Update in hematology.

Variations in the rate of response to a given dose of warfarin have been problematic. Effective daily doses can range from as low as 0.5 mg to higher than 60 mg. In an effort to make sense of the puzzle, Aithal and colleagues conducted a case–control study to determine whether genetic differences in the cytochrome P450 system influence the individual variability in dose requirements for warfarin. An asymmetric carbon in warfarin (C9) produces the enantiomers R-warfarin and S-warfarin, which are metabolized by different enzymes. S-warfarin, which is three times more potent than R-warfarin, is metabolized by the cytochrome P450 CYP2C9. The authors used polymerase chain reaction to evaluate the two allelic forms of CYP2C9 that have only 5% and 12% of the activity of the wild-type enzyme in patients with low-dose warfarin requirements (#1.5 mg/d; n 5 36), those with normal dose requirements who were being treated in an anticoagulation clinic (clinic controls; n 5 52), and normal persons (n 5 100). The odds ratio for having one or more of the two variant alleles in the low-dose warfarin group compared with the normal population was 6.21. Twenty percent of patients in the low-dose group and 2% of clinic controls had two variant alleles. For the low-dose group compared with clinic controls, the odds ratio for excessive international normalized ratios at initiation of warfarin treatment was 5.97. The low-dose group was also at increased risk for bleeding complications (rate ratio, 3.68) compared with clinic controls. On the basis of these results, the researchers surmised that heterozygosity or homozygosity for the two allelic forms of CYP2C9 are associated with lower warfarin dose requirements. From our point of view, this study provides strong evidence for the role of genetic variation in the cytochrome P450 system in influencing this variability. The genetic variability may also accentuate the response to drugs that are known to induce increased sensitivity to warfarin. This study further supports the initiation of warfarin therapy at a daily dose of 5 mg, as shown in an earlier article (1).