Polymorphism Induced Sensitivity to Warfarin: A Review of the Literature
Purchase on Springer.com
$39.95 / €34.95 / £29.95*
Rent the article at a discountRent now
* Final gross prices may vary according to local VAT.
Warfarin is a widely prescribed anticoagulant used for prophylaxis and treatment of venous and arterial thrombosis. Although warfarin is considered very efficacious, it has substantial risks associated with its use, specifically the risk of hemorrhage. Genetic variants associated with the metabolism of (S)-warfarin by cytochrome P450 2C9 may have specific implications on untoward effects. Twelve CYP2C9 allelic variants have been identified, of which CYP2C9*3 and CYP2C9*2 are the most clinically important. Studies have demonstrated that initial dosing of warfarin with CYP2C9*3 with a five-milligram dose caused an increase in the international normalized ratio and significant risk of bleeding. Studies conducted with CYP2C9*2, on the other hand are conflicting. Some data suggest that the CYP2C9*2 variant is associated with an increased propensity for bleeding whereas other studies do not demonstrate a substantial risk of adverse events. Researchers suggest that detection of genetic variants in susceptible individuals will not only decrease the risks associated with warfarin therapy but also decrease costs of adverse events.
- Blann A, Hewitt J, Siddiqui F, et al. Racial background is a determinant of averagewarfarin dose required to maintain the INR between 2.0 and 3.0. British Journal of Haematology 1999;107(1):207-209.
- Takahashi H, Echizen H. Pharmacogenetics of warfarin elimination and its clinical implications. Clin Pharmacokinet 2001;40(8):587-603.
- Redman A. Implications of cytochrome P450 2C9 polymorphism on warfarin metabolism and dosing. Pharmacotherapy 2001;21:235-241.
- Hirsh J, Dalen J, Anderson D, et al. Oral anticoagulants mechanisms of action, clinical effectiveness, and optimal therapeutic range. Chest 1998;114:445S-469S.
- Kovacs M, Roger M, Anderson D, et al. Comparison of 10 mg and 5 mg warfarin initiation nomograms together with low-molecular-weight heparin for outpatient treatment of acute venous thromboembolism. Ann Intern Med 2003;138:1714-1719.
- Pirmohamed M. Pharmacogenetics and pharmacogenomics.Br J Clin Pharmacol 2001;52:345-347.
- Kaminsky L, Zhang Z. Human P450 metabolism of warfarin.Pharmacol Ther 1996;1:67-74.
- The Human Cytochrome P450 (CYP) Allele Nomenclature Committee. CYP2C9 allele nomenclature. www.imm.ki.se/ CYPalleles/cyp2c9.htm (accessed 2003 May 10).
- Ingelman-Sundberg M, Oscarson M, McLellan R. Polymorphic human cytochrome P450 enzymes: An opportunity for individualized drug treatment. Trends in Pharmacological Sciences 1999;20:342-349.
- Hirsh J. Optimal intensity and monitoring warfarin. Am J Cardiology 1995;75:39B-42B.
- Higashi M, Veenstra D, Midori Kondo L, et al.Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy.JAMA 2002;287:1690-1698.
- Tabrizi A, Zehnbaucer B, Borecki I, et al. The frequency and effects of cytochrome P450 2C9 polymorphisms in patients receiving warfarin. The American Journal of Surgeons 2002;194:267-273.
- Taube J, Halsall D, Baglin T. Influence of cytochrome P-450 CYP2C9 polymorphisms onwarfarin sensitivity and risk of over-anticoagulation in patients on long-term treatment. Blood 2000;96:1816-1819.
- Loebstein R, Yonath H, Peleg D, et al. Interindividual variability in sensitivity to warfarin–Nature or nurture? Clin Pharmacol Ther 2001;70:159-164.
- Aithal GP, Day CP, Kesteven PJ, Daly AK. Association of polymorphisms in the cytochrome P450 CYP2C9 with 212. warfarin dose requirement and risk of bleeding complications.Lancet 1999;353:717-719.
- Tabrizi A, Mcgrath S, Blinder M, et al. Extreme warfarin sensitivity associated with multiple cytochrome P450 polymorphisms.Am J Hematol 2001;67:144-146.
- Leung A, Chow H, Kwong Y, et al. Genetic polymorphisms in exon 4 of cytochrome P450 CYP2C9 may be associated with warfarin sensitivity in Chinese patients. Blood 2001;98:2584-2587.
- Hiratsuka M, Agastuma Y, Mizugaki M. Rapid detection of CYP2C9*3 alleles by real-time fluorescence PCR based on SYBR green. Molecular Genetics and Metabolism 1999;68:357-362.
- Burian M, Grosch S, Tegeder I, et al. Validation of a new flourogenic real-time PCR assay for detection of CYP2C9 allelic variants and CYP2C9 allelic distribution in a German population. Br J Clin Pharmacol 2002;54:518-521.
- Takahashi H, Kashima T, Kimura S, et al. Determination of unbound warfarin enantiomers in human plasma and 7-hydroxywarfarin in human urine by chiral stationaryphase liquid chromatography with ultraviolet or fluorescence and on-line circular dichroism detection. Journal of Chromatography B 1997;701:71-80.
- Lafata J, Martin S, Kaatz S, et al. The cost-effectiveness of different management for patients on chronic warfarin therapy. J Gen Intern Med 2000;15:31-37.
- Ross J, Ginsburg G. The integration of molecular diagnostics with therapeutics. Am J Clin Pathol 2003;119(1):26-36.
- Polymorphism Induced Sensitivity to Warfarin: A Review of the Literature
Journal of Thrombosis and Thrombolysis
Volume 15, Issue 3 , pp 205-212
- Cover Date
- Print ISSN
- Online ISSN
- Kluwer Academic Publishers
- Additional Links
- warfarin metabolism
- Industry Sectors