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EE Moore Denver Health / University of Colorado Denver Disclosure : Haemonetics & TEM Research Support CRASH-2 Trial : RCT / 274 Hospitals / 40 Countries 20,211 Adult : SBP < 90 or HR > 110 within 8 Hr Mortality : 14.5% vs 16.0% ( p < .04) Death due to Bleeding : 4.9% vs 5.7% ( p < .08 ) Blood Transfusion … Only 50% of Patients No Reduction in Transfusion ( ~ 6 Units RBC ) Lancet 2010 CRASH-2 Trial : RCT / 274 Hospitals / 40 Countries Relative Risk < 1 hr = 0.68 1 - 3 hr = 0.70 > 3 hr = 1.44 Lancet 2011 TIC : Factor Depletion vs Fibrinolysis PC 1 Surgery 2014 PC 2 PC 3 Eigenvalue 4.73 1.13 0.922 % Variance 59% 14% 12% ACT 74 * -26 -6 K 80 * 5 18 angle -96 * -9 -12 MA -92 * -35 3 LY30 15 95 TMRTG 8 -3 98 * -3 MRTG -81 * -25 -11 TTG -90 * -37 3 * Shock Enhances Fibrinolysis … Tissue Injury Inhibits Fibrinolysis Trauma Study Population • 193 patients 70% male, Age 44 • Median ISS 29 ( IQR 22-36 ) • Median BD 9 ( IQR 6-13 ) • 21% Mortality Postinjury Spectrum of Fibrinolysis PATHOLOGIC N=156 ( 71% ) PHYSIOLOGIC N=37 ( 19% ) HYPERFIBRINOLYSIS N=33 ( 17% ) Uncontrolled Bleeding Mortality = 19 ( 58% ) Exsanguination FIBRINOLYSIS SHUTDOWN Microvascular Occlusion Mortality = 20 ARDS/MOF ( 16% ) N=123 ( 64% ) Maintenance Fibrinolysis Vascular Patency Mortality = 1Homeostasis ( 3% ) Clinical Outcomes : Fibrinolysis J Trauma 2014 Fibrinolysis Phenoype : Mortality 12 10 Hemorrhage /CA 8 TBI 6 4 MOF/Sepsis 2 0 Hyper Shutdown Physiologic Hyperfibrinolysis = PAI-1 Depletion Fibrinolysis Shutdown = Excessive PAI-1 TPA Levels TPA Challenge Non PAI1 Inhibitio n TPA ? ? tPA Augmentation ? tPA Complexed % LY30 Fibrinogen Direct tPA Inhibition Fibrin Degradation Products Sc-tPA PAI-1 Direct Plasmin Inhibition Alpha 2 Macroglobulin TAFI Alpha 2 Anti-plasmin Cross linking (factor XIII) Granule (Alpha, Dense) Fibrin Polymer Plasminogen and sc-tPA Converted Plasmin and tc-tPA Potential Mechanisms For Phenotypes • Red Blood Cell Degradation in Major Trauma Proteomics: Metabolomics: Shock Wohlauer et al 2010 J Metabolomics D’alessandro In press • Platelet Transfusion Associated with MOF –Granules contain anti-fibrinolytics Study Methods • Citrated Volunteers Whole Blood – % replaced with Lysed • Own RBCs • Donor Platelets • Leukoreduced RBCS • tPA TEG Challenge – – – – Exogenous tPA mixed with blood Run on TEG 75ng/ml final concentration Ly30: Lysis at 30 min used for assessment of fibrinolysis Lysed RBCs Enhance tPA Mediated Fibrinolysis at a Low Dose Lysed Platelets Shutdown Fibrinolysis at a Low Dose Credits : UCD Trauma Research Team Ani Banerjee Kirk Hansen Angela Sauaia Chris Silliman Carl Barnett Denis Bensrad Walt Biffl Clay Burlew Chuck Fox Jerry Jurkovich Fred Pieracci Rob Stoval Mike Chapman Theresa Chin Eduardo Gonzalez Hunter Moore Max Wohlauer Sarah Ammons Jim Chandler Andrea Emard Cortney Fleming Arsen Ghasabyan Ray Shepard-Singh NIH P50 GM 4922 NIH T32 GM 08315 NIH UM1 HL 129877 Thank you !!! X TF Va Xa VIIa IIa VIII / vWF VIIIa TF-Bearing Cell TF VIIa IXa IX IX Va Platelet II X IXa VIIa V Xa VIIIa IIa Va Activated Platelet IXa VIIIa Xa X Va IIa Hyperfibrinolysis : Early Mortality Shutdown : Delayed Mortality Shutdown Hyperfibrinolysis Postinjury Hyperfibrinolysis Hypoxia Tissue Injury Genetics Co –Morbidity Medication Adrenaline Endothelial Dysfunction •Acidosis Activated Protein C •Hypothermia Histones Elastase HMGB1 Complement sThrombomodulin Heparan Sulfate sCD40L tPA Plasmin ? •Dilution PAI-1 •Consumption FXIIIa FibrinolysiS TRAUMA INDUCED COAGULOPATHY Tissue Factor Thrombin TIC : Principal Component Analysis Kutcher, Cohen et al J Trauma 2013 Blood Component Transfusion Incidence of Postinjury Fibrinolysis • Denver = 2% Activations ( 17 % M Transfusion ) • Houston = 2% Activations • Lyon = 6% Activations • Salzburg = 8% Activations • Los Angeles = • San Francisco = ( 10% M Transfusion ) ( 20% M Transfusion ) Recent Trauma Experience in the US J Trauma 2014