Vitamin K's Delicate Balancing ActApril 2006
By Julius G. Goepp, MD
Other Effects of Vitamin K Antagonists
Supporting active vitamin K-dependent Gla-proteins in patients on warfarin is also a good idea in light of what we have learned about the importance of these proteins in tissues besides blood. Because warfarin inhibits activation of Gla-proteins, it has the potential to reverse vitamin K’s effects, causing reduced calcification of bone and increased calcification of blood vessels. Both laboratory and clinical evidence support this suspicion.42 Warfarin blocked vitamin D-induced production of the bone protein osteocalcin in a laboratory model;69 subsequently, doses of warfarin comparable to those used in humans reduced bone strength and volume in laboratory rats.70 Reduced bone mineral density has been observed in warfarin-treated patients,71 and an association between the chronic use of warfarin and fracture risk has been reported in humans.72,73 A recent study of children on long-term warfarin therapy found significantly lower bone mineral density in the lumbar spine of treated patients than in a group of randomly selected controls.74
Arterial calcification, which is prevented by vitamin K-dependent matrix proteins, might also be influenced by warfarin treatment.14 Arterial calcification has been produced experimentally in rats by treatment with warfarin.40,41 In a 2005 study of older patients with known calcification of the aortic valve, those who had been on long-term oral anticoagulation therapy had markedly more calcium in their coronary arteries and aortic valves than did patients who had not been on such treatment.75
In addition to its effects on the coagulation cascade, vitamin K is now known to be involved in many of the body’s most critical functions. Bone mineralization and vascular calcification, two bodily functions affected by aging, are fundamentally related to each other through the actions of vitamin K. It is becoming increasingly clear that vitamin K antagonists (like warfarin) may have the unintended effects of exacerbating osteoporosis and atherosclerosis. Fortunately, the very science that revealed this new threat probably holds the answer to preventing it.
In 2005, a Japanese study demonstrated that the Gla-proteins governing coagulation require higher doses of warfarin for inhibition than do those that control bone mineralization.76 If confirmed, this exciting finding raises the possibility that careful, low-dose vitamin K supplementation could prevent warfarin’s deleterious effects on bone and blood vessel calcification, while preserving its beneficial effect of anticoagulation. University of Texas researchers have already demonstrated the safety and benefit of low-dose vitamin K supplementation in patients taking warfarin.68
Patients taking warfarin (Coumadin®) or other vitamin K antagonists should talk with their doctors about this recent literature, to learn whether regular, low-dose supplements of vitamin K (100 mcg/day), taken under careful medical supervision, may be right for them. Because of the considerable evidence for increasing the daily recommended dose of vitamin K,14,15,17,20 people who are not taking anticoagulant medication may want to consider beginning daily supplements of vitamin K to support the Gla-proteins that can slow osteoporosis and reduce arterial calcification.36 For people in good health, doses of 10 mg to 40 mg have been used.39
1. Saltzman JR, Russell RM. The aging gut. Nutritional issues. Gastroenterol Clin North Am. 1998 Jun;27(2):309-24.
2. Moriuchi S, Hosoya N. Changes of vitamin status and calcium metabolism in aging. J Nutr Sci Vitaminol.(Tokyo). 1985 Dec;31 SupplS11-4.
3. Tsaioun KI. Vitamin K-dependent proteins in the developing and aging nervous system. Nutr Rev. 1999 Aug;57(8):231-40.
4. Saunders LZ. Frank Schofield (1889-1970) and anticoagulant therapy. Med Herit. 1986 Jul;2(4):310-2.
5. Meier B. Blood thinning in heart patients. Ther Umsch. 1995 Oct;52(10):661-71.
6. Dorffler-Melly J, Schmidli J, Mahler F. Anticoagulation and antiaggregation in patients with peripheral arterial occlusive diseases. Ther Umsch. 2003 Jan;60(1):36-42.
7. Mueller RL, Scheidt S. History of drugs for thrombotic disease. Discovery, development, and directions for the future. Circulation. 1994 Jan;89(1):432-49.
8. Miggiano GA, Robilotta L. Vitamin K and diet: problems and prospects. Clin Ter. 2005 Jan;156(1-2):41-6.
9. Israels LG, Israels ED, Saxena SP. The riddle of vitamin K1 deficit in the newborn. Semin Perinatol. 1997 Feb;21(1):90-6.
10. Kowdley KV. Lipids and lipid-activated vitamins in chronic cholestatic diseases. Clin Liver Dis. 1998 May;2(2):373-89.
11. Krahenbuhl S. Consequences of cholestasis from the hepatologist’s viewpoint. Schweiz Med Wochenschr. 1997 May 10;127(19):821-8.
12. Mager DR, McGee PL, Furuya KN, Roberts EA. Prevalence of vitamin K deficiency in children with mild to moderate chronic liver disease. J Pediatr Gastroenterol Nutr. 2006 Jan;42(1):71-6.
13. Sokol RJ. Fat-soluble vitamins and their importance in patients with cholestatic liver diseases. Gastroenterol Clin North Am. 1994 Dec;23(4):673-705.
14. Berkner KL, Runge KW. The physiology of vitamin K nutriture and vitamin K-dependent protein function in atherosclerosis. J Thromb Haemost. 2004 Dec;2(12):2118-32.
15. Shoji S. Vitamin K and vascular calcification. Clin Calcium. 2002 Aug;12(8):1123-8.
16. Plaza SM, Lamson DW. Vitamin K2 in bone metabolism and osteoporosis. Altern Med Rev. 2005 Mar;10(1):24-35.
17. Booth SL, Suttie JW. Dietary intake and adequacy of vitamin K. J Nutr. 1998 May;128(5):785-8.
18. Davidson RT, Foley AL, Engelke JA, Suttie JW. Conversion of dietary phylloquinone to tissue menaquinone-4 in rats is not dependent on gut bacteria. J Nutr. 1998 Feb;128(2):220-3.
19. Thijssen HH, Drittij-Reijnders MJ. Vitamin K status in human tissues: tissue-specific accumulation of phylloquinone and menaquinone-4. Br J Nutr. 1996 Jan;75(1):121-7.
20. Askim M. Vitamin K in the Norwegian diet and osteoporosis. Tidsskr Nor Laegeforen. 2001 Sep 20;121(22):2614-6.
21. Jesty J, Beltrami E. Positive feedbacks of coagulation: their role in threshold regulation. Arterioscler Thromb Vasc Biol. 2005 Dec;25(12):2463-9.
22. Bern M. Observations on possible effects of daily vitamin K replacement, especially upon warfarin therapy. JPEN J Parenter Enteral Nutr. 2004 Nov;28(6):388-98.
23. Espana F, Medina P, Navarro S, et al. The multifunctional protein C system. Curr Med Chem Cardiovasc Hematol Agents. 2005 Apr;3(2):119-31.
24. Dahlback B, Villoutreix BO. The anticoagulant protein C pathway. FEBS Lett. 2005 Jun 13;579(15):3310-6.
25. Matsuzaka T, Tanaka H, Fukuda M, et al. Relationship between vitamin K dependent coagulation factors and anticoagulants (protein C and protein S) in neonatal vitamin K deficiency. Arch Dis Child. 1993 Mar;68(3 Spec No):297-302.
26. Esmon CT. Coagulation inhibitors in inflammation. Biochem Soc Trans. 2005 Apr;33(Pt 2):401-5.
27. Vermeer C, Shearer MJ, Zittermann A, et al. Beyond deficiency: potential benefits of increased intakes of vitamin K for bone and vascular health. Eur J Nutr. 2004 Dec;43(6):325-35.
28. Okano T. Vitamin D, K and bone mineral density. Clin Calcium. 2005 Sep;15(9):1489-94.
29. McLean RR, Booth SL, Kiel DP, et al. Association of dietary and biochemical measures of vitamin K with quantitative ultrasound of the heel in men and women. Osteoporos Int. 2006 Jan 6;1-8.
30. Kaneki M. Vitamin K2 as a protector of bone health and beyond. Clin Calcium. 2005 Apr;15(4):605-10.
31. Bonjour JP, Schurch MA, Rizzoli R. Nutritional aspects of hip fractures. Bone. 1996 Mar;18(3 Suppl):139S-44S.
32. Weber P. The role of vitamins in the prevention of osteoporosis—a brief status report. Int J Vitam Nutr Res. 1999 May;69(3):194-7.
33. Iwasaki Y, Yamato H, Murayama H, et al. Menatetrenone prevents osteoblast dysfunction in unilateral sciatic neurectomized rats. Jpn J Pharmacol. 2002 Sep;90(1):88-93.
34. Kishimoto H. Vitamin K and bone quality. Clin Calcium. 2004 Apr;14(4):621-6.
35. Iwamoto J, Takeda T, Ichimura S. Combined treatment with vitamin k2 and bisphosphonate in postmenopausal women with osteoporosis. Yonsei Med J. 2003 Oct 30;44(5):751-6.
36. Ryan-Harshman M, Aldoori W. Bone health. New role for vitamin K? Can Fam Physician. 2004 Jul;50:993-7.
37. Adams J, Pepping J. Vitamin K in the treatment and prevention of osteoporosis and arterial calcification. Am J Health Syst Pharm. 2005 Aug 1;62(15):1574-81.
38. Nieves JW. Osteoporosis: the role of micronutrients. Am J Clin Nutr. 2005 May;81(5):1232S-39S.
39. Available at: http://www.pdrhealth.com/drug_info/nmdrugprofiles/nutsupdrugs/vit_0267.shtml. Accessed February 8, 2006.
40. Bostrom K, Demer LL. Regulatory mechanisms in vascular calcification. Crit Rev Eukaryot Gene Expr. 2000;10(2):151-8.
41. Price PA, Faus SA, Williamson MK. Bisphosphonates alendronate and ibandronate inhibit artery calcification at doses comparable to those that inhibit bone resorption. Arterioscler Thromb Vasc Biol. 2001 May;21(5):817-24.
42. Demer LL, Tintut Y, Parhami F. Novel mechanisms in accelerated vascular calcification in renal disease patients. Curr Opin Nephrol Hypertens. 2002 Jul;11(4):437-43.
43. Devaraj S, Rosenson RS, Jialal I. Metabolic syndrome: an appraisal of the pro-inflammatory and procoagulant status. Endocrinol Metab Clin North Am. 2004 Jun;33(2):431-53.
44. Seyama Y, Wachi H. Atherosclerosis and matrix dystrophy. J Atheroscler Thromb. 2004;11(5):236-45.
45. Schurgers LJ, Teunissen KJ, Knapen MH, et al. Novel conformation-specific antibodies against matrix gamma-carboxyglutamic acid (Gla) protein: undercarboxylated matrix Gla protein as marker for vascular calcification. Arterioscler Thromb Vasc Biol. 2005 Aug;25(8):1629-33.
46. Geleijnse JM, Vermeer C, Grobbee DE, et al. Dietary intake of menaquinone is associated with a reduced risk of coronary heart disease: the Rotterdam Study. J Nutr. 2004 Nov;134(11):3100-5.
47. Villines TC, Hatzigeorgiou C, Feuerstein IM, O’Malley PG, Taylor AJ. Vitamin K1 intake and coronary calcification. Coron Artery Dis. 2005 May;16(3):199-203.
48. Kurnik D, Lubetsky A, Loebstein R, Almog S, Halkin H. Multivitamin supplements may affect warfarin anticoagulation in susceptible patients. Ann Pharmacother. 2003 Nov;37(11):1603-6.
49. Collier S, Fulhan J, Duggan C. Nutrition for the pediatric office: update on vitamins, infant feeding and food allergies. Curr Opin Pediatr. 2004 Jun;16(3):314-20.
50. Cornelissen M, von KR, Loughnan P, Schubiger G. Prevention of vitamin K deficiency bleeding: efficacy of different multiple oral dose schedules of vitamin K. Eur J Pediatr. 1997 Feb;156(2):126-30.
51. Eguchi T, Nakase H, Morimoto T, et al. Postoperative intracranial hemorrhage due to vitamin K deficiency: report of two cases. No Shinkei Geka. 1992 Jan;20(1):73-7.
52. Huilgol VR, Markus SL, Vakil NB. Antibiotic-induced iatrogenic hemobilia. Am J Gastroenterol. 1997 Apr;92(4):706-7.
53. Gordon BG, Haire WD, Stephens LC, Kotulak GD, Kessinger A. Protein C deficiency following hematopoietic stem cell transplantation: optimization of intravenous vitamin K dose. Bone Marrow Transplant. 1993 Jul;12(1):73-6.
54. Booth SL, Lichtenstein AH, O’Brien-Morse M, et al. Effects of a hydrogenated form of vitamin K on bone formation and resorption. Am J Clin Nutr. 2001 Dec;74(6):783-90.
55. Shetty HG, Woods F, Routledge PA. The pharmacology of oral anticoagulants: implications for therapy. J Heart Valve Dis. 1993 Jan;2(1):53-62.
56. Hathcock JN. Metabolic mechanisms of drug-nutrient interactions. Fed Proc. 1985 Jan;44(1 Pt 1):124-9.
57. Sebastian JL, Tresch DD. Use of oral anticoagulants in older patients. Drugs Aging. 2000 Jun;16(6):409-35.
58. Weiss P, Soff GA, Halkin H, Seligsohn U. Decline of proteins C and S and factors II, VII, IX and X during the initiation of warfarin therapy. Thromb Res. 1987 Mar 15;45(6):783-90.
59. Rieder MJ, Reiner AP, Gage BF, et al. Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. N Engl J Med. 2005 Jun 2;352(22):2285-93.
60. Veenstra DL, You JH, Rieder MJ, et al. Association of Vitamin K epoxide reductase complex 1 (VKORC1) variants with warfarin dose in a Hong Kong Chinese patient population. Pharmacogenet Genomics. 2005 Oct;15(10):687-91.
61. Dentali F, Ageno W. Management of coumarin-associated coagulopathy in the non-bleeding patient: a systematic review. Haematologica. 2004 Jul;89(7):857-62.
62. Crowther MA, Donovan D, Harrison L, McGinnis J, Ginsberg J. Low-dose oral vitamin K reliably reverses over-anticoagulation due to warfarin. Thromb Haemost. 1998 Jun;79(6):1116-8.
63. Crowther MA, Julian J, McCarty D, et al. Treatment of warfarin-associated coagulopathy with oral vitamin K: a randomized controlled trial. Lancet. 2000 Nov 4;356(9241):1551-3.
64. Duong TM, Plowman BK, Morreale AP, Janetzky K. Retrospective and prospective analyses of the treatment of overanticoagulated patients. Pharmacotherapy. 1998 Nov;18(6):1264-70.
65. Gunther KE, Conway G, Leibach L, Crowther MA. Low-dose oral vitamin K is safe and effective for outpatient management of patients with an INR>10. Thromb Res. 2004;113(3-4):205-9.
66. Poli D, Antonucci E, Lombardi A, et al. Safety and effectiveness of low dose oral vitamin K1 administration in asymptomatic out-patients on warfarin or acenocoumarol with excessive anticoagulation. Haematologica. 2003 Feb;88(2):237-8.
67. Shetty HG, Backhouse G, Bentley DP, Routledge PA. Effective reversal of warfarin-induced excessive anticoagulation with low dose vitamin K1. Thromb Haemost. 1992 Jan 23;67(1):13-5.
68. Reese AM, Farnett LE, Lyons RM, et al. Low-dose vitamin k to augment anticoagulation control. Pharmacotherapy. 2005;25(12):1746-51.
69. Koshihara Y, Hoshi K, Ishibashi H, Shiraki M. Vitamin K2 promotes 1alpha,25(OH)2 vitamin D3-induced mineralization in human periosteal osteoblasts. Calcif Tissue Int. 1996 Dec;59(6):466-73.
70. Simon RR, Beaudin SM, Johnston M, Walton KJ, Shaughnessy SG. Long-term treatment with sodium warfarin results in decreased femoral bone strength and cancellous bone volume in rats. Thromb Res. 2002 Feb 15;105(4):353-8.
71. Philip WJ, Martin JC, Richardson JM, et al. Decreased axial and peripheral bone density in patients taking long-term warfarin. QJM. 1995 Sep;88(9):635-40.
72. Booth SL, Mayer J. Warfarin use and fracture risk. Nutr Rev. 2000 Jan;58(1):20-2.
73. Hansen LB, Vondracek SF. Prevention and treatment of nonpostmenopausal osteoporosis. Am J Health Syst Pharm. 2004 Dec 15;61(24):2637-54.
74. Barnes C, Newall F, Ignjatovic V, et al. Reduced bone density in children on long-term warfarin. Pediatr Res. 2005 Apr;57(4):578-81.
75. 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 Sep 15;96(6):747-9.
76. Hara K, Kobayashi M, Akiyama Y. Comparison of inhibitory effects of warfarin on gamma-carboxylation between bone and liver in rats. J Bone Miner Metab. 2005;23(5):366-72.
77. Shah NS, Lazarus MC, Bugdodel R, et al. The effects of topical vitamin K on bruising after laser treatment. J Am Acad Dermatol. 2002 Aug;47(2):241-4.
78. Nouso K, Uematsu S, Shiraga K, et al. Regression of hepatocellular carcinoma during vitamin K administration. World J Gastroenterol. 2005 Nov 14;11(42):6722-4.
79. Yoshiji H, Kuriyama S, Noguchi R, et al. Amelioration of carcinogenesis and tumor growth in the rat liver by combination of vitamin K2 and angiotensin-converting enzyme inhibitor via anti-angiogenic activities. Oncol Rep. 2006 Jan;15(1):155-9.
80. Kuriyama S, Hitomi M, Yoshiji H, et al. Vitamins K2, K3 and K5 exert in vivo antitumor effects on hepatocellular carcinoma by regulating the expression of G1 phase-related cell cycle molecules. Int J Oncol. 2005 Aug;27(2):505-11.
81. Enokimura N, Shiraki K, Kawakita T, et al. Vitamin K analog (compound 5) induces apoptosis in human hepatocellular carcinoma independent of the caspase pathway. Anticancer Drugs. 2005 Sep;16(8):837-44.
82. Hitomi M, Yokoyama F, Kita Y, et al. Antitumor effects of vitamins K1, K2 and K3 on hepatocellular carcinoma in vitro and in vivo. Int J Oncol. 2005 Mar;26(3):713-20.
83. Lin C, Kang J, Zheng R. Vitamin K3 triggers human leukemia cell death through hydrogen peroxide generation and histone hyperacetylation. Pharmazie. 2005 Oct;60(10):765-71.
84. Yokoyama T, Miyazawa K, Yoshida T, Ohyashiki K. Combination of vitamin K2 plus imatinib mesylate enhances induction of apoptosis in small cell lung cancer cell lines. Int J Oncol. 2005 Jan;26(1):33-40.
85. Gad A, Tanaka E, Matsumoto A, et al. Assessment of KL-6 as a tumor marker in patients with hepatocellular carcinoma. World J Gastroenterol. 2005 Nov 14;11(42):6607-12.
86. Iso Y, Sawada T, Shimoda M, et al. Solitary AFP- and PIVKA-II-producing hepatoid gastric cancer with giant lymph node metastasis. Hepatogastroenterology. 2005 Nov;52(66):1930-2.
87. Hasegawa Y, Tomita K, Hashimoto K, et al. Des-gamma-carboxy prothrombin (PIVKA-II)-producing mediastinal embryonal carcinoma with features of hepatoid differentiation. Anticancer Res. 2005 Nov;25(6C):4569-71.
88. Dahlback B, Villoutreix BO. Regulation of blood coagulation by the protein C anticoagulant pathway: novel insights into structure-function relationships and molecular recognition. Arterioscler Thromb Vasc Biol. 2005 Jul;25(7):1311-20.
89. Gage BF, Birman-Deych E, Radford MJ, Nilasena DS, Binder EF. Risk of osteoporotic fracture in elderly patients taking warfarin: results from the National Registry of Atrial Fibrillation 2. Arch Intern Med. 2006 Jan 23;166(2):241-6.
90. Tang QY, Kukita T, Ushijima Y, et al. Regulation of osteoclastogenesis by Simon extracts composed of caffeic acid and related compounds: successful suppression of bone destruction accompanied with adjuvant-induced arthritis in rats. Histochem Cell Biol. 2005 Oct 5;1-11.
91. Schurgers LJ, Aebert H, Vermeer C, Bultmann B, Janzen J. Oral anticoagulant treatment: friend or foe in cardiovascular disease? Blood. 2004 Nov 15;104(10):3231-2.
92. Braam LA, Hoeks AP, Brouns F, et al. Beneficial effects of vitamins D and K on the elastic properties of the vessel wall in postmenopausal women: a follow-up study. Thromb Haemost. 2004 Feb;91(2):373-80.