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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
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