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Blood, 15 April 2007, Vol. 109, No. 8, pp. 3607. This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Sconce, E. Articles by Kamali, F. Search for Related Content PubMed PubMed Citation Articles by Sconce, E. Articles by Kamali, F. Related Collections Brief Reports Related Letter in Blood Online Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  CORRESPONDENCE Vitamin K supplementation during oral anticoagulation: cautions To the editor: 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 Authorship 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{at}email.unc.edu. Darrel W. Stafford, Harold R. Roberts, and Cees Vermeer References Sconce E, Avery P, Wynne H, Kamali F. Vitamin K supplementation can improve stability of anticoagulation for patients with unexplained variability in response to warfarin. Blood Prepublished November 16, 2006, as DOI 10.1182/blood-2006-09-049262.[Abstract/Free Full Text] Stafford DW. The vitamin K cycle. J Thromb Haemost 2005; 3:1873–1878.[CrossRef][Medline] [Order article via Infotrieve] Ronden JE, Thijssen HH, Vermeer C. Tissue distribution of K-vitamers under different nutritional regimens in the rat. Biochim Biophys Acta 1998; 1379:16–22.[Medline] [Order article via Infotrieve] Price PA, Faus SA, Williamson MK. Warfarin causes rapid calcification of the elastic lamellae in rat arteries and heart valves. Arterioscler Thromb Vasc Biol 1998; 18:1400–1407.[Abstract/Free Full Text] Koos R, Mahnken AH, Muhlenbruch G, et al. Relation of oral anticoagulation to cardiac valvular and coronary calcium assessed by multislice spiral computed tomography. Am J Cardiol 2005; 96:747–749.[CrossRef][Medline] [Order article via Infotrieve] Schurgers LJ, Aebert H, Vermeer C, Bultmann B, Janzen J. Oral anticoagulant treatment: friend or foe in cardiovascular disease? Blood 2004; 104:3231–3232.[Abstract/Free Full Text] Spronk HM, Soute BA, Schurgers LJ, Thijssen HH, De Mey JG, Vermeer C. Tissue-specific utilization of menaquinone-4 results in the prevention of arterial calcification in warfarin-treated rats. J Vasc Res 2003; 40:531–537.[CrossRef][Medline] [Order article via Infotrieve] Schurgers LJ and Vermeer C. Differential lipoprotein transport pathways of K-vitamins in healthy subjects. Biochim Biophys Acta 2002; 1570:27–32.[Medline] [Order article via Infotrieve] Kaneki M, Hosoi T, Ouchi Y, Orimo H. Pleiotropic actions of vitamin K: protector of bone health and beyond? Nutrition 2006; 22:845–852.[CrossRef][Medline] [Order article via Infotrieve] Ikeda Y, Iki M, Morita A. Intake of fermented soybeans, natto, is associated with reduced bone loss in postmenopausal women: Japanese Population-Based Osteoporosis (JPOS) Study. J Nutr 2006; 136:1323–1328.[Abstract/Free Full Text] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Letter in Blood Online: Response: vitamin K supplementation during oral anticoagulation: no real cause for concern Elizabeth Sconce, Hilary Wynne, and Farhad Kamali Blood 2007 109: 3607-3608. [Full Text] [PDF] Related Article in Blood Online: Response: vitamin K supplementation during oral anticoagulation: no real cause for concern Elizabeth Sconce, Hilary Wynne, and Farhad Kamali Blood 2007 109: 3607-3608. [Full Text] [PDF] This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Sconce, E. Articles by Kamali, F. Search for Related Content PubMed PubMed Citation Articles by Sconce, E. Articles by Kamali, F. Related Collections Brief Reports Related Letter in Blood Online Related Article in Blood Online Social Bookmarking                   What's this?

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