Reversal of anticoagulation is dependent on the type of anticoagulant and indication for reversal (ie.

Cooperation during warfarin therapy would have significant consequences, as VKD proteins function in numerous physiologies in many tissues, but may be poorly carboxylated and dysfunctional if the second activity is not ubiquitously expressed similar to VKORC1. This activity therefore appears to cooperate with VKORC1 to accomplish full KO reduction. In contrast, 293 cells expressing factor IX and this reductase activity showed much less inhibition of carboxylation. Uncoupling was revealed because a second activity, a warfarin-resistant quinone reductase, was not present.

The results indicate that warfarin uncouples the 2 reactions that fully reduce KO. Carboxylation that required only K to KH 2 reduction was inhibited much less than observed with the KO substrate that requires full VKORC1 reduction (eg, 2.5-fold vs 70-fold, respectively, in cells expressing wild-type VKORC1 and factor IX). The K to KH 2 reaction was analyzed using low K concentrations that result from inhibition of KO to K. Carboxylation was much more strongly inhibited (∼400-fold) than KO reduction (two- to threefold). Warfarin inhibition of KO to K reduction and carboxylation that requires full reduction were compared in wild-type VKORC1 or mutants (Y139H, Y139F) that cause warfarin resistance. Our dissection of full reduction vs the individual reactions revealed a surprising mechanism of warfarin inhibition. VKORC1 produces KH 2 in 2 reactions: reduction of vitamin K epoxide (KO) to quinone (K), and then KH 2. The anticoagulant warfarin inhibits the vitamin K oxidoreductase (VKORC1), which generates vitamin K hydroquinone (KH 2) required for the carboxylation and consequent activation of vitamin K–dependent (VKD) proteins.

Warfarin antidote vitamin k