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Key Points

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  • Drug summary:

    • Warfarin (Coumadin) is a commonly prescribed vitamin K antagonist for the prevention of thromboembolism. However, the drug has a very narrow therapeutic index and a large interindividual variability in response, in part due to inherited genetic variability within genes involved in warfarin pharmacokinetics and pharmacodynamics.

    • Clinical indications for anticoagulation therapy include atrial fibrillation, mechanical heart valves, deep venous thrombosis, and dilated cardiomyopathies.

    • Interindividual and interethnic variability in therapeutic warfarin dose requirements is responsible for frequent adverse drug reactions and underutilization due to its toxicity.

    • Several factors affect warfarin dosage, including age, body weight, concomitant medications, and DNA sequence variants in cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase subunit 1 (VKORC1).

    • Common variant CYP2C9 and VKORC1 alleles are associated with impaired warfarin metabolism and sensitivity to warfarin, respectively, both resulting in lower therapeutic dose requirements.

    • Individuals with impaired warfarin metabolism and/or increased sensitivity require decreased dosage to avoid their international normalized ratio (INR) increasing beyond the target range (typically 2-3). Increased INR values can be associated with morbidity and mortality due to major bleeding episodes.

    • Although many variant CYP2C9 and VKORC1 alleles are found in several major racial and ethnic groups, some are specific to various subpopulations.

    • Pharmacogenetic dosing algorithms including both clinical and genetic variables have been developed that predict the therapeutic warfarin dose.

    • Clinical testing for variant CYP2C9 and VKORC1 alleles is available and generalized FDA-approved dosing recommendations are now noted on the warfarin package insert.

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  • Monogenic forms:

    • Rare heterozygous coding region VKORC1 mutations cause warfarin resistance (OMIM #122700). These mutations make VKORC1 less susceptible to warfarin inhibition, and generally result in doses in excess of 80 mg/wk to maintain appropriate anticoagulation. Homozygosity for these rare mutations results in combined deficiency of vitamin K-dependent clotting factors type 2 (OMIM #607473), which is responsive to oral administration of vitamin K.

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  • Family history or heritability:

    • The genetic determinants of warfarin dose variability are inherited germline variants, not acquired mutations.

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  • Environmental factors:

    • Age, diet, gender, body size, comorbidities, and concomitant medications are other factors that influence warfarin dosing.

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  • Genome-wide associations:

    • To date, three genome-wide association studies (GWAS) primarily using Caucasian patients have confirmed previous CYP2C9 and VKORC1 candidate gene studies, and have identified a small role for cytochrome P450 4F2 (CYP4F2) in warfarin dose variability.

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  • Pharmacogenomics:

    • CYP2C9, VKORC1, and CYP4F2 have been estimated to account for approximately 10%, 25%, and 2.5% of the variability in warfarin dosing among individuals. Although the variant alleles of these genes may be less common in certain racial or ethnic groups, their effect on warfarin dose variability remains constant.

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Clinical Characteristics, Management, and Treatment

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Warfarin is the most commonly used oral anticoagulant worldwide. Indications for warfarin therapy include the treatment and prevention of venous and arterial thromboembolism, including deep venous thrombosis, pulmonary embolus, atrial ...

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