EE Moore EE Moore Denver Health / University of Colorado DenverDenver Health / University of Colorado Denver

Disclosure : Haemonetics & TEM Research SupportDisclosure : Haemonetics & TEM Research Support

EE Moore EE Moore Denver Health / University of Colorado DenverDenver Health / University of Colorado Denver

Disclosure : Haemonetics & TEM Research SupportDisclosure : Haemonetics & TEM Research Support

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 )

CRASH-2 Trial : RCT / 274 Hospitals / 40 Countries

Lancet 2010

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

TIC : Factor Depletion vs FibrinolysisTIC : Factor Depletion vs Fibrinolysis

  PC 1 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 * -3  

TMRTG 8 -3 98 *

MRTG -81 * -25 -11  

TTG -90 * -37 3  

SurgerySurgery20142014

Shock Enhances Fibrinolysis …Tissue Injury Inhibits Fibrinolysis

Trauma Study PopulationTrauma Study Population

• 193 patients

70% male, Age 44

• Median ISS 29 ( IQR 22-36 )

• Median BD 9 ( IQR 6-13 )

• 21% Mortality21% Mortality

Postinjury Spectrum of FibrinolysisPostinjury Spectrum of Fibrinolysis

Microvascular Occlusion Vascular PatencyUncontrolled 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% )

Clinical Outcomes : FibrinolysisClinical Outcomes : Fibrinolysis

J Trauma2014

Fibrinolysis Phenoype : MortalityFibrinolysis Phenoype : Mortality

Hyperfibrinolysis = PAI-1 Depletion

Fibrinolysis Shutdown = Excessive PAI-1

TPATPA TPATPA

? tPA ? tPA ComplexedComplexed

? tPA ? tPA ComplexedComplexed

Non PAI-1

Inhibition

Non PAI-1

Inhibition

? tPA Augmentation

? tPA Augmentation

??

TPA ChallengeTPA Challenge

% LY30% LY30

TP

A L

evel

s

PlateletPlateletFibrin Polymer

Plasminogen and sc-tPAConverted

Plasmin and tc-tPA

Granule(Alpha, Dense)

Granule(Alpha, Dense)

Sc-tPA

PAI-1

??

TAFIAlpha 2 Anti-plasmin

Cross linking (factor XIII)

Fibr

inol

ysis

Fibr

inol

ysis

Fibrin DegradationProducts

Alpha 2 Macroglobulin

Alpha 2 Macroglobulin

Direct tPA Inhibition

Direct Plasmin Inhibition

FibrinogenFibrinogen

Potential Mechanisms For PhenotypesPotential Mechanisms For Phenotypes

• Red Blood Cell Degradation in Major TraumaRed Blood Cell Degradation in Major TraumaProteomics: Shock Wohlauer et al 2010Proteomics: Shock Wohlauer et al 2010

Metabolomics: J Metabolomics D’alessandro In pressMetabolomics: J Metabolomics D’alessandro In press

• Platelet Transfusion Associated with MOFPlatelet Transfusion Associated with MOF–Granules contain anti-fibrinolyticsGranules contain anti-fibrinolytics

Study MethodsStudy Methods

• Citrated Volunteers Whole BloodCitrated 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

Lysed RBCs Enhance tPA Mediated Lysed RBCs Enhance tPA Mediated Fibrinolysis at a Low DoseFibrinolysis at a Low Dose

Lysed Platelets Shutdown Lysed Platelets Shutdown Fibrinolysis at a Low DoseFibrinolysis at a Low Dose

Credits : UCD Trauma Research Team Credits : UCD Trauma Research Team

Mike ChapmanTheresa ChinEduardo GonzalezHunter MooreMax Wohlauer

Ani BanerjeeKirk HansenAngela SauaiaChris Silliman

NIH P50 GM 4922NIH P50 GM 4922NIH T32 GM 08315NIH T32 GM 08315NIH UM1 HL 129877NIH UM1 HL 129877

Sarah Ammons Jim ChandlerAndrea EmardCortney FlemingArsen GhasabyanRay Shepard-Singh

Carl BarnettDenis BensradWalt BifflClay BurlewChuck FoxJerry JurkovichFred PieracciRob Stoval

Thank you !!!Thank you !!!

TF-Bearing CellTF-Bearing Cell

Activated PlateletActivated Platelet

PlateletPlateletTFTF

VIIIaVIIIa VaVa

VIIIaVIIIa VaVa

VaVa

VIIaVIIa

TFTFVIIaVIIa

XX

XaXa IIaIIa

IXIXVV VaVa

IIII

VIII / vWFVIII / vWF

VIIIaVIIIa

IIII

IXaIXa

XXIXIX

XX

IXaIXa

IXaIXaVIIaVIIa

XaXa

IIaIIa

IIaIIa

XaXa

Hyperfibrinolysis : Early MortalityHyperfibrinolysis : Early Mortality Shutdown : Delayed MortalityShutdown : Delayed Mortality

Hyperfibrinolysis

Shutdown

Postinjury HyperfibrinolysisPostinjury Hyperfibrinolysis

Genetics

Co –Morbidity

Medication

HypoxiaHypoxia Tissue InjuryTissue Injury

AdrenalineAdrenaline

HistonesHistonesElastaseElastase HMGB1HMGB1ComplementComplement

HistonesHistonesElastaseElastase HMGB1HMGB1ComplementComplement

Endothelial DysfunctionEndothelial Dysfunction

Activated Protein CActivated Protein C tPA tPA PlasminPlasmin

PAI-1PAI-1

FibrinolysiFibrinolysiSS

TRAUMA INDUCED COAGULOPATHYTRAUMA INDUCED COAGULOPATHY

•AcidosisAcidosis

•HypothermiaHypothermia

•DilutionDilution

•ConsumptionConsumption

??

Tissue FactorTissue FactorThrombinThrombin

FXIIIa

sThrombomodulinsThrombomodulinHeparan SulfateHeparan SulfatesCD40LsCD40L

TIC : Principal Component AnalysisTIC : Principal Component Analysis

Kutcher, Cohen et alJ Trauma 2013

Blood Component TransfusionBlood Component Transfusion

Incidence of Postinjury FibrinolysisIncidence of Postinjury Fibrinolysis

• DenverDenver == 2% Activations ( 17 % M Transfusion )2% Activations ( 17 % M Transfusion )• HoustonHouston = 2% Activations= 2% Activations

• Lyon Lyon = 6% Activations = 6% Activations• SalzburgSalzburg = 8% Activations = 8% Activations

• Los Angeles Los Angeles = ( 10% M Transfusion )= ( 10% M Transfusion )• San Francisco San Francisco = ( 20% M Transfusion )= ( 20% M Transfusion )

Recent Trauma Experience in the US

J Trauma 2014