Warfarin dosing and cytochrome P450 2C9 polymorphisms

Hylton V. Joffe; Ruliang Xu; F. Bradley Johnson; Janina Longtine; Nils Kucher; Samuel Z. Goldhaber

doi:10.1160/TH04-02-0083

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2004; 91(06): 1123-1128
DOI: 10.1160/TH04-02-0083

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

Warfarin dosing and cytochrome P450 2C9 polymorphisms

Hylton V. Joffe^*

¹Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA

,

Ruliang Xu^*

²Department of Pathology, Mount Sinai School of Medicine, New York, USA

,

F. Bradley Johnson

³Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA

,

Janina Longtine

⁴Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA

,

Nils Kucher

⁵Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA

,

Samuel Z. Goldhaber

⁵Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA

› Institutsangaben

Abstract

Summary

Two cytochrome P450 2C9 (CYP2C9) polymorphisms, CYP2C9*2 and *3, metabolize warfarin inefficiently. We assessed the extent to which these polymorphisms explain very low warfarin dose requirements and hemorrhagic complications after excluding non-genetic determinants of warfarin dosing. In this retrospective observational study, 73 patients with stable warfarin doses for ≥1 month and International Normalized Ratios (INR) of 2.0–3.0 were enrolled from our Anticoagulation Clinic. Seventeen patients required ≤2 mg (low-dose), 41 required 4–6 mg (moderate-dose), and 15 required ≥10 mg (high-dose) of daily warfarin. CYP2C9 genotyping was assessed by PCR amplification and restriction enzyme digestion analysis of DNA isolated from circulating leukocytes. The CYP2C9 polymorphisms independently predicted low warfarin requirements after adjusting for Body Mass Index, age, acetaminophen use, and race (OR 24.80; 95% CI 3.83–160.78). At least one polymorphism was present in every patient requiring ≤1.5 mg of daily warfarin, and 88%, 37%, and 7% of the low-, moderate-, and high-dose groups, respectively. All homozygotes and compound-heterozygotes for the variant alleles were in the low-dose group. Rates of excessive (INR>6.0) anticoagulation (and bleeding) were 4.5 (6.0), 7.9 (7.9), and 14.7 (0) per 100 patient-years in the wild-types, heterozygotes, and compound heterozygotes/homozygotes, respectively. In conclusion, CYP2C9*2 or *3 compound heterozygotes and homozygotes have low warfarin requirements even after excluding liver disease, excessive alcohol or acetaminophen consumption, low body weight, advancing age, and drug interactions. These polymorphisms increase the rate of excessive anticoagulation, but this risk does not appear to be associated with higher bleeding rates when anticoagulation status is closely monitored.

Keywords

Anticoagulants - metabolism - genetics - hemorrhage

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Referenzen

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