and anti-thrombotic pharmocology Tom Williams Coagulation and anti-thrombotic pharmocology Tom Williams

Basics of haemostasis Vasospasm Platelet plug Clot Formation Cascade of clotting factors Zymogen to protease Components of clots Fibrin Platelets

Classic View Intrinsic Pathway AKA Contact Activation Pathway F-XII Binds to collagen / -ve charged surface Hageman factor Prekallikrein & HMWK Activates F-XI Activates F-IX Activates F-X Minor role Extrinsic Pathway Tissue Factor Pathway Generates ‘Thrombin Burst’ TF (F-III / thromboplastin) combines with & activates F-VII Activates F-X & F-IX Generates Thrombin that activates F-VIII Major role

Final Common Pathway Activates F-VIII & F-IX (tenase complex) Activates F-X Prothrombin to Thrombin Fibrinogen to Fibrin

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Platelets Bind to collagen with gp Ia/IIa Bound together with vWBF & Fibrinogen (gp IIb/IIIa complex) Activated by ADP Collagen Thrombin Arachidonic Acid Thromboxane A2

Others vWBF Calcium Phospholipids Found within platelet granules Ligand for platelet adhesion & carrier protein for F-VIII Calcium Phospholipids Found within platelet granules

Regulation Tissue Factor Pathway Inhibitior Antithrombin III Activated by F-Xa Inactivates F-VIIa - Tissue Factor complex Antithrombin III Inactivates thrombin, F-IXa, F-Xa, F-XIa Thrombomodulin Converts thrombin into an anticoagulant Protein C & S Protein C activated by thrombin (post thrombomodulin) Inactivates F-Va & F-VIIIa

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Fibrinolysis Plasminogen from the liver Incorporated into clots as they form Tissue Plasminogen Activators (TPA) converts to plasmin Cleaves fibrin into soluble degradation products Degradation products inhibit action of thrombin

Warfarin Prevents the reduction of Vit K Inhibits carboxylation of Factors II, VII, IX & X Protein C also Vit K dependent Slow onset of action (12h +) as acts on protein synthesis so has no effect on circulating proteins. Metabolised by the liver Monitored by INR or prothrombin time

Heparin Sulfated mucopolysaccharide Catalyses the action of Antithrombin III Inactivates thrombin, F-IXa, F-Xa, F-XIa LMWH catalyse the interaction with F-Xa Partial renal excretion UFH monitored by APTT Antagonised by protamine Long term use causes osteoporosis HITs

Fibrinolytics Streptokinase t-PA Anti-fibrinolytic From -haemolytic strep Forms a complex with plasminogen causing enzymatic activity Antigenic (anaphylactic & reduced action) t-PA Recombinant tissue type plasminogen activators Not antigenic Anti-fibrinolytic Tranexamic Acid Inhibitor of plasminogen activation Aprotinin Inhibits free plasmin

Measurement of Coagulation Prothrombin Time (PT) Extrinsic & Common pathway Time to clot with Tissue Factor & Ca2+ Normal 11-15s INR is the ratio of PT to a standard sample Activated Partial Thromboplastin Time (APTT) Intrinsic & Common pathway Time to clot with kaolin & Ca2+ Normal 35-40s

Other tests Specific clotting factor levels Thrombin Time Activated Clotting Time (NPT) Bleeding Time (NPT) Thromboelastometry (NPT)

Haemophilia Von Willebrand’s Disease Haemophilia Most common Poor platelet aggregation & low F-VIII 3 types (Low, Weird, very Low) Treated with desmopressin, FFP or cryo Haemophilia A - Factor VIII Desmopressin Recombinant factor B - Factor IX

DIC Generalised intravascular activation of haemostatic mechanism Widespread fibrin formation Activation of fibrinolysis Consumption of platelets & coag factors Haemorrhage dominant feature Due to depleted factors, excessive fibrinolysis & inhibition by FDP Mortality >80% in severe cases Diagnosed with high D-Dimer & low coag factors & (sometimes) low platelets

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