Maureane Hoffman MD PhD Professor of Pathology Duke University Medical Center maureanedukeedu Hemostasis vs Thrombosis Hemostasis stops bleeding Thrombosis forms a blood clot in an artery or vein of a living person ID: 1010832
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1. Evolving Models of HemostasisMaureane Hoffman, MD, PhDProfessor of PathologyDuke University Medical Centermaureane@duke.edu
2. Hemostasis vs ThrombosisHemostasis stops bleedingThrombosis forms a blood clot in an artery or vein of a living personBlood clotting or coagulation can happen anyplace – living creature or test tube
3. Blood Coagulation in the Host Response to Injury
4. Early ideas on blood clottingHippocrates, 400 BC Blood clots when it coolsWilliam Hewson, 1770 Blood clots when exposed to air. Non-cellular part of blood responsible for clotting
5. The royal families of Europe were afflicted by hemophilia through Queen Victoria, which brought a lot of attention to the study of blood clotting
6. Queen Victoria’s Affected Offspring
7. Morawitz, P. Beiträge zur Kenntniss der Blutgerinnung. Dtsch Arch Klin Med 1904;79:1-28 Morawitz proposed a biochemical model of blood coagulation
8. Based on the Morawitz Model,Two Groups Developed an Assayfor the Prothrombin Level in the 1930’s1. Quick AJ. The development and use of the prothrombin tests. Circulation 1959; 19(1):92–962. Smith HP, Warner ED, Brinkhous KM. Prothrombin deficiency and the bleeding tendency in liver injury (chloroform intoxication). J Exp Med 1937;66(6):801–811“Thromboplastin” + Prothrombin + Calcium =ThrombinExcess “Thromboplastin” and a fixed amount of calcium were added to plasma. The rate of thrombin generation would then only depend on the concentration of prothrombin
9. The “Prothrombin Time” (PT) was normal in hemophilia, but prolonged in patients with liver disease1. Quick AJ. The development and use of the prothrombin tests. Circulation 1959;19(1):92–962. Smith HP, Warner ED, Brinkhous KM. Prothrombin deficiency and the bleeding tendency in liver injury (chloroform intoxication). J Exp Med 1937;66(6):801–811“Thromboplastin” + Prothrombin + Calcium =Thrombin
10. The partial thromboplastin time(PTT) was developed in the 1950’s to assay the deficient factor in hemophiliaThe clotting times of normal and hemophilic plasmas progressively diverged as the thromboplastin reagent was diluted1. Langdell RD, Wagner RH, Brinkhous KM. Effect of antihemophilic factor on one-stage clotting tests; a presumptive test for hemophilia and a simple one-stage antihemophilic factor assay procedure. J Lab Clin Med 1953;41(4):637–647.2. Margolis J. The kaolin clotting time; a rapid one-stage method for diagnosis of coagulation defects. J Clin Pathol 1958;11(5):406–409
11. More and more factors were discovered and named different things by different investigators, and it all went down hill from there…..Hemophilia C factorLabile FactorLaki-Lorand FactorPavlovsky FactorPlasma Thromboplastic FactorPlasma Thromboplastic Factor APlasma Thromboplastin Antecedent (PTA) Plasma Thromboplastin ComponentPlasmakininPlatelet CofactorProaccelerinProconvertinProthrombokinaseProtransglutamidasePrower FactorRobbins FactorSerum FactorSerum Prothrombin Conversion Accelerator (SPCA)Stable FactorStuart FactorStuart-Prower FactorThrombokatalysinfibrinogenprothrombinaccelerator (AC-) globulinAntihemophiliac FactorAntihemophilic Factor BAntihemophilic Globulin (AHG)Antihemophilic Globulin AAutoprothrombin IAutoprothrombin IIAutoprothrombin IIIBeta cothromboplastinChristmas FactorContact Factor CothromboplastinFacteur Antihemophilique AFibrin Stabilizing FactorThromboplastic Plasma ComponentThromboplastinogenHageman FactorHemophilia A factorHemophilia B Factor
12. In 1958 the International Society on Thrombosis and Hemostasis convened a conference to standardize the nomenclatureThat’s how we got all those roman numerals
13.
14. Factor VI was at one time used to designate activated Factor V.Coagulation ProteinsFactorSynonymsFunctionIFibrinogenpolymer unitIIProthrombinproteaseIIITissue thromboplastin, tissue factorcofactorIVCalciumVAccelerator globulin. proaccelerin, labile factorcofactorVIIProconvertin, stable factorproteaseVIIIAntihemophilic factor or globulincofactorFactorSynonymsFunctionIXChristmas factor, plasma thromboplastin componentproteaseXStuart factor, Stuart-Prower factorproteaseXIPlasma thromboplastin antecedentproteaseXIIHageman factorproteaseXIIIFibrin stabilizing factor, fibrinoligaseFibrin crosslinker----Prekallikrein (Fletcher factor)protease----High-molecular-weight kininogen (Fitzgerald factor)cofactor
15. …… but nobody knew then how those factors interacted to turn liquid plasma into a fibrin clotThat’s why the roman numerals aren’t in order in the coagulation cascade - making it even harder for us to remember
16. In the 1960’s the coagulation factors were organized into a“cascade” or “waterfall” modelMacfarlane RG. An enzyme cascade in the blood clotting mechanism, and its function as a biological amplifier. Nature. 1964;202:498-499.Davie EW, Ratnoff OD. Waterfall sequence for intrinsic blood clotting. Science. 1964;145:1310-1312
17. Davie & RatnoffScience 1964;145:1310-1312Landmark description of coagulation as a biological amplifier
18. Extrinsic PathwayPTFactor IXaFactor VIIIaFactor XIaFactor XIFibrinogenFactor XII/HMK/PKFactor IXFactor XaFactor VaFactor XThrombinProthrombinFibrinFactor XFactor VIIaTissue FactorIntrinsic PathwayaPTT
19. The Coagulation “Cascade” Model and the PT/aPTT Tests Developed in TandemThus, the cascade model is an accurate reflection of results obtained in these common clinical lab tests. However, it isn’t an accurate reflection of hemostasis in vivo ………..
20. The “Cascade” model leads us to believe that the clotting time in the PT or PTT should predict hemostatic function in vivo
21. Factor IXaFactor VIIIaFactor XIaFactor XIFibrinogenFactor XII/HMK/PKFactor IXFactor XaFactor VaThrombinProthrombinFibrinFactor XIntrinsic Pathway/aPTTProlonged aPTT Variable bleedingProlonged aPTT Severe bleedingProlonged aPTT No bleeding
22. Why do hemophiliacs have such a severe bleeding tendency? Hemophilia only affects the “intrinsic” pathway
23. Extrinsic PathwayFactor IXaFactor VIIIaFactor XIaFactor XIFXII/HMK/PK Factor IXFactor XaFactor VaFactor XProthrombinFibrinFactor XFactor VIIaTissue FactorIntrinsic PathwayThrombinPTaPTTFibrinogenWhy is the “extrinsic” pathway not sufficient for hemostasis?
24. Can including cells in our model help explain some clinical observations that the “cascade” model cannot?
25. Our group proposed that acell-based model might explain some aspects of hemostasis that the “protein-centered” cascade model does notHoffman M, Monroe DM: A cell-based model of hemostasis. Thromb Haemost. 2001;85:958-965.
26. Cell-based conceptual model of hemostasis
27. TF forms a“hemostatic envelope” around the vessel
28. Platelets Adhere & Are Partially Activated at Sites of Injury
29. IIIIaVIII/vWFXIXIaPlateletVaVVIIIa + vWFVVIIaVIIaVIIaXXaTF-Bearing CellTFTFTFVaActivated PlateletVaXIaVIIIaPriming Amountof Thrombin AmplificationHoffman & Monroe: A Cell-Based Model of Hemostasis. Thromb Haemostas, 85:958-65, 2001
30. XIaXaIXaXIIIIaIXActivated PlateletVaXIaVIIIaIIaVIII/vWFXIXIaPlateletVaVVIIIa + vWFVIXVIIaTFPITF-Bearing CellTFVIIaVIIaXaXaTFTFVaPropagationLarge amountOf thrombinHoffman & Monroe: A Cell-Based Model of Hemostasis. Thromb Haemostas, 85:958-65, 2001
31. Clot StabilizationFibrinogenIIaFXIII
32. The extrinsic pathway acts in vivo to initiate coagulationBearing CellPT Assayin vivoAdapted from: Monroe DM and Hoffman, M: What does it take to make the perfect clot? Arterio Thromb Vasc Biol 26:41-48, 2006
33. The intrinsic pathway acts on the platelet surface to generate large amounts of thrombin (propagation phase)in vivoAdapted from: Monroe DM and Hoffman, M: What does it take to make the perfect clot? Arterio Thromb Vasc Biol 26:41-48, 2006aPTT
34. Take-home messagesThe cascade model helps us interpret the PT and aPTT testsThe PT and aPTT give information about procoagulant levels, but do not necessarily reflect bleeding riskA cell-based model gives us insight into hemostatic mechanisms in vivo