EE Moore Denver Health University of Colorado Denver

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 EE Moore Denver Health / University of Colorado Denver Disclosure : Haemonetics &

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

CRASH-2 Trial : RCT / 274 Hospitals / 40 Countries 20, 211 Adult :

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

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 Eigenvalue Surgery 2014 PC 1 4. 73

TIC : Factor Depletion vs Fibrinolysis Eigenvalue Surgery 2014 PC 1 4. 73 PC 2 1. 13 PC 3 % Variance 59% ACT 74 * -26 -6 K 80 * 5 18 angle -96 * -9 -12 MA -92 * -35 3 -3 -3 98 * LY 30 15 TMRTG 8 14% 0. 922 95 12% * MRTG -81 * -25 -11 TTG -90 * -37 3

Shock Enhances Fibrinolysis … Tissue Injury Inhibits Fibrinolysis

Shock Enhances Fibrinolysis … Tissue Injury Inhibits Fibrinolysis

Trauma Study Population • 193 patients 70% male, Age 44 • Median ISS 29

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% )

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 ( 16% ) ARDS/MOF N=123 ( 64% ) Maintenance Fibrinolysis Vascular Patency Mortality = Homeostasis 1 ( 3% )

Clinical Outcomes : Fibrinolysis J Trauma 2014

Clinical Outcomes : Fibrinolysis J Trauma 2014

 Fibrinolysis Phenoype : Mortality 12 10 Hemorrhage /CA 8 TBI 6 4 MOF/Sepsis

Fibrinolysis Phenoype : Mortality 12 10 Hemorrhage /CA 8 TBI 6 4 MOF/Sepsis 2 0 Hyper Shutdown Physiologic

Hyperfibrinolysis = PAI-1 Depletion

Hyperfibrinolysis = PAI-1 Depletion

Fibrinolysis Shutdown = Excessive PAI-1

Fibrinolysis Shutdown = Excessive PAI-1

TPA Levels TPA Challenge Non PAI 1 Inhibitio n TPA ? ? t. PA

TPA Levels TPA Challenge Non PAI 1 Inhibitio n TPA ? ? t. PA Augmentation ? t. PA Complexed % LY 30

Fibrinogen Fibrin Degradation Products Direct t. PA Inhibition Sc-t. PA PAI-1 is ys ol

Fibrinogen Fibrin Degradation Products Direct t. PA Inhibition Sc-t. PA PAI-1 is ys ol br in Alpha 2 Macroglobulin Fi ? Direct Plasmin Inhibition Granule (Alpha, Dense) t e l e t Pla Fibrin Level Inhibition TAFI Alpha 2 Anti-plasmin Cross linking (factor XIII) Fibrin Polymer Plasminogen and sc-t. PA Converted Plasmin and tc-t. PA

Potential Mechanisms For Phenotypes • Red Blood Cell Degradation in Major Trauma Proteomics: Shock

Potential Mechanisms For Phenotypes • Red Blood Cell Degradation in Major Trauma Proteomics: Shock Wohlauer et al 2010 Metabolomics: 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

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

Lysed RBCs Enhance t. PA Mediated Fibrinolysis at a Low Dose

Lysed RBCs Enhance t. PA Mediated Fibrinolysis at a Low Dose

Lysed Platelets Shutdown 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

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 P 50 GM 4922 NIH T 32 GM 08315 NIH UM 1 HL 129877

Thank you !!! X TF Va Xa VIIa VIII / v. WF VIIIa TF-Bearing

Thank you !!! X TF Va Xa VIIa VIII / v. WF VIIIa TF-Bearing Cell TF VIIa IX VIIIa Xa Platelet VIIIa Xa X IIa Va Activated Platelet IXa Va II X IXa VIIa IX V Va IIa

Hyperfibrinolysis : Early Mortality Shutdown : Delayed Mortality Shutdown Hyperfibrinolysis

Hyperfibrinolysis : Early Mortality Shutdown : Delayed Mortality Shutdown Hyperfibrinolysis

 Postinjury Hyperfibrinolysis Hypoxia Tissue Injury Genetics Co –Morbidity Medication • Acidosis • Hypothermia

Postinjury Hyperfibrinolysis Hypoxia Tissue Injury Genetics Co –Morbidity Medication • Acidosis • Hypothermia • Dilution • Consumption Adrenaline Endothelial Dysfunction Activated Protein C Histones Elastase HMGB 1 Complement s. Thrombomodulin Heparan Sulfate s. CD 40 L t. PA Plasmin ? Tissue Factor Thrombin PAI-1 FXIIIa Fibrinolysi. S TRAUMA INDUCED COAGULOPATHY

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

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

Blood Component Transfusion

Blood Component Transfusion

Incidence of Postinjury Fibrinolysis • Denver = 2% Activations ( 17 % M Transfusion

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

Recent Trauma Experience in the US J Trauma 2014

Recent Trauma Experience in the US J Trauma 2014