Warfarin inhibits which enzyme, leading to decreased synthesis of vitamin K–dependent clotting factors?

• A. Vitamin K epoxide reductase (VKORC1)
• B. Thrombin
• C. Plasmin
• D. Factor XIII

Answer: (A)

Warfarin works by blocking the vitamin K cycle, specifically inhibiting vitamin K epoxide reductase. This enzyme normally recycles vitamin K epoxide back to its active reduced form, which is needed for gamma-carboxylation of glutamate residues on clotting factors II, VII, IX, and X (and proteins C and S). Without that gamma-carboxylation, these factors are produced in an inactive form, so their ability to participate in coagulation is markedly reduced. That’s why there is decreased functional synthesis of vitamin K–dependent clotting factors. The other enzymes listed—thrombin, plasmin, and factor XIII—are not part of this vitamin K cycle and are not inhibited by warfarin.