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Physion
 

Physion

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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

Physion Physion Presentation Transcript

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