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Massive traumatic bleeding: The multi-factorial complex nature of

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.

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Massive traumatic bleeding: The multi-factorial complex nature of

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  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. Trauma Is the leading cause of death in the young Hemorrhage is a major cause of death in trauma MILITARY TRAUMA CIVILIAN TRAUMA 289 FATALITIES: 49% PENETRATING, 48% BLUNT CNS-DOW 5% MULTI-KIA 13% MOF 7% MOF-DOW 4% CNS 42% Other 6% SHOCK-DOW 3% EXSANG 39% CNS + EXSANG 6% CNS-KIA 31% EXSANG-KIA 44% KIA – killed in action; DOW – died of wound; MOF – multiple organ failure. WDMET Vietnam war 1967–1969; 8000 CASUALTIES. Sauaia A et al. J Trauma. 1995; 38:185-193. 140,000 deaths/year in the US

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

  4. Incidence of coagulopathy correlates with ISSin civil trauma Brohi K: J. Trauma (2003) 55:1127 (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 trauma4-6 times beyond expected from the injury severity Brohi K: J. Trauma (2003) 55:1127 (n=1088) Similar results: • The German Trauma Registry (n=8724); Maegele M. Injury 2007 38:298 • US Army in Iraq . Niles S. J. Trauma. 2008;64:1459.

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

  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. Incidence of coagulopathy depends on its definition (expressed by PT and PTT) K. Brohi ;Curr Opin Crit Care 13:680–685. 2007 Niles 2008# INR>.1.5 391 38% 17 4% 24% Gonzalez 2007 INR>1.2 (most 1.8) 97 70%) INR≥2 mortality>50%( # 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. Hypothermia 37° C 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 • a2-Antiplasmin reduced  hyperfibrinolysis 33° C Wolberg A: J Trauma (2004) 56:1221

  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 Mortality in % 50% 40% 30% 20% 10% < 32 32.0 1 – 33 330 1 – 34 Wang H: Crit Care Med 2005;33:1296 340 1 – 35 350 1 – 36 360 1 – 37

  12. Acidosis compromises coagulation 500 400 300 200 100 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 Platelets 107/µl pH 7,4 pH 7,1 300 200 100 50 Fibrinogen mg/dl pH 7,4 pH 7,1 Martini W: J Trauma (2006) 61: 99

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

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

  15. Anemia compromises coagulation • 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.

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

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

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

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

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

  21. High mortality (84%) increases with sevirity of fibrinolysis Thromboelastography • 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 H. Schochl, trauma hospital , Zalzburg, Austria; unpublished

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

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

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

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

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

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

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

  29. The blood bank: from (problematic) provider to partner in massively bleeding patientsPär 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. Thank you for your participation,I hope it was usefull • Overview of rFVIIa

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