Chinedu Okocha, Pharm D. Candidate

University Of Colorado School of Pharmacy

 The formation of a clot is as a result of two hemostatic pathways: the primary and the secondary hemostatic pathways.¹ The primary pathway involves the formation of a platelet plug via platelet adhesion to the damaged subendothelium, granule release and then platelet activation. The end result of this biochemical pathway is platelet aggregation¹ (activated platelets sticking to each other) and the growth of the platelet plug.

  The secondary pathway involves the formation of fibrin. Clotting factors produced in the liver interact with each other to activate fibrinogen to an end-product – fibrin monomer, which then polymerizes in to an insoluble gel.¹ Individual polymers/chains of fibrin are then cross-linked, which then stabilizes the platelet plug.

  In order for clotting factors II, VII, IX and X to be active, they need to be carboxylated and this is dependent on the reduced form of vitamin K (vitamin KH₂).^2,3 Vitamin KH₂ is generated when vitamin K is reduced by vitamin K reductase. During carboxylation of the clotting factors, vitamin KH₂ is simultaneously oxidized to vitamin K epoxide (vitamin KO). Vitamin KO is in turn recycled to vitamin K by vitamin KO reductase. Warfarin mainly inhibits vitamin KO reductase, but it also weakly inhibits vitamin K reductase,² as indicated in

  Although these two pathways are separate events, they are closely linked to each other. For example, during the formation of a clot, thrombin (factor IIa), induces platelet activation and conversely platelet activation accelerates the plasma coagulation via clotting factors.

  Therefore, warfarin has no direct activity/effect on the platelets at any dose, but may have an indirect activity on them by inhibiting the activation of factor II (prothrombin) to factor IIa (thrombin). Inhibition of factor II would minimize the induction of platelet activation.

References

1. Handin RI. Bleeding and Thrombosis. In: Braunwald E, Fauci AS, Isselbacher KJ, Kasper DL, Hauser SL, Longo DL et al. Harrison’s Online Electronic Medical Library. 15^th ed. Columbus: Mcgraw-Hill Companies 2003.
2. Hirsh J, Dalen JF, Anderson DR, Poller L, Bussey H, Ansell J et al. Oral Anticoagulants: Mechanism of Action, Clinical Effectiveness, and Optimal Therapeutic Range. Chest 2001;119:8S – 21S
3. Hyers TM, Agnelli G, Hull RD, Morris TA, Samama M, Tapson T, Weg JG
   Antithrombotic Therapy for Venous Thromboembolic Disease. Chest, Jan 2001; 119: 176S - 193.