Anticoagulation theory 2_students_

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  • 1. Anticoagulation TheoryTo Bleed or Not to Bleed
  • 2. Coagulation Basics• Ability of the body to control flow of bloodfollowing vascular injury is needed for survival• Hemostasis: process of blood clotting andthen the subsequent dissolution of the clotfollowing repair of injured tissue
  • 3. Coagulation Basics• Hemophilia: tendency to bleed• Thrombophilia: tendency to clot
  • 4. Hemostasis• Maintains circulating blood in fluid state• Disrupts blood flow due to vessel injury tominimize anoxia and cellular death• Facilitates maintenance of vascular integrityfollowing injury
  • 5. Hemostasis• Normally, there’s a balance between:– Fibrin formation (thrombin mediated)– Fibrin dissolution (plasmin mediated)• Balance accomplished by interactions among:– Blood vessels– Platelets– Coagulation proteins– Fibrinolysis
  • 6. Hemostasis• Complex interaction of cellular componentsand plasma proteins that once activated,result in clot formation to plug the vesselinjury• Has components necessary for limitingexcessive formation of clots and thosenecessary for dissolving the clots over time
  • 7. Hemostasis• Balance between procoagulants and downregulators• Perturbation of this balance results in eitherbleeding or pathologic clot formation– You either don’t clot when you need to or clotwhen you don’t need to
  • 8. HemostasisCoagulation FibrinolysisBleeding ThrombosisThrombosis Bleeding
  • 9. Excessive Coagulation/Deficient FibrinolysisCoagulationFibrinolysisThrombosisThrombosis
  • 10. Excessive Fibrinolysis/Deficient CoagulationCoagulationFibrinolysisBleedingBleeding
  • 11. Hemostatic Process: Five Steps1. Vascular phase2. Platelet phase3. Coagulation phase4. Clot retraction5. Fibrinolysis
  • 12. Primary Hemostasis• Process of forming a platelet plug at the sit ofvessel injury• Consists of vasoconstriction and plateletadhesion
  • 13. Vasoconstriction (Vascular phase)• “Tightening” of blood vessels to divert bloodflow around the damaged vessel• Enhances contact activation of platelets andcoagulation factors
  • 14. Platelet Adhesion (Platelet phase)• Platelets become activated and aggregate atthe site of injury, forming a temporary, loose,platelet plug
  • 15. Secondary Hemostasis• To stabilize the initially loose platelet plug, asequence of enzymatic reactions is initiatedwhich culminates in fibrin strands forming atthe platelet plug• Fibrin mesh (clot) is formed and entraps theplug
  • 16. Coagulation phase• Fibrin-forming system• Coagulation factors interact with each otherto form a fibrin clot• Reinforces the platelet plug
  • 17. Coagulation Factors• Proteins normally present in the blood• Most are produced by the liver• Normally “turned off” (inactive)• Designated by roman numerals• Common names are significant of patients’last names who were deficient with the factor• “a” signals the factor in its “active” form
  • 18. Coagulation Cascade• Sequence of biochemical reactions that forman insoluble gel (clot)• Converts fibrinogen to fibrin• Domino or waterfall effect• Each factor is converted into its active form bythe preceding factor
  • 19. ENDOTHELIALDAMAGEEndothelium secretes VWF which makes platelets stick to the injuredvessel and cause platelet aggregationEndothelium secretes Tissue Factors thatactivate the Extrinsic systemEXTRINSIC SYSTEMINTRINSIC SYSTEMFactor VIIXII CONTACT HMKXIIaKALXI XIaIX IXaENDOTHELIUMCa++PlasminogenPlasminStable Fibrin Clot Fibrin DegradationProductsFibrinXIIIaThrombin+ PF3 Factor VIIaX XaV + Ca++ + PF3ProthrombinFibrinogenFactor XIIIActivated Protein CProtein CProtein SCa++Tissue FactorVIIIVIIIAntithrombin III
  • 20. Extrinsic Pathway• Activated when endothelial cells are injured and tissuefactor is released• Activated Factor VII and tissue factor bind to form acomplex– This complex, plus calcium, activates Factor XTissue FactorVII VIIaCa+X Xa(Protrombin) II IIa (Thrombin)Fibrinogen FibrinPF3 Ca++
  • 21. Intrinsic Pathway• Requires clotting factorsVIII-XII• Initiation occurs whenfactor XII is exposed to anegatively chargedsurface– Termed the contactphase• Exposure of collagen to avessel surface is theprimary stimulus for thecontact phasePrekalikrein KalikreinXII XIIaXI XIaIX IXaX XaPF3 Ca++
  • 22. Common Pathway• Activated by either extrinsic or intrinsic pathway• When Factor Xa binds to the platelet surface, a complexis formed composed of platelet phospholipid, calciumand Factor Va– Complex converts prothrombin to thrombin which in turnconverts fibrinogen to fibrinX Xa(Prothrombin) ThrombinFibrinogen FibrinPF3Ca++
  • 23. Clot Generation• Endothelial damage  vWF  platelets stickto endothelium (adhesion)  exposure ofcollagen fibrils  stimulates platelets to sticktogether (aggregation)• Activation of coagulation– Tissue factor on the surface of monocytes andendothelium activate various factors that lead tothe formation of thrombin
  • 24. Clot Generation• Thrombin changes properties of fibrinogen polymerization  fibrin  meshwork  clot• Fibrinolysis: dissolution of the fibrin clot– Initiation of clot lysis begins concurrently with theactivation of the clotting cascade• Endothelium  plasminogen  plasmin degrades fibrin  FDP
  • 25. Fibrinolysis• Body’s way of keeping coagulation from becomingexcessive and occluding the blood vessels• Function of plasmin that circulates as the inactiveproenzyme plasminogenFibrinogenSolubleFibrinInsoluble (stable)Fibrin ClotFDPs PlasminogenPlasminTissuePlasminogenActivatorD
  • 26. Regulation• Balance between coagulation and fibrinolyticprocesses must be maintained– Otherwise, excess clotting or fibrinolysis will occur• Body has inhibitors to regulate the systemAntithrombin Protein C Protein S Plasmin InhibitorSTOP
  • 27. ENDOTHELIALDAMAGEEndothelium secretes VWF which makes platelets stick to the injuredvessel and cause platelet aggregationEndothelium secretes Tissue Factors thatactivate the Extrinsic systemEXTRINSIC SYSTEMINTRINSIC SYSTEMFactor VIIXII CONTACT HMKXIIaKALXI XIaIX IXaENDOTHELIUMCa++PlasminogenPlasminStable Fibrin Clot Fibrin DegradationProductsFibrinXIIIaThrombin+ PF3 Factor VIIaX XaV + Ca++ + PF3ProthrombinFibrinogenFactor XIIIActivated Protein CProtein CProtein SCa++Tissue FactorVIIIVIIIAntithrombin III
  • 28. Venous Thrombotic Event (VTE)• Thrombophilia– Hypercoagulable state due to inherited(hereditary/genetic) defects or acquired defects inone or several factors of the coagulation cascade• Thrombophilia causes DVT (deep veinthrombosis) or PE (pulmonary embolism)
  • 29. Thrombotic Alert #1• How many patients in the US are diagnosedwith deep vein thrombosis each year?More than 500,000
  • 30. Thrombotic Alert #2• How many pulmonary embolisms arediagnosed each year in the US?More than 630,000
  • 31. Thrombotic Alert #3• How many deaths are attributed to PE eachyear?Approximately 200,000 deaths
  • 32. Research Indicates…• Approximately 100,000 of these deaths arepreventable• Half of pulmonary emboli are not diagnoseduntil…AUTOPSY
  • 33. COAGULATION DISORDERS
  • 34. Hereditary/Genetic IrreversibleFactor I (Fibrinogen)• Afibrinogenemia– Total absence of measurable fibrinogen– Rare congenital disorder• Hypofibrinogenemia– Below normal levels of fibrinogen– Treated by cryoprecipitate or FFP• Dysfibrinogenemia– Altered structure of the fibrinogen molecule– Usually asymptomatic but has been associatedwith both bleeding and thrombotic events
  • 35. Factor V (Proaccelerin)Gene Defect• Cofactor in coagulation cascade• Deficiency causes bleeding but…– Factor V mutation (Factor V Leiden) causesthrombotic events due to impaired degradation ofFactor V resulting in continued thrombingeneration• Most common cause of thrombophilia
  • 36. Defects in Prothrombin Gene• Second most common cause of thrombophilia• Prothrombin does not break down– Keeps on activating thrombin to convertfibrinogen into a fibrin clot
  • 37. Defects of Methyl TetrahydrofolateReductase (MTHFR) Enzyme• MTHFR breaks down homocysteine• Deficiency of MTHFR increases homocysteine,leading to thrombosis• Acquired homocysteinemia is due todeficiency of folate, vitamins B6 and B12
  • 38. Less Common• Antithrombin III deficiency• Protein C deficiency• Protein S deficiency
  • 39. Factor VIII (Antihemophilic Factor)• Composed of a coagulant portion and vWF(vonWillebrand Factor)• Acute phase reactant– Increase in inflammation, stress, pregnancy andinfection which can lead to clot formation• Defect or absence of coagulant portion causesclassic Hemophilia A• Deficiency in vWF portion causesvonWillebrand’s Disease
  • 40. Acquired/Environmental Risk Factorsfor VTE• Extended bed rest• Malignancy (cancer)• Oral contraceptives(estrogen)• Hormonal replacementtherapy• Pregnancy and recentsurgery• Trauma• Obesity/inactivity• Antiphospholipidantibodies (APA)• AnticardiolipinAntibodies (ACA)• Lupus Anticoagulants(LA)• Inflammatory boweldisease (IBD)
  • 41. Most Commonly RequestedCoagulation Tests• Prothrombin Time (PT)• Activated Partial Thromboplastin Time(aPTT/PTT)• Fibrinogen Assay• Factor Assays• D-Dimer• FDP• Bleeding Time
  • 42. Pathways/Tests• PT monitors extrinsic pathway– PT monitors coumadin therapy• aPTT/PTT monitors intrinsic pathway– aPTT/PTT monitors heparin therapy• PT and aPTT/PTT both monitor the commonpathway