Study of environmental and genetic factors determining warfarin toxicity

Ravindra Nath Sahay, Kaustubh Dilip Salagre, Khushali Rajesh Dedhia


Background: Warfarin is widely used anticoagulant in treatment and prevention of thrombosis. Despite its common use, warfarin can be associated with bleeding complications because of its narrow therapeutic index. A review of many studies show average yearly rates of warfarin related bleeding as high as 0.5% , 4.9% , 15% for fatal, major, minor bleeding complications. The study is to determine age, gender, pharmacogenetics, drugs influencing warfarin toxicity in Indian patients.

Methods: Observational and cross-sectional study was conducted over period of 1 year after obtaining institutional ethics committee permission. Written and informed consent was taken from patients admitted in tertiary care hospital who fulfilled inclusion and exclusion criteria.

Results: Most common age for Warfarin toxicity in our study was between 30 to 39 years (22.5%) with mean of 42.9 years. Bleeding risk was higher in elderly with 14 out of 26 patients with age >50 years had bleeding manifestations. Toxicity was more prevalent in female (60%). 40% patients were on drugs interacting with warfarin; NSAIDS (Nonsteroidal Anti-Inflammatary Drug) and antibiotics were the most common interacting drugs. In our study, 17.5% patients had acute liver disease and one patient had deranged creatinine (2.6). 40% of patients had VKORC1 variants and 35% of patients had CYP2C9 variants. Maximum patients developed toxicity within 15-30 days of initiation of warfarin.

Conclusions: Warfarin toxicity has multifactorial cause. Drugs and Genetic variation are most common factors influencing warfarin toxicity. Warfarin toxicity has low mortality rate, although it increases with (International Normalised Ratio) INR>10 and with increasing age.


INR, Warfarin toxicity

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Hirsh J, Fuster V, Ansell J, Halperin JL. American Heart Association/American College of Cardiology Foundation guide to warfarin therapy. J Am Coll Cardiol. 2003;41:1633-52.

Wang B, Wang, J, Huang, SQ, Su HH, Zhou SF. Genetic Polymorphism of the Human Cytochrome P450 2C9 Gene and Its Clinical Significance. Curr. Drug. Metab. 2009;10:781-834.

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.

Tabrizi AR, Zehnbauer BA, Borecki IB, McGrath SD, Buchman TG, Freeman BD. The frequency and effects of cytochrome P450 (CYP) 2C9 polymorphisms in patients receiving warfarin. J. Am. Coll. Surg. 2002;194:267-73.

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.

Wadelius M, Sorlin K, Wallerman O, Karlsson J, Yue QY, Magnusson PK, et al. Warfarin sensitivity related to CYP2C9, CYP3A5, ABCB1 (MDR1) and other factors. Pharmacogenomics J. 2004;4:40-8.

Froom P, Miron E, Barak M. Oral anticoagulants in the elderly. Br J Haematol. 2003;120:526.

Hayes BD, Klein-Schwartz W, Barrueto F Jr. Polypharmacy and the geriatric patient. Clin Geriatr Med. 2007;23:371-90.

Gurwitz JH, Avorn J, Ross-Degnan D, Choodnovskiy I, Ansell J. Aging and the Anticoagulant Response to Warfarin Therapy. Ann Intern Med. 1992;116(11):901-4.

Teklay G, Shiferaw N, Legesse B, Bekele ML. Drug-drug interactions and risk of bleeding among inpatients on warfarin therapy: a prospective observational study. Thromb J. 2014;12:20.

Narum S, Solhaug V, Myhr K, Johansen PW, Brørs O, Kringen MK. Warfarin-associated bleeding events and concomitant use of potentially interacting medicines reported to the Norwegian spontaneous reporting system. Br J Clin Pharmacol. 2011;71(2):254-62.

Glasheen JJ, Fugit RV, Prochazka AV. The risk of over anticoagulation with antibiotic use in outpatients on stable warfarin regimens. J Gen Intern Med. 2005;20(7):653-6.

Ghaswalla PK, Harpe SE, Tassone D, Slattum PW. Warfarin-antibiotic interactions in older adults of an outpatient anticoagulation clinic. Am J Geriatr Pharmacother. 2012;10(6):352-60.

Snaith A, Pugh J, Simpson CR, McLay JS. The potential for interaction between warfarin and coprescribed medication. A retrospective study in primary care. Am J Cardiovasc Drugs. 2008;8(3):207-12.

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.

Mammen EF. Coagulation abnormalities in liver disease. Hematol Oncol Clin North Am. 1992;6:1247-57.

Dreisbach AW, Japa S, Gebrekal AB, Mowry SE, Lertora JJ, Kamath BL, et al. Cytochrome P4502C9 activity in end stage renal disease. Clin Pharmacol Ther. 2003;73:475-7.

Ganeval D, Fischer AM, Barre J, Pertuiset N, Dautzenberg MD, Jungers P, et al. Pharmacokinetics of warfarin in the nephrotic syndrome and effect on vitamin k-dependent clotting factors. Clin Nephrol. 1986;25:75-80.

Voora D, Eby C, Linder MW, Milligan PE, Bukaveckas BL, McLeod HL, et al. Prospective dosing of warfarin based on cytochrome P-450 2C9 genotype. Thromb Haemost. 2005;93:700-5.

Margaglione M1, Colaizzo D, D'Andrea G, Brancaccio V, Ciampa A, Grandone E, et al. Genetic modulation of oral anticoagulation with warfarin. Thromb. Haemost. 2000;84:775-8.

Unge P, Svedberg LE, Nordgren A, Blom H, Andersson T, Lagerström PO, et al. A study of the interaction of omeprazole and warfarin in anticoagulated patients. Br J Clin Pharmacol. 1992;34(6):509-12.

Takahashi H, Echizen H. Pharmacogenetics of warfarin elimination and its clinical implications. Clin. Pharmacokinet. 2001;40:587-603.

Schwarz UI, Ritchie MD, Bradford Y, Li C, Dudek SM, Frye-Anderson A, et al. Genetic determinants of response to warfarin during initial anticoagulation. N Engl J Med. 2008;358(10):999-1008.

Mahé I, Bertrand N, Drouet L, Bal Dit Sollier C, Simoneau G, Mazoyer E, et al. Interaction between paracetamol and warfarin in patients: a double-blind, placebo-controlled, randomized study. Haematologica. 2006;91(12):1621-7.

Iwuchukwu OF, Ramirez AH, Shi Y, Bowton EA, Kawai VK, Schildcrout JS, et al. Genetic determinants of variability in warfarin response after the dose-titration phase. Pharmacogenet Genomics. 2016;26(11):510-6.