EE Moore Denver Health / University of Colorado Denver Disclosure : Haemone;cs & TEM Research Support Fibrinolysis : Long History Many Question • John Hunter : 1794 – Edinburgh … clinical observation • Albert Dastre : 1893 – Paris … “fibrinolysis” Physiologic Fibrinolysis Systemic thrombin binds to a protease-‐ac;vated receptor … with release of ;ssue plasminogen ac;vator ( tPA ) Pathologic Fibrinolysis • TEG detected pathologic fibrinolysis • Empiric EACA during anhepatic phase Starzl et al Surgery 1963 Thombelastography Liver Transplantation … Pattern Recognition 3 / 4 Liver Transplant Survivors EACA = Multiple Pulmonary Emboli 75% Mortality “If treatment should become necessary for a hemorrhagic diathesis, it should be guided by frequent measures of clotting parameters.” Starzl et al Arch Surg 1966 Physiologic vs Pathologic Fibrinolysis Apro;nin – Plasmin Inhibitor Blood Conserva;on using An;fibrinoly;cs in a Randomized Trial ( BART ) • Myocardial Infarc;on • Renal Failure • Mortality 2008 Trauma Experience • Brohi, Cohen 2007 • Denver – 2009 TEG documented lysis • Correla>on of fibrinolysis and death • CRASH II trial CRASH-2 Trial : RCT / 274 Hospitals / 40 Countries 20,211 Adult : SBP < 90 or HR > 110, within 8 Hr Tranexamic Acid 1 gm / 10 min + 1 gm / 8hr Mortality : 14.5% vs 16.0% ( p < .04) Death due to Bleeding : 4.9% vs 5.7% ( p < .08 ) BUT : RR = 0.91 RR = 0.85 No Documented Fibrinolysis Blood Transfusion … Only 50% of Patients No Reduction in Transfusion ( ~ 6 Units RBC ) Lancet 2010 CRASH-2 Trial : RCT / 274 Hospitals / 40 Countries RR < 1 hr = 0.68 RR 1-3 hr = 0.70 RR > 3hr = 1.44 Lancet 2011 Plasmin Effects Beyond Fibrinolysis – Induces release of IL-1, TNF, and CD40 by peripheral monocytes ( similar to LPS ) – Induces post-translational modifications to IL-8 increasing activity – Platelet activator via PAR-4 ( bi-phasic response depending on concentration ) – Proposed receptors in monocytes / macrophages PAR-1, PAR-4, annexin-A2, TLR4, H2B – Cleaves complement C3 and C5 creating anaphylotoxins J Thromb Haemostasis 2005 Fibrinolysis = Euglobulin Lysis Time H4 Pooled Plasma 2.000 Absorbance (405 nm) 1.500 1.000 0.500 0.000 -0.500 0 120 240 360 480 600 Time > 4 Hours to Perform Time (minutes) Manco - Johnson Thromb Res 2003 TEG & ROTEM Early Detection Fibrinolysis Postinjury Fibrinolysis : S/P MVC 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 ) Principal Component Analysis Multivariate statistical technique that reduces the number of variables of the dataset into a smaller number of components. TIC : Principal Component Analysis Kutcher, Cohen et al J Trauma 2013 TIC : Factor Depletion vs Fibrinolysis PC 1 Surgery 2014 PC 2 PC 3 Eigenvalue 4.73 1.13 % Variance 59% 14% 12% ACT 74 * -6 K 80 * -26 5 18 angle -96 * -9 -12 MA -92 * -35 3 LY30 15 TMRTG 8 95 0.922 * -3 -3 98 MRTG -81 * -25 -11 TTG -90 * -37 3 * Physiologic vs Pathologic Fibrinolysis Shock Enhances Fibrinolysis … Tissue Injury Inhibits Fibrinolysis Clinical Outcomes : Fibrinolysis J Trauma 2014 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% ) Postinjury Spectrum of Fibrinolysis 12 10 Hemorrhage /CA 8 TBI 6 4 MOF/Sepsis 2 0 Hyper Shutdown Physiologic Recent Trauma Experience in the US Fibrinolysis Regulation Plasminogen TXA tPA PAI- 1 Plasmin Plasmin Regulation fibrin fibrin fibrin Hyperfibrinolysis = PAI-‐1 Deple;on Fibrinolysis Shutdown = Excessive PAI-1 Physiologic Vs Shutdown TPA Challenge Physiologic LY30 1.7% Shutdown Ly30 0.5% Lysed Red Blood Cells Enhance tPA Mediated Fibrinolysis vs Lysed Platelets Shutdown tPA mediated Fibrinolysis Red Blood Cell Lysate Indirectly Enhances tPA Mediated Fibrinolysis Platelet Lysate Directly Inhibits tPA Mediated Fibrinolysis Postinjury Hyperfibrinolysis Hypoxia Gene;cs Co –Morbidity Medica;on Adrenaline • Dilu;on • Consump;on tPA Ac;vated Protein C ? Histones Elastase HMGB1 Complement Tissue Factor Thrombin sThrombomodulin Heparan Sulfate sCD40L Endothelial Dysfunc;on • Acidosis • Hypothermia Tissue Injury Plasmin PAI-‐1 FXIIIa FibrinolysiS TRAUMA INDUCED COAGULOPATHY Conclusion Antifibrinolytic Medication … Selective – Majority of seriously injured = shutdown of fibrinolysis But … Civilian Experience is Different from Military Mechanisms of Fibrinolysis Warrant Further Investigation Credits : UCD Trauma Research Team Ani Banerjee Kirk Hansen Angela Sauaia Chris Silliman 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 Xa VIIIa Platelet VIIIa Xa X IIa Va Activated Platelet IXa Va II X IXa VIIa V Va IIa TXA : Presumed Mechanism Lysine Aminocaproic acid Tranexamic acid Blocks fibrinogen to plasminogen / plasmin Inhibits alpha2-‐an;plasmin to plasmin Experimental – Plasmin Activity • Plasma – 30 minutes • Liver -90 minutes • Heart – 120 minutes • Kidney - 30/60/90 : 120 TXA : Potential SAE • Thromboembolism Early : ? Pre-‐exis;ng = Coronary Stent ? Injury = Caro;d / Vertebral Delayed : DVT / Pulmonary Embolism Cerebral Infarc;on • Seizures S/P CABG – TXA Binds GABA Receptor • Acute Kidney Injury • Central Re;nal Artery Thrombosis Differen;al Inhibited FF-‐TEG 100 ng/ml tPA in Whole Blood LY 30 DIFF-‐TEG Detec;on Threshold for tPA is Superior to CK-‐TEG DIFF-‐TEG Improved Detec;on Threshold CK-‐TEG Detec;on Threshold >2x Higher Rapid Detec;on of Fibrinolysis rTEG FF + TXA FF Field Blood – ELT analysis 600 500 ELT (minutes) Survived Death 400 300 200 100 0 0 0.5 1 1.5 2 2.5 LY30 (%) 3 3.5 4 4.5 5 Red Blood Cell Lysate Enhance tPA Mediated Fibrinolysis Red Blood Cell and Platelet Lysate Reduce Clotting Time Thrombelastography = Early Identification of Fibrinolysis EPL : Percent Lysis Fibrinolysis Viscoelastic Coagulation Assessment r TEG ROTEM Tissue Factor + Kaolin ACT = 78 - 110 sec INTEM ( Ellagic ) EXTEM ( TF ) CT = 122 - 208 43 - 82 Angle = 66 - 82 degrees Angle = 70 - 81 65 - 80 degrees MA = 54 - 72 mm MCF = 51 - 72 52 – 70 mm G = ….. < 15 % < 15 % LY30 = 5.3 - 12.4 dynes/cm < 7.5 % Functional Fibrinogen ML = FIBTEM APTEM HEPTEM sec Amplilute ( mm ) Rapid Thrombelastography ACT ED Thoracotomy : SW LV … Prehospital CPR 11 min Antifibrinolytic Agents • Aminocaproic Acid … lysine binding site plasminogen • Tranexamic Acid … lysine binding site ( 10 X ) • Aprotinin … directly inhibits plasmin ( thrombotic complications ) Military : Tranexamic Acid (MATTERS) Afghanistan : 2009 - 2011 US / UK Random < 2010 > Routine MTP TXA 1 gm, Repeat “Judgment” Overall ( n = 896 ) MT ( n = 231 ) TXA None TXA None Cryo 1.6 0.5 1.6 0.7 DVT 2.4 0.2 3.2 0 PE 2.7 0.3 1.6 0.5 Mort -‐ 24 10% 12% 10% 15% Mort -‐ D/C 17% 24% 15% 28% Morrison et al Arch Surg 2012 Hyperfibrinolysis Phenotypes (A) Fulminant HF … immediate breakdown of the clot (B) Intermediate HF … breakdown of the clot between 30 and 60 min. (C) Late HF … clot lysis aker more than 60 min. Schochl et al J Trauma 2009 Biomarker or Mediator Johansson et al J Trauma 2012 Plasminogen Activation ? Physiologic vs Pathologic Fibrinolysis Thromboelastometry (TEM) underes;mates the incidence and severity of fibrinolysis. Hyperfibrinolysis defined by func;onal lysis ROTEM ML > 15% Moderate = ML < 15% and PAP complex > 1500 μg L−1; Severe = ML > 15% and PAP complex > 1500 μg L−1) Func;onal clot lysis (dark bars) was only measurable with very high PAP complex levels ( PAP complex < 1500 μg L−1– 8.8% vs. PAP complex > 20 000 μg L−1– 30.3%). Raza, Brohi et al J Thrombo Haemostasis 2013 Physiologic vs Pathologic Fibrinolysis Outcomes associated with moderate and severe fibrinolysis. Higher mortality … in the moderate group ( 12% ) and the severe group ( 40% ) Raza, Brohi et al J Thromb Haemostasis 2013 TEG vs ROTEM • Blood from healthy volunteers • tPA (100 ng/ml) added to one vial • TEG (Tissue Factor, Kaolin, Func>onal Fibrinogen) and ROTEM (EXTEM, INTEM, FIBTEM) Normal tPA TEG LY 30 Threshold for Hyperfibrinolysis 3% Coqon, Holcomb et al J Trauma 2012 TIC : Principal Component Analysis Kutcher, Cohen et al J Trauma 2013 Role of Disseminated Intravascular Coagulation Fibrinogen Controversies in Postinjury Hemostasis X TF Va Xa VIIa IIa VIII / vWF VIIIa TF-Bearing Cell TF VIIa IXa IX IX Xa VIIIa Platelet VIIIa Xa X IIa Va Activated Platelet IXa Va II X IXa VIIa V Va IIa
© Copyright 2024 ExpyDoc
