Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate®

Biology of warfarin and modulators of INR control

Russell D Hull, MBBS, MSc
David A Garcia, MD
Section Editor
Lawrence LK Leung, MD
Deputy Editor
Jennifer S Tirnauer, MD


Warfarin and other vitamin K antagonists (VKAs, also called coumarins; eg, acenocoumarol, phenprocoumon, fluindione) are used in a variety of clinical settings. Use of VKAs is challenging because their therapeutic range is narrow and dosing is affected by many factors including drug interactions, diet, and genetic variation in warfarin and vitamin K metabolism. Time spent with a prothrombin time/international normalized ratio (PT/INR) above the therapeutic range increases the risk of bleeding, and time spent below the therapeutic range increases the risk of thromboembolic complications.

This topic review discusses the biology, mechanism of action, and factors that modulate INR control during anticoagulation with a VKA.

Warfarin administration, and management of warfarin-associated bleeding and supratherapeutic INR, are discussed in detail separately. (See "Warfarin and other VKAs: Dosing and adverse effects" and "Management of warfarin-associated bleeding or supratherapeutic INR" and "Reversal of anticoagulation in warfarin-associated intracerebral hemorrhage".)


Mechanism of action — Warfarin and related vitamin K antagonists (VKAs) block the function of the vitamin K epoxide reductase complex in the liver, leading to depletion of the reduced form of vitamin K that serves as a cofactor for gamma carboxylation of vitamin K-dependent coagulation factors [1]. The epoxide reductase is needed to recycle vitamin K between reduced and epoxide forms. Without gamma carboxylation, the vitamin K-dependent factors, including factors II (prothrombin), VII, IX, and X, are immunologically detectable, but they cannot function because they cannot adequately bind calcium and phospholipid membranes needed for their hemostatic function [2]. (See "Vitamin K and the synthesis and function of gamma-carboxyglutamic acid".)

Gamma carboxylation of glutamic acid residues occurs at the time of protein synthesis; it does not affect the structure or function of existing proteins. Thus, the ultimate anticoagulant effect of VKAs is delayed until the previously synthesized, functional clotting factors are cleared from the circulation. Depletion of both factor X and factor II (prothrombin) is important for clinical efficacy, and factor II has the longest half-life of the vitamin K-dependent factors (approximately three days) [3,4]. Thus, the desired anticoagulant effect of a VKA does not occur for at least three days after drug initiation despite prolongation of the prothrombin time (PT) at earlier time points. The initial prolongation of the PT is due primarily to depletion of factor VII, which has a short half-life (four to six hours) (figure 1) [5]. (See 'PT/INR prolongation' below.)


Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: May 2017. | This topic last updated: Apr 28, 2017.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. Ansell J, Hirsh J, Hylek E, et al. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133:160S.
  2. Ansell J, Hirsh J, Poller L, et al. The pharmacology and management of the vitamin K antagonists: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126:204S.
  3. Lind SE, Callas PW, Golden EA, et al. Plasma levels of factors II, VII and X and their relationship to the international normalized ratio during chronic warfarin therapy. Blood Coagul Fibrinolysis 1997; 8:48.
  4. Zivelin A, Rao LV, Rapaport SI. Mechanism of the anticoagulant effect of warfarin as evaluated in rabbits by selective depression of individual procoagulant vitamin K-dependent clotting factors. J Clin Invest 1993; 92:2131.
  5. O'Reilly RA, Aggeler PM. Studies on coumarin anticoagulant drugs. Initiation of warfarin therapy without a loading dose. Circulation 1968; 38:169.
  6. Clouse LH, Comp PC. The regulation of hemostasis: the protein C system. N Engl J Med 1986; 314:1298.
  7. http://www.who.int/bloodproducts/ivd/thromboplastin_reagents/en/ (Accessed on May 01, 2015).
  8. Smith SA, Morrissey JH. Properties of recombinant human thromboplastin that determine the International Sensitivity Index (ISI). J Thromb Haemost 2004; 2:1610.
  9. Brandjes DP, Heijboer H, Büller HR, et al. Acenocoumarol and heparin compared with acenocoumarol alone in the initial treatment of proximal-vein thrombosis. N Engl J Med 1992; 327:1485.
  10. Kaatz S. Determinants and measures of quality in oral anticoagulation therapy. J Thromb Thrombolysis 2008; 25:61.
  11. Phillips KW, Ansell J. Outpatient management of oral vitamin K antagonist therapy: defining and measuring high-quality management. Expert Rev Cardiovasc Ther 2008; 6:57.
  12. Batke-Hastings S, Carman TL. Sublingual administration of warfarin: a novel form of delivery. Vasc Med 2008; 13:123.
  13. http://packageinserts.bms.com/pi/pi_coumadin.pdf (Accessed on May 01, 2015).
  14. Holbrook AM, Pereira JA, Labiris R, et al. Systematic overview of warfarin and its drug and food interactions. Arch Intern Med 2005; 165:1095.
  15. Beinema M, Brouwers JR, Schalekamp T, Wilffert B. Pharmacogenetic differences between warfarin, acenocoumarol and phenprocoumon. Thromb Haemost 2008; 100:1052.
  16. Ellis DJ, Usman MH, Milner PG, et al. The first evaluation of a novel vitamin K antagonist, tecarfarin (ATI-5923), in patients with atrial fibrillation. Circulation 2009; 120:1029.
  17. Whitlock RP, Fordyce CB, Midei MG, et al. A randomised, double blind comparison of tecarfarin, a novel vitamin K antagonist, with warfarin. The EmbraceAC Trial. Thromb Haemost 2016; 116:241.
  18. Fihn SD, Gadisseur AA, Pasterkamp E, et al. Comparison of control and stability of oral anticoagulant therapy using acenocoumarol versus phenprocoumon. Thromb Haemost 2003; 90:260.
  19. Mentré F, Pousset F, Comets E, et al. Population pharmacokinetic-pharmacodynamic analysis of fluindione in patients. Clin Pharmacol Ther 1998; 63:64.
  20. Bates SM, Greer IA, Middeldorp S, et al. VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141:e691S.
  21. http://packageinserts.bms.com/pi/pi_coumadin.pdf (Accessed on June 02, 2015).
  22. 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 2007; 109:2419.
  23. Lefrère JJ, Guyon F, Horellou MH, et al. [Resistance to vitamin K antagonists. 6 cases]. Ann Med Interne (Paris) 1986; 137:384.
  24. Hallak HO, Wedlund PJ, Modi MW, et al. High clearance of (S)-warfarin in a warfarin-resistant subject. Br J Clin Pharmacol 1993; 35:327.
  25. Hulse ML. Warfarin resistance: diagnosis and therapeutic alternatives. Pharmacotherapy 1996; 16:1009.
  26. Pérez-Andreu V, Roldán V, López-Fernández MF, et al. Pharmacogenetics of acenocoumarol in patients with extreme dose requirements. J Thromb Haemost 2010; 8:1012.
  27. Visser LE, Penning-van Bees FJ, Kasbergen AA, et al. Overanticoagulation associated with combined use of antibacterial drugs and acenocoumarol or phenprocoumon anticoagulants. Thromb Haemost 2002; 88:705.
  28. Witt DM, Delate T, Clark NP, et al. Twelve-month outcomes and predictors of very stable INR control in prevalent warfarin users. J Thromb Haemost 2010; 8:744.
  29. Garcia D, Ageno W, Bussey H, et al. Prevention and treatment of bleeding complications in patients receiving vitamin K antagonists, Part 1: Prevention. Am J Hematol 2009; 84:579.
  30. Nelson WW, Desai S, Damaraju CV, et al. International normalized ratio stability in warfarin-experienced patients with nonvalvular atrial fibrillation. Am J Cardiovasc Drugs 2015; 15:205.
  31. Rohde LE, de Assis MC, Rabelo ER. Dietary vitamin K intake and anticoagulation in elderly patients. Curr Opin Clin Nutr Metab Care 2007; 10:1.
  32. Nutescu EA, Shapiro NL, Ibrahim S, West P. Warfarin and its interactions with foods, herbs and other dietary supplements. Expert Opin Drug Saf 2006; 5:433.
  33. Johnson MA. Influence of vitamin K on anticoagulant therapy depends on vitamin K status and the source and chemical forms of vitamin K. Nutr Rev 2005; 63:91.
  34. Costa GL, Lamego RM, Colosimo EA, et al. Identifying potential predictors of high-quality oral anticoagulation assessed by time in therapeutic international normalized ratio range: a prospective, long-term, single-center, observational study. Clin Ther 2012; 34:1511.
  35. Rombouts EK, Rosendaal FR, van der Meer FJ. Influence of dietary vitamin K intake on subtherapeutic oral anticoagulant therapy. Br J Haematol 2010; 149:598.
  36. 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.
  37. Juurlink DN. Drug interactions with warfarin: what clinicians need to know. CMAJ 2007; 177:369.
  38. Sullivan DM, Ford MA, Boyden TW. Grapefruit juice and the response to warfarin. Am J Health Syst Pharm 1998; 55:1581.
  39. Norwood DA, Parke CK, Rappa LR. A Comprehensive Review of Potential Warfarin-Fruit Interactions. J Pharm Pract 2015; 28:561.
  40. Srinivas NR. Cranberry juice ingestion and clinical drug-drug interaction potentials; review of case studies and perspectives. J Pharm Pharm Sci 2013; 16:289.
  41. Haber SL, Cauthon KA, Raney EC. Cranberry and warfarin interaction: a case report and review of the literature. Consult Pharm 2012; 27:58.
  42. Zikria J, Goldman R, Ansell J. Cranberry juice and warfarin: when bad publicity trumps science. Am J Med 2010; 123:384.
  43. Li Z, Seeram NP, Carpenter CL, et al. Cranberry does not affect prothrombin time in male subjects on warfarin. J Am Diet Assoc 2006; 106:2057.
  44. Clapauch SH, Benchimol-Barbosa PR. Warfarin resistance and caffeine containing beverages. Int J Cardiol 2012; 156:e4.
  45. Rose AJ, Hylek EM, Ozonoff A, et al. Patient characteristics associated with oral anticoagulation control: results of the Veterans AffaiRs Study to Improve Anticoagulation (VARIA). J Thromb Haemost 2010; 8:2182.
  46. Diug B, Evans S, Lowthian J, et al. The unrecognized psychosocial factors contributing to bleeding risk in warfarin therapy. Stroke 2011; 42:2866.
  47. Levine M, Pizon AF, Padilla-Jones A, Ruha AM. Warfarin overdose: a 25-year experience. J Med Toxicol 2014; 10:156.
  48. Delaney JA, Opatrny L, Brophy JM, Suissa S. Drug drug interactions between antithrombotic medications and the risk of gastrointestinal bleeding. CMAJ 2007; 177:347.
  49. Schelleman H, Bilker WB, Brensinger CM, et al. Fibrate/Statin initiation in warfarin users and gastrointestinal bleeding risk. Am J Med 2010; 123:151.
  50. Lopes RD, Horowitz JD, Garcia DA, et al. Warfarin and acetaminophen interaction: a summary of the evidence and biologic plausibility. Blood 2011; 118:6269.
  51. Feldstein AC, Smith DH, Perrin N, et al. Reducing warfarin medication interactions: an interrupted time series evaluation. Arch Intern Med 2006; 166:1009.
  52. van Dijk KN, Plat AW, van Dijk AA, et al. Potential interaction between acenocoumarol and diclofenac, naproxen and ibuprofen and role of CYP2C9 genotype. Thromb Haemost 2004; 91:95.
  53. Knijff-Dutmer EA, Van der Palen J, Schut G, Van de Laar MA. The influence of cyclo-oxygenase specificity of non-steroidal anti-inflammatory drugs on bleeding complications in concomitant coumarine users. QJM 2003; 96:513.
  54. Johnson SG, Witt DM, Eddy TR, Delate T. Warfarin and antiplatelet combination use among commercially insured patients enrolled in an anticoagulation management service. Chest 2007; 131:1500.
  55. Johnson SG, Rogers K, Delate T, Witt DM. Outcomes associated with combined antiplatelet and anticoagulant therapy. Chest 2008; 133:948.
  56. García Rodríguez LA, Lin KJ, Hernández-Díaz S, Johansson S. Risk of upper gastrointestinal bleeding with low-dose acetylsalicylic acid alone and in combination with clopidogrel and other medications. Circulation 2011; 123:1108.
  57. Kwan D, Bartle WR, Walker SE. The effects of acetaminophen on pharmacokinetics and pharmacodynamics of warfarin. J Clin Pharmacol 1999; 39:68.
  58. Thijssen HH, Soute BA, Vervoort LM, Claessens JG. Paracetamol (acetaminophen) warfarin interaction: NAPQI, the toxic metabolite of paracetamol, is an inhibitor of enzymes in the vitamin K cycle. Thromb Haemost 2004; 92:797.
  59. Mahé I, Bertrand N, Drouet L, et al. Paracetamol: a haemorrhagic risk factor in patients on warfarin. Br J Clin Pharmacol 2005; 59:371.
  60. Mahé I, Bertrand N, Drouet L, et al. Interaction between paracetamol and warfarin in patients: a double-blind, placebo-controlled, randomized study. Haematologica 2006; 91:1621.
  61. Parra D, Beckey NP, Stevens GR. The effect of acetaminophen on the international normalized ratio in patients stabilized on warfarin therapy. Pharmacotherapy 2007; 27:675.
  62. Zhang Q, Bal-dit-Sollier C, Drouet L, et al. Interaction between acetaminophen and warfarin in adults receiving long-term oral anticoagulants: a randomized controlled trial. Eur J Clin Pharmacol 2011; 67:309.
  63. Hylek EM, Heiman H, Skates SJ, et al. Acetaminophen and other risk factors for excessive warfarin anticoagulation. JAMA 1998; 279:657.
  64. Clark NP, Delate T, Riggs CS, et al. Warfarin interactions with antibiotics in the ambulatory care setting. JAMA Intern Med 2014; 174:409.
  65. Alexandra JF, Pautas E, Gouin-Thibault I, et al. Overanticoagulation with coumarin and cutaneous azole therapy. Ann Intern Med 2008; 148:633.
  66. Pottegård A, Henriksen DP, Madsen KG, et al. Change in International Normalized Ratio Among Patients Treated With Dicloxacillin and Vitamin K Antagonists. JAMA 2015; 314:296.
  67. Fischer HD, Juurlink DN, Mamdani MM, et al. Hemorrhage during warfarin therapy associated with cotrimoxazole and other urinary tract anti-infective agents: a population-based study. Arch Intern Med 2010; 170:617.
  68. Choonara IA, Cholerton S, Haynes BP, et al. Stereoselective interaction between the R enantiomer of warfarin and cimetidine. Br J Clin Pharmacol 1986; 21:271.
  69. Bell WR, Anderson KC, Noe DA, Silver BA. Reduction in the plasma clearance rate of warfarin induced by cimetidine. Arch Intern Med 1986; 146:2325.
  70. Niopas I, Toon S, Aarons L, Rowland M. The effect of cimetidine on the steady-state pharmacokinetics and pharmacodynamics of warfarin in humans. Eur J Clin Pharmacol 1999; 55:399.
  71. Serlin MJ, Sibeon RG, Breckenridge AM. Lack of effect of ranitidine on warfarin action. Br J Clin Pharmacol 1981; 12:791.
  72. Desmond PV, Mashford ML, Harman PJ, et al. Decreased oral warfarin clearance after ranitidine and cimetidine. Clin Pharmacol Ther 1984; 35:338.
  73. O'Reilly RA. Comparative interaction of cimetidine and ranitidine with racemic warfarin in man. Arch Intern Med 1984; 144:989.
  74. Toon S, Hopkins KJ, Garstang FM, Rowland M. Comparative effects of ranitidine and cimetidine on the pharmacokinetics and pharmacodynamics of warfarin in man. Eur J Clin Pharmacol 1987; 32:165.
  75. Teichert M, van Noord C, Uitterlinden AG, et al. Proton pump inhibitors and the risk of overanticoagulation during acenocoumarol maintenance treatment. Br J Haematol 2011; 153:379.
  76. Nathisuwan S, Dilokthornsakul P, Chaiyakunapruk N, et al. Assessing evidence of interaction between smoking and warfarin: a systematic review and meta-analysis. Chest 2011; 139:1130.
  77. Nadkarni A, Oldham MA, Howard M, Berenbaum I. Drug-drug interactions between warfarin and psychotropics: updated review of the literature. Pharmacotherapy 2012; 32:932.
  78. Zierler-Brown SL, Kyle JA. Oral varenicline for smoking cessation. Ann Pharmacother 2007; 41:95.
  79. Yamaori S, Koeda K, Kushihara M, et al. Comparison in the in vitro inhibitory effects of major phytocannabinoids and polycyclic aromatic hydrocarbons contained in marijuana smoke on cytochrome P450 2C9 activity. Drug Metab Pharmacokinet 2012; 27:294.
  80. Ge B, Zhang Z, Zuo Z. Updates on the clinical evidenced herb-warfarin interactions. Evid Based Complement Alternat Med 2014; 2014:957362.
  81. Yamreudeewong W, Wong HK, Brausch LM, Pulley KR. Probable interaction between warfarin and marijuana smoking. Ann Pharmacother 2009; 43:1347.
  82. La Rosa FG, Clarke SH, Lefkowitz JB. Brodifacoum intoxication with marijuana smoking. Arch Pathol Lab Med 1997; 121:67.
  83. Roth JA, Bradley K, Thummel KE, et al. Alcohol misuse, genetics, and major bleeding among warfarin therapy patients in a community setting. Pharmacoepidemiol Drug Saf 2015; 24:619.
  84. Limdi NA, Limdi MA, Cavallari L, et al. Warfarin dosing in patients with impaired kidney function. Am J Kidney Dis 2010; 56:823.
  85. Liu G, Long M, Hu X, et al. Effectiveness and Safety of Warfarin in Dialysis Patients With Atrial Fibrillation: A Meta-Analysis of Observational Studies. Medicine (Baltimore) 2015; 94:e2233.
  86. Nelson WW, Desai S, Damaraju CV, et al. International normalized ratio stabilization in newly initiated warfarin patients with nonvalvular atrial fibrillation. Curr Med Res Opin 2014; 30:2437.
  87. Witt DM, Delate T, Clark NP, et al. Outcomes and predictors of very stable INR control during chronic anticoagulation therapy. Blood 2009; 114:952.
  88. van Walraven C, Forster AJ. Anticoagulation control in the peri-hospitalization period. J Gen Intern Med 2007; 22:727.
  89. Shikata E, Ieiri I, Ishiguro S, et al. Association of pharmacokinetic (CYP2C9) and pharmacodynamic (factors II, VII, IX, and X; proteins S and C; and gamma-glutamyl carboxylase) gene variants with warfarin sensitivity. Blood 2004; 103:2630.
  90. 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.
  91. 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.
  92. Schwarz UI, Ritchie MD, Bradford Y, et al. Genetic determinants of response to warfarin during initial anticoagulation. N Engl J Med 2008; 358:999.
  93. 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.
  94. Cooper GM, Johnson JA, Langaee TY, et al. A genome-wide scan for common genetic variants with a large influence on warfarin maintenance dose. Blood 2008; 112:1022.
  95. Wadelius M, Chen LY, Lindh JD, et al. The largest prospective warfarin-treated cohort supports genetic forecasting. Blood 2009; 113:784.
  96. Bodin L, Verstuyft C, Tregouet DA, et al. Cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1) genotypes as determinants of acenocoumarol sensitivity. Blood 2005; 106:135.
  97. 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.
  98. Montes R, Ruiz de Gaona E, Martínez-González MA, et al. The c.-1639G > A polymorphism of the VKORC1 gene is a major determinant of the response to acenocoumarol in anticoagulated patients. Br J Haematol 2006; 133:183.
  99. Loebstein R, Dvoskin I, Halkin H, et al. A coding VKORC1 Asp36Tyr polymorphism predisposes to warfarin resistance. Blood 2007; 109:2477.
  100. Wang D, Chen H, Momary KM, et al. Regulatory polymorphism in vitamin K epoxide reductase complex subunit 1 (VKORC1) affects gene expression and warfarin dose requirement. Blood 2008; 112:1013.
  101. Limdi NA, Wadelius M, Cavallari L, et al. Warfarin pharmacogenetics: a single VKORC1 polymorphism is predictive of dose across 3 racial groups. Blood 2010; 115:3827.
  102. O'Reilly RA, Pool JG, Aggeler PM. Hereditary resistance to coumarin anticoagulant drugs in man and rat. Ann N Y Acad Sci 1968; 151:913.
  103. Alving BM, Strickler MP, Knight RD, et al. Hereditary warfarin resistance. Investigation of a rare phenomenon. Arch Intern Med 1985; 145:499.
  104. Bodin L, Perdu J, Diry M, et al. Multiple genetic alterations in vitamin K epoxide reductase complex subunit 1 gene (VKORC1) can explain the high dose requirement during oral anticoagulation in humans. J Thromb Haemost 2008; 6:1436.
  105. Schmeits PC, Hermans MH, van Geest-Daalderop JH, et al. VKORC1 mutations in patients with partial resistance to phenprocoumon. Br J Haematol 2010; 148:955.
  106. Aithal GP, Day CP, Kesteven PJ, Daly AK. Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet 1999; 353:717.
  107. Leung AY, Chow HC, Kwong YL, et al. Genetic polymorphism in exon 4 of cytochrome P450 CYP2C9 may be associated with warfarin sensitivity in Chinese patients. Blood 2001; 98:2584.
  108. Hermida J, Zarza J, Alberca I, et al. Differential effects of 2C9*3 and 2C9*2 variants of cytochrome P-450 CYP2C9 on sensitivity to acenocoumarol. Blood 2002; 99:4237.
  109. Taube J, Halsall D, Baglin T. Influence of cytochrome P-450 CYP2C9 polymorphisms on warfarin sensitivity and risk of over-anticoagulation in patients on long-term treatment. Blood 2000; 96:1816.
  110. Joffe HV, Xu R, Johnson FB, et al. Warfarin dosing and cytochrome P450 2C9 polymorphisms. Thromb Haemost 2004; 91:1123.
  111. Higashi MK, Veenstra DL, Kondo LM, et al. Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy. JAMA 2002; 287:1690.
  112. Schalekamp T, van Geest-Daalderop JH, de Vries-Goldschmeding H, et al. Acenocoumarol stabilization is delayed in CYP2C93 carriers. Clin Pharmacol Ther 2004; 75:394.
  113. Meckley LM, Wittkowsky AK, Rieder MJ, et al. An analysis of the relative effects of VKORC1 and CYP2C9 variants on anticoagulation related outcomes in warfarin-treated patients. Thromb Haemost 2008; 100:229.
  114. Margaglione M, Colaizzo D, D'Andrea G, et al. Genetic modulation of oral anticoagulation with warfarin. Thromb Haemost 2000; 84:775.
  115. Caldwell MD, Awad T, Johnson JA, et al. CYP4F2 genetic variant alters required warfarin dose. Blood 2008; 111:4106.
  116. Pérez-Andreu V, Roldán V, Antón AI, et al. Pharmacogenetic relevance of CYP4F2 V433M polymorphism on acenocoumarol therapy. Blood 2009; 113:4977.
  117. Daneshjou R, Gamazon ER, Burkley B, et al. Genetic variant in folate homeostasis is associated with lower warfarin dose in African Americans. Blood 2014; 124:2298.