Format

Send to

Choose Destination
J Thromb Haemost. 2010 May;8(5):1012-7. doi: 10.1111/j.1538-7836.2010.03800.x. Epub 2010 Feb 9.

Pharmacogenetics of acenocoumarol in patients with extreme dose requirements.

Author information

1
University of Murcia, Centro de Hemodonación, Murcia, Spain.

Abstract

SUMMARY BACKGROUND:

There is currently intense debate as to whether pharmacogenetic algorithms for estimating the initial dose of coumarins provide a more accurate dose than the fixed-dose approach. Recently, it has been suggested that the greatest benefit of pharmacogenetic algorithms is observed in patients with extreme dose requirements.

OBJECTIVES:

To identify clinical and genetic factors that better characterize patients who need extreme acenocoumarol doses for steady anticoagulation state.

PATIENTS/METHODS:

We reviewed 9538 patients with a steady acenocoumarol dose from three Spanish hospitals, selecting 83 who took <or= 5.00 mg week(-1) (percentile 5, p5) and 203 taking >or= 30.00 mg week(-1) (p95). We also selected patients matched by gender and age taking 13.50-14.00 mg week(-1) (p50). We genotyped VKORC1 (rs9923231), CALU (rs1043550), GGCX (rs699664), CYP2C9 (rs1799853; rs1057910), CYP4F2 (rs2108622) and F7 (rs5742910) single-nucleotide polymorphisms (SNPs).

RESULTS:

Comparison between p5 and p95 revealed five parameters with significant differences: body surface area (BSA) (P = 0.006), age, VKORC1, CYP2C9 and CYP4F2 genotypes (all P < 0.001). First VKORC1, and second, CYP2C9 SNPs played a strong effect by determining extreme doses, particularly in p95. Only one out of 203 p95 had the VKORC1 A-1639A genotype, but this subject was CYP2C9*1/*1. In contrast, nine out of 83 p5 carried the VKORC1 G-1639G genotype, although six of them were CYP2C9*3 homozygotes and another two were heterozygotes. Surprisingly, CYP4F2 V433M SNP displayed prevalences that suggest that its influence might only be evident when patients are treated with high doses.

CONCLUSION:

Two clinical data, age and BSA, and three SNPs in the VKORC1, CYP2C9 and CYP4F2 genes strongly predict outlier patients treated with acenocoumarol.

[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for Wiley
Loading ...
Support Center