American Heart Association/American College of Cardiology Foundation Guide to Warfarin Therapy

Abstract

Mechanism of Action of Coumarin Anticoagulant DrugsWarfarin, a coumarin derivative, produces an anticoagulant effect by interfering with the cyclic interconversion of vitamin K and its 2,3 epoxide (vitamin K epoxide).Vitamin K is a cofactor for the carboxylation of glutamate residues to ␥-carboxyglutamates (Gla) on the N-terminal regions of vitamin K-dependent proteins (Figure 1).[1][2][3][4][5][6] These proteins, which include the coagulation factors II, VII, IX, and X, require ␥-carboxylation by vitamin K for biological activity.By inhibiting the vitamin K conversion cycle, warfarin induces hepatic production of partially decarboxylated proteins with reduced coagulant activity.7,8 Carboxylation promotes binding of the vitamin K-dependent coagulation factors to phospholipid surfaces, thereby accelerating blood coagulation.9 -11 ␥-Carboxylation requires the reduced form of vitamin K (vitamin KH 2 ).Coumarins block the formation of vitamin KH 2 by inhibiting the enzyme vitamin K epoxide reductase, thereby limiting the ␥-carboxylation of the vitamin K-dependent coagulant proteins.In addition, the vitamin K antagonists inhibit carboxylation of the regulatory anticoagulant proteins C and S. The anticoagulant effect of coumarins can be overcome by low doses of vitamin K 1 (phytonadione) because vitamin K 1 bypasses vitamin K epoxide reductase (Figure 1).Patients treated with large doses of vitamin K 1 (usually Ͼ5 mg) can become resistant to warfarin for up to a week because vitamin K 1 accumulating in the liver is available to bypass vitamin K epoxide reductase.Warfarin also interferes with the carboxylation of Gla proteins synthesized in bone.[12][13][14][15] Although these effects contribute to fetal bone abnormalities when mothers are treated with warfarin during pregnancy, 16,17 there is no evidence that warfarin directly affects bone metabolism when administered to children or adults.The American Heart Association makes every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship or a personal, professional, or business interest of a member of the writing panel.Specifically, all members of the writing group are required to complete and submit a Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest.