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My bloody head: Diagnosis and management of coagulopathy and traumatic brain injury by Associate Professor Samuel Galvagno

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Associate Professor Samuel Galvagno: My bloody head: Diagnosis and management of coagulopathy and traumatic brain injury.
From CICM ASM PROGRAM 2019.

Published in: Health & Medicine
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My bloody head: Diagnosis and management of coagulopathy and traumatic brain injury by Associate Professor Samuel Galvagno

  1. 1. R ADAMS COWLEY SHOCK TRAUMA CENTER My Bloody Head! Diagnosis and Management of Coagulopathy and Traumatic Brain Injury Sam Galvagno, DO, PhD, FCCM Col, USAF, MC, SFS Associate Professor Medical Director, Lung Rescue Unit (LRU) University of Maryland School of Medicine R Adams Cowley Shock Trauma Center Baltimore, MD, USA
  2. 2. R ADAMS COWLEY SHOCK TRAUMA CENTER Disclosures • United States Air Force Reserve • UpToDate® Author • One time honorarium from Haemonetics ® • Department of Defense Funding
  3. 3. R ADAMS COWLEY SHOCK TRAUMA CENTER maryland.ccproject.com
  4. 4. R ADAMS COWLEY SHOCK TRAUMA CENTER Objectives • Review the pathophysiology of traumatic brain injury and acute traumatic coagulopathy • List pros and cons of conventional tests versus viscoelastic monitoring • Describe management strategies for reversal of anticoagulants
  5. 5. R ADAMS COWLEY SHOCK TRAUMA CENTER Not a chance! Look at the TEG!You must give more FFP now!
  6. 6. R ADAMS COWLEY SHOCK TRAUMA CENTER Epidemiology • Prevalence of acute traumatic coagulopathy in TBI: 20-30% • Highly variable due to definitions • Higher mortality with severe TBI (>40%) • Strongly associated with progressive hemorrhagic injury and intracranial hemorrhage • Warfarin: doubles the risk of poor outcomes • Not necessarily so with antiplatelets Epstein DS. Injury 2014. Harhangi BS. Acta Neuroshir 2008. Talving P J Trauma 2009. Abdelmalik PA. Neurocrit Care 2016. Albert V. Hematol Oncol Stem Cell Ther 2019. Lustenberger T. Injury 2010.
  7. 7. R ADAMS COWLEY SHOCK TRAUMA CENTER The risk of dying with TBI and coagulopathy is 10x higher than in patients without coagulopathy Harhangi BS. Acta Neurochir 2008.
  8. 8. Meagle M. Lancet Neurol 2017.
  9. 9. R ADAMS COWLEY SHOCK TRAUMA CENTER Pathophysiology • Tissue factor hypothesis • Intravascular vs. extravascular? • Maladaptive Protein C response • Depletion  Hypercoagulability • Activation  Hyperfibrinolysis Albert V. Hematol Oncol Stem Cell ther 2019. Giesen PL. Semin Thromb Hemost 2000. Cohen MJ. J Trauma 2007. Wu X. J Trauma Acute Care Surg 2014. Halpern CH. J Neurotrauma 2008. Gando J. Trauma 1999. • Hyperfibrinolysis • Low incidence (2.5-7%) • High mortality • tPA release, ↓ factor VII activity
  10. 10. R ADAMS COWLEY SHOCK TRAUMA CENTER Platelet Dysfunction “Exhaustion”
  11. 11. R ADAMS COWLEY SHOCK TRAUMA CENTER Defending the Glycocalyx Kozar RA. Anesth Analg 2011. Pati S. J Trauma 2010. Albert V. Med Sci 2018.
  12. 12. Hypoperfusion Lustenberger T. J Trauma 2010.
  13. 13. R ADAMS COWLEY SHOCK TRAUMA CENTER PROPPR Secondary Analysis Lower SBP Higher HR Lower Plt Higher PT TBI + HS Other Groups Galvagno SM. J Trauma Acute Care Surg 2017.
  14. 14. R ADAMS COWLEY SHOCK TRAUMA CENTER Transfusions Galvagno SM. J Trauma Acute Care Surg 2017.
  15. 15. R ADAMS COWLEY SHOCK TRAUMA CENTER Adjusted Analysis: Mortality Group Odds Ratio 95% Conf. Interval TBI+HS 10.6 4.8-23.2 HS only 2.6 1.2-5.4 TBI only 8.2 3.4-19.5 Age Treatment Group Blunt Injury Total Products Received Time to Randomization Galvagno SM. J Trauma Acute Care Surg 2017.
  16. 16. R ADAMS COWLEY SHOCK TRAUMA CENTER Diagnosis
  17. 17. R ADAMS COWLEY SHOCK TRAUMA CENTER Lab Tests Meagle M. Transfusion 2013.
  18. 18. R ADAMS COWLEY SHOCK TRAUMA CENTER Acquired coagulopathy of traumatic brain injury defined by routine laboratory tests: which laboratory values matter? Joseph B, Aziz H, Znagbar B, et al.al. University of Arizona, Tucson, AZ, USA J Trauma Acute Care Surg. 2014; 76. • Platelet count < 100K • OR 4 (1.7-10) • INR 1.5 • OR 2 (1.1-4.3) Predictors of Progression on Head CT
  19. 19. R ADAMS COWLEY SHOCK TRAUMA CENTER INR Superior? • INR > 1.25 associated with in-hospital mortality • INR superior to TEG for detecting warfarin • INR > 1.3 found more frequently in TBI patients • Normalization of INR associated with improved mortality Yuan YY. Scand J Trauma Resusc Emerg Med 2018. Gozal YM. Surg Neurol Int 2017. Zehtababchi S. Resuscitation 2008. Epstein DS. J Clin Neuroscience 2016.
  20. 20. R ADAMS COWLEY SHOCK TRAUMA CENTER Coagulation parameters and risk of progressive hemorrhagic injury after traumatic brain injury: A systematic review and meta-analysis Zhang D, Gong S, Jin H, et al. t al. Changzheng Hospital, Shanghai, China BioMed Research International 2015; 1-10. • Standard lab tests are not great • Positive associations for risk of progression: • PT, D-dimer, INR • Higher fibrinogen and platelets associated with lower risk for progression • INR > D-dimer > fibrinogen > platelets
  21. 21. VIIa XII XI IX XI IXa VIII X V Va VIIIa XIa IX IXa Xa IXa VIIIa Va Prothrombinase Prothrombin Thrombin Fibrinogen Fibrin Thrombin + Ca + Acidic Phospholipids 2+ Prothrombin Thrombin Activated Platelet Initial Phase Amplification Propagation Tissue Factor TEG Parameter Replacement r time CT- clotting time Alpha angle / k (kinetics) CFT- clot formation time FFP / PCC Cryoprecipitate / Fibrinogen MA- Maximum Amplitude MCF - Maximum clot firmness Platelets / DDAVP LY (x) - Estimated % lysis (at x min) CL (x) - clot lysis (at x min) Antifibrinolytic ROTEM Parameter TEG and the Cell Based Model for Coagulation Hoffman and Cichon. Transfusion 2013.
  22. 22. R ADAMS COWLEY SHOCK TRAUMA CENTER Severe traumatic brain injury is associated with a unique coagulopathy phenotype Samuels JM, Moore EE, Silliman CC, et al.t al. University of Colorado, USA J Trauma Acute Care Surg. 2019; 86. • Low angle (<65o) • (RR 2.22; 95% CI 1.38-3.56) • Abnormal ACT • (RR 1.53; 95% CI 1.08-2.16) • Decreased functional fibrinogen (FFLEV) • (RR 1.67; 95% CI 1.16-2.39) • Hyperfibrinolysis rare • INR not informative
  23. 23. R ADAMS COWLEY SHOCK TRAUMA CENTER Other TEG Studies • Folkerson et al., 2018 • ↑ ACT (r-time), MA < 55 mm, angle < 65o, LY30 > 30%, Platelets < 150,000 • Odds of death: 2.2 (1.1-4.4) • Gozal et al., 2017 • r-time ↑ in 43% with CT progression • Davis et al., 2013 • ↑ ADP and arachidonic acid receptor inhibition • Level of inhibition correlated with severity • Kunio et al., 2012 • ↑ mortality with ↑ r-time, ↓MA • Martin et al., 2018 • More abnormalities found on TEG in penetrating TBI
  24. 24. R ADAMS COWLEY SHOCK TRAUMA CENTER TEG Limitations • Insensitive to warfarin effect • Can’t detect DOAC effect • TEG6s ® NOAC assay in development • Obesity • Acidosis • Alcohol • Normal tests seen with: • Mechanical bleeding • Hypothermia • Platelet inhibitors • Platelet dysfunction • Von Willebrand’s disease • DOACS
  25. 25. Cochrane Review: Conclusion “ No evidence on the accuracy of TEG and very little evidence on the accuracy of ROTEM…Undermined by small number of included studies…concerns about risk of bias relating to the index test…” Hunt H. Cochrane Database Syst Rev 2015.
  26. 26. R ADAMS COWLEY SHOCK TRAUMA CENTER ADP Receptor Inhibition Severe TBI Uninjured Control Castellino FJ. J Trauma Acute Care Surg 2014.
  27. 27. R ADAMS COWLEY SHOCK TRAUMA CENTER Multiple Electrode Aggregometry (MEA) Multiplate ® Lindblad C. Frontiers Neurology 2018. COX Inhibitor Effect Platelet Transfusion Response
  28. 28. Treatment
  29. 29. R ADAMS COWLEY SHOCK TRAUMA CENTER
  30. 30. R ADAMS COWLEY SHOCK TRAUMA CENTER
  31. 31. VIIa XII XI IX XI IXa VIII X V Va VIIIa XIa IX IXa Xa IXa VIIIa Va Prothrombinase Prothrombin Thrombin Fibrinogen Fibrin Thrombin + Ca + Acidic Phospholipids 2+ Prothrombin Thrombin Activated Platelet Initial Phase Amplification Propagation Tissue Factor TEG Parameter Replacement r time CT- clotting time Alpha angle / k (kinetics) CFT- clot formation time FFP / PCC Cryoprecipitate / Fibrinogen MA- Maximum Amplitude MCF - Maximum clot firmness Platelets / DDAVP LY (x) - Estimated % lysis (at x min) CL (x) - clot lysis (at x min) Antifibrinolytic ROTEM Parameter TEG Based Treatment
  32. 32. Brandy Tumbler Wine Glass Champagne Flute Test Tube Upside Down Martini Glass Do Nothing FFP Cryo Platelets TXA
  33. 33. R ADAMS COWLEY SHOCK TRAUMA CENTER Plasma Resuscitation • Both FFP and LP decrease brain lesion size and improve neurological recovery  FFP associated with downregulation of inflammatory pathway genes • Pathogen-reduced FFP may decrease brain edema • Early prehospital use of plasma associated with improved neurological / functional outcome Georgoff PE. J Neurotrauma 2017. Silleson M. J Am Coll Surg 2017. Halaweish I. J Am Coll Surg 2015. Halaweish I. J Trauma Acute Care Surg 2016. Genet GF. J Neurotrauma 2017. Hernandez MC. J Trauma Acute Care Surg 2017. Leeper CM. J Trauma Acute Care Surg 2018. Zhang LM. World Neurosurg 2017. • Over-resuscitation associated with fibrinolysis shutdown in pediatric TBI  Poor prognosis • Increased FFP independently associated with ARDS, pneumonia, mortality in TBI PROCON
  34. 34. R ADAMS COWLEY SHOCK TRAUMA CENTER • PAMPer trial: multicenter, cluster- randomized • 2 units thawed plasma • 23 vs. 33% mortality  Adjusted risk of death 39% lower in plasma group • No differences in secondary outcomes except fewer transfusions needed and lower PT in plasma group
  35. 35. R ADAMS COWLEY SHOCK TRAUMA CENTER PCCs • Warfarin • Time to reversal significantly shorter • Time delay to operations decreased • In Conjunction with FFP • 25 U/kg corrected INR faster • ↓ red cell transfusion requirement • ↓ time to craniotomy Yanamadala V. J Clin Neuroscience 2014. Joseph B. Neurosurgery 2015. Allison TA. J Intensive Care Med 2018. • DOAC Reversal • 35 U/kg • Only 13 patients • Hemostasis achieved in 80% • FFP vs. PCC for Traumatic ICH • Shorter time to reversal • No difference in mortality or thrombosis
  36. 36. R ADAMS COWLEY SHOCK TRAUMA CENTER Marino & Galvagno. The Little ICU Book 2017.
  37. 37. R ADAMS COWLEY SHOCK TRAUMA CENTER Antiplatelet Reversal • Discontinue the agent (!) • No procedure? No platelet transfusion! • Transfuse if on ADP inhibitor or aspirin • Testing: • Platelet mapping, MEA • Empirically treat if specialized testing not available • Initial dose: 1 x 6-pack of apheresis platelets • Single dose of ddAVP (0.4 mg/kg IV)
  38. 38. R ADAMS COWLEY SHOCK TRAUMA CENTER
  39. 39. R ADAMS COWLEY SHOCK TRAUMA CENTER Thank you! sgalvagno@som.umaryland.edu
  40. 40. R ADAMS COWLEY SHOCK TRAUMA CENTER Other Tests  ROTEM  Less studies in trauma  VN-ASA test  Detects ASA use  Gozal YM, Sur Neurol Int 2017  Platelet Function Analyzer (PFA-100)  SYND-1 (Albert, 2018)
  41. 41. Viscoelastic Fibrinolytic Spectrum Walsh M. Semin Thromb Hemost 2017 Moore EB. J Trauma Acute Care Surg 2014, 2015. Moore HB. Fibrinolysis. In: Gonzalez E et al. Trauma Induced Coagulopathy 2016.
  42. 42. R ADAMS COWLEY SHOCK TRAUMA CENTER • R-time normal in 45.5% of subjects with INR 2.9 • Sensitivity for warfarin effect: 54.5% • False negative rate: 45.5% • Similar results for RapidTEG TEG is insensitive to warfarin effects Dunham CM. Thrombosis Journal 2014. Nascimento B. Transfusion 2012.
  43. 43. R ADAMS COWLEY SHOCK TRAUMA CENTER Non-vitamin K Oral Anticoagulants (NOACs) • No standardized point-of-care test available to evaluate anticoagulant effects of NOACs • New automated TEG®6s NOAC assay  Direct thrombin inhibitor / Anti-Factor Xa assay • >92% sensitivity, > 95% specificity for detecting NOAC therapy • May be an effective tool for identifying NOAC therapy Bliden KP. J Thromb Thrombolysis 2017.
  44. 44. R ADAMS COWLEY SHOCK TRAUMA CENTER Obesity • Clot strength (MA) higher on admission for obese patients • For every 5 kg/m2 increase BMI, 85% greater odds of thromobembolic complication Obese trauma patients are often HYPERcoagulable Kornblith LZ J Trauma Acute Care Surg 2015. Branco BC. Shock 2014.
  45. 45. R ADAMS COWLEY SHOCK TRAUMA CENTER Acidosis • Acidemia-induced coagulopathy is worse at the level of the capillary (microcirculation) • pH in injured tissue ≅ 6.2 • Coagulation activity is altered in acidic environments • All 5 TEG ® variables affected TEG may not reflect what is going on at microcirculatory level Campbell JE. J Trauma Acute Care Surg 2015. Lv X. Am J Emerg Med 2017.
  46. 46. R ADAMS COWLEY SHOCK TRAUMA CENTER Howard BM. J Trauma Acute Care Surg 2014. Howard BM. J Trauma Acute Care Surg 2018. Karamanos E. Eur J Trauma Emerg Surg 2013. Lustenberger T. J Neurotrauma 2011. Rao AJ. World Neurosurgery 2018. R time increased by 3.8 seconds for every 10 mg/dL increase in alcohol!

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