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COAGULATION & ANTICOAGULATION

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  1. COAGULATION & ANTICOAGULATION Dr Rakesh Jain

  2. Coagulation • A set of reactions in which blood is transformed from a liquid to a gel • Coagulation follows intrinsic and extrinsic pathways • The final three steps of this series of reactions are: • Prothrombin activator is formed • Prothrombin is converted into thrombin • Thrombin catalyzes the joining of fibrinogen into a fibrin mesh

  3. Current Concept of coagulation

  4. The “extrinsic” or tissue factor pathway consists of FVIIa/TF complex and FXa/Va complex. It operates on TF-bearing cell to initiate the coagulation process. • The “intrinsic” pathway does not include FXII or its cofactors PK and HMWK, which do not appear to be necessary for hemostasis. • The “intrinsic” pathway to consist of FXI(a), FIXa/VIIIacomplex, and FXa/Va complex. It operates on the platelet surface during the propagation phase to generate a burst of thrombin. • Both pathways are needed for hemostasis, because they operate on different surfaces and play distinct roles.

  5. Anticoagulants Parenteral • Unfractionated heparin • LMWH • Fondaparinux Direct Thrombin Inhibitors • Hirudin • Argatroban • Bivalirudin Oral • Vitamin K antagonist – Warfarin • Thrombin Inhibitor – Dabigatran • Xa inhibitor - Rivaroxaban

  6. Parenteral Anticoagulants

  7. Heparin • Is a sulfated polysaccharide • Commercial heparin is derived from porcine intestinal mucosa Mechanism of Action Activate antithrombin and accelerating the rate at which it inhibits clotting enzymes - thrombin & factor Xa

  8. Pharmacology • Requires parenteral administration – s/c or continuous intravenous infusion • Intravenous route is most often used for therapeutic purposes • Binds to endothelium and plasma proteins • Heparin binding to endothelial cells explains its dose-dependent clearance • Plasma t 1/2 is 30 to 60 min with bolus iv doses of 25 and 100 U/kg

  9. Levels of heparin - binding proteins in plasma vary from person to person - so anticoagulant response to fixed or weight-adjusted doses of heparin is unpredictable • Coagulation monitoring is essential to ensure therapeutic response

  10. Monitoring Anticoagulant Effect of Heparin • aPTT or anti–factor Xa level is used • aPTTterapeutic range : 2 to 3 fold prolongation • Anti factor Xa therapeutic range : 0.3 to 0.7 unit/ml • In heparin resistant cases anti factor Xa is prefered - elevated plasma levels of fibrinogen & factor VIII (a/c phase proteins) shorten aPTT but have no effect on anti–factor Xa levels

  11. Dosage • Prophylaxis 5000 U s/c twice or thrice daily • Therapeutic In ACS : 5000 U / 70 U/Kg bolus followed by 12 to 15 U /Kg/hr infusion In VTE :5000 U / 80 U/kg bolus followed by 18 U /kg/hr infusion

  12. Limitations Mechanism Limited absorption of long heparin chains Binds to endothelial cells Binds to plasma proteins Neutralized by PF 4 released fm activated platelets • Poor bioavailability • Dose-dependent clearance • Variable anticoagulant response • Reduced activity in vicinity of platelet-rich thrombi

  13. Side Effects • Bleeding Protamine sulfate neutralizes heparin in pts with serious bleeding. 1 mg of intravenous protamine sulfate neutralizes 100 units of heparin • Thrombocytopenia HIT is an antibody-mediated process Occurs 5 to 14 d after initiation of therapy Plt count < 100,000 or decrease in plt count of 50% or more from baseline

  14. Osteoporosis In 30% of pts on long-term heparin therapy • Elevated Levels of Transaminases

  15. LMWH • Smaller fragments of heparin • Prepared from UFH by controlled enzymatic or chemical depolymerization • Advantages Better bioavailability & ↑ half-life after s/c inj Dose-independent clearance Predictable anticoagulant response Lower risk of HIT and Osteoporosis

  16. Monitoring • Usually not required • If necessary anti–factor Xa is measured • May be done in renal insufficiency , obesity , pregnancy , mechanical valves

  17. Dosing Prophylaxis : 4000 to 5000 U s/c Once daily Treatment : VTE : 150 to 200 U /kg Once daily or 100 U/Kg twice daily ACS : 100 to 120 U /kg twice daily • Complication Bleeding , Thrombocytopenia , Osteoporosis - but less than UFH

  18. Fontaparinux • Synthetic analogue of the antithrombin-binding pentasaccharide sequence • Exhibits complete bioavailability after s/c injection • Plasma half-life is 17 hrs Dose • Prophylaxis : 2.5 mg once daily • Treatment of VTE : 7.5 mg once daily (5mg if wt<50kg , 10mg if wt >100 kg)

  19. Parenteral Direct Thrombin Inhibitors

  20. Oral Anticoagulants Warfarin • water-soluble vitamin K antagonist • interferes with synthesis of vitKdependent clotting proteins : factor II,VII, IX, X , proteins C and S • Almost completely absorbed fm GI tract • Levels peak 90 min after drug administration • Plasma half life 36 to 42 hours • 97% bound to albumin

  21. Mechanism of Action

  22. Monitoring • Prothrombin Time • INR • Target INR : 2 to 3 in mechanical valves 2.5 to 3.5 Dose • 5 to 10 mg • Concomitant treatment with parenteral anticoagulant until INR has been therapeutic range for at least 2 consecutive days

  23. Side Effects Bleeding – major side effect • If INR 3.5 to 4.5 : Withheld warfarin till normalises • INR > 4.5 : vitamin K 1mg sublingual • Serious bleeding : 10 mg vit K slow iv , FFP supplementation for Vit K dependent clotting proteins • Bleeding in therapeutic range – investigate for cause Skin Necrosis : rare complication • Occurs 2 to 5 d after initiation of therapy • occurs in pts with deficiencies of protein C or S

  24. Pregnancy – teratogenic • nasal hypoplasia & stippled epiphyses • Causes fetal bleeding • Warfarin is contraindicated in 1st and 3rd trimesters

  25. New Oral Anticoagulants

  26. Fibrinolytic drugs • Used to degrade thrombi • Approved fibrinolytic agents include SK , urokinase, alteplase , tenecteplase and reteplase • Act by converting proenzyme, plasminogen, to plasmin • SK ,UK are not fibrin specific while others are fibrin specific • Nonspecific agents , activate circulating plasminogen resulting in generation of unopposed plasmin that can trigger systemic lytic state

  27. Streptokinase • Does not directly convert plasminogen to plasmin • It forms complex with plasminogen which activate additional plasminogen to plasmin • Not fibrin specific • Dose : 1.5 million units infusion over 30 to 60 min • SK is antigenic • Transient hypotension due to plasmin mediated bradikinin release

  28. Urokinase • Derived from cultured fetal kidney cells • Directly converts plasminogen to plasmin Alteplase • Recombinant form of single-chain t-PA • Has limited fibrin specificity • Given as an iv infusion over 60 to 90 min • The total dose of alteplase usually ranges from 90 to 100 mg

  29. Reteplase • Recombinant t-PA derivative, reteplase is a single-chain variant • Given as two intravenous boluses separated by 30 min

  30. Tenecteplase • A genetically engineered variant of t-PA • longer half-life than t-PA • More fibrin-specific than t-PA • For coronary fibrinolysis, tenecteplase is given as a single iv bolus

  31. THANK YOU