Review of the coagulation system


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Review of the coagulation system

  1. 1. Coagulation System Gerald A. Soff M.D. 1
  2. 2. Coagulation Cascade  Choose one or more of the following;  1. If I could memorize all of “CDs”, 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 is factor 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!    2
  3. 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 3
  4. 4. A Series Of Perspectives On The Coagulation System/Cascade 4
  5. 5. Original Publication Of Coagulation Cascade: Davie, EW & Ratnoff, OD. (1964) Waterfall sequence for intrinsic blood clotting. Science 145, 1310–1312 5
  6. 6. 6
  7. 7. Conceptual Model of Hemostasis From Sidney Harris. 7
  8. 8. 8
  9. 9. Contact System XII, PK, HMWK Tissue Factor XI Intrinsic Pathway VII IX, VIII Extrinsic Pathway X, V II Fibrinogen (I) Common Pathway Fibrin Monomer XIII Cross-Linked Fibrin Clot 9
  10. 10. Coagulation Factors; Enzymes 10
  11. 11. Serine Protease •Serine, Aspartic acid, Histidine amino acids in catalytic domain. 11
  12. 12. 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”, i.e. waterfall. – One activated molecule activates multiple at subsequent stages. – The product of one step is an enzyme for the next step. 12
  13. 13. Coagulation System Is Best Understood As Series of Membrane-Bound Complexes: Enzyme/Cofactor/Substrate  (Modified from Furie B, Furie BC: The molecular basis of blood coagulation. Cell 53:505, 1988.) in Hoffman’s Hematology Text. 13
  14. 14. 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
  15. 15. Tissue Factor (TF) Expression In The Vessel Wall.  45 kDa transmembrane glycoprotein  Expressed in blood vessels Adventitia  Brain  Lung  Placenta  Mackman N, The Role of Tissue Factor and Factor VIIa in Hemostasis. Anesth Analg 2009;108:1447–52. 15
  16. 16. Membrane-Bound TF Initiates Coagulation Cascade Enzyme: VII Cofactor: TF Substrate: Factor IX, Factor X 16
  17. 17. Procoagulant Enzyme Complexes  Complex 1 – Tissue factor, VIIa, IX and X  Complex 2 (Tenase complex) – IXa, VIIIa, and X  Complex 3 (prothrombinase complex) – Xa, Va, and prothrombin (II)  All complexes on a negatively charged phospholipid (usually platelet) membrane. 17
  18. 18. Procoagulant Enzyme Complexes Enzyme Cofactor Substrate Product TF:VII VII/VIIa Tissue Factor IX, X IXa, Xa Tenase complex IXa VIIIa X Xa Prothrombinase complex Xa Va II (Prothrombin) IIa (Thrombin) 18
  19. 19. 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
  20. 20. Fibrinogen Cleavage by Thrombin and Cross-Linkage of Monomers By F XIIIa  20
  21. 21. XII, PK, HMWK Intrinsic Pathway Tissue Factor XI VII IX, VIII Extrinsic Pathway V, X Common Pathway II Fibrinogen (I) Fibrin Monomer XIII Cross-Linked Fibrin Clot 21
  22. 22. So You Think You Understand The Coagulation System? don’t deficiencies of “Contact Factors” result in bleeding?  Why do different deficiencies of “Intrinsic Pathway” factors lead to markedly different severity of bleeding, (or no bleeding)?  Why 22
  23. 23. XII, PK, HMWK Intrinsic Pathway No bleeding Factor XI Deficiency: Mild to no bleeding XI IX, VIII Hemophilia A, B: Severe Bleeding V, X II Fibrinogen (I) Fibrin Monomer XIII Cross-Linked Fibrin Clot 23
  24. 24. Tissue Factor:VIIa “Crosses” Arms Of The Coagulation Cascade To Activate Factor IX IX TF:VIIa IXa X  X VII Tissue Factor TFPI Xa Complex of TF;VIIa can activate Factor X, but primary procoagulant effect is via activation of factor IX to IXa. 24
  25. 25. Tissue Factor IX TF:VIIa IXa X TFPI VIIIa X Xa II Fibrinogen (I) Va IIa (Thrombin) Coagulation Cascade Made Simple (And Mostly Accurate) Fibrin Monomer XIII Cross-Linked Fibrin Clot 25
  26. 26. How are Factors V, VIII, XI, XIII Activated? 26
  27. 27. Thrombin Feedback; Activation of Factors V, VIII, XI, XIII Tissue Factor IX XI XIa TF:VIIa X TFPI IXa VIII VIIIa X Xa Va V IIa (Thrombin) II Fibrinogen (I) XIII Fibrin XIIIa Cross-Linked Fibrin Clot 27
  28. 28. 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. Deficiencies not as sevee as VIII, IX, but more clinically relevant than XII, Prekallikrein, High Molecular Weight Kininogen. 28
  29. 29. 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. 29
  30. 30. CARBOXYGLUTAMIC ACID COO-COO- COOCH2 O2,CO2 CH2 CH2 NH3+ CH COOGlu CH Vit K Carboxylase NH3+ CH COO-carboxy Glu 30
  31. 31. Vitamin K Mediated -Carboxylation of Glutamic Acid 31
  32. 32. 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.  32
  33. 33. Hemostatic Balance 33
  34. 34. Endothelial Cell-Dependent Anticoagulant Processes      Heparan Sulfate: AT III Thrombomodulin: Protein C: Protein S ADPase (CD39) Tissue Factor Pathway Inhibitor Nitric Oxide 34
  35. 35. 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
  36. 36. 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
  37. 37. 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
  38. 38. 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
  39. 39. Fibrinolytic System Constituents 39
  40. 40. Fibrinolysis Release of D-Dimer Plasminogen tPA Plasmin Digestion of Fibrin Cross-Linked Fibrin 40
  41. 41. Fibrin/Fibrinogen Degradation Products 41
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