Current pharmacogenetic developments in oral anticoagulation therapy: The influence of variant VKORC1 and CYP2C9 alleles

Johannes Oldenburg; Carville G. Bevans; Andreas Fregin; Christof Geisen; Clemens Müller-Reible; Matthias Watzka

doi:10.1160/TH07-07-0454

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2007; 98(03): 570-578
DOI: 10.1160/TH07-07-0454

Theme Issue Article

Schattauer GmbH

Current pharmacogenetic developments in oral anticoagulation therapy: The influence of variant VKORC1 and CYP2C9 alleles

Johannes Oldenburg

¹Institute for Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Bonn, Germany

,

Carville G. Bevans

²Department of Structural Biology, Max Planck Institute of Biophysics, Frankfurt am Main, Germany

,

Andreas Fregin

³Institute of Human Genetics, University of Würzburg, Würzburg, Germany

,

Christof Geisen

⁴DRK Blood Donor Service Baden Württemberg-Hessen, Frankfurt am Main, Germany

,

Clemens Müller-Reible

³Institute of Human Genetics, University of Würzburg, Würzburg, Germany

,

Matthias Watzka

¹Institute for Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Bonn, Germany

› Author Affiliations

Abstract

Summary

For decades coumarins have been the most commonly prescribed drugs for therapy and prophylaxis of thromboembolic conditions. Despite the limitation of their narrow therapeutic dosage window, the broad variation of intra- and inter-individual drug requirement, and the relatively high incidence of bleeding complications,prescriptions for coumarins are increasing due to the aging populations in industrialised countries.The identification of the molecular target of coumarins,VKORC1, has greatly improved the understanding of coumarin treatment and illuminated new perspectives for a safer and more individualized oral anticoagulation therapy. Mutations and SNPs within the translated and non-translated regions of the VKORC1 gene have been shown to cause coumarin resistance and sensitivity,respectively. Besides the known CYP2C9 variants that affect coumarin metabolism, the haplotype VKORC1*2 representing a frequent SNP within the VKORC1 promoter has been identified as a major determinant of coumarin sensitivity,reducingVKORC1 enzyme activity to 50% of wild type. Homozygous carriers of the VKORC1*2 allele are strongly predisposed to coumarin sensitivity. Using individualized dose adaptation, a significant reduction of bleeding complications can be expected, especially in the initial drug saturation phase. Furthermore, concomitant application of low dose vitamin K may significantly reduce intra-individual coumarin dose variation and, thus, may stabilize oral anticoagulation therapy. The use of new pharmacogenetics-based dosing schemes and the concomitant application of low-dose vitamin K with coumarins will decidedly influence the current practice of oral anticoagulation and greatly improve coumarin drug safety.

Keywords

VKORC1 - CYP2C9 - acenocoumarol - phenprocoumon - warfarin - genotype

Full Text

References

References
1 Palareti G, Manotti C, D’Angelo A. et al. Thrombotic events during oral anticoagulant treatment: results of the inception-cohort, prospective, collaborative ISCOAT study: ISCOAT study group (Italian Study on Complications of Oral Anticoagulant Therapy). Thromb Haemost 1997; 78: 1438-1443.
2 Baglin TP, Rose PE. Guidelines on oral anticoagulation. Br J Haematol 1998; 101: 374-387.
3 Anand SS, Yusuf S. Oral anticoagulant therapy in patients with coronary artery disease: a meta-analysis. J Am Med Assoc 1999; 282: 2058-2067.
4 Kuijer PM, Hutten BA, Prins MH. et al. Prediction of the risk of bleeding during anticoagulant treatment for venous thromboembolism. Arch Intern Med 1999; 159: 457-460.
5 Beyth RJ, Milligan PE, Gage BF. Risk factors for bleeding in patients taking coumarins. Curr Hematol Rep 2002; 1: 41-49.
6 Wilkinson TJ, Sainsbury R. Evaluation of a warfarin initiation protocol for older people. Intern Med J 2003; 33: 465-467.
7 Kamali F, Khan TI, King BP. et al. Contribution of age, body size, and CYP2C9 genotype to anticoagulant response to warfarin. Clin Pharmacol Ther 2004; 75: 204-212.
8 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.
9 Li T, Chang CY, Jin DY. et al. Identification of the gene for vitamin K epoxide reductase. Nature 2004; 427: 541-544.
10 Rieder MJ, Reiner AP, Gage BF. et al. Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. N Engl J Med 2005; 352: 2285-2293.
11 Yuan HY, Chen JJ, Lee MT. et al. A novel functional VKORC1 promoter polymorphism is associated with inter-individual and inter-ethnic differences in warfarin sensitivity. Hum Mol Genet 2005; 14: 1745-1751.
12 Harrington DJ, Underwood S, Morse C. et al. Pharmacodynamic resistance to warfarin associated with a Val66Met substitution in vitamin K epoxide reductase complex subunit 1. Thromb Haemost 2005; 93: 23-26.
13 Bodin L, Horellou MH, Flaujac C. et al. A vitamin K epoxide reductase complex subunit-1 (VKORC1) mutation in a patient with vitamin K antagonist resistance. J Thromb Haemost 2005; 3: 1533-1535.
14 D’Ambrosio RL, D’Andrea G, Cafolla A. et al. A new vitamin K epoxide reductase complex subunit-1 (VKORC1) mutation in a patient with decreased stability of CYP2C9 enzyme. J Thromb Haemost 2007; 5: 191-193.
15 Loebstein R, Dvoskin I, Halkin H. et al. A coding VKORC1 Asp36Tyr polymorphism predisposes to warfarin resistance. Blood 2007; 109: 2477-2480.
16 Sconce EA, Khan TI, Wynne HA. et al. The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen. Blood 2005; 106: 2329-2333.
17 Tham LS, Goh BC, Nafziger A. et al. A warfarindosing model in Asians that uses single-nucleotide polymorphisms in vitamin K epoxide reductase complex and cytochrome P450 2C9. Clin Pharmacol Ther 2006; 80: 346-355.
18 Sconce EA, Kamali F. Appraisal of current vitamin K dosing algorithms for the reversal of over-anticoagulation with warfarin: the need for a more tailored dosing regimen. Eur J Haematol 2006; 77: 457-462.
19 Wadelius M, Chen LY, Downes K. et al. Common VKORC1 and GGCX polymorphisms associated with warfarin dose. Pharmacogenomics J 2005; 5: 262-270.
20 Carlquist JF, Horne BD, Muhlestein JB. et al. Genotypes of the cytochrome p450 isoform, CYP2C9, and the vitamin K epoxide reductase complex subunit 1 conjointly determine stable warfarin dose: a prospective study. J Thromb Thrombolysis 2006; 22: 191-197.
21 Fennerty A, Dolben J, Thomas P. et al. Flexible induction dose regimen for warfarin and prediction of maintenance dose. Br Med J (Clin Res Ed) 1984; 288: 1268-1270.
22 Loh PC, Morgan K, Wynne H. Anticoagulation of older patients: a need to modify current practice. Age Ageing 2000; 29: 551.
23 Tie JK, Nicchitta C, von Heijne G. et al. Membrane topology mapping of vitamin K epoxide reductase by in vitro translation/cotranslocation. J Biol Chem 2005; 280: 16410-16416.
24 Goodstadt L, Ponting CP. Vitamin K epoxide reductase: homology, active site and catalytic mechanism. Trends Biochem Sci 2004; 29: 289-292.
25 Rost S, Fregin A, Hunerberg M. et al. Site-directed mutagenesis of coumarin-type anticoagulant-sensitive VKORC1: evidence that highly conserved amino acids define structural requirements for enzymatic activity and inhibition by warfarin. Thromb Haemost 2005; 94: 780-786.
26 Jin DY, Tie JK, Stafford DW. The conversion of vitamin K epoxide to vitamin K quinone and vitamin K quinone to vitamin K hydroquinone uses the same active site cysteines. Biochemistry 2007; 46: 7279-7283.
27 Myszka DG, Swenson RP. Synthesis of the photoaffinity probe 3-(p-azidobenzyl)-4-hydroxycoumarin and identification of the dicoumarol binding site in rat liver NAD(P)H:quinone reductase (EC 1.6.99.2). J Biol Chem 1991; 266: 4789-4797.
28 Ma Q, Cui K, Xiao F. et al. Identification of a glycine- rich sequence as an NAD(P)H-binding site and tyrosine 128 as a dicumarol-binding site in rat liver NAD(P)H:quinone oxidoreductase by site-directed mutagenesis. J Biol Chem 1992; 267: 22298-22304.
29 Dam H. The antihaemorrhagic vitamin of the chick. Biochem J 1935; 29: 1237-1285.
30 Fleser LF. Synthesis of vitamin K1. J Amer Chem Soc 1939; 61: 3467-3475.
31 Almquist HJ, Klose AA. A derivative of vitamin K1. J Biol Chem 1939; 130: 791-793.
32 MacCorquodale DW, Cheney LC, Binkley SB. et al. The constitution and synthesis of vitamin K1. J Biol Chem 1939; 131: 357-370.
33 Nobel F, 1943 C. Edward A. Doisy – The Nobel Prize in Physiology or Medicine 1943:. Biography. 1943.
34 Wikipedia. Warfarin.. Available from: http://en.//wikipedia.org/wiki/Warfarin Accessed June 26, 2007.
35 Stahmann MA, Huebner CF, Link KP. Studies on the hemorrhagic sweet clover disease. V. Identification and synthesis of the hemorrhagic agent. J Biol Chem 1941; 138: 513-527.
36 Lehmann J. Effect of coumarin and dicoumarin on prothrombin level. Lancet 1943; I: 458-459.
37 Rhoads JE, Walker J, Panzer L. Control of blood coagulability with coumarin and other drugs. Use of basal doses of dicoumarol with intramuscular injections of heparin for sustained anticoagulant effect. Northwest Medicine 1943; 42: 182-185.
38 Barker NW, Allen EV, Waugh JM. The use of dicumarol [3,3‘-methylenebis(4-hydroxycoumarin)] in the prevention of postoperative thrombophlebitis and pulmonary embolism. Proc Staff Meetings Mayo Clinic 1943; 18: 102-107.
39 European Patent Office.. European Patent CH229084(A)/BE449545 for dicoumarol to Hoffmann-LaRoche &Co.AG; patent application for first coumarin derivative. Available from: http://v3.espace net.com/origdoc?PRT=yes&DB=EPODOC&IDX=BE449545&F=0&RPN=CH229084&DOC=ca9940e78e35eea7671edd986007ae7e25 Accessed July 12, 2007.
40 The Nobel Foundation Website. the Nobel Prize in Physiology or Medicine 1943. http://nobelprize.org nobel_prizes/medicine/laureates/1943/index.html Accessed March 14 2007.
41 Link KP. The discovery of dicoumarol and its sequels. Circulation 1959; 19: 97-107.
42 Bell RG, Matschiner JT. Vitamin K activity of phylloquinone oxide. Arch Biochem Biophys 1970; 141: 473-476.
43 Whitlon DS, Sadowski JA, Suttie JW. Mechanism of coumarin action: significance of vitamin K epoxide reductase inhibition. Biochemistry 1978; 17: 1371-1377.
44 D’Andrea G, D’Ambrosio RL, Di Perna P. et al. A polymorphism in the VKORC1 gene is associated with an interindividual variability in the dose-anticoagulant effect of warfarin. Blood 2005; 105: 645-649.
45 Chu PH, Huang TY, Williams J. et al. Purified vitamin K epoxide reductase alone is sufficient for conversion of vitamin K epoxide to vitamin K and vitamin K to vitamin KH2. Proc Natl Acad Sci USA 2006; 103: 19308-19313.
46 Wajih N, Hutson SM, Wallin R. Disulfide-dependent protein folding is linked to operation of the vitamin K cycle in the endoplasmic reticulum. A protein disulfide isomerase-VKORC1 redox enzyme complex appears to be responsible for vitamin K1 2,3-epoxide reduction. J Biol Chem 2007; 282: 2626-2635.
47 Reinhart C, Haase W, Rost S. et al. High-level heterologous expression and purification of functional human vitamin K 2,3-epoxide reductase (hVKORC1): The N-terminus is inaccessible to in situ labeling in membranes. Mol Biol Cell 2005; (Suppl. 16) Abstract 12a.
48 Bevans CG, Tran H, Haase W. et al. Site-directed mutations improve high-level production and homogeneous purification of an affinity-tagged chimeric human vitamin K 2,3-epoxide reductase-green fluorescent protein construct (hVKORC1-EGFPmut) in Pichia pastoris for structure/function analysis. Mol Biol Cell 2006; 17 (Suppl) Abstract.
49 Poetzsch B, Madlener K. Gerinnungskonsil: Rationelle Diagnostik und Therapie von Gerinnungsstörungen. Georg Thieme Verlag; New York: 2002
50 Wajih N, Sane DC, Hutson SM. et al. Engineering of a recombinant vitamin K-dependent gamma-carboxylation system with enhanced gamma-carboxyglutamic acid forming capacity: evidence for a functional CXXC redox center in the system. J Biol Chem 2005; 280: 10540-10547.
51 Chan E, McLachlan A, O’Reilly R. et al. Stereochemical aspects of warfarin drug interactions: use of a combined pharmacokinetic-pharmacodynamic model. Clin Pharmacol Ther 1994; 56: 286-294.
52 Takahashi H, Echizen H. Pharmacogenetics of warfarin elimination and its clinical implications. Clin Pharmacokinet 2001; 40: 587-603.
53 Ufer M. Comparative pharmacokinetics of vitamin K antagonists: warfarin, phenprocoumon and acenocoumarol. Clin Pharmacokinet 2005; 44: 1227-1246.
54 Hignite C, Uetrecht J, Tschanz C. et al. Kinetics of R andS warfarin enantiomers. Clin Pharmacol Ther 1980; 28: 99-105.
55 Rettie AE, Korzekwa KR, Kunze KL. et al. Hydroxylation of warfarin by human cDNA-expressed cytochrome P-450: a role for P-4502C9 in the etiology of (S)-warfarin-drug interactions. Chem Res Toxicol 1992; 5: 54-59.
56 Kaminsky LS, Zhang ZY. Human P450 metabolism of warfarin. Pharmacol Ther 1997; 73: 67-74.
57 Thijssen HH, Flinois JP, Beaune PH. Cytochrome P4502C9 is the principal catalyst of racemic acenocoumarol hydroxylation reactions in human liver microsomes. Drug Metab Dispos 2000; 28: 1284-1290.
58 Thijssen HH, Drittij MJ, Vervoort LM. et al. Altered pharmacokinetics of R- and S-acenocoumarol in a subject heterozygous for CYP2C9*3. Clin Pharmacol Ther 2001; 70: 292-298.
59 Lapple F, von Richter O, Fromm Martin F. et al. Differential expression and function of CYP2C isoforms in human intestine and liver. Pharmacogenetics 2003; 13: 565-575.
60 Ingelman-Sundberg M, Daly AK, Nebert DW. et al Homepage of the Human Cytochrome P450 (CYP) Allele Nomenclature Committee Advisory Board 2007. http://www.cypalleles.ki.se Accessed March 14, 2007.
61 Lee CR, Goldstein JA, Pieper JA. Cytochrome P450 2C9 polymorphisms: a comprehensive review of the in-vitro and human data. Pharmacogenetics 2002; 12: 251-263.
62 Gage BF, Eby C, Milligan PE. et al. Use of pharmacogenetics and clinical factors to predict the maintenance dose of warfarin. Thromb Haemost 2004; 91: 87-94.
63 Sanderson S, Emery J, Higgins J. CYP2C9 gene variants, drug dose, and bleeding risk in warfarintreated patients: a HuGEnet systematic review and meta-analysis. Genet Med 2005; 7: 97-104.
64 Chan E, McLachlan AJ, Pegg M. et al. Disposition of warfarin enantiomers and metabolites in patients during multiple dosing with rac-warfarin. Br J Clin Pharmacol 1994; 37: 563-569.
65 Takahashi H, Wilkinson GR, Nutescu EA. et al. Different contributions of polymorphisms in VKORC1 and CYP2C9 to intra- and inter-population differences in maintenance dose of warfarin in Japanese, Caucasians and African-Americans. Pharmacogenet Genomics 2006; 16: 101-110.
66 Schalekamp T, Oosterhof M, van Meegen E. et al. Effects of cytochrome P450 2C9 polymorphisms on phenprocoumon anticoagulation status. Clin Pharmacol Ther 2004; 76: 409-417.
67 Tai G, Farin F, Rieder MJ. et al. In-vitro and in-vivo effects of the CYP2C9*11 polymorphism on warfarin metabolism and dose. Pharmacogenet Genomics 2005; 15: 475-481.
68 Allabi Aurel C, Gala J-L, Desager J-P. et al. Genetic polymorphisms of CYP2C9 and CYP2C19 in the Beninese and Belgian populations. Br J Clin Pharmacol 2003; 56: 653-657.
69 Zhang Z, Fasco MJ, Huang Z. et al. Human cytochromes P4501A1 and P4501A2: R-warfarin metabolism as a probe. Drug Metab Dispos 1995; 23: 1339-1346.
70 Zhou S, Chan E, Lim Lee Y. et al. Therapeutic drugs that behave as mechanism-based inhibitors of cytochrome P450 3A4. Curr Drug Metab 2004; 5: 415-442.
71 Sconce EA, Daly AK, Khan TI. et al. APOE genotype makes a small contribution to warfarin dose requirements. Pharmacogenet Genomics 2006; 16: 609-611.
72 Vecsler M, Loebstein R, Almog S. et al. Combined genetic profiles of components and regulators of the vitamin K-dependent gamma-carboxylation system affect individual sensitivity to warfarin. Thromb Haemost 2006; 95: 205-211.
73 Loebstein R, Vecsler M, Kurnik D. et al. Common genetic variants of microsomal epoxide hydrolase affect warfarin dose requirements beyond the effect of cytochrome P450 2C9. Clin Pharmacol Ther 2005; 77: 365-372.
74 Toon S, Heimark LD, Trager WF. et al. Metabolic fate of phenprocoumon in humans. J Pharm Sci 1985; 74: 1037-1040.
75 Rettie AE, Wienkers LC, Gonzalez FJ. et al. Impaired (S)-warfarin metabolism catalysed by the R144C allelic variant of CYP2C9. Pharmacogenetics 1994; 4: 39-42.
76 Haining RL, Hunter AP, Veronese ME. et al. Allelic variants of human cytochrome P450 2C9: baculovirusmediated expression, purification, structural characterization, substrate stereoselectivity, and prochiral selectivity of the wild-type and I359L mutant forms. Arch Biochem Biophys 1996; 333: 447-458.
77 Crespi CL, Miller VP. The R144C change in the CYP2C9*2 allele alters interaction of the cytochrome P450 with NADPH:cytochrome P450 oxidoreductase. Pharmacogenetics 1997; 7: 203-210.
78 Ieiri I, Tainaka H, Morita T. et al. Catalytic activity of three variants (Ile, Leu, and Thr) at amino acid residue 359 in human CYP2C9 gene and simultaneous detection using single-strand conformation polymorphism analysis. United States: Department of Hospital Pharmacy, Faculty of Medicine, Tottori University; Yonago, Japan: 2000
79 Dickmann LJ, Rettie AE, Kneller MB. et al. Identification and functional characterization of a new CYP2C9 variant (CYP2C9*5) expressed among African Americans. Mol Pharmacol 2001; 60: 382-387.
80 Geisen C, Watzka M, Sittinger K. et al. VKORC1 haplotypes and their impact on the inter-individual and inter-ethnical variability of oral anticoagulation. Thromb Haemost 2005; 94: 773-779.
81 Obayashi K, Nakamura K, Kawana J. et al. VKORC1 gene variations are the major contributors of variation in warfarin dose in Japanese patients. Clin Pharmacol Ther 2006; 80: 169-178.
82 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; 15: 687-691.
83 Pelz HJ, Rost S, Hunerberg M. et al. The genetic basis of resistance to anticoagulants in rodents. Genetics 2005; 170: 1839-1847.
84 Geisen C, Spohn G, Sittinger K. et al. A novel mutation in the vitamin K epoxide reductase complex subunit 1 (VKORC1) causes moderately increased coumarin doses. J Thromb Haemost. 2005 .
85 Oldenburg J, Bevans CG, Muller CR. et al. Vitamin K epoxide reductase complex subunit 1 (VKORC1): the key protein of the vitamin K cycle. Antioxid Redox Signal 2006; 8: 347-353.
86 Schalekamp T, Boink GJ, Visser LE. et al. CYP2C9 genotyping in acenocoumarol treatment: is it a cost-effective addition to international normalized ratio monitoring?. Clin Pharmacol Ther 2006; 79: 511-520.
87 Schwarz UI. Clinical relevance of genetic polymorphisms in the human CYP2C9 gene. Eur J Clin Invest 2003; 33 (Suppl. 02) 23-30.
88 Redman AR, Dickmann LJ, Kidd RS. et al. CYP2C9 genetic polymorphisms and warfarin. Clin Appl Thromb Hemost 2004; 10: 149-154.
89 Kidd RS, Curry TB, Gallagher S. et al. Identification of a null allele of CYP2C9 in an African-American exhibiting toxicity to phenytoin. Pharmacogenetics 2001; 11: 803-808.
90 Reitsma PH, van der Heijden JF, Groot AP. et al. A C1173T dimorphism in the VKORC1 gene determines coumarin sensitivity and bleeding risk. PLoS Med 2005; 2: e312.
91 Quteineh L, Verstuyft C, Descot C. et al. Vitamin K epoxide reductase (VKORC1) genetic polymorphism is associated to oral anticoagulant overdose. Thromb Haemost 2005; 94: 690-691.
92 Schalekamp T, Brasse BP, Roijers JF. et al. VKORC1 and CYP2C9 genotypes and acenocoumarol anticoagulation status: interaction between both genotypes affects overanticoagulation. Clin Pharmacol Ther 2006; 80: 13-22.
93 Verstuyft C, Morin S, Robert A. et al. Early acenocoumarol overanticoagulation among cytochrome P450 2C9 poor metabolizers. Pharmacogenetics 2001; 11: 735-737.
94 Takahashi H, Kashima T, Nomoto S. et al. Comparisons between in-vitro and in-vivo metabolism of (S)-warfarin: catalytic activities of cDNA-expressed CYP2C9, its Leu359 variant and their mixture versus unbound clearance in patients with the corresponding CYP2C9 genotypes. Pharmacogenetics 1998; 8: 365-373.
95 Chu K, Wu SM, Stanley T. et al. A mutation in the propeptide of Factor IX leads to warfarin sensitivity by a novel mechanism. J Clin Invest 1996; 98: 1619-1625.
96 Oldenburg J, Quenzel EM, Harbrecht U. et al. Missense mutations at ALA-10 in the factor IX propeptide: an insignificant variant in normal life but a decisive cause of bleeding during oral anticoagulant therapy. Br J Haematol 1997; 98: 240-244.
97 Hamberg AK, Dahl ML, Barban M. et al. A PK-PD model for predicting the impact of age, CYP2C9, and VKORC1 genotype on individualization of warfarin therapy. Clin Pharmacol Ther 2007; 81: 529-538.
98 Schalekamp T, Brasse BP, Roijers JF. et al. VKORC1 and CYP2C9 genotypes and phenprocoumon anticoagulation status: interaction between both genotypes affects dose requirement. Clin Pharmacol Ther 2007; 81: 185-193.
99 Higashi MK, Veenstra DL, Kondo LM. et al. Association between CYP2C9 genetic variants and anticoagulation- related outcomes during warfarin therapy. J Am Med Assoc 2002; 287: 1690-1698.
100 Visser LE, van Schaik RH, van Vliet M. et al. Allelic variants of cytochrome P450 2C9 modify the interaction between nonsteroidal anti-inflammatory drugs and coumarin anticoagulants. Clin Pharmacol Ther 2005; 77: 479-485.
101 Oldenburg J. Vitamin K intake and stability of oral anticoagulant treatment. Thromb Haemost 2005; 93: 799-800.
102 Schurgers LJ, Aebert H, Vermeer C. et al. Oral anticoagulant treatment: friend or foe in cardiovascular disease?. Blood 2004; 104: 3231-3232.
103 Sconce E, Khan T, Mason J. et al. Patients with unstable control have a poorer dietary intake of vitamin K compared to patients with stable control of anticoagulation. Thromb Haemost 2005; 93: 872-875.
104 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.