Holley on Coagulation Management
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Anthony Holley, a world famous transfusion and coagulation guru, draws on his military, ED and ICU experience and talks about the most recent blood transfusion guidelines. They are a great resource and can be downloaded here. This talk is different to the last one he gave at Bedside Critical Care 2012!
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Holley on Coagulation Management
- 1. Reconsidering Coagulopathy and it’s Management ? Anthony Holley Intensivist Royal Brisbane & Women’s Hospital Bedside Critical Care 2012
- 2. http://www.nba.gov.au/guidelines/order/index.html http://www.nba.gov.au/guidelines/review.html Bedside Critical Care 2012
- 3. Exsanguination Haemorrhage remains a major and potentially reversible cause of all trauma deaths. More pronounced in the setting of penetrating trauma. Current literature from the Afghanistan and Iraq conflicts report that as many as 15% of casualties require massive transfusions Mortality in this group is 20-50% Bedside Critical Care 2012
- 4. Classically Trauma-induced Coagulopathy Bleeding Coagulopathy Acidosis Hypothermia Kashuk JL, Moore EE, Millikan JS, Moore JB. Major abdominal vascular trauma—a unified approach. J Trauma 1982; 22:672-679. Bedside Critical Care 2012
- 5. TOWARDS A DEFINITION, CLINICAL AND LABORATORY CRITERIA, AND A SCORING SYSTEM FOR DISSEMINATED INTRAVASCULAR COAGULATION The consensual definition of DIC as proposed by the ISTH “DIC is an acquired syndrome characterized by the intravascular activation of coagulation with loss of localization arising from different causes. It can originate from and cause damage to the microvasculature, which if sufficiently severe, can produce organ dysfunction” Fletcher B. Taylor et al on behalf of the Scientific Subcommittee on Disseminated Intravascular Coagulation (DIC) of the International Society on Thrombosis and Haemostasis (ISTH) 2001
- 6. Diagnostic algorithm for the diagnosis of overt DIC 1.Risk assessment: Does the patient have a underlying disorder known to be associated with overt DIC? If yes: proceed; If no: do not use this algorithm; 2. Order global coagulation tests (platelet count, prothrombin time (PT), fibrinogen, soluble fibrin monomers or fibrin degradation products) 3. Score global coagulation test results platelet count (>100 = 0; <100 = 1; <50= 2) elevated fibrin-related marker (e.g. soluble fibrin monomers/fibrin degradation products) (no increase: 0; moderate increase: 2; strong increase: 3) prolonged prothrombin time (< 3 sec.= 0; > 3 sec. but < 6 sec.= 1; > 6 sec. = 2) fibrinogen level (> 1.0 gram/l = 0; < 1.0 gram/l = 1) 4. Calculate score 5. If > 5: compatible with overt DIC; repeat scoring daily If < 5: suggestive (not affirmative) for non-overt DIC; repeat next 1-2 days Bedside Critical Care 2012
- 7. Clinical conditions that may be associated with overt DIC 1.sepsis/severe infection (any micro-organism) 2.trauma (e.g. polytrauma, neurotrauma, fat embolism) 3.organ destruction (e.g. severe pancreatitis) 4.malignancy - solid tumors - myeloproliferative/lymphoproliferative malignancies 5.obstetrical calamities - amniotic fluid embolism - abruptio placentae 6.vascular abnormalities - Kasabach-Merrit Syndrome - large vascular aneurysms 7.severe hepatic failure 8.severe toxic or immunologic reactions - snake bites - recreational drugs - transfusion reactions - transplant rejection Bedside Critical Care 2012
- 8. Diagnostic algorithm for the diagnosis of overt DIC 2. Order global coagulation tests (platelet count, prothrombin time (PT), fibrinogen, soluble fibrin monomers or fibrin degradation products) 3. Score global coagulation test results platelet count (>100 = 0; <100 = 1; <50= 2) elevated fibrin-related marker (e.g. soluble fibrin monomers/fibrin degradation products) (no increase: 0; moderate increase: 2; strong increase: 3) prolonged prothrombin time (< 3 sec.= 0; > 3 sec. but < 6 sec.= 1; > 6 sec. = 2) fibrinogen level (> 1.0 gram/l = 0; < 1.0 gram/l = 1) 4. Calculate score 5. If > 5: compatible with overt DIC; repeat scoring daily If < 5: suggestive (not affirmative) for non-overt DIC; repeat next 1-2 days Bedside Critical Care 2012
- 9. A Time to Consider 1.Mechanism of coagulopathy 2.Tranexamic acid 3.Product ratios 4.Activated factor VII 5.Best modality to assess coagulopathy Bedside Critical Care 2012
- 10. Dilution? Little or no dilutional effect of crystalloid therapy on the standard tests of coagulation either in vitro or in healthy volunteers Colloid vs Crystalloid Coagulopathy was present in 10% of patients who received less than 500 ml of fluid ? Alternative mechanism Bedside Critical Care 2012
- 11. Hypothermia? Moderate/severe hypothermia present < 9% of trauma patients Relationship between hypothermia, shock and injury severity is a weak independent predictor of mortality (OR 1.19) Very little effect of moderate hypothermia on coagulation proteases. Significant effects on function and clinical bleeding only at temperatures < 33°C. Bedside Critical Care 2012
- 12. Acidaemia? Effects of IV HCL acid on human volunteers. Definite dose–response of acidaemia on clotting function by thromboelastometry. Little clinically significant effect on protease function down to a pH of 7.2 in in-vitro studies Animal studies: pH of 7.1 produces only a 20% prolongation of the PT & APTT. Bedside Critical Care 2012
- 13. Consumption? Consumption regarded as a primary cause of traumatic coagulopathy Little evidence for consumption of clotting factors as a relevant mechanism In patients without shock coagulation times are never prolonged, regardless of the amount of thrombin generated Bedside Critical Care 2012
- 14. Time to Challenge the Dogma? “None of these appears to be responsible for acute coagulopathy, and it appears that shock is the prime initiator of the process!" Bedside Critical Care 2012
- 15. Classically Trauma-induced Coagulopathy yr u n j I Hyperfibrinolysis Bleeding Coagulopathy APC Acidosis Hypothermia Bedside Critical Care 2012
- 16. Drivers of Traumatic Coagulopathy? Shock and systemic hypoperfusion? Dose-dependent prolongation of clotting times with increasing systemic hypoperfusion. Base deficit (BD) as a surrogate for perfusion 2% of patients with a BD < 6 mEq/l had prolonged clotting times 20% of patients with a BD > 6 mEq/l. Bedside Critical Care 2012
- 17. Mechanism of Acute Traumatic Coagulopathy Acute coagulopathy in massive transfusion appears to be due to activation of anticoagulant and fibrinolytic pathways. Thrombomodulin–protein C pathway is implicated. Bedside Critical Care 2012
- 18. Procoagulant Antifibrinolytic activity Activity Thrombus Normal Haemostasis Bleeding fibrinolytic Anticoagulant activity Activity Bedside Critical Care 2012
- 19. Protein C Activation With tissue hypoperfusion the endothelium expresses thrombomodulin which complexes with thrombin. Less thrombin is available to cleave fibrinogen Thrombin complexed to thrombomodulin activates protein C, which inhibits cofactors V and VIII Bedside Critical Care 2012
- 20. Protein C Anticoagulant Pathway Bedside Critical Care 2012
- 21. Biological Response Pathological in Shock Tissues subjected to low-flow states generate an anticoagulant milieu Avoids thrombosis of vascular beds. Bedside Critical Care 2012
- 22. Hyperfibrinolysis Trauma is associated with increased fibrinolytic activity. Tissue plasminogen activator (tPA) is released from the endothelium following injury and ischaemia. Local control mechanism to reduce propagation of clot to normal vasculature Bedside Critical Care 2012
- 23. Hyperfibrinolysis APC Reduction in plasminogen activator inhibitor-1 (PAI-1) levels in tissue hypoperfusion
- 24. A new understanding of coagulopathy in trauma: potential therapeutic implications. 2012 Yearbook of Intensive Care and Emergency Medicine. Edited J.-L. Vincent. Springer. Read M, Holley A
- 25. Tranexamic acid Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial CRASH-2 trial collaborators. The Lancet. 2010;376:23-32 Bedside Critical Care 2012
- 26. Tranexamic Acid ACEM ASM 2010 Tranexamic Acid Plasminogen activator Fibrinolysis Blockade Blockade Plasminogen Plasmin Bedside Critical Care 2012
- 27. Bedside Critical Care 2012
- 28. The Study Prospective double blind 274 hospitals 40 countries n=20211 Tranexamic (n=10 060) acid vs placebo (10115) 1 g over 10 minutes then 1 g over 8 hours Primary outcome: in hospital four week mortality Bedside Critical Care 2012
- 29. Tranexamic Acid Bedside Critical Care 2012
- 30. Tranexamic Acid Bedside Critical Care 2012
- 31. But............ Entrance criteria soft (HR>110 bpm, SBP<90 mmHg) 70% of patients SBP > 90 mmHg Only 16% of patients SBP <75 mmHg No reduction in blood transfusion observed Median no. of RBC units transfused = 3 in both groups Needs to be given within three hours of injury Bedside Critical Care 2012
- 32. Tranexamic acid safely reduces the risk of death in bleeding trauma patients! Bedside Critical Care 2012
- 33. Ratios Bedside Critical Care 2012
- 34. Ratios Bedside Critical Care 2012
- 35. Holcomb JB, Wade CE, Michalek JE, Chisholm GB, Zarzabal LA, Schreiber MA, Gonzalez EA, Pomper GJ, Perkins JG, Spinella PC, Williams KL, Park MS. Increased plasma and platelet to red blood cell ratios improves outcome in 466 massivelyBedside Critical Care 2012 transfused civilian trauma patients. Ann Surg 2008; 248:447-458 .
- 36. Product Ratios Massive data base ~ 25 000 16% transfused 11.4% received massive transfusions Logistic regression identified the ratio of FFP to PRBC use as an independent predictor of survival. Higher the ratio of FFP:PRBC the greater probability of survival. The optimal ratio in this analysis was an FFP:PRBC ratio of 1:3 or less. Teixeira PG, Inaba K, Shulman I, Salim A, Demetriades D, Brown C, Browder T, Green D, Rhee P. Impact of plasma transfusion in massively transfused trauma patients. J Trauma 2009; 66:693-697 . Bedside Critical Care 2012
- 37. Practice Point In patients with critical bleeding requiring massive transfusion, insufficient evidence was identified to support or refute the use of specific ratios of RBCs to blood components. Bedside Critical Care 2012
- 38. Bedside Critical Care 2012
- 39. Activated Factor VII Bedside Critical Care 2012 were enrolled. 143 blunt, 137 penetrating. 301 trauma patients
- 40. Randomized prospective trial 573 patients No effect on mortality No effect on thrombotic events Trial stopped early for lack of efficacy! Hauser et al. J Trauma. 2010 Sep;69(3):489- 500 Bedside Critical Care 2012
- 41. Bedside Critical Care 2012
- 42. Levi M, Levy JH, Andersen HF, Truloff D. Safety of recombinant activated factor VII in randomized clinical trials. N Engl J Med 2010;363:1791-1800. Bedside Critical Care 2012
- 43. Bedside Critical Care 2012
- 44. Recommendation 2 The routine use of rFVIIa in trauma patients with critical bleeding requiring massive transfusion is not recommended because of its lack of effect on mortality (Grade B) and variable effect on morbidity (Grade C). Bedside Critical Care 2012
- 45. Practice Point Bedside Critical Care 2012 1. An MTP should include advice on the administration of rFVIIa when conventional measures – including surgical haemostasis and component therapy – have failed to control critical bleeding. 2. NB: rFVIIa is not licensed for this use. Its use should only be considered in exceptional circumstances where survival is considered a credible outcome 3. When rFVIIa is administered to patients with critical bleeding requiring massive transfusion, an initial dose of 90 μg/kg is reasonable.
- 46. Summary More to coagulopathy than acidosis, hypothermia and dilution. Almost certainly hypoperfusion is the principle driver. Acidosis, hypothermia and dilution certainly contribute. Despite advances in our understanding we haven’t yet found the magic bullet. We will have to wait for the definitive word on product ratios. Tranexamic acid given early seems to be safe and effective and we are unlikely to get better evidence than CRASH2 Bedside Critical Care 2012
- 47. Thank You Bedside Critical Care 2012
Notes de l'éditeur
- (> 10 units in 24 hours)
- In each study, the time from injury to admission was relatively short at a median of 70–75 min. In the London study there was minimal prehospital fluid administration (median 500 ml) and we identified no relationship between fluid administration and the incidence of coagulopathy [6] . Higher volumes of fluid were given in the German study (mean 2200 ml) and there was a clear dilution effect, with coagulopathy present in more than 50% of patients who received more than 3 l of fluid in the prehospital phase [8•] . This may be a result of colloid use in this study as there appears to be little or no dilutional effect of crystalloid therapy on the standard tests of coagulation either in vitro [11] or in healthy volunteers [12] . Coagulopathy was still present, however, in 10% of patients who received less than 500 ml of fluid, suggesting an alternative mechanism is responsible.
- None of the retrospective studies that identified early coagulopathy specifically reported patient temperature on admission. Moderate or severe hypothermia is present in less than 9% of trauma patients [13,14] . Although there is a relationship between hypothermia, shock and injury severity it remains a weak independent predictor of mortality (odds ratio 1.19) [14] . There is, however, very little effect of temperature on coagulation proteases at these temperatures, and significant effects on function and clinical bleeding are observed only at temperatures below 33°C [15–17] .
- Acidemia affects the function of the coagulation proteases. Clinically it is difficult to separate the effects of acidemia per se and the effects of shock and tissue hypoperfusion. A recent study [18] examined the effects of intravenous administration of hydrochloric acid on human volunteers. While there was a definite dose–response effect of acidemia on clotting function as measured by thromboelastometry, clotting times were not prolonged. This is consistent with in-vitro studies for which there is little clinically significant effect on protease function down to a pH of 7.2 [16] and in animal studies for which a pH of 7.1 produces only a 20% prolongation of the prothrombin and partial thromboplastin times [17] . Whatever the exact effect of acidemia on coagulation function, it appears not to be reversible by simple correction of the acidosis [19,20] .
- Consumption of clotting factors has always been regarded as a primary cause of traumatic coagulopathy [1] . There is little evidence, however, to support consumption of clotting factors as a relevant mechanism for acute traumatic coagulopathy, and nothing to suggest a process of disseminated intravascular coagulation (DIC). There is certainly activation of the tissue-factor dependent extrinsic pathway and a linear relationship between thrombin generation and injury severity [9••] . In patients without shock, however, coagulation times are never prolonged, regardless of the amount of thrombin generated [9••] . Further, fibrinogen levels are rarely decreased in patients with acute traumatic coagulopathy [19] . A commonly held belief is that traumatic brain injury releases ‘thromboplastins’ into the circulation which then lead to a consumptive or DIC-like coagulopathy. Again, however, there is no evidence to support this, and we [21] and others [22] have refuted the presence of a specific brain injury-related coagulopathy.
- Shock and tissue hypoperfusion strong independent risk factor for poor outcomes in trauma no patient with a normal base deficit had prolonged prothrombin or partial thromboplastin times, regardless of injury severity or the amount of thrombin generated. In contrast there was a dose-dependent prolongation of clotting times with increasing systemic hypoperfusion. Only 2% of patients with a base deficit under 6 mEq/l had prolonged clotting times, compared with 20% of patients with a base deficit over 6 mEq/l. Higher injury severity increased the incidence and severity of coagulopathy in shocked patients. Fibrinogen and platelet levels were normal in all patients. Shock and systemic hypoperfusion appears to be the key driver of acute traumatic coagulopathy.
- We were not able to measure activated protein C levels in this study due to the assay's complexity at the time. The activation of protein C, however, was strongly suggested by a dose-dependent prolongation of clotting times as protein C levels fell below normal. Corroborating this, we found that in the presence of hypoperfusion and increased levels of thrombomodulin, fibrinogen levels remained normal, indicating that less thrombin was available to cleave fibrinogen (as it was complexed to thrombomodulin). Nevertheless, confirmation of the generation of activated protein C in hypoperfusion is required to verify this hypothesis. Intuitively, however, it seems appropriate that
- Trauma is associated with increased fibrinolytic activity. Raised D-dimer levels following injury have been identified in many studies [9••,27] . Activation of fibrinolysis occurs as tissue plasminogen activator (tPA) is released from the endothelium following injury and ischemia [28–30] . This is a local control mechanism to reduce propagation of clot to normal vasculature, and our study was consistent with these findings [9••] . We also, however, identified a reduction in plasminogen activator inhibitor-1 (PAI-1) levels in patients with tissue hypoperfusion, who had almost twice the levels of tPA than patients without shock. Activated protein C in excess will consume PAI-1 [31] and thus lead to a ‘de-repression’ of fibrinolytic activity and systemic hyperfibrinolysis ( Fig. 2 ).
- Activated protein C in excess will consume PAI-1 and thus lead to a ‘de-repression’ of fibrinolytic activity and systemic hyperfibrinolysis