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Normal Hemostasis Galila Zaher Consultant Hematologist KAUH
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Function of Haemostasis Prevention of blood loss from intact vessels Arrest of bleeding from damaged vessels Blood vessel reaction to injury Platelet plug formation at site of damage
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BLOOD CLOTTING Plasma protein clotting factors Plasma protein clotting factors Vascular endothelium Platelets
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COAGULOPATHIES Bleeding Thrombosis Bleeding Thrombosis Clotting factors Natural anticoagulant Clotting factors Natural anticoagulant platelets platelets
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Normal Hemostasis 1.Vessel wall 2.Platelet 3.Blood coagulation 4.Fibrinolytic system 5.Inhibitors 1.Local vasoconstriction (noradrenaline & serotonin) 2.Platelet release thromboxane A 2 (a vasoconstrictor) 3.Prostacyclin is released counters effects of thromboxane A 2
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Hemostasis
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Normal Hemostasis 1.Vessel wall 2.Platelet 3.Blood coagulation 4.Fibrinolytic system 5.Inhibitors Adhesion Shape change Aggregation Release Reaction
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Adhesion GpIIb/IIIa Platelet Activation GpIIb/IIIa Aggregation ADP Adrenaline Platelet GpIb Exposed Collagen Endothelium vWF COLLAGEN GpIIb/IIIa Aggregation GpIIb/IIIa Aggregation Adhesion ADP Adrenaline THROMBIN
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Clot formation Platelet activation Primary hemostasis Count&function Immediate Fibrin generation Secondary hemostasis Plasma clotting factors Delayed
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VWF The largest multimers of vWF greater adhesive & prothrombotic potential more sites to interact with: Substrates in extra-cellular matrices and Platelet receptors.
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F.VIII:C F. VIIIC:Ag vWF:Ag vWF B:Co vWF R:Co
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Functions of vWF Platelet Adhesion (to extracellular matrices):GP Ib-IX-V complex Platelet Adhesion to each other (Aggregation):Mediated by vWF & fibrinogen binding to: GPIb-IX-V & GP IIb-IIIa
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Clotting factor production Liver: source of plasma clotting factors except VWF except VWF Factor VIII: produced by liver & endothelium endothelium VWF: endothelial cells & megakaryocytes Vitamin K dependent clotting factors are: II, VII, IX, X II, VII, IX, X
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NamesFactors Fibrinogen ProthrombinThromboplastinCalcium Labile factor Stable factor Antihemophilic factor Antihemophilic factor B Stuart-Power factor Plasma thromboplastin antecedent (PTA) Hagman factor Fibrin stablizing factors IIIIIIIVVVIIVIIIIXXXIXIIXIII
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COAGULATION PATHWAYS Intrinsic & extrinsic pathways “conclude” in the common pathway Intrinsic pathway clotting factors Extrinsic pathway clotting factors Common pathway clotting factors
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Intrinsic Pathway All clotting factors are within the blood vessels Clotting slower Activated partial thromboplastin test (aPTT) Extrinsic Pathway Initiating factor is outside blood vessels - tissue factor Clotting faster Prothrombin test (PT)
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The “Cascade”, “Waterfall” model:
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Macfarlane (1964), Davie & Ratnoff (1964)} Drawbacks of the ‘cascade model’: i.Model inadequate to explain pathways leading to hemostasis in vivo ii.Deficiency of FXII, HMK,PK does not cause bleeding iii.Activation of FX by the extrinsic pathway does not compensate for the lack of FVIII or FIX in hemophiliacs
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Platelet Thrombin VIIIa XIa IXa TF VIIa Xa Prothrombin Fibroblast Initiation Amplification Activated platelets XIaIXaXa Prothrombin Thrombin Propagation
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TF–independent mechanism of rFVIIa enhanced hemostasisTF–independent mechanism of rFVIIa enhanced hemostasis
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Alternative (Cell-based) Model The initiation phase: Commences on TF-bearing cells (fibroblasts) Commences on TF-bearing cells (fibroblasts) FXa, IXa & thrombin FXa, IXa & thrombin Initiation of the coagulation process Initiation of the coagulation process The amplification phase: Coagulation moves from TF-bearing cells to Coagulation moves from TF-bearing cells to activated platelets, activated platelets, The propagation phase: The active proteases combine with cofactors on The active proteases combine with cofactors on platelet surface to generate thrombin; platelet surface to generate thrombin; End-result is fibrin polymerization End-result is fibrin polymerization
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1.Vessel wall 2.Platelet 3.Blood coagulation 4.Fibrinolytic system 5.Inhibitors 1. Fibrin is digested by enzymes from plasma and from cells. 2. Endothelium replaces the fibrin Fibrinolysis
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Plasminogen PlasminogenTPA Thrombin Thrombin XIIa XIIa Plasmin Plasmin
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Activation of fibrinolysis plasminogen thrombin plasmin damaged cells t-PA PAI cross-linked fibrin fibrinogen FDP (X,Y,D,E) X-FDP (D-Dimer, cross-linked oligomers, DD/E...) antiplasmin extrinsic pathway inflammation trauma mental/physical stress
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Generation Of Fibrin and D-Dimer D E D E DD E E F XIIIa fibrin fibrin polymer DD E D E D E DD E cross-linked fibrin (clot) fibrinogen E DD E thrombin FpA, FpB D-dimer cross- linkage E D E D E D E D E D E D E E DD E E D E D E E DD E
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COAGLATION INHIBITORS Antithrombin (FXIa, IXa, Xa & IIa) Protein C/S complex (F Va & F VIIIa) Tissue factor pathway inhibitor -(TFPI)
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VIIIa Pc Ps PAI-1 Lysis of fibrin ATIII Xa VaXIIaXII VIIaVII XIa IXIXa XI X X IIaII FibrinFibrinogen
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Factor IXa -FVIIIa Factor Xa +FVa Factor XIa Factor IIa (thrombin) FibrinogenFibrin TFPI Anti Thrombin III Protein C Tissue factor + Factor VIIa
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The “Cascade”, “Waterfall” model:
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Intrinsic pathway XII ---> XIIa XI---------XIa IX --------> IXa + VIIIAPC PC +PS Ca +PL X----------------------> Xa[Common pathway] V+Ca+PL Prothrombin -------------> thrombin AT v fibrinogen--------------> fibrin Extrinsic pathway VII + TF ----->VIIa/TF
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