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Applied Sciences Lecture Course Physiology of coagulation Mahesh Nirmalan MD, FRCA, PhD Consultant, Critical Care Medicine Manchester Royal Infirmary Hemostasis • Blood must be fluid • Must coagulate (clot) at appropriate time – Rapid – Localized – Reversible Thrombosis…inappropriate coagulation Fibrinogen → Fibrin Natural heparin like molecules that inactivate thrombin Thrombin Anti-thrombotic Thrombosis mechanisms Thrombomodulin Fibrinolysis When bound to thrombin Breakdown of fibrin 1. Activates Protein C Plasmin (Plasminogen) 2. Inactivates clotting factors tPA Clotting or thrombosis Rudolph Virchow Components of haemostasis COAGULATION PROTEINS Endothelium Platelets Endothelium PROCOAGULANT ANTICOAGULANT Plasminogen activator inhibitors Plasminogen activators Fibrinolytic inhibitors Protein C→ Activated Protein C Thrombin/Thrombomodulin Thrombin/Thrombomodulin Tissue Factor Prostacyclin Von Tissue inhibitors Willibrand Factor Factor Pro-coagulant role of the damaged endothelium • Synthesises tissue factor when damaged – Acquires the tissue factor from macrophages – Tissue factor, when bound to VIIa is the major activator of the extrinsic pathway • Major site for the synthesis and storage of vWF – Increased Platelet adhesion – Carrier protein for Factor VIII • Inhibition of Fibrinolysis – Thrombin activated fibrinolytic inhibitor – Plasminogen activator inhibitor Platelets • Anucleate sub-cellular fragments • Arise from megakaryocytes in the marrow • Normal count: 200-400 thousand/μl • Several surface receptors • Activated by contact with extra-cellular matrix • Aggregation to form a platelet plug • Stabilisation by the formation of a fibrin clot Platelets-2 • Contact with collagen • Swelling and pseudopod formation • Contractile proteins contract forcefully • Release of platelet granules • Increased adhesion • Adhere to collagen and vWF • ADP and Thromboxane production • Cascade of events lead to a platelet plug Anti-platelet agents • Inhibition of COX mediated Thromboxane synthesis: Aspirin • ADP receptor inhibition: Clopidogrel • Platelet phosphodiesterase inhibition: Dipyridamole Haemostasis • Primary – Vasoconstriction – Platelet plug formation • Secondary – Coagulation – Organisation of clot www.homepage.montana.edu/~awmsg/Coagulation.ppt www.homepage.montana.edu/~awmsg/Coagulation.ppt Secondary haemostasis & Coagulation proteins Newer models of coagulation: beyond the scope of this lecture Traditional models of coagulation Fibrinogen Fibrin Thrombin Fibrinogen Fibrin Factor 2 Produced in the Liver Vit K dependant Post translational modification Prothrombin (II) Xa Va Thrombin (IIa) Fibrinogen Fibrin Extrinsic Pathway TF Prothrombin VIIa Xa Va Thrombin Fibrinogen Fibrin Intrinsic pathway XIIa Extrinsic Pathway XIa TF Prothrombin IXa VIIa VIIIa Xa Va Thrombin Fibrinogen Fibrin Intrinsic pathway XIIa Extrinsic Pathway XIa TF Prothrombin IXa VIIa VIIIa Xa Va Thrombin Unstable clot Fibrinogen Fibrin XIIIa Stable clot Fibrin APTT/ACT Intrinsic pathway Prothrombin time XIIa Extrinsic Pathway XIa TF Prothrombin IXa VIIa VIIIa Xa Va + + Soft clot Thrombin Fibrinogen Fibrin XIIIa Hard clot Fibrin Hemophilia A Deficiency or nonfunctional VIII X linked recessive Females: asymptomatic careers 1:5-10,000 male births Hemophilia B Deficiency or nonfunctional IX X linked recessive Females: asymptomatic careers 1:20-30,000 male births Physiologic Inhibitors of coagulation • Antithrombin III • Activated Protein C + protein S – Inactivates Va and VIIIa (via proteolysis) • Thrombomodulin (EC glycoprotein) – Binds to thrombin – Decreases ability to produce fibrin – Increases ability to activate Protein C Heparin • Naturally occurring mucopolysaccharide • Very acidic • A heterogeneous group of substances • Inactivates thrombin and Xa • High affinity bonding with Anti-thrombin-3 • Neutralised by Protamine • Chemical neutralisation • PT and APTT will be prolonged • Monitored through APTT • More functional tests available: Heparinase test Role of vitamin K • Some clotting factors require a post-translational modification before they are active in clotting • These factors are II, VII, IX, X, proteins C and S • This PTM involves the addition of a COO- to certain Glutamate residues in the clotting factors • Gamma-carboxyglutamate residues • Essential for Ca2+ binding • This PTM requires vitamin K Inhibitors of coagulation • Vitamin K antagonists (in vivo only) • Ca chelators (in vitro only) – EDTA – Citrate – Oxalate • Heparin (in vivo and in vitro) Disseminated intravascular coagulation • Uncontrolled coagulation • Concurrent Fibrinolysis • Depletion of all clotting factors→bleeding • Consumptive coagulopathy • Increase in products of fibrin breakdown • Severe sepsis, massive trauma/tissue breakdown, burns, pancreatitis, obstetric (placental abruption), amniotic fluid embolism Clot removal Fibrinolysis Plasmin Fibrin Fibrin degradation Products (FDP) •Thrombolytic agents Fibrinolysis •Streptokinase •Urokinase Plasminogen •tPA •Alteplase: Recombinant tPA natural tPA •MI, acute stroke, PE Plasmin Fibrin Fibrin Split Products (FSP) Inhibitors of fibrinolysis Plasminogen activator inhibitors (PAIs) In excessive bleeding DIC after CPB Bleeding after prostatectomy 1. Tranexamic acid 2. α2-antiplasmin (serpin) Should be used only after functional assays of clotting: Thrombo Elasto Graphy (TEG) Poor clotting or excessive clot lysis Clotting studies • FBC: Platelet count & platelet function studies • PT • APTT • Fibrinogen level • FDP • D-Dimers • Individual factor assays • Anti-Xa activity : for monitoring LMWH Figures obtained from freely accessible internet sites. No personal or Institutional credit is claimed. ??
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