Vitamin K: The coagulation vitamin that became omnipotent

 

 Permissions and Reprints

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.

• References

• 1 Dam H, Schonheyder F. A deficiencydiseasein chicks resembling scurvy. Biochem J 1934; 28: 1355-1359.
  CrossrefPubMedGoogle Scholar
• 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.
  CrossrefPubMedGoogle Scholar
• 3 Dam H. The antihaemorrhagic vitamin of the chick. Biochem J 1935; 29: 1273-1285.
  CrossrefPubMedGoogle Scholar
• 4 Almquist HJ, Stokstad ELR. Hemorrhagic chick disease of dietaryorigin. J Biol Chem 1935; 111: 105-113.
  PubMedGoogle Scholar
• 5 Schønheyder F. The quantitative determination of vitamin K. I. Biochem J 1936; 30: 890-896.
  CrossrefPubMedGoogle Scholar
• 6 Dam H, Schønheyder F, Tage-Hansen E. Studies on the mode of action of vitamin K. Biochem J 1936; 30: 1075-1079.
  CrossrefPubMedGoogle Scholar
• 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.
  PubMedGoogle Scholar
• 8 Quick AJ. The development and use of the prothrombin tests. Circulation 1959; 19: 92-96.
  CrossrefPubMedGoogle Scholar
• 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.
  PubMedGoogle Scholar
• 10 Almquist HJ. Purification of the antihemorrhagic vitamin. J Biol Chem 1936; 114: 241-245.
  PubMedGoogle Scholar
• 11 Almquist HJ. Purification of the antihemorrhagic vitamin by distillation. J Biol Chem 1936; 115: 589-591.
  PubMedGoogle Scholar
• 12 Dam H, Greiger A, Glavind J. et al. Isoliering des Vitamins K in hochgereinigter Form. Helv Chim Acta 1939; 22: 310-313.
  CrossrefPubMedGoogle Scholar
• 13 Binkley SB, Mac Corquodale DW, Thayer SA. et al. The isolation of vitaminK₁ . J Biol Chem 1939; 130: 219-234.
  PubMedGoogle Scholar
• 14 McKee RW, Binkley SB, Mac Corquodale DW. et al. The isolation of vitamins K₁ and K₂ . J Am Chem Soc 1939; 61: 1295.
  PubMedGoogle Scholar
• 15 Binkley SB, Mac Corquodale DW, Cheney LC. et al. Derivatives of vitamins K₁ and K₂ . J Am Chem Soc 1939; 61: 1612-1613.
  CrossrefPubMedGoogle Scholar
• 16 Suttie JW. Vitamin K. In: Handbook of lipid research: The fat-soluble vitamins. 1^st ed. Plenum Press; 1978. pp. 211-277.
  Google Scholar
• 17 Dam H, Glavind J. Vitamin K in human pathology. Lancet 1938; 231: 720-721.
  CrossrefPubMedGoogle Scholar
• 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.
  CrossrefPubMedGoogle Scholar
• 19 Lehmann J. Vitamin K as a prophylactic in 13.000 infants. Lancet 1944; 243: 493-494.
  CrossrefPubMedGoogle Scholar
• 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.
  CrossrefPubMedGoogle Scholar
• 21 Dam H. The discovery of vitamin K, its biological functions and the rapeutical application. Nobel Lecture, December 12, 1946.
  PubMedGoogle Scholar
• 22 Jacobsen BK, Dam H. Vitamin Kinbacteria. Biochim Biophys Acta 1960; 40: 211-216.
  CrossrefPubMedGoogle Scholar
• 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.
  CrossrefPubMedGoogle Scholar
• 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.
  CrossrefPubMedGoogle Scholar
• 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.
  PubMedGoogle Scholar
• 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.
  CrossrefPubMedGoogle Scholar
• 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.
  PubMedGoogle Scholar
• 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.
  PubMedGoogle Scholar
• 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.
  CrossrefPubMedGoogle Scholar
• 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.
  CrossrefPubMedGoogle Scholar
• 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.
  CrossrefPubMedGoogle Scholar
• 32 Wu SM, Stanley TB, Mutucumarana VP. et al. Characterization of the gamma-glutamylcarboxylase. Thromb Haemost 1997; 78: 599-604.
  Article in Thieme ConnectPubMedGoogle Scholar
• 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.
  CrossrefPubMedGoogle Scholar
• 34 Suttie JW. Vitamin K-dependent carboxylase. Ann Rev Biochem 1985; 54: 459-477.
  CrossrefPubMedGoogle Scholar
• 35 Lian JB, Friedman PA. Thevitamin K-dependent synthesis of gamma-carboxyglutamic acidbybone microsomes. J Biol Chem 1978; 253: 6623-6626.
  PubMedGoogle Scholar
• 36 de Boer-van den Berg MA, Verstijnen CP, Vermeer C. Vitamin K-dependent carboxylase in skin. J Invest Dermatol 1986; 87: 377-380.
  CrossrefPubMedGoogle Scholar
• 37 Vermeer C. Bijwerkingen vanoraleantistollingstherapie?. Ned T Geneesk 1982; 126: 2394.
  PubMedGoogle Scholar
• 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.
  CrossrefPubMedGoogle Scholar
• 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.
  CrossrefPubMedGoogle Scholar
• 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.
  CrossrefPubMedGoogle Scholar
• 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.
  CrossrefPubMedGoogle Scholar
• 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.
  CrossrefPubMedGoogle Scholar
• 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.
  PubMedGoogle Scholar
• 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.
  Article in Thieme ConnectPubMedGoogle Scholar
• 45 Meier M, Weng LP, Alexandrakis E. et al. Tracheo-bronchial stenosis in Keutel syndrome. Eur Respir J 2001; 17: 566-569.
  CrossrefPubMedGoogle Scholar
• 46 Berkner KL. The vitamin K-dependent carboxylase. Annu Rev Nutr 2005; 25: 127-149.
  CrossrefPubMedGoogle Scholar
• 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.
  PubMedGoogle Scholar
• 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.
  CrossrefPubMedGoogle Scholar
• 49 Schurgers LJ, Aebert H, Vermeer C. et al. Oral anticoagulant treatment: friend or foe in cardiovascular dis-ease?. Blood 2004; 104: 3231-3232.
  CrossrefPubMedGoogle Scholar
• 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.
  CrossrefPubMedGoogle Scholar
• 51 Hall JG, Pauli RM, Wilson KM. Maternal and fetal sequelae of anticoagulation during pregnancy. Am J Med 1980; 68: 122-140.
  CrossrefPubMedGoogle Scholar
• 52 Howe AM, Webster WS. The warfar in embryopathy: a rat model showing maxillonasal hypoplasia and other skeletal disturbances. Teratology 1992; 46: 379-390.
  CrossrefPubMedGoogle Scholar
• 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.
  CrossrefPubMedGoogle Scholar
• 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.
  CrossrefPubMedGoogle Scholar
• 55 Reese AM, Farnett LE, Lyons RM. et al. Low-dose vitamin K to augment anticoagulation control. Pharmacotherapy 2005; 25: 1746-1751.
  CrossrefPubMedGoogle Scholar
• 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.
  CrossrefPubMedGoogle Scholar
• 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.
  CrossrefPubMedGoogle Scholar
• 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.
  PubMedGoogle Scholar
• 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.
  CrossrefPubMedGoogle Scholar
• 60 Stafford DW, Roberts H, Vermeer C. Vitamin K supplementation during oral anticoagulation: cautions. Blood 2007; 109: 3607.
  PubMedGoogle Scholar
• 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.
  PubMedGoogle Scholar
• 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.
  CrossrefPubMedGoogle Scholar
• 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.
  CrossrefPubMedGoogle Scholar
• 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.
  CrossrefPubMedGoogle Scholar
• 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.
  CrossrefPubMedGoogle Scholar
• 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.
  CrossrefPubMedGoogle Scholar
• 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.
  CrossrefPubMedGoogle Scholar
• 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.
  CrossrefPubMedGoogle Scholar
• 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.
  CrossrefPubMedGoogle Scholar
• 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.
  Article in Thieme ConnectPubMedGoogle Scholar
• 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.
  CrossrefPubMedGoogle Scholar
• 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.
  CrossrefPubMedGoogle Scholar
• 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.
  PubMedGoogle Scholar