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Warfarin Resistance, Genetic Testing

Warfarin sodium is an orally administered anticoagulant drug that is marketed most as Coumadin®. Warfarin affects the vitamin K - dependent clotting factors II, VII, IX, and X. Warfarin is thought to interfere with clotting factor synthesis by inhibiting the C1 subunit of the vitamin K epoxide reductase (VKORC1) enzyme complex, thereby reducing the regeneration of vitamin K1 epoxide. The elimination of warfarin is almost entirely by metabolic conversion to inactive metabolites by cytochrome P450 (CYP) enzymes in liver cells. CYP2C9 is the principal cytochrome P450 enzyme that modulates the anticoagulant activity of warfarin. From the results of clinical studies, genetic variation in the CYP2C9 and/or VKORC1 genes can, in concert with clinical factors, predict how each individual responds to warfarin.

There is perhaps no drug whose therapeutic range is functionally as narrow as that of warfarin. It is widely recognized that dosing of warfarin is difficult, and this has resulted in the development over the last years of the International Normalized Ratio (INR) monitoring system. The INR is routinely reported as the ratio of the patient's prothrombin time to that of a reference population, corrected for the sensitivity of the thromboplastin reagent used. Warfarin dosing is typically adjusted to maintain the INR at 2.5 ± 0.5 and at 3.0 ± 0.5 for higher-risk patients, including those with certain mechanical heart valves.

The clinical value of warfarin

Warfarin is indicated for the prophylaxis and treatment of venous thrombosis and pulmonary embolism, for thromboembolic complications associated with atrial fibrillation and cardiac valve replacement, and in the post-myocardial infarction setting where it is used to reduce the risk of death, recurrent myocardial infarction, and thromboembolic events.

Warfarin and dosing variability

Warfarin dosing is highly variable between individuals. Several factors affect warfarin dosing, including nongenetic factors (drug-drug interactions, environmental factors, including diet, alcohol consumption, and smoking), and genetic factors. There is ample evidence that genetic factors explain about 40% of warfarin dosing variability.

Two generalized clinical scenarios exist for warfarin dosing: warfarin resistance and warfarin sensitivity. Warfarin resistance is an infrequently encountered clinical scenario that may be due to mutations in the vitamin K epoxide reductase complex 1 gene (VKORC1), a recently identified target of warfarin inhibition. These mutations make VKORC1 less susceptible to warfarin inhibition. Heterozygosity leads to increased warfarin requirements, generally more than 80 mg/week to maintain appropriate anticoagulation status. Complete inactivation of VKORC1 causes a rare syndrome of multiple coagulation factor defects (combined deficiency of vitamin k-dependent clotting factors, type 2) that is responsive to oral administration of vitamin K.

The more frequent clinical scenario is warfarin sensitivity. In this context, warfarin is used for anticoagulation to produce an increase in the prothrombin time, as expressed by the INR, to between 2 and 3 (or between 2.5 and 3.5 for some artificial heart valves). Some individuals are sensitive to warfarin, requiring decreased dosing; otherwise, the INR may increase significantly above their target range. Major bleeding episodes, including cerebrovascular bleeds, are significant adverse events leading to morbidity and mortality. These are associated with warfarin sensitivity and INR >5.

Genes and polymorphisms that are independent predictors of warfarin dosing variability

Genetic variability of warfarin dosing has been attributed to polymorphisms in genes that encode the enzymes that metabolize warfarin, the targets of warfarin inhibition in the vitamin K cycle, the gene responsible for vitamin K-dependent γ-carboxylation of proteins, and polymorphisms within coagulation factors.

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