Genetic factors most correlated with warfarin dose requirements are variations in the genes encoding the enzymes cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKOR). Patients receiving warfarin who possess one or more genetic variations in CYP2C9 and VKORC1 are at increased risk of adverse drug events and require significant dose reductions to achieve a therapeutic international normalized ratio (INR). A 74-year-old white female with atrial fibrillation was initiated on a warfarin dose of 2 mg PO daily, which resulted in multiple elevated INR measurements and three clinically significant hemorrhagic events and four vitamin K antidote treatments over a period of less than two weeks. Genetic analysis later revealed that she had the homozygous variant genotypes of CYP2C9*3*3 and VKORC1-1639 AA. Warfarin dosing was subsequently restarted and stabilized at 0.5？mg PO daily with therapeutic INRs. This is the first case report of a white female with these genotypes stabilized on warfarin, and it highlights the value of pharmacogenetic testing prior to the initiation of warfarin therapy to maximize efficacy and minimize the risk of adverse drug events. 1. Introduction Warfarin is the most widely used anticoagulant in the world and has been consistently shown to be effective at preventing emboli in patients with prosthetic heart valves or atrial fibrillation [1]. Achieving a safe and effective warfarin maintenance dose can take weeks or months after the initiation of therapy due to its narrow therapeutic range and wide interindividual dose variation [2]. Unexpected sensitivity to warfarin commonly results in prolonged bleeding caused by excessive anticoagulation and warfarin is the number one cause of hospitalization due to an adverse drug event in the USA [3]. Clinical factors including age, height, weight, gender, race, diet, smoking, comorbidities, prosthetic heart valve, and other medications contribute to the dose variability of warfarin, but genetic factors have been shown to be the largest contributor to the dose variability of warfarin [2, 3]. The two genetic factors that are most correlated with warfarin dose requirements are variations in the genes encoding the enzymes cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKOR) [1]. CYP2C9 is the primary enzyme responsible for inactivating warfarin. The CYP2C9*3 variant allele has been shown to cause an 80% decrease in enzymatic activity of CYP2C9 and therefore contributes to the dose variance of warfarin [4]. The pharmacological target for warfarin is inhibition of the VKOR
References
[1]
N. Eriksson and M. Wadelius, “Prediction of warfarin dose: why, when and how?” Pharmacogenomics, vol. 13, no. 4, pp. 429–440, 2012.
[2]
J. F. Carlquist and J. L. Anderson, “Using pharmacogenetics in real time to guide warfarin initiation: a clinician update,” Circulation, vol. 124, no. 23, pp. 2554–2559, 2011.
[3]
D. S. Budnitz, M. C. Lovegrove, N. Shehab, and C. L. Richards, “Emergency hospitalizations for adverse drug events in older Americans,” The New England Journal of Medicine, vol. 365, no. 21, pp. 2002–2012, 2011.
[4]
K. Takanashi, H. Tainaka, K. Kobayashi, T. Yasumori, M. Hosakawa, and K. Chiba, “CYP2C9 Ile359 and Leu359 variants: enzyme kinetic study with seven substrates,” Pharmacogenetics, vol. 10, no. 2, pp. 95–104, 2000.
[5]
T. Li, C.-Y. Chang, D.-Y. Jin, P.-J. Lin, A. Khvorova, and D. W. Stafford, “Identification of the gene for vitamin K epoxide reductase,” Nature, vol. 427, no. 6974, pp. 541–544, 2004.
[6]
M. J. Rieder, A. P. Reiner, B. F. Gage et al., “Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose,” The New England Journal of Medicine, vol. 352, no. 22, pp. 2285–2293, 2005.
[7]
H.-Y. Yuan, J.-J. Chen, M. T. M. Lee et al., “A novel functional VKORC1 promoter polymorphism is associated with inter-individual and inter-ethnic differences in warfarin sensitivity,” Human Molecular Genetics, vol. 14, no. 13, pp. 1745–1751, 2005.
[8]
T. Fukuda, T. Tanabe, M. Ohno et al., “Warfarin dose requirement for patients with both VKORC1 3673A/A and CYP2C9*3/*3 genotypes,” Clinical Pharmacology and Therapeutics, vol. 80, no. 5, pp. 553–554, 2006.
[9]
Coumadin, Package Insert, Bristol-Myers Squibb, Princeton, NJ, USA, 2011.
[10]
T. E. Klein, R. B. Altman, N. Eriksson, et al., “Estimation of the warfarin dose with clinical and pharmacogenetic data,” The New England Journal of Medicine, vol. 360, no. 8, pp. 753–764, 2009.
[11]
G. R. Grice, P. E. Milligan, C. Eby, and B. F. Gage, “Pharmacogenetic dose refinement prevents warfarin overdose in a patient who is highly warfarin-sensitive,” Journal of Thrombosis and Haemostasis, vol. 6, no. 1, pp. 207–209, 2008.
[12]
T. Goto, M. Miura, A. Murata et al., “Standard warfarin dose in a patient with the CYP2C9*3/*3 genotype leads to hematuria,” Clinica Chimica Acta, vol. 411, no. 17-18, pp. 1375–1377, 2010.
[13]
L. Gao, L. He, J. Luo et al., “Extremely low warfarin dose in patients with genotypes of CYP2C9*3/*3 and VKORC1-1639A/A,” Chinese Medical Journal, vol. 124, no. 17, pp. 2767–2770, 2011.
[14]
B. F. Gage, C. Eby, J. A. Johnson et al., “Use of pharmacogenetic and clinical factors to predict the therapeutic dose of warfarin,” Clinical Pharmacology and Therapeutics, vol. 84, no. 3, pp. 326–331, 2008.
