1 / 37

COAGULATION & ANTICOAGULATION

COAGULATION & ANTICOAGULATION. Dr Rakesh Jain. 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

anne-lott
Download Presentation

COAGULATION & ANTICOAGULATION

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  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

More Related