Dietary vitamin K influences intra‐individual variability in anticoagulant response to warfarin

Abstract

SummaryThe relationship between dietary intake of vitamin K, fat, plasma vitamin K concentrations and anticoagulation response to warfarin within individuals, as well as the contribution of dietary vitamin K to differences in warfarin dose requirements between individuals were investigated in 53 patients on warfarin therapy who had stably controlled anticoagulation. Each patient completed a dietary record of all foods consumed on a daily basis for 4 weeks. Each week a blood sample was taken for measurement of the international normalized ratio (INR), plasma vitamin K, triglycerides and warfarin enantiomer concentrations. The patients' genotype for CYP2C9 was also determined. Regression analysis of the data showed that, for each increase of 100 lg in the daily dietary intake of vitamin K averaged over 4 d, the INR was reduced by 0AE2. There was no correlation between warfarin daily dose and average daily dietary vitamin K intake when calculated over 28 d. The regression model for warfarin dose showed that, while dietary vitamin K had no effect, CYP2C9 genotype (P ¼ 2%) and age (P < 1%) significantly contributed to inter-patient variability in warfarin dose requirements. A consistent intake of vitamin K could reduce intrapatient variability in anticoagulation response and thus improve the safety of warfarin therapy.

Vitamin K deficiency amplifies anticoagulation response to ximelagatran: possible implications for direct thrombin inhibitors and their clinical safety

“…However, since the activation of thrombin is inextricably linked with the vitamin K cycle in the coagulation cascade, there is the possibility that the pharmacological activity of direct thrombin inhibitors could be influenced by alterations in vitamin K availability. The enhanced pharmacological activity of warfarin in vitamin K deficient rats observed in this study confirms the well-established impact of vitamin K deficiency on anticoagulation response to warfarin in man [4][5][6][8][9][10]. This study also demonstrates that overt vitamin K deficiency enhances the anticoagulant activity of the direct thrombin inhibitor, ximelagatran, in rats.…”

“…It has been suggested that alterations in dietary vitamin K may also explain some of the intra-patient variability [4][5][6]. Vitamin K, in its hydroquinone form, is an essential co-factor for the carboxylation of the glutamic acid residues of the amino-terminals of the coagulation proteins II, VII, IX and X, leading to their activation.…”

“…Warfarin causes anticoagulation by inhibiting the reductase enzymes, which generate vitamin K hydroquinone from vitamin K epoxide in the liver, thus preventing activation of the clotting proteins [7]. The availability of vitamin K thus plays a role in determining the effectiveness of warfarin, and dietary modification by either lowering or increasing vitamin K intake can increase or decrease patients' sensitivities to the drug [5,[8][9][10].…”

Vitamin K supplementation can improve stability of anticoagulation for patients with unexplained variability in response to warfarin

“…6,12 Earlier we showed that in patients with stable control of anticoagulation, for every 100-g increase in vitamin K intake in the previous 4 days, INR falls by 0.2, 16 further exemplifying the relationships between dietary vitamin K and anticoagulation response.…”

Novel anticoagulants in atrial fibrillation stroke prevention

“…A large and increasing number of drugs interact with warfarin leading to over-anticoagulation, under-anticoagulation, or increased bleeding [Holbrook et al 2005;Juurlink, 2007]. Differences in the dietary content of vitamin K are known to profoundly alter the pharmacodynamic effects of warfarin [Franco et al 2004;Khan et al 2004;Kurnik et al 2004;Schurgers et al 2004;Couris et al 2006;Rohde et al 2007;De Assis et al 2009]. Warfarin is extensively metabolized in the liver by the cytochrome P-450 2C9 (CYP2C9) isoenzyme.…”