Genetic factors include the following. (1) There is a common mutation in the gene coding for the cytochrome P450 2C9 hepatic microsomal enzyme that is responsible for the oxidative metabolism of the more potent warfarin S-isomer. This mutation is independently responsible for the reduced warfarin requirements seen in individuals with one or more combinations of these polymorphisms (Table 1). Several investigations have shown that these mutations are also associated with an increase in adverse clinical outcomes. (2) There is hereditary resistance to warfarin. This occurs in rats as well as in human beings, and patients with genetic warfarin resistance require doses that are 5-fold to 20-fold higher than average to achieve an anticoagulant effect. This disorder is attributed to an altered affinity of the warfarin receptor, which results in an increase in the plasma warfarin levels required to achieve an anticoagulant effect.
Table 1—Observed Frequency of CYP2C9 Variants Among Various Ethnic Groups
| Ethnic Groups | CYP2C9* 1 | CYP2C9*2 | CYP2C9*3 | CYP2C9*4 | CYP2C9*5 |
| Point mutation | Arg144/IIc359 | Cys144/IIc359 | Arg144/Leu351 | Arg144/Thr359 | Arg144/Glu360 |
| Whites | 79-86% | 8-19.1% | 6-10% | ND | ND |
| Indigenous Canadians | 91% | 3% | 6% | ND | ND |
| African Americans | 98.5% | 1 -3.6% | 0.5-1.5% | ND | 2.3% |
| Asians | 95-98.3% | 0 | 1.7-5% | 0-1.6% | 0 |
CYP2C92, CYP2C93, CYP2C94, and CYP2C95 represent genetic polymorphisms of the wild-type enzyme, CYP2C9*1. ND = not determined. Table reproduced with permission of Wittkowsky.
(3) A mutation in the factor IX propeptide causes selective reduction in factor IX during treatment with coumarin drugs without excessive prolongation of the prothrombin time (PT). Factor IX activity decreases to about 1 to 3% of normal, while levels of other vitamin K-dependent coagulation factors decrease to 30 to 40% of normal. Two distinct missense mutations involving the propeptide-coding region have been described. They are estimated to occur in < 1.5% of the population and are expressed as selectively increased sensitivity to the coumarin-mediated reduction of factor IX activity. This selective marked reduction in factor IX activity has been reported to increase the risk of bleeding during anticoagulant.
Environmental factors such as drugs, diet, and various disease states can alter the pharmacokinetics of warfarin (Table 2). Consequently, the international normalized ratio (INR) should be measured more frequently than the usual 4-week interval when virtually any drug or herbal medicine is added or withdrawn from the regimen of a patient treated with warfarin. Drugs such as cholestyramine can reduce the anticoagulant effect of warfarin by reducing its absorption.