CMAJ • August 14, 2007; 177 (4). doi:10.1503/cmaj.1070081.
© 2007 Canadian Medical Association or its licensors
All editorial matter in CMAJ represents the opinions of the authors and not necessarily those of the Canadian Medical Association.
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Letters

Genetic analysis to prevent warfarin complications

Giuseppe Lippi, MD, Gian Luca Salvagno, MD and Gian Cesare Guidi, MD

Sezione di Chimica e Microscopia Clinica, Dipartimento di Scienze Morfologico-Biomediche, Università degli Studi di Verona, Verona, Italy

Warfarin is the most widely used oral anticoagulant therapy for patients with thrombosis. Owing to the notoriously narrow therapeutic range of this drug, small variations in dosing may result in hemorrhagic or thrombotic complications. We read with interest the recent CMAJ article by Natalie Oake and colleagues, in which the authors concluded that improved anticoagulation control could decrease the likelihood of almost half of all anticoagulant-associated adverse events.1

A variety of physiologic and pharmacologic factors modulate the patient's compliance with warfarin therapy, including the pharmacokinetics of warfarin, the bioavailability of vitamin K and the metabolic fate of the vitamin-K-dependent coagulation factors.2 It has consistently been reported that analysis of the genes encoding cytochrome P450 2C9 and the C1 subunit of the vitamin K 2,3-epoxide reductase complex, 2 pivotal enzymes affecting compliance with therapy, might enable physicians to estimate warfarin dosage more precisely, thereby improving the global efficiency of the titration process and reducing the likelihood of hemorrhagic and thromboembolic events. These 2 genotypes along with age, sex and body weight account for up to 60% of the variance in daily maintenance dose of warfarin.3–6 Therefore, construction of dense genetic maps based on single nucleotide polymorphisms for both of these genes might be a powerful aid to dissecting the polygenic traits of drug response. When combined with an analysis of specific ethnic, clinical, environmental and psychological factors, such a tool could assist clinicians to define a warfarin dose–response phenotype that could be used to improve the quality of dose management. This might be a crucial step toward individualized medicine.6

Footnotes

Competing interests: None declared.


REFERENCES

  1. Oake N, Fergusson DA, Forster AJ, et al. Frequency of adverse events in patients with poor anticoagulation: a meta-analysis. CMAJ 2007;176(11):1589-94.[Abstract/Free Full Text]
  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(3 Suppl):204S-33S.
  3. Kealey C, Chen Z, Christie J, et al. Warfarin and cytochrome P450 2C9 genotype: possible ethnic variation in warfarin sensitivity. Pharmacogenomics 2007;8:217-25.[CrossRef][Medline]
  4. Zhu Y, Shennan M, Reynolds KK, et al. Estimation of warfarin maintenance dose based on VKORC1 (-1639 G>A) and CYP2C9 genotypes. Clin Chem 2007;53(7):1199-205.[Abstract/Free Full Text]
  5. Caldwell MD, Berg RL, Zhang KQ, et al. Evaluation of genetic factors for warfarin dose prediction. Clin Med Res 2007;5:8-16.[Abstract/Free Full Text]
  6. Krynetskiy E, McDonnell P. Building individualized medicine: prevention of adverse reactions to warfarin therapy. J Pharmacol Exp Ther DOI 10.1124/jpet.106.117952v1. Epub 2007 May 11 ahead of print.




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