1. EE Moore EE Moore Denver Health / University of Colorado Denver Denver Health / University of Colorado Denver Disclosure : Haemonetics & TEM Research Support Disclosure : Haemonetics & TEM Research Support EE Moore EE Moore Denver Health / University of Colorado Denver Denver Health / University of Colorado Denver Disclosure : Haemonetics & TEM Research Support Disclosure : Haemonetics & TEM Research Support

2. 20,211 Adult : SBP 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 ) CRASH-2 Trial : RCT / 274 Hospitals / 40 Countries Lancet 2010

3. Relative Risk < 1 hr = 0.68 1 - 3 hr = 0.70 > 3 hr = 1.44 CRASH-2 Trial : RCT / 274 Hospitals / 40 Countries Lancet 2011

4. TIC : Factor Depletion vs Fibrinolysis TIC : Factor Depletion vs Fibrinolysis PC 1 PC 2 PC 3 Eigenvalue4.73 1.13 0.922 % Variance59% 14% 12% ACT74*-26 -6 K80*5 18 angle-96*-9 -12 MA-92*-35 3 LY3015 95*-3 TMRTG8 -3 98* MRTG-81*-25 -11 TTG-90*-37 3 Surgery2014

5. Shock Enhances Fibrinolysis … Tissue Injury Inhibits Fibrinolysis

6. Trauma Study Population 193 patients 70% male, Age 44 Median ISS 29 ( IQR 22-36 ) Median BD 9 ( IQR 6-13 ) 21% Mortality21% Mortality

7. Postinjury Spectrum of Fibrinolysis Microvascular Occlusion Vascular Patency Uncontrolled Bleeding N=37 ( 19% ) N=37 ( 19% ) N=156 ( 71% ) N=156 ( 71% ) N=33 ( 17% ) N=33 ( 17% ) N=123 ( 64% ) N=123 ( 64% ) Mortality = 19 ( 58% ) Mortality = 19 ( 58% ) Mortality = 20 ( 16% ) Mortality = 20 ( 16% ) Mortality = 1 ( 3% ) Mortality = 1 ( 3% )

8. Clinical Outcomes : Fibrinolysis J Trauma 2014

9. Fibrinolysis Phenoype : Mortality Fibrinolysis Phenoype : Mortality

10. Hyperfibrinolysis = PAI-1 Depletion

11. Fibrinolysis Shutdown = Excessive PAI-1

12. TPATPA ? tPA Complexed Non PAI- 1 Inhibitio n ? tPA Augmentation ? ? TPA Challenge % LY30 TPA Levels

13. Platelet Fibrin Polymer Plasminogen and sc-tPA Converted Plasmin and tc-tPA Granule (Alpha, Dense) Granule (Alpha, Dense) Sc-tPA PAI-1 ? ? TAFI Alpha 2 Anti-plasmin Cross linking (factor XIII) Fibrinolysis Fibrin Degradation Products Alpha 2 Macroglobulin Direct tPA Inhibition Direct Plasmin Inhibition Fibrinogen

14. Potential Mechanisms For Phenotypes Red Blood Cell Degradation in Major TraumaRed Blood Cell Degradation in Major Trauma Proteomics: Shock Wohlauer et al 2010 Metabolomics: J Metabolomics D’alessandro In press Platelet Transfusion Associated with MOFPlatelet Transfusion Associated with MOF –Granules contain anti-fibrinolytics

15. Study Methods Citrated Volunteers Whole Blood –% replaced with Lysed Own RBCs Donor Platelets Leukoreduced RBCS tPA TEG ChallengetPA TEG Challenge –Exogenous tPA mixed with blood –Run on TEG –75ng/ml final concentration –Ly30: Lysis at 30 min used for assessment of fibrinolysis

16. Lysed RBCs Enhance tPA Mediated Fibrinolysis at a Low Dose

17. Lysed Platelets Shutdown Fibrinolysis at a Low Dose

18. Credits : UCD Trauma Research Team Mike Chapman Theresa Chin Eduardo Gonzalez Hunter Moore Max Wohlauer Ani Banerjee Kirk Hansen Angela Sauaia Chris Silliman NIH P50 GM 4922 NIH T32 GM 08315 NIH UM1 HL 129877 Sarah Ammons Jim Chandler Andrea Emard Cortney Fleming Arsen Ghasabyan Ray Shepard-Singh Carl Barnett Denis Bensrad Walt Biffl Clay Burlew Chuck Fox Jerry Jurkovich Fred Pieracci Rob Stoval

19. Thank you !!! TF-Bearing Cell Activated Platelet Platelet TF VIIIa Va VIIIa Va Va VIIa TF VIIa X Xa IIa IX VVa II VIII / vWF VIIIa II IXa X IX X IXa IXa VIIa Xa IIa IIa Xa

21. Hyperfibrinolysis : Early Mortality Shutdown : Delayed Mortality Hyperfibrinolysis Shutdown

22. Postinjury Hyperfibrinolysis Postinjury Hyperfibrinolysis Genetics Co –Morbidity Medication Hypoxia Tissue Injury Adrenaline HistonesElastaseHMGB1ComplementHistonesElastaseHMGB1Complement Endothelial Dysfunction Activated Protein C tPA Plasmin PAI-1 Fibrinolysi S TRAUMA INDUCED COAGULOPATHY TRAUMA INDUCED COAGULOPATHY AcidosisAcidosis HypothermiaHypothermia DilutionDilution ConsumptionConsumption ? Tissue Factor Thrombin FXIIIa sThrombomodulin Heparan Sulfate sCD40L

23. TIC : Principal Component Analysis TIC : Principal Component Analysis Kutcher, Cohen et al J Trauma 2013

24. Blood Component Transfusion

25. Incidence of Postinjury Fibrinolysis Denver = 2% Activations ( 17 % M Transfusion )Denver = 2% Activations ( 17 % M Transfusion ) Houston = 2% ActivationsHouston = 2% Activations Lyon = 6% ActivationsLyon = 6% Activations Salzburg = 8% ActivationsSalzburg = 8% Activations Los Angeles = ( 10% M Transfusion )Los Angeles = ( 10% M Transfusion ) San Francisco = ( 20% M Transfusion )San Francisco = ( 20% M Transfusion )

26. Recent Trauma Experience in the US J Trauma 2014