Vitamin K supplementation during oral anticoagulation: cautions

In response to the paper by Sconce et al,¹  we would like to point out that we have previously suggested the possibility of using vitamin K as a buffer to increase the stability of oral anticoagulation therapy.²  However, we suggested the use of vitamin K₂ instead of vitamin K₁. The potential danger of giving K₁ with warfarin is that it may increase the arterial calcification risk. There are several indications that the use of K₂ may have at least the same ability to stabilize oral anticoagulation and appears to prevent arterial calcification. The drawbacks of using K₁ as a buffer to stabilize the anticoagulation response include the following: (1) K₁ has a relatively short half-life (1-2 hours), so that a single daily dose may result in substantial fluctuations of circulating and tissue K₁ concentrations. Therefore, the stability of anticoagulation may be further improved by using a vitamin K species with a longer half-life. (2) K₁ is taken up preferentially by the liver³  so that extrahepatic tissues are more susceptible to vitamin K deficiency than the liver. This effect is exacerbated when K₁ and warfarin are combined; indeed, this combination has been used by Price et al to induce rapid arterial calcification.⁴  Although the amount of warfarin used by Price et al to induce calcification in rats is higher than would normally be used in oral anticoagulation therapy, there are reports that patients on long-time normal warfarin therapy have increased calcification of aortic valves.^5,6  Therefore, though increasing both K₁ intake and warfarin dosage may improve oral anticoagulation stability, it probably also increases vascular calcification risk.^5,6 

A major advantage of K₂ is that it is not preferentially targeted to the liver. A number of tissues—including the vessel wall—accumulate K₂ at high levels.⁶  This results in protection by K₂ but not by K₁ against warfarin-induced calcification.⁷  Also, K₂ can be used in the liver equally as well as K₁. Of the commercially available forms, we recommend MK-7 (NattoPharma, Oslo, Norway; or E. T. Horn, La Mirada, CA). MK-7 is transported to extrahepatic tissues via low-density lipoprotein (LDL).⁸  A further advantage of MK-7 is that it has a relatively long half-life (3 days). This longer half-life will probably result in more stable anticoagulation.

Although vitamin K₂ may have signaling functions independent from its role in gamma glutamyl carboxylation, supplementation with vitamin K₂ (MK-7) in doses as high as 45 mg/day seems to have no adverse effects.⁹  Indeed, it seems to impede the growth of certain tumors and also to promote vascular health,⁹  and reduces fractures in postmenopausal women.¹⁰ 

Based on these considerations, we propose that a new trial be designed in which patients on anticoagulation therapy receive MK-7 rather than K₁. At first it will be necessary to adjust the International Normalized Ratio (INR) based upon the dose of MK-7 and warfarin. These patients should also be followed to determine the extent to which this protocol prevents arterial calcification. In this regard, it is noteworthy that the risk of cardiovascular calcification by oral anticoagulation therapy (even without additional K₁) is receiving increasing attention.^5,6 

Conflict-of-interest disclosure: D.W.S. has applied for patents on VKOR and its use in predicting warfarin dosage. C.V. is a consultant for E. T. Horn and does contract research for NattoPharma.

Correspondence: Darrel W. Stafford, e-mail: dws@email.unc.edu.