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coagulation system

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  • 1. Coagulation System Gerald A. Soff M.D.
  • 2. Pre-Lecture Quiz!• Choose one or more of the following;• 1. If I could memorize all of the bones and muscles in the body, why can’t I remember the blasted coagulation cascade?• 2. O.K., so I figured out Factors I, II, V, VII, VIII, IX, X, XI, and XII. So where the hell are factors III, IV, and VI?• 3. And why do they use Roman Numerals? I can’t read my damned notes!• 4. Who cares about this stuff anyway, I’m going into oncology!
  • 3. Hemostasis• Hemostasis; “The processes of keeping the blood liquid in the vasculature” – Prevention of hemorrhage following vascular injury. – Prevention of excessive clotting (thrombosis) in the vasculature.• Primary Hemostasis; – Vascular forces (vasoconstriction) and platelet plug• Secondary Hemostasis; – The coagulation factors• Physiologic Anticoagulation processes – Neutralize activated factors where vessels are intact. – Fibrinolysis
  • 4. Original Publication Of Coagulation Cascade:Davie, E. W., and Ratnoff, O. D. (1964) Waterfall sequence for intrinsic blood clotting. Science 145, 1310–1312
  • 5. emedicine.medscape.com
  • 6. Conceptual Model of Hemostasis From Sidney Harris.
  • 7. XII, PK, HMWK Tissue FactorIntrinsic XIPathway VII IX, VIII Extrinsic Pathway X, V Common Pathway II Fibrinogen (I) Fibrin Monomer XIII Cross-Linked Fibrin Clot
  • 8. Coagulation Cascade General Features• Clotting factors (Factor II, VII, etc.) are zymogens (or proenzymes), which are activated to an active enzyme by limited proteolysis. – The enzymes in the coagulation system are serine proteinases. (Serine, Aspartic acid, Histidine amino acids in catalytic domain)• Cofactors of Cascade – Factors V and VIII• The system is a “cascade” in that there is amplification. – One activated molecule activates multiple at subsequent stages. – The product of one step is an enzyme for the next step.
  • 9. Coagulation Factors; Enzymes
  • 10. Serine Protease•Serine, Aspartic acid, Histidine amino acids in catalytic domain.
  • 11. Coagulation Factors; Cofactors
  • 12. XII, PK, HMWK Tissue FactorIntrinsic XIPathway VII IX, VIII Extrinsic Pathway X, V Common Pathway II Fibrinogen (I) Fibrin Monomer XIII Cross-Linked Fibrin Clot
  • 13. Tissue Factor; Initiation of Coagulation Cascade Primary process, in vivo, is the extrinsic pathway. Tissue factor can be expressed by monocytes, fibroblasts, smooth muscle, endothelial cells. Tissue Factor is released in the vessel wall, following exposure to endotoxin, inflammation, injury. Tissue Factor binds/activates Factor VII TF:VIIa complex binds and activates Factor IX to IXa (and to a minor degree X to Xa).
  • 14. Tissue Factor Circulates in Cell- Derived Microparticles.Boulanger et al. Hypertension, 2006 Hugel et al, Physiology 20: 22-27, 2005
  • 15. Surface Complexes of Enzyme:Cofactor:Substrate, The essence of the coagulation cascade• (Modified from Furie B, Furie BC: The molecular basis of blood coagulation. Cell 53:505, 1988.) in Hoffman’s Hematology Text.
  • 16. Membrane-Bound TF Initiates Coagulation Cascade
  • 17. Procoagulant Enzyme Complexes• Complex 1 – Tissue factor, factors VIIa, IX and X• Complex 2 (Tenase complex) – Factor IXa, VIII and X• Complex 3 (prothrombinase complex) – Factor Xa, factor V, and prothrombin• All complexes on a negatively charged phospholipid (usually platelet) membrane.
  • 18. Contact System: Initiation of Intrinsic PathwayFactor XII, Prekallikrein, High- Molecular-Weight KininogenMinimal contribution to clotting, although it can activate Factor XI.Possible role in blood pressure regulation, fibrinolysis, and inflammation.
  • 19. Contact System:Initiation of Intrinsic Pathway Factor XII Prekallikrein High Molecular Weight Kininogen
  • 20. • Why do deficiencies of “Contact Factors” not result in bleeding?• Why do deficiencies of “Intrinsic Pathway” lead to markedly different severity of bleeding, (or no bleeding)?
  • 21. XII, PK, HMWK Tissue FactorIntrinsic XIPathway VII IX, VIII Extrinsic Pathway V, X Common Pathway II Fibrinogen (I) Fibrin Monomer XIII Cross-Linked Fibrin Clot
  • 22. Initiation of Extrinsic Pathway By Tissue Factor IX TF:VIIa VII Tissue Factor IXa X TFPI X Xa Complex of TF;VIIa can activate Factor X, but primary procoagulant effect is via activation of factor IX to IXa.
  • 23. Tissue Factor IX TF:VIIa Coagulation CascadeIXa X TFPIVIIIa Made X Xa Simple Va (And Mostly II IIa (Thrombin) Accurate) Fibrinogen (I) Fibrin Monomer XIII Cross-Linked Fibrin Clot
  • 24. How are Factors V, VIII, XI, XIII Activated?
  • 25. Thrombin Feedback;Activation of Factors V, VIII, XI, XIII IX Tissue Factor XI XIa TF:VIIa IXa X TFPI VIII VIIIa X Xa Va V II IIa (Thrombin) Fibrinogen (I) Fibrin XIII XIIIa Cross-Linked Fibrin Clot
  • 26. Role of Factor XI• Factor XI is component of a positive feedback loop,• Thrombin activates Factor XI (along with V, VIII, and XIII), which generates more thrombin.• Results in augmentation of fibrin generation.
  • 27. VITAMIN K DEPENDENT CARBOXYLASE• Post-translational modification• Factors II, VII, IX, X; – Proteins C & S• Converts several glutamic acid residues to γ-carboxyglutamic acid• Confers calcium binding and lipid binding on these proteins.
  • 28. CARBOXYGLUTAMIC ACID COO- COO-COO- CH2 O2,CO2 CH CH2 CH2NH3+ CH NH3+ CH Vit K COO- Carboxylase COO- Glu -carboxy Glu
  • 29. Vitamin K Mediated-Carboxylation of Glutamic Acid
  • 30. Vitamin K-Dependent Factors• Factors II (Prothrombin), VII, IX, X• Protein C, Protein S• All are enzymes, except protein S.• -Carboxylation of Glutamic Acid allows for binding to calcium, and complex formation.• While both procoagulants and anticoagulants are affected, the net effect of vitamin K deficiency or antagonism is anticoagulation.
  • 31. Thrombin-Activatable Fibrinolysis Inhibitor (TAFI)• Also known as plasma carboxypeptidase B2• TAFI is activated by Thrombin:Thrombomodulin.• After thrombin activation, the mature protein down-regulates fibrinolysis.
  • 32. Hemostatic Balance
  • 33. Endothelial Cell-Dependent Anticoagulant Processes• Heparan Sulfate: AT III• Thrombomodulin: Protein C: Protein S• ADPase (CD39)• Tissue Factor Pathway Inhibitor• Nitric Oxide
  • 34. Heparan:Antithrombin III Deficiency first described in 1965. – (Egeberg O. Inherited antithrombin III deficiency causing thrombophilia. Thromb Diath Haemorrh 13:516-30, 1965) AT III neutralizes the active enzymes in the coagulation system. Dominant Inheritance.
  • 35. Antithrombin III• Antithrombin III (Antithrombin)• When heparan sulfate (on endothelial cells) or heparin (mast cells, pharmaceutical) binds to AT III, the AT III undergoes a conformational change and binds to the active enzymes of the clotting cascade.• Thrombin (IIa), IXa, Xa, XIa are inhibited by Heparin/Heparan:ATIII. – Factor VIIa is resistant to AT III.
  • 36. Protein C/Protein S System • Constituents; – Protein C – Protein S – Thrombomodulin – Endothelial cell protein C receptor (EPCR • Activated Protein C (With cofactor Protein S) inactivates Va and VIIIa, the cofactors of the cascade – (Probable role in augmenting fibrinolysis.) • EPCR localizes Protein C/Ca to endothelial cell surface. – May have role in sepsis.
  • 37. Fibrinolytic PathwayPlasminogen; – Activated to Plasmin (a serine proteinase) – Plasmin proteolyzes fibrin and fibrinogenPlasminogen Activators; – t-PA (Tissue-Plasminogen Activator) • Localizes to fibrin clot – u-PA (Urokinase-Plasminogen Activator) • Localizes to cell membrane uPA receptor. – Released by endothelial cells.Inhibitors/Serpins – PAI-1, PAI-2; Plasminogen Activator Inhibitors – 2-Antiplasmin.
  • 38. Fibrinolytic System Constituents
  • 39. Fibrinolysis Release of D-Dimer Digestion of tPA Plasmin FibrinPlasminogen Cross-Linked Fibrin
  • 40. Cell Surface Activation of Plasminogen
  • 41. Fibrin/FibrinogenDegradation Products
  • 42. Fibrin/Fibrinogen Degradation Products