Association between Low Plasma Phylloquinone Concentration and Warfarin Sensitivity in Japanese Patients

Warfarin sensitivity exhibits marked interindividual variability, partly explained by genetic polymorphisms affecting vitamin K (VK) metabolism. However, the association between plasma VK concentrations and warfarin sensitivity remains unclear. We investigated this association in Japanese patients receiving warfarin therapy. Blood samples from patients aged ≥20 years were analyzed for genetic polymorphisms associated with warfarin sensitivity, warfarin concentrations, and plasma concentrations of phylloquinone (PK) and menaquinone-4 (MK4). The warfarin sensitivity index (WSI) was calculated as the change in prothrombin time-international normalized ratio per S-warfarin-equivalent concentration. Among 105 patients, plasma PK and MK4 concentrations were not significantly correlated with WSI when analyzed as continuous variables (p = 0.297 and p = 0.118, respectively). To determine whether plasma VK concentrations provided additional predictive information, WSI prediction models with and without VK variables were compared. Incorporating an indicator of plasma PK concentration <0.20 ng/mL improved model performance, whereas MK4-based models showed no clear improvement. In multivariable analysis, a plasma PK concentration <0.20 ng/mL was independently associated with a higher WSI after adjustment for established clinical and genetic factors (B = 0.703, 95% confidence interval, 0.057-1.349; p = 0.033). These findings suggest that a low plasma PK concentration may explain some of the interindividual variability in warfarin sensitivity beyond that accounted for by genetic polymorphisms. Direct measurement of plasma PK may provide additional information for understanding increased warfarin sensitivity in patients with low VK status.