Physiologyof Coagulation


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  • Essential cofactor for FVIIa FVIIa: inefficient serine protease. Complex with TF and oriented to phospholipid membrane Phospholipid surface increases the rate of substrate activation (FX, FIX) by 10 4 -10 7
  • Physiologyof Coagulation

    1. 1. The Physiology of coagulation How to clot But not too much
    2. 2. Basis <ul><li>Blood flows through intact vessels </li></ul><ul><ul><li>Resting state is designed to keep blood flowing </li></ul></ul><ul><ul><li>Arteries: rapid flow. Injury requires a plug </li></ul></ul><ul><ul><ul><li>Rapid, localised, controlled. </li></ul></ul></ul><ul><ul><ul><li>minimise blood flow compromise </li></ul></ul></ul><ul><ul><li>Veins: slower, intermittent flow </li></ul></ul><ul><ul><ul><li>Systemic anticoagulant </li></ul></ul></ul><ul><ul><ul><li>clot dissolving system </li></ul></ul></ul>
    3. 3. <ul><li>Complex activating and inhibition system </li></ul><ul><li>Five components </li></ul><ul><ul><li>Vessels </li></ul></ul><ul><ul><li>Platelets </li></ul></ul><ul><ul><li>Coagulation factors (clot forming) </li></ul></ul><ul><ul><li>Coagulation inhibitors (clot controlling) </li></ul></ul><ul><ul><li>Fibrinolysis (clot dissolving) </li></ul></ul>
    4. 4. Haemostasis <ul><li>Vasoconstriction </li></ul><ul><li>Platelets activated by thrombin form a platelet plug </li></ul><ul><li>Fibrin mesh forms via activation of the coagulation system to strengthen the clot </li></ul><ul><li>Clot dissolution via plasmin </li></ul><ul><li>Normal blood flow past the clot </li></ul>
    5. 7. Platelet shape change <ul><li>Pseudopod formation </li></ul><ul><li>Interact with adjacent platelets </li></ul><ul><li>Contract later to consolidate the platelet plug in process of clot retraction </li></ul>
    6. 8. Platelet adhesion <ul><li>Platelet receptors (integrins) </li></ul><ul><ul><li>Glycoprotein Ib/IX </li></ul></ul><ul><ul><li>Glycoprotein Ia/IIa </li></ul></ul><ul><li>Ligands interact with receptors </li></ul><ul><ul><li>Von Willebrand factor </li></ul></ul><ul><ul><ul><li>Large (high molecular weight) multimers </li></ul></ul></ul><ul><ul><li>collagen </li></ul></ul>
    7. 10. Platelet release reaction <ul><li>Stimuli </li></ul><ul><ul><li>Adrenaline, collagen, ADP, thrombin </li></ul></ul><ul><li>Release of preformed active substances from granules </li></ul><ul><ul><li>ADP, serotonin, lysozyme,factor V, thrombospondin </li></ul></ul><ul><li>Activate the prostaglandin pathway </li></ul><ul><ul><li>Thromboxane A2 via cyclooxygenase </li></ul></ul><ul><li>Calcium release </li></ul><ul><li>Glycoprotein IIb/II activation </li></ul>
    8. 11. Platelet Phospholipid Arachadonic acid Endoperoxidases Thromboxane A2 Calcium flux Phospholipase A2 Cyclooxygenase Thromboxane synthase Phosphodiesterase
    9. 12. Platelet aggregation <ul><li>Platelet receptor </li></ul><ul><ul><li>Glycoprotein IIb/IIIa </li></ul></ul><ul><li>Ligands </li></ul><ul><ul><li>Von Willebrand factor </li></ul></ul><ul><ul><li>Fibrinogen </li></ul></ul><ul><li>IRREVERSIBLE aggregation -> Plug </li></ul>
    10. 15. Coagulation forms fibrin mesh <ul><li>Biological amplification system which converts soluble fibrinogen to an insoluble fibrin meshwork which coverts the primary platelet plug to a firm, definitive stable clot. </li></ul><ul><li>Required local concentration of clotting factors at site of injury </li></ul><ul><li>Surface mediated reactions on exposed collagen, platelet phospholipid or tissue factor </li></ul>
    11. 16. General concepts <ul><li>Coagulation factors act as proteases when activated (serine proteases) </li></ul><ul><li>Zymogens (inactive eg fibrinogen) converted to enzymes/proteins by limited proteolysis </li></ul><ul><li>Complex formation requiring calcium, phospholipid surface, cofactors </li></ul><ul><li>Thrombin converts fibrinogen to fibrin monomer </li></ul><ul><li>Fibrin monomer crosslinked to fibrin </li></ul><ul><li>Forms &quot;glue&quot; for platelet plug </li></ul>
    12. 17. Cascade effect -> amplification 2x10 8 mol Fibrin mesh 1 mol
    13. 19. Coagulation cascade XII XI IX X VIII Prothrombin (II) thrombin fibrinogen fibrin STABILISED FIBRIN V, Ca, P/L VII Intrinsic pathway Extrinsic pathway XIII APTT PT
    14. 20. X Xa II (Prothrombin) IIa (Thrombin) INITIATION VIIa TF Va VIIIa Va XIa
    15. 21. AMPLIFICATION IXa Xa-Va-II Prothrombinase Platelet IXa- VIIa-X “ tenase” TF IX VIIa THROMBIN (IIa) FIBRIN
    16. 22. Fibrinogen -> fibrin <ul><li>Thrombin cleaves fibrinogen </li></ul><ul><ul><li>Fibrinopeptide release </li></ul></ul><ul><ul><li>Fibrin monomers </li></ul></ul><ul><ul><li>Spontaneously link to form a loose polymer </li></ul></ul><ul><ul><li>Fibrin meshwork is stabilised by factor XIIIa (activated by thrombin and calcium) </li></ul></ul>
    17. 24. Inhibitors: ANTI-coagulants <ul><li>Antithrombin III </li></ul><ul><ul><li>Directly inactivates serine proteases </li></ul></ul><ul><ul><li>Thrombin and Xa. Also: IXa and Xia </li></ul></ul><ul><ul><li>Potentiated by heparin </li></ul></ul><ul><li>Protein C </li></ul><ul><ul><li>Inhibits (cleaves) the cofactors VIIIa and Va </li></ul></ul><ul><ul><li>Significantly decreases the rate of clot formation </li></ul></ul><ul><ul><li>Needs to be activated </li></ul></ul>
    18. 25. <ul><li>Protein S: </li></ul><ul><ul><li>Enhances activity of protein C </li></ul></ul><ul><li>Thrombomodulin </li></ul><ul><ul><li>Activated by thrombin </li></ul></ul><ul><ul><li>Binds to thrombin to alter its conformation </li></ul></ul><ul><ul><li>Complex activates protein C </li></ul></ul><ul><li>Tissue pathway factor inhibitor </li></ul><ul><ul><li>Inhibits FVIIa-tissue factor complex </li></ul></ul>
    19. 26. Anticoagulants <ul><li>Too little or ineffective </li></ul><ul><ul><li>Extensive clot </li></ul></ul><ul><li>Too much </li></ul><ul><ul><li>Bleeding </li></ul></ul><ul><li>Therapeutics </li></ul><ul><ul><li>Heparin </li></ul></ul><ul><ul><li>Activated protein C </li></ul></ul><ul><ul><li>TPFI inhibitor </li></ul></ul>
    20. 27. Fibrinolysis <ul><li>Prevents excessive fibrin deposition </li></ul><ul><li>Allows closely coupled with fibrin formation </li></ul><ul><li>Localised surface bound phenomenon that is catalysed by fibrin formation </li></ul>
    21. 28. Components: fibrinolysis <ul><li>Plasminogen -> plasmin </li></ul><ul><li>Plasminogen activators </li></ul><ul><li>Inactivators of plasminogen </li></ul><ul><li>Inhibitors of plasmin </li></ul>
    22. 29.                                                                           
    23. 30. Effect of plasmin <ul><li>Lyses factor V and VIII </li></ul><ul><li>Proteolysis of fibrinogen </li></ul><ul><ul><li>Removes small peptides </li></ul></ul><ul><li>Degradation of fibrin </li></ul><ul><ul><li>Fibrin degradation products (FDP)s </li></ul></ul><ul><ul><li>D-Dimers </li></ul></ul>
    24. 32. Blood Vessel: endothelium <ul><li>Active </li></ul><ul><li>Haemostasis factors </li></ul><ul><ul><li>Von Willebrand factor </li></ul></ul><ul><ul><li>Tissue factor – expressed after injury </li></ul></ul><ul><li>Anticoagulant factors </li></ul><ul><ul><li>ATIII, protein S, thrombomodulin </li></ul></ul><ul><li>Fibrinolysis </li></ul><ul><ul><li>Tissue plasminogen activator </li></ul></ul>
    25. 34. Haemostatic response <ul><li>Vasoconstriction </li></ul><ul><ul><li>Initial slowing of blood flow to injured area </li></ul></ul><ul><ul><li>Smooth muscle in arterioles </li></ul></ul><ul><ul><li>Vasoactive substances </li></ul></ul><ul><li>Platelet primary plug formation </li></ul><ul><ul><li>Collagen/VWF </li></ul></ul><ul><ul><li>Glycoprotein Ib/IX and IIb/IIIa </li></ul></ul><ul><ul><li>Aggregation with arachadonic acid pathway </li></ul></ul>
    26. 35. Haemostatic response <ul><li>Stabilsation of the platlelet plug with fibrin </li></ul><ul><ul><li>Tissue factor activation of coagulation cascade </li></ul></ul><ul><ul><li>Thrombin burst </li></ul></ul><ul><ul><li>Formation of fibrin meshwork </li></ul></ul>
    27. 36. Haemostasis reaction <ul><li>Regulation of fibrin clot </li></ul><ul><ul><li>Activation of fibrinolysis </li></ul></ul><ul><ul><li>Tissue plasminogen activator </li></ul></ul><ul><ul><li>Plasmin -> FDPs </li></ul></ul>
    28. 37. A test tube is not a person <ul><li>Coagulation in vivo </li></ul><ul><ul><li>Temperature </li></ul></ul><ul><ul><li>pH </li></ul></ul><ul><ul><li>Calcium </li></ul></ul><ul><li>That is: hypothermic , acidotic, hypocalcaemic patients don’t clot </li></ul>