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EXAMINATION OF COAGULATION AND FIBRINOLYSIS

EXAMINATION OF COAGULATION AND FIBRINOLYSIS. MUDr. Pavel Maruna Dept. of Pathological Physiology 1st Faculty of Medicine. I. Physiology. Hemostasis. = The physiologic process protecting the integrity of the vascular system after tissue injury. Bleeding is halted to minimize blood loss.

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EXAMINATION OF COAGULATION AND FIBRINOLYSIS

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  1. EXAMINATION OF COAGULATION AND FIBRINOLYSIS MUDr. Pavel Maruna Dept. of Pathological Physiology 1st Faculty of Medicine

  2. I. Physiology

  3. Hemostasis • = The physiologic process protecting the integrity of the vascular system after tissue injury. • Bleeding is halted to minimize blood loss. • The hemostatic mechanisms include following steps: • 1. Rest phase - To maintain blood in a fluid state while circulating within the vascular system • 2. After injury - To arrest bleeding at the site of injury by formation of hemostatic plug • 3. Restitution - To ensure the removal of the hemostatic plug when healing is complete

  4. Hemostasis • Hemostasis is an integral part of • stress reaction • inflammatory response X Protective role Pathophysiol. role non-specific defense mechanism thrombosis / embolism atherosclerosis

  5. Hemostasis Hemostasis as a physiological process must be: 1. Rapid 2. Localized 3. Reversible Inappropriate hemostasis: - Thrombosis / embolism - DIC - bleeding / blood loss

  6. Hemostasis Vessel wall Endothelium Platelets Plasma coagulation system

  7. Endothelium Antithrombotic Properties • Anti-platelet activities: • Covers highly thrombogenic basement membrane • Uninjured endothelium does not bind platelets • PGI2 and NO from endothelium inhibit platelet binding • ADPase counters the platelet aggregating effects of ADP

  8. Endothelium Antithrombotic Properties • Anticoagulant activities: • Heparin-like molecules ... activate anti-thrombin III (inactivates active proteases) • Thrombomodulin ... changes specificity of thrombin (activates protein C , which inactivates factors Va and VIIIa • tPA ... activates fibrinolysis via plasminogen to plasmin

  9. Endothelium Prothrombotic Properties • Synthesis of von Willebrand factor • Release of tissue factor • Production of PAI (plasminogen activator inhibitors) • Membrane phospholipids bind and facilitate activation of clotting factors via Ca bridges

  10. Endothelium Vessel injury Antithrombogenic Thrombogenic (Favors fluid blood) (Favorsclotting)

  11. Vasoconstriction Primary hemostasis Secondary hemostasis Fibrinolysis

  12. Intrinsic pathway Coagulation XIIa Extrinsic Pathway XIa TF Prothrombin IXa VIIa VIII VIIIa Xa V Va Soft clot Thrombin Fibrinogen Fibrin XIIIa Hard clot Fibrin

  13. Coagulation • Enzymatic cascade (amplification) • Several serine proteases • Produced by liver (most) • Require vitamin K (several) • 3 protein cofactors (not enzymes) • Requires Ca 2+ • Reversible (via production of plasmin)

  14. Coagulation

  15. Coagulation

  16. Coagulation Thrombin Fibrinogen Fibrin

  17. Coagulation Prothrombin Xa Va Thrombin Fibrinogen Fibrin

  18. Coagulation Extrinsic Pathway TF Prothrombin VIIa Xa Va Thrombin Fibrinogen Fibrin

  19. Intrinsic pathway Coagulation XIIa Extrinsic Pathway XIa TF Prothrombin IXa VIIa VIIIa Xa Va Thrombin Fibrinogen Fibrin

  20. Intrinsic pathway Coagulation XIIa Extrinsic Pathway XIa TF Prothrombin IXa VIIa VIIIa Xa Va Soft clot Thrombin Fibrinogen Fibrin XIIIa Hard clot Fibrin

  21. Intrinsic pathway Coagulation XIIa Extrinsic Pathway XIa TF Prothrombin IXa VIIa VIII VIIIa Xa V Va Soft clot Thrombin Fibrinogen Fibrin XIIIa Hard clot Fibrin

  22. Revised tissue factor pathway Extrinsic Pathway IX TF Prothrombin (II) IXa VIIa Xa Thrombin (IIa) New: Production of IXa Interaction of intrinsic and extrinsic pathways

  23. Revised tissue factor pathway IX TF Prothrombin (II) IXa VIIa Xa TFPI TFI Thrombin (IIa) New: TFPI = Tissue Factor Pathway Inhibitor ... inhibition of Xa and VIIa

  24. Revised tissue factor pathway Kunitz-type protease inhibitor (kringles) 34 and 41 kD forms in plasma (C-term truncation) Activities: - direct inhibition of Xa - inhibition VIIa-TF complex in a [Xa]-dependent manner - bounding to LDL, HDL and Lp (a) ~10% present in platelets (endothelium also) IX TF Prothrombin (II) IXa VIIa Xa TFPI TFI New: TFPI = Tissue Factor Pathway Inhibitor ... inhibition of Xa and VIIa

  25. Revised tissue factor pathway Net results: Production of IXa Production of small amounts of thrombin (IIa) No or only little fibrin formed!

  26. Revised tissue factor pathway • VIIa forms via binding of VII to TF • VIIa activates some XXa • Xa converts a small amount of II to IIa; this thrombin is used to produce small amts of VIIIa and Va • As the concentration of TF-VIIa-Xa-IIa increases, TFPI inactivates this complex stopping further production of thrombin. • IXa, with VIIIa (produced as above), produces Xa; this Xa with Va producesnew thrombin; this thrombin produces more VIIIa and Va and now we get lots of thrombin and fibrin.

  27. Revised tissue factor pathway IX TF Prothrombin IXa VIIa VIII VIIIa Xa V Va Soft clot Thrombin Fibrinogen Fibrin XIIIa Hard clot Fibrin

  28. Revised tissue factor pathway V VIII Thrombin (IIa) Va VIIIa

  29. Role of vitamin K Factors II, VII, IX, X, proteins C and S require a post-translational modification before their activation This PTM requires vitamin K This PTM involves the addition of a COO- to certain Glu residues in the clotting factors resulting in the formation of several g-carboxy glutamates

  30. Role of vitamin K

  31. Physiologic inhibitors of coagulation • Antithrombin III • SERPIN • Activated Protein C + protein S • Inactivates Va and VIIIa (via proteolysis) • mutation: Factor V Leiden (APC resistance) • Thrombomodulin • Binds to thrombin • Decreases ability to produce fibrin • Increases ability to activate Protein C

  32. Non-physiologic inhibitors of coagulation • Vitamin K antagonists (in vivo only) • Ca chelators (in vitro only) • EDTA • Citrate • Oxalate • Heparin (in vivo and in vitro)

  33. Fibrinolysis ... Clot removal

  34. Fibrinolysis Plasmin Fibrin Fibrin Split Products (FSP)

  35. Fibrinolysis Plasminogen bacterial enzymes (streptokinase) tPA uPA Plasmin Fibrin Fibrin Split Products (FSP)

  36. Fibrinolysis Inhibitors of fibrinolysis Plasminogen PAI tPA a2-antiplasmin ... SERPINs Plasmin Fibrin Fibrin Split Products (FSP)

  37. Fibrinolysis

  38. II. Pathology

  39. Coagulopathies Congenital Acquired

  40. Coagulopathies Congenital Acquired Hemophilia A ... f VIII Hemophilia B ... f IX Hemophilia C ... f XI Dys- / A- fibrinogenemia F V defic. (parahemophilia) F XIII defic. APC resistance

  41. Coagulopathies Congenital Acquired Liver proteosynthesis Vitamin K defic. - obstructive icterus - intestin. resorption Anticoagulant therapy - Dicumarol - Heparin

  42. Vasculopathies Congenital Acquired Mb. Rendu-Osler-Weber = hereditary hemorrhagic teleangiectasia AD, TGFbeta1 rec. Ehlers-Danlos Sy. = defects in collagen synthesis Purpura Henoch-Schönlein Scorbut Steroid purpura Purpura simplex and senilis

  43. Genetic examination Hemophilia A X-linked recessive 1 : 10 000

  44. Clinical signs Large hemorrhage after a small injury Arthral hemorrhage Secondary arthropathy Hemophilia

  45. Clinical signs Thrombocytopenia Petechiae, pigmentation

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