1. Massive traumatic bleeding: The multi-factorial complex nature of Institute of Thrombosis Hemostasis and The National Hemophilia Center, Sheba medical Center, Tel Hashomer, Uri Martinowitz MD Member, Hemorrhage Control Steering Committee, The U.S. Army Medical Research and Materiel Command USAMARC, The Combat Casualty Care Research Program CCRP

2. MILITARY TRAUMA CNS-KIA 31 % MULTI-KIA 13% MOF-DOW 4% CNS-DOW 5% SHOCK-DOW 3% EXSANG-KIA44% KIA – killed in action; DOW – died of wound; MOF – multiple organ failure. WDMET Vietnam war 1967– 1969; 8000 CASUALTIES. CNS 42% EXSANG39% CNS + EXSANG 6% MOF 7% Other 6% Sauaia A et al. J Trauma. 1995; 38:185-193 38:185-193. Trauma Is the leading cause of death in the young Hemorrhage is a major cause of death in trauma CIVILIAN TRAUMA 289 FATALITIES: 49% PENETRATING, 48% BLUNT 140,000 deaths/year in the US

3. Massive Hemorrhage in Trauma (and “controlled” trauma.) “Surgical” bleed Massive ” combined” bleed “Late” coagulopathy Activation  consumption hemodilution, anemia, metabolic, hypothermia Early coagulopathy (10 min.) Hypoperfusion  acidosis, hyperfibrinolysis,Prot. C pathway activation by thrombin with” systemic anticoagulation” ??? Brohi K. J. Trauma 2008: 64 :1211 Trauma induced coagulopathy (TIC)

4. Brohi K: J. Trauma (2003) 55:1127 Incidence of coagulopathy correlates with ISS in civil trauma (Kaufman CR,J. trauma 1997,Cosgriff N. J. Trauma 1997) ISS-injury Severity score. >15 =severe injury

5. Coagulopathy is associated with increased mortality in civil trauma 4-6 times beyond expected from the injury severity Brohi K: J. Trauma (2003) 55:1127  The German Trauma Registry (n=8724); (n=1088) Maegele M. Injury 2007 38:298. Niles S. J. Trauma. 2008;64:1459.  US Army in Iraq Similar results:

6. E. Gonzalez J. Trauma 2007 Severity of early ICU coagulopathy is predictive of mortality in civil trauma

7. Early Coagulopathy of Trauma in Combat Casualties The trend of INR associated with mortality with 95% CI by univariate analysis S. Niles, D. McLaughlin, J. Perkins et al J. Trauma. 2008;64:1459 –1465.

8. K. Brohi ;Curr Opin Crit Care 13:680–685. 2007 Gonzalez 2007 INR>1.2 (most 1.8) 97 70% ) INR≥2 mortality>50%( Incidence of coagulopathy depends on its definition (expressed by PT and PTT) Niles 2008# INR>.1.5 391 38% 17 4% 24% # Military

9. Traumatic induced coagulopathy(TIC) Blood loss, hypoperfusion  acidosis Activation of coagulation  Consumption  Hyperfibrinolysis Dilution Fluids rescusitation Inbalanced massive transfusions Fibrinogen reduction and polimerization defects Severe anemia -platelets dysfunction Hypothermia

10. Platelets Thrombocytopenia Sequestration in liver and spleen Villalobos T: J Cin Invest (1958) 37:1 Platelet dysfunction Adhesion and aggregation Kermode J: Blood (1999) 94:199 Coagulation factors Reduction of the enzymatic activity not impaired > 33° C Increased fibrinolytic activity PAI 1 reduced  2-Antiplasmin reduced  hyperfibrinolysis Wolberg A: J Trauma (2004) 56:1221 37° C 33° C

11. Admission hypothermia and outcome after major trauma 5% (1921 pts)  CT ≤35°C increased mortality for the full cohort (OR 3,03; 95% CI 2,62–3,51) group with brain injury (OR 2,21;CI 1,62–3,03) independent age ISS and mechanism of injury route of temperature measurement Wang H: Crit Care Med 2005;33:1296 < 32 32.0 1 – 33 330 1 – 34 340 1 – 35 350 1 – 36 360 1 – 37 50% 40% 30% 20% 10% Mortality in %

12. Acidosis compromises coagulation Platelets Thrombocytopenia Platelet dysfunction Marumo M: Thromb Res (2001) 104:353 Coagulation factors Reduce fibrinogen and Decreased MCF Engstrom M: J. Trauma (2006) 61:624 Fibrinogen Platelets mg/dl 10 7 /µl 300 200 100 50 500 400 300 200 100 pH 7,4 pH 7,1 pH 7,4 pH 7,1 Martini W: J Trauma (2006) 61: 99

13. Inhibition of 70% at pH 7.0 as compared to 7.4 Effect of pH on Thrombin Generation on phospholipid vesicles Meng ZH et al, J Trauma. 2003;55:886-891. Acidosis compromises coagulation

14. Martini WJ J. Trauma 2005 Coagulopathic effect of combined hypothermia and acidosis

15. Anemic patients tend to bleed more in surgery Ht 35 vs. 31 at end of CPB =blood loss X4-5 Patients with bleeding diathesis (uremia, Glanzmans’, irradiation colitis, angiodisplasia etc.) bleed less with correction of Hb (EPO). RBC transfusion is an important hemostatic treatment.In massive bleedings the goal is to achieve Ht 30-35,Hb 10-11. Anemia compromises coagulation

16. Effect of Hct on platelet deposition on damaged arterial segments Hct = 40%, PLTs = 200,000/mcL Hct = 20%, PLTs = 200,000/mcL Hct = 20%, PLTs = 50,000/mcL Transfusion 1994; 34:542-9 1 2 3 Anemia Anemia + thrombocytopenia Normal

17. Starch based fluids (HES solutions) & Dextran ► Interfere with the measurement of fibrinogen - ”false” high levels ► Impairs fibrin polymerization ► Impaired Platelet function Contribution to acidosis ► Saline 0.9% pH 4.5 - 7 ► Ringer Lactate pH 6 - 7.5 Hemodilution by PRBC and fluids : effects of fluids on coagulation Prough DS &, Anesthesiol. 1999 Hiippala ST. Blood Coagul Fibrinolysis 1995,Trieb J, T&H 1997Jamnicki M, Anesthesia. 1999 Undiluted blood clot 65% dilution with gelatin Fries D, Br J Anaesth. 2005

18. May explain increased bleeding at fibrinogen levels above 2 g/L Blome M et al., Thromb Haemost 2005;93:1101-1107 Fibrinogen level (Claus) in hemodilution does not discriminate functional from nonfunctional proteins Fibrinogen (Claus) 2.03g/L H. Schochl, Salzburg ;unpublished

19. Fenger-Eriksen C., Br J Anaesth. 2005 Interference to fibrin polymerization 55% dilution

20. H. Schockle,unpublished, with permission Hyperfibrinolysis Underestimated – no routine tests (Except TEG) Common in trauma? severe form in~20% of patients with ISS>15 May develop early-within minutes (TBI) M.Vorweg & M.Doehn,unpublished,with permissionon M.Vorweg & M.Doehn,unpublished,with permissionon Hyperfibrinolysis according to ISS and organ of injury

21. Complete lysis < 30min –ER: 11 –ICU: 3 –Survivor: 0 Complete lysis 30 – 60 min –ER: 3 –ICU: 4 –Survivor: 0 Complete lysis > 60 min –EM: 0 –ICU: 5 –Survivor: 5 High mortality (84%) increases with sevirity of fibrinolysis H. Schochl, trauma hospital, Zalzburg, Austria; unpublished Thromboelastography

22. Fibrinogen level on admission to ER H. Schochl, trauma hospital, Zalzburg, Austria; unpublished n = 180

23. Coagulopathy is underestimated - we only see the tip of the iceberg Acidosis hypothermia platelets dysfunction fibrinolysis Hemodilution Anemia Consumption Lag time of 45-60 min. to results Fibrinogen dysfunction

24. Rohrer MJ, Crit Care Med 1992. Hypothermic coagulopathy is underestimated Coagulation tests are performed in test tubes at 37°C Coagulation process is taking place on cell membranes in body temperature of the patient Effect of temp. on PT and PTT The effect of temp. on platelets function is not assessed

25. Coagulation Fluid Clot Fluid Fibrinolysis Clot formation Benni Sorensen 2008 with permission Standard coagulation test are of limited value Standard coagulation test are of limited value they only detect initiation of clot formation PT/PTT TT,ACT

26. Thromboelastography -real time clot analysis Continuous registration of clot firmness Fibrinogen function Platelets function

27. Thrombin Generation measurement 1.Lag time 2.Pick height 3.ETP-Endogenous thrombin potential (area under curve) 1 3 2 Research tool,not a real time test, commercial kits are developed Routine coagulation tests

28. Surgical hemostasis Reversal of acidosis ?. Inhibition of rVIIa. Platelets and Fib. may be needed Inhibition of fibrinolysis Avoidance of massive Fluid resuscitation Hemostatic bandages and glues Prevention and correction of hypothermia (not a limiting factor for rFVIIa) Threshold of Hb? Age of blood? Early FFP 1:1 RBC:FFP Instead 1-4/6 Platelets (goal: >100,000) rFVIIa Hemostatic resuscitation of traumatic coagulopathy 1:1:1:1 fibrinogen (goal >1g/L ? >4g/L

29. The blood bank: from (problematic) provider to partner in massively bleeding patients Pär I. Johansson, Transfusion 2007 Aug. 47:176-181s (Anesth.+transfus Early hemostatic rescusitation

30. Pro-hemostatic agents :   Extra-vascular (surgical): ● Fibrin glues ● New hemostatic polymers  Intravascular - ● Fibrinolytic / proteolytic inhibitors ● Coagulation factors (cryo, FFP) and platelets ● Coagulation factor concentrates PCC, APCC, fibrinogrn FXIII, platelets substitutes ● DDAVP … ● New generation of Injury-specific hemostatic agents. (rFVIIa, Xa / PL, pdVIIa/Xa,mutants rFVIIa)

31. Conclusion Coagulopathy is common in major trauma, its severity correlates with bleeding and mortality Hypothermia, acidosis, hemodilution are important confounders of the coagulation process Hyperfibrinolysis is underestimated Fibrinogen depletes early in severe trauma Standard coagulation test are of limited value Thrombelastography could be helpful in detecting coagulopathy and monitor treatment

32. Overview of rFVIIa Thank you for your participation,I hope it was usefull