Vitamin K: The coagulation vitamin that became omnipotent

Summary

Vitamin K, discovered in the 1930s, functions as cofactor for the post-translational carboxylation of glutamate residues. Gammacarboxy glutamic acid (Gla)-residues were first identified in prothrombin and coagulation factors in the 1970s; subsequently, extra-hepatic Gla proteins were described,including osteocalcin and matrix Gla protein (MGP). Impairment of the function of osteocalcin and MGP due to incomplete carboxylation results in an increased risk for developing osteoporosis and vascular calcification, respectively, and is an unexpected side effect of treatment with oral anticoagulants. It is conceivable that other side effects, possible involving growth-arrest-specific gene 6 (Gas6) protein will be identified in forthcoming years. In healthy individuals, substantial fractions of osteocalcin and MGP circulate as incompletely carboxylated species, indicating that the majority of these individuals is subclinically vitamin K-deficient. Potential new application areas for vitamin K are therefore its use in dietary supplements and functional foods for healthy individuals to prevent bone and vascular disease, as well as for patients on oral anticoagulant treatment to offer them protection against coumarin-induced side effects and to reduce diet-induced fluctuations in their INR values.

Keywords

Vitamin K - matrix Gla protein - osteocalcin - oral anticoagulants - diagnostics

 

• References

• 1 Dam H, Schonheyder F. A deficiencydiseasein chicks resembling scurvy. Biochem J 1934; 28: 1355-1359.
• 2 McFarlane WD, Graham WR, Richardson F. The fat-soluble vitamin requirements of the chick: The vitaminA and vitamin Dcontent of fish meal and meat meal. Biochem J 1931; 25: 358-366.
• 3 Dam H. The antihaemorrhagic vitamin of the chick. Biochem J 1935; 29: 1273-1285.
• 4 Almquist HJ, Stokstad ELR. Hemorrhagic chick disease of dietaryorigin. J Biol Chem 1935; 111: 105-113.
• 5 Schønheyder F. The quantitative determination of vitamin K. I. Biochem J 1936; 30: 890-896.
• 6 Dam H, Schønheyder F, Tage-Hansen E. Studies on the mode of action of vitamin K. Biochem J 1936; 30: 1075-1079.
• 7 Quick AJ. The coagulation defect in sweet clover disease and in the hemorrhagic chick disease of dietary origin: A consideration of the source of prothrombin. Am J Physiol 1937; 118: 260-271.
• 8 Quick AJ. The development and use of the prothrombin tests. Circulation 1959; 19: 92-96.
• 9 Campbell HA, Link KP. Studies on the hemorrhagic sweet cloverdisease. IV. The isolationand crystallization of the antihemorrhagic agent. J Biol Chem 1940; 138: 21-33.
• 10 Almquist HJ. Purification of the antihemorrhagic vitamin. J Biol Chem 1936; 114: 241-245.
• 11 Almquist HJ. Purification of the antihemorrhagic vitamin by distillation. J Biol Chem 1936; 115: 589-591.
• 12 Dam H, Greiger A, Glavind J. et al. Isoliering des Vitamins K in hochgereinigter Form. Helv Chim Acta 1939; 22: 310-313.
• 13 Binkley SB, Mac Corquodale DW, Thayer SA. et al. The isolation of vitaminK₁ . J Biol Chem 1939; 130: 219-234.
• 14 McKee RW, Binkley SB, Mac Corquodale DW. et al. The isolation of vitamins K₁ and K₂ . J Am Chem Soc 1939; 61: 1295.
• 15 Binkley SB, Mac Corquodale DW, Cheney LC. et al. Derivatives of vitamins K₁ and K₂ . J Am Chem Soc 1939; 61: 1612-1613.
• 16 Suttie JW. Vitamin K. In: Handbook of lipid research: The fat-soluble vitamins. 1^st ed. Plenum Press; 1978. pp. 211-277.
• 17 Dam H, Glavind J. Vitamin K in human pathology. Lancet 1938; 231: 720-721.
• 18 Waddell WW, Guerry D. Therole of vitamin Kin the etiology, prevention, and treatment of hemorrhage in the newborn infant. Part II,. J Ped 1939; 15: 802-811.
• 19 Lehmann J. Vitamin K as a prophylactic in 13.000 infants. Lancet 1944; 243: 493-494.
• 20 Zetterstrom R. H. C. P. Dam (1895-1976), and E. A. Doisy (1893-1986): the discovery of antihaemorrhagic vitamin and its impact on neonatal health. Acta Paediatr 2006; 95: 642-644.
• 21 Dam H. The discovery of vitamin K, its biological functions and the rapeutical application. Nobel Lecture, December 12, 1946.
• 22 Jacobsen BK, Dam H. Vitamin Kinbacteria. Biochim Biophys Acta 1960; 40: 211-216.
• 23 Hart JP, Shearer MJ, Klenerman L. et al. Electro-chemical detection of depressed circulatinglevels of vitamin K1 in osteoporosis. J Clin Endocrinol Metab 1985; 60: 1268-1269.
• 24 Suhara Y, Kamao M, Tsugawa N. et al. Method for the determination of vitamin Khomologues in human plasma using high-performance liquid chromatography-tandem mass spectrometry. Anal Chem 2005; 77: 757-763.
• 25 Guy’s and St Thomas’ NHS Foundation Trust.. Human Nutrias is Institute; The vitamin K External Quality Assurance Scheme (KEQAS). Available at: http://www.gstt.nhs.uk/services/managednetworksoncologyandhaem/chat/hnu/keqas.aspx Accessed on April 10, 2007.
• 26 Stenflo J, Fernlund P, Egan W. et al. Vitamin K dependent modifications of glutamic acidresidues in prothrombin. Proc Natl Acad Sci USA 1974; 71: 2730-2733.
• 27 Nelsestuen GL, Zytkovicz TH, Howard JB. The mode of action of vitamin K. Identification of gamma-carboxyglutamic acid as a component of prothrombin. J Biol Chem 1974; 249: 6347-6350.
• 28 Esmon CT, Sadowski JA, Suttie JW. A newcarboxylationreaction. The vitamin K-dependent incorporation of H-14-CO3- into prothrombin. J Biol Chem 1975; 250: 4744-4748.
• 29 Wu SM, Morris DP, Stafford DW. Identification and purificationtonear homogeneity of the vitamin K-dependent carboxylase. Proc Natl Acad Sci USA 1991; 88: 2236-2240.
• 30 Chu PH, Huang TY, Williams J. et al. Purifiedvitamin Kepoxide reductase alone is sufficient for conversion of vitamin Kepoxide to vitamin K and vitamin Ktovitamin KH2. Proc Natl Acad Sci USA 2006; 103: 19308-19313.
• 31 Rost S, Fregin A, Ivaskevicius V. et al. Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2. Nature 2004; 427: 537-541.
• 32 Wu SM, Stanley TB, Mutucumarana VP. et al. Characterization of the gamma-glutamylcarboxylase. Thromb Haemost 1997; 78: 599-604.
• 33 Chu PH, Huang TY, Williams J. et al. Purifiedvitamin Kepoxide reductase alone is sufficient for conversion of vitamin Kepoxide to vitamin K and vitamin Ktovitamin KH2. Proc Natl Acad Sci USA 2006; 103: 19308-19313.
• 34 Suttie JW. Vitamin K-dependent carboxylase. Ann Rev Biochem 1985; 54: 459-477.
• 35 Lian JB, Friedman PA. Thevitamin K-dependent synthesis of gamma-carboxyglutamic acidbybone microsomes. J Biol Chem 1978; 253: 6623-6626.
• 36 de Boer-van den Berg MA, Verstijnen CP, Vermeer C. Vitamin K-dependent carboxylase in skin. J Invest Dermatol 1986; 87: 377-380.
• 37 Vermeer C. Bijwerkingen vanoraleantistollingstherapie?. Ned T Geneesk 1982; 126: 2394.
• 38 Hauschka PV, Lian JB, Gallop PM. Direct identification of the calcium-binding aminoacid, gamma-carboxyglutamate, in mineralized tissue. Proc Natl Acad Sci USA 1975; 72: 3925-3929.
• 39 Price PA, Otsuka AA, Poser JW. et al. Characterization of agamma-carboxyglutamic acid-containing proteinfrom bone. Proc Natl Acad Sci USA 1976; 73: 1447-1451.
• 40 Price PA, Urist MR, Otawara Y. Matrix Gla protein, a new gamma-carboxyglutamic acid-containing protein which is associated with the organic matrix of bone. Biochem Biophys Res Commun 1983; 117: 765-771.
• 41 Luo G, Ducy P, McKee MD. et al. Spontaneous calcification of arteries and cartilage in micelacking matrix GLA protein. Nature 1997; 386: 78-81.
• 42 Munroe PB, Olgunturk RO, Fryns JP. et al. Mutations in the gene encoding the human matrix Gla protein cause Keutel syndrome. Nat Genet 1999; 21: 142-144.
• 43 Hur DJ, Raymond GV, Kahler SG. et al. Anovel MGP mutation in a consanguineous family: review of the clinical and molecular characteristics of Keutel syndrome. Am J Med Genet A 2005; 135: 36-40.
• 44 Keutel J, Jorgensen G, Gabriel P. A new autosomal-recessive hereditary syndrome. Multiple peripheral pulmonary stenosis, brachytelephalangia, inner-ear deafness, ossification or calcification of cartilages. Dtsch Med Wochenschr 1971; 96: 1676-1681 passim.
• 45 Meier M, Weng LP, Alexandrakis E. et al. Tracheo-bronchial stenosis in Keutel syndrome. Eur Respir J 2001; 17: 566-569.
• 46 Berkner KL. The vitamin K-dependent carboxylase. Annu Rev Nutr 2005; 25: 127-149.
• 47 Pastoureau P, Vergnaud P, Meunier PJ. et al. Osteopenia and bone-remodeling abnormalities in warfarin-treated lambs. J Bone Miner Res 1993; 8: 1417-1426.
• 48 Gage BF, Birman-Deych E, Radford MJ. et al. Risk of osteoporotic fracture in elderlypatientstaking warfarin: results from the National Registry of Atrial Fibrillation 2. Arch Intern Med 2006; 166: 241-246.
• 49 Schurgers LJ, Aebert H, Vermeer C. et al. Oral anticoagulant treatment: friend or foe in cardiovascular dis-ease?. Blood 2004; 104: 3231-3232.
• 50 Koos R, Mahnken AH, Muhlenbruch G. et al. Relation of oral anticoagulation to cardiac valvular and coronary calcium assessed by multislicespiral computed tomography. Am J Cardiol 2005; 96: 747-749.
• 51 Hall JG, Pauli RM, Wilson KM. Maternal and fetal sequelae of anticoagulation during pregnancy. Am J Med 1980; 68: 122-140.
• 52 Howe AM, Webster WS. The warfar in embryopathy: a rat model showing maxillonasal hypoplasia and other skeletal disturbances. Teratology 1992; 46: 379-390.
• 53 Howe AM, Lipson AH, de Silva M. et al. Severe cervical dysplasia and nasal cartilage calcification following prenatal warfarin exposure. Am J Med Genet 1997; 71: 391-396.
• 54 Sconce E, Avery P, Wynne H. et al. Vitamin K supplementation can improve stability of anticoagulation for patients with unexplained variability in response to warfarin. Blood 2007; 109: 2419-2423.
• 55 Reese AM, Farnett LE, Lyons RM. et al. Low-dose vitamin K to augment anticoagulation control. Pharmacotherapy 2005; 25: 1746-1751.
• 56 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.
• 57 Spronk HM, Soute BA, Schurgers LJ. et al. Tissue-specific utilization of menaquinone-4 results in the prevention of arterial calcification in warfarin-treated rats. J Vasc Res 2003; 40: 531-537.
• 58 Schurgers LJ, Spronk HM, Soute BA. et al. Regression of warfarin-induced medial elastocalcinosis by high intake of vitamin Kinrats. Blood 2007; 109: 2823-2831.
• 59 Schurgers LJ, Teunissen KJ, Hamulyak K. et al. Vitamin K-containing dietary supplements: comparison of synthetic vitamin K1 and natto-derived menaqui-none-7. Blood 2007; 109: 3279-3283.
• 60 Stafford DW, Roberts H, Vermeer C. Vitamin K supplementation during oral anticoagulation: cautions. Blood 2007; 109: 3607.
• 61 Knapen MH, Schurgers LJ, Vermeer C. Vitamin K(2) supplementation improves hip bone geometry and bone strength indices in postmenopausal women. Osteoporos Int. 2007 in press.
• 62 Schurgers LJ, Teunissen KJ, Knapen MH. et al. Novelcon formation-specific antibodies against matrix gamma-carboxyglutamic acid(Gla)protein: undercarboxylated matrix Gla protein as marker for vascular calcification. Arterioscler Thromb Vasc Biol 2005; 25: 1629-1633.
• 63 Szulc P, Chapuy MC, Meunier PJ. et al. Serum undercarboxylated osteocalcin is a marker of therisk of hip fracture: a three year follow-up study. Bone 1996; 18: 487-488.
• 64 Braam LA, Dissel P, Gijsbers BL. et al. Assay for Human Matrix Gla Protein in Serum: Potential Applications in the Cardiovascular Field. Arterioscler Thromb Vasc Biol 2000; 20: 1257-1261.
• 65 Binkley NC, Krueger DC, Engelke JA. et al. Vitamin K supplementation reduces serum concentrations of under-gamma-carboxylated osteocalcin in healthy young and elderly adults. Am J Clin Nutr 2000; 72: 1523-1528.
• 66 Binkley NC, Krueger DC, Kawahara TN. et al. A high phylloquinone in take is required to achieve maximaloste ocalcin gamma-carboxylation. Am J Clin Nutr 2002; 76: 1055-1060.
• 67 Booth SL, Tucker KL, Chen H. et al. Dietary vitamin K intakes are associated with hip fracture but not with bone mineral density in elderly men and women. Am J Clin Nutr 2000; 71: 1201-1208.
• 68 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; 134: 3100-3105.
• 69 Braam LA, Knapen MH, Geusens P. et al. Vitamin K1 supplementation retards bone loss in postmenopausal women between 50 and 60 years of age. Calcif Tissue Int 2003; 73: 21-26.
• 70 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; 91: 373-380.
• 71 Hafizi S, Dahlback B. Gas6 and protein S. Vitamin K-dependent ligands for the Axl receptor tyrosine kinase subfamily. Febs J 2006; 273: 5231-5244.
• 72 Nakano T, Kawamoto K, Kishino J. et al. Requirement of gamma-carboxyglutamic acid residues for the biological activity of Gas6: contribution of endogenous Gas6 to the proliferation of vascular smooth muscle cells. Biochem J 1997; 323: 387-392.
• 73 Schurgers LJ, Dissel PEP, Spronk HMH. et al. Role of vitamin K and vitamin K-dependent proteins in vascular calcification. Z Kardiol 2001; 90 (Suppl. 03) 57-63.