Wobbling with warfarin

All physicians who have used warfarin as an oral anticoagulant—and that includes most of us—know of the great variability in the prothrombin time measured in a patient given a specific dose of warfarin. We have interpreted this as due to the variation of the counterbalancing vitamin K in the patient's diet, variations in metabolism of warfarin in different people, and wobble in accuracy of the prothrombin time measurement due to variations in sample handling, anticoagulant to whole blood ratios, or instrument errors. Given the narrow therapeutic index for warfarin, we titrate the warfarin dose against the prothrombin time, as standardized using the International Normalized Ratio (INR). In the report by Shikata and colleagues (page 2630), we finally begin to get to the molecular basis of warfarin sensitivity. Warfarin is a racemic mixture of (R)-warfarin and (S)-warfarin; (S)-warfarin is more potent in inhibiting vitamin K–dependent carboxylation. Warfarin sensitivity is correlated in part to the presence of a relatively infrequent allele of cytochrome P450 known as CYP2C9^*3. In the presence of this allele, (S)-warfarin clearance was reduced and the INR increased for a given plasma concentration of warfarin. In addition, polymorphisms in the genes encoding the vitamin K–dependent proteins and the vitamin K–dependent carboxylase are analyzed. As one might predict, any mutation/polymorphism that decreased functional activities of proteins within the pathway monitored by the prothrombin time would lead to a decrease in the INR for a given plasma warfarin concentration—and vice versa. There were 4 independent functional polymorphisms identified, including the Thr165Met in prothrombin and -402G>A (37-bp repeat)₆ and -746T>C in factor VII. Multiple regression analysis identified CYP2C9^*3 in cytochrome 450, and Thr165Met and -402G>A in prothrombin and (CAA repeat)_n in the vitamin K–dependent carboxylase as associated with warfarin sensitivity. These results suggest that genotyping of the genes encoding the carboxylase, cytochrome P450, and some of the vitamin K–dependent protein can predict warfarin response.