Warfarin, a juggler's demise

Abstract

Warfarin, an anticoagulant therapy used by millions worldwide, inhibits vitamin K epoxide reductase complex subunit 1 (VKORC1), thereby dampening the carboxylation and the procoagulant potential of vitamin K–dependent coagulation factors. However, the detailed molecular mechanism by which warfarin inhibits VKORC1 remains the subject of debate.^, In this issue of Blood, Rishavy et al puts this issue to rest by demonstrating that warfarin inhibits VKORC1 via a mechanism termed “the uncoupling of VKORC1.” The uncoupling of VKORC1 is significant because it highlights a potential cooperation of VKORC1 with a second warfarin-resistant vitamin K quinone reductase, thereby explaining how considerable carboxylation can proceed despite the presence of warfarin, and this may have direct implications for warfarin dosing in patients.

Inhibition of the vitamin K cycle by warfarin. KH₂ is converted to KO during the carboxylation of Glu to Gla residues by γ-glutamyl carboxylase. Under normal physiologic conditions in the liver, VKORC1 efficiently recycles KO back to KH₂ in a 2-step reaction, generating K as an intermediate product (left side). The uncoupling of the 2 VKORC1-mediated reactions (KO→K and K→KH₂) in the presence of warfarin, as described by Rishavy et al, causes a loss in efficiency of VKORC1 for the full recycling of KO to KH₂ and a loss in carboxylation. However, because warfarin uncouples the reaction rather than directly inhibits the reaction, VKORC1 can still generate considerable amounts of the K intermediary. The completion of the final step (K→KH₂) then becomes dependent on the extent to which the second warfarin-resistant vitamin K quinone reductase (2nd VKR) is present and active. Thus, although VKORC1 is responsible for the full recycling of KO to KH₂ in the absence of warfarin, the recycling pathway changes in the presence of warfarin and requires cooperation of VKORC1 and the 2nd VKR. The degree of carboxylation in the presence of warfarin is therefore dependent on the expression and activity of 2nd VKR (indicated by the dotted arrows), the identity of which remains unknown to date.