Genetic determinants of response and adverse effects following vitamin K antagonist oral anticoagulants

Parameshwar S., Rashmi R., Dattatreya P. V.


Background: Vitamin K antagonist anticoagulants (warfarin/acenocoumarol) are commonly used anticoagulants that require careful clinical management to balance the risks of over anticoagulation and bleeding with those of under anticoagulation and clotting. Genetic variants of the enzyme that metabolizes vitamin K antagonist anticoagulant, cytochrome P-450 2C9 (CYP2C9), and of a key pharmacologic target of vitamin K antagonists anticoagulant, vitamin K epoxide reductase (VKORC1), contribute to differences in patients' responses to various anticoagulant doses. Methods: In thirty patients on oral vitamin K antagonist anticoagulant therapy, presented with either clotting manifestations (valve thrombosis, pulmonary embolism and DVT) or prolonged INR/bleeding manifestations, we assessed CYP2C9 genotypes, VKORC1 haplotypes, clinical characteristics, response to therapy (as determined by the international normalized ratio [INR]), and bleeding events.

Results: Of the thirty patients, thirteen patients INR was high and four patients presented with major bleeding and four with minor bleeding manifestations. Out of thirteen patients with high INR, ten patients showed CYP2C9 polymorphism (*1/*3 and *2/*3) of poor metabolizer genotype. Most of the high INR patients were recently started on oral vitamin K antagonist anticoagulant. Most patients presented with clotting manifestations with below therapeutic INR are noncompliant with anticoagulants.

Conclusions: The results of this study suggest that the CYP2C9 polymorphisms are associated with an increased risk of over anticoagulation and of bleeding events among patients on vitamin K antagonists’ anticoagulant setting.  Screening for CYP2C9 variants may allow clinicians to develop dosing protocols and surveillance techniques to reduce the risk of adverse drug reactions in patients receiving vitamin K antagonist anticoagulants. However the cost-effectiveness of genotyping of patients must be considered.               




Vitamin K antagonists, CYP2C9 polymorphism, VKORC1 haplotypes, International normalized ratio

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Ansell J, Hirsh J, Poller L, Bussey H, Jacobson A, Hylek E. The pharmacology and management of the vitamin K antagonists: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126:3 Suppl:204S-233S.

Hirsh J, Dalen J, Anderson DR, Poller L, Bussey H, Ansell J, et al. Oral anticoagulants. Chest. 2001;119(suppl 1):8-21.

Kearon C, Ginsberg JS, Kovacs MJ, Anderson DR, Wells P, Julian JA et al. Comparison of low-intensity warfarin therapy with conventional-intensity warfarin therapy for long-term prevention of recurrent venous thromboembolism. N Engl J Med. 2003; 349:631-9.

Levine MN, Raskob G, Landefeld S, Kearon C. Hemorrhagic complications of anticoagulant treatment. Chest. 2001;119:1 Suppl:108S-21S.

Takahashi H, Wilkinson GR, Padrini R, Echizen H. CYP2C9 and oral anticoagulation therapy with acenocoumarol and warfarin: similarities yet differences. Clin Pharmacol Ther. 2004;75:376-80.

Kaminsky LS, Zhang ZY. Human P450 metabolism of warfarin. Pharmacol Ther. 1997;73:67-74.

Higashi MK, Veenstra DL, Kondo LM, Wittkowsky AK, Srinouanprachanh SL, Farin FM, et al. Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy. JAMA. 2002;287:1690-8.

Veenstra DL, Blough DK, Higashi MK, Farin FM, Srinouanprachan S, Rieder MJ, et al. CYP2C9 haplotype structure in European American warfarin patients and association with clinical outcomes. Clin Pharmacol Ther. 2005;77:353-64.

Rettie AE, Haining RL, Bajpai M, Levy RH. A common genetic basis for idiosyncratic toxicity of warfarin and phenytoin. Epilepsy Res.1999;35:253-5.

Rettie AE, Korzekwa KR, Kunze KL, Lawrence RF, Eddy AC, Aoyama T, et al. Hydroxylation of warfarin by human cDNA-expressed cytochrome P450. Chem Res Toxicol. 1992;5:54-9.

Crespi CL, Miller VP. The R144C change in the CYP2C9*2 allele alters interaction of the cytochrome-P450withNADPH: cytochrome-P450 oxidoreductase. Pharmacogenetics. 1997;7:203-10.

Takanashi K, Tainaka H, Kobayashi K, Yasumori T, Hosakawa M, Chiba K.CYP2C9 Ile359 and Leu359 variants. Pharmacogenetics. 2000;10:95-104.

Furuya H, Fernandez-Salguero P, Gregory W, Taber H, Steward A, Gonzalez FJ, et al. Genetic polymorphism of CYP2C9 and its effect on warfarin maintenance dose requirement in patients undergoing anticoagulation therapy. Pharmacogenetics. 1995;5:389-92.

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;353:717-9.

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;96:1816-9.

Loebstein R, Yonath H, Peleg D, Almog S, Rotenberg M, Lubetsky A, et al. Interindividual variability in sensitivity to warfarin-nature or nurture? Clin Pharmacol Ther. 2001;70:15964.

Cain D, Hutson SM, Wallin R. Assembly of the warfarin-sensitive vitamin K 2,3-epoxide reductase enzyme complex in the endoplasmic reticulum membrane. J Biol Chem. 1997;272:29068-75.

Rieder MJ, Reiner AP, Gage BF. Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. N Engl J Med.. 2005;352:2285-93.

FDA approves updated warfarin (Coumarin) prescribing information. Press release of the Food and Drug Administration, August 16, 2007.

FDA clears genetic lab test for warfarin sensitivity. Press release of the Food and Drug Administration, September 17, 2007.

Beyth RJ, Quinn L, Landefeld CS. A multicomponent intervention to prevent major bleeding complications in older patients receiving warfarin: a randomized, controlled trial. Ann Intern Med. 2000;133:687-95.

McMahan DA, Smith DM, Carey MA, Zhou XH. Risk of major hemorrhage for outpatients treated with warfarin. J Gen Intern Med. 1998;13:311-6.

Sullivan-Klose TH1, Ghanayem BI, Bell DA, Zhang ZY, Kaminsky LS, Shenfield GM, et al. The role of the CYP2C9-Leu359 allelic variant in the tolbutamide polymorphism. Pharmacogenetics. 1996;6:341-9.

Schwarz UI, Ritchie MD, Bradford Y. Genetic Determinants of Response to Warfarin during Initial Anticoagulation. N Engl J Med. 2008;358:999-1008.

Stubbins MJ, Harries LW, Smith G, Tarbit MH, Wolf CR. Genetic analysis of the human cytochrome P450 CYP2C9 locus. Pharmacogenetics. 1996;6:429-39.

Fihn SD, McDonell M, Martin D, Henikoff J, Vermes D, Kent D et al. Risk factors for complications of chronic anticoagulation. Ann Intern Med. 1993;118:511-20.

Yasar U, Eliasson E, Dahl ML, Johansson I, Ingelman-Sundberg M, Sjöqvist F. Validation of methods for CYP2C9 genotyping. Biochem Biophys Res Commun. 1999;254:628-31.

Veenstra DL, Higashi MK, Phillips KA. Assessing the cost-effectiveness of pharmacogenomics. AAPS Pharmsci. 2000;2:2-9.