopenia If the accompanying clinical circumstances suggest this (e.g., postpartum bleeding,

after weaning from cardiopulmonary bypass pump, or after administration of protamine), the patient should be treated with antifibrinolytics and fibrinogen before

Dietmar Fries. TRANSFUSION 2013;53:91S-95S

The management of massive transfusion in the elective surgical setting

Transfus Apheresis Sci 2002; 27:83-92

Fibrinogen concentrate