Warfarin (Coumadin) has been around for decades. It works by interfering with several of the proteins in the coagulation pathway by blocking “Factor IV,” or calcium, binding, that enables the function of several of them, including Factor 10 and Factor 2 (thrombin) and Proteins C and S, as well as osteocalcin. (e.g. see Hauschka P, V, Osteocalcin: The Vitamin K-Dependent Ca2+-Binding Protein of Bone Matrix. Pathophysiol Haemos Thromb 1986;16:258-272)
Proteins are post-translationally modified by specific γ-glutamyl carboxylation. It is believed this reaction is the only known metabolic role of the vitamin K-dependent enzyme that carries out this carboxylation. ref
Carboxylation is facilitated by Vitamin K (phylloquinone, and also menaquinone.) warfarin / coumadin displaces Vitamin K from the enzyme for post-translational carboxylation of the proteins of the coagulation pathway. (see Suttie, J. W. 2001. Vitamin K-dependent Carboxylase. eLS. .)
Assessing for the proper effective dose of warfarin involves the blind titering of a warfarin dose against a dietary unknown, vitamin K ingestion, by the patient. Rational dosing would merely involve the use of a fixed-ratio Vitamin K vs. warfarin, which would be likely in several fold excess of the usual doses of warfarin, and containing enough Vitamin K to render the dietary variable a minor quantity.
Measurement of the efficacy of the combined drug in test patients would merely involve the calculation of the variance of the INR as well as the target amount. I’d suggest by sheer wild guessing that the variance would be greatly decreased, and the big outliers – the INR of 7.0 as happened to my patient – would vanish.
- Titer the warfarin up to INR >= 3.0
- Titer it down to 2.0 by Vitamin K.
- Titer again to 2.5 by adding warfarin.
- Assess the fixed ratio.
In fact, you could calculate the Vitamin K in the diet and effectively absorbed, just by looking for the “excess” vitamin K.