Vitamin K and oral anticoagulation: thought for food.

Oral anticoagulants are one of the most commonly prescribed classes of drugs in the pharmacopoeia. The pharmacology and monitoring of oral anticoagulants are notoriously complex. Numerous variables determine the ultimate anticoagulant effect of this important medication, including patients’ age, vitamin K intake and absorption, plasma transport, hepatic uptake and metabolism, synthetic rates of the vitamin K– dependent coagulation proteins, drug-drug interactions, and other comorbid diseases that affect hemostasis. Management of oral anticoagulation is further complicated by problems inherent to the monitoring of prothrombin time, an issue that has been partially addressed by the use of the international normalized ratio (INR) (1,2). Surprisingly, one of the least studied of the variables is the effect of dietary vitamin K intake on the stability of anticoagulation. In a 1994 literature review, Wells et al (3) found only two articles that fulfilled level 1 evidence criteria and that evaluated the interaction of dietary vitamin K with warfarin. Neither article addressed interactions arising within the range of dietary intake of the nonhospitalized, free-living population. In this issue of the Journal, Franco and colleagues (4) evaluate the role of dietary vitamin K on oral anticoagulation with warfarin and phenprocoumon (an alternative form of warfarin) among patients from an anticoagulation clinic. In the first phase of the study, vitamin K intake, measured with a simple dietary questionnaire, was independently and inversely associated with the INR in 39 stably anticoagulated patients. In the second phase, 12 patients completed a randomized crossover study of a high versus a low vitamin K diet, administered in a controlled hospital environment. The authors again showed a statistically significant inverse relation between dietary vitamin K and change in INR. Franco et al appear to be the first to investigate the effect of manipulating dietary vitamin K in a prospective, interventional study of patients on stable oral anticoagulation. The effect of varying dietary intake of vitamin K was limited to a short observation period because of possible clinical complications of over- or underanticoagulation. However, one would anticipate accentuation of the observed effects if the experimental diets had been continued for a longer period of time. A change in INR was observed later with the low vitamin K diet compared with the high vitamin K diet. The more rapid effect of the high vitamin K diet is likely due to the immediate antagonistic effect of increased hepatic vitamin K on the oral anticoagulant, coupled with the rapid carboxylation of descarboxy-vitamin K– dependent hemostatic proteins stored in hepatocytes (5). Vitamin K acts as a cofactor for the hepatic, posttranslational modification of amino terminal glutamic acid residues to 4-carboxyglutamic acid (Gla) in the vitamin K– dependent clotting factors (factors II, VII, IX, and X, as well as proteins C, S, and Z) and a wide range of proteins in other organ systems. Gla is necessary for the normal functioning of the family of vitamin K– dependent clotting proteins. Warfarin inhibits the synthesis of Gla residues by blocking the reduction of vitamin K oxidized in the hepatic carboxylation cycle (Figure, B and C).