Genetic Response to Warfarin in Healthy Subjects

Warfarin is a highly effective oral anticoagulant that is increasingly prescribed in the United States. It has a narrow therapeutic window, however, that represents an inherent limitation, such that insufficient and excessive levels of anticoagulation are associated with elevated risks of thrombosis and bleeding particularly frequent early in the initial dose-finding phase of therapy. Typically, anticoagulation is achieved through empiric dosing and titration with consideration of certain variables and frequent assessment of the international normalized ratio (INR). Despite these precautions, conventional dosing strategies are associated with therapeutic levels of anticoagulation only about half the time on treatment. Recently, genetic variants, specifically variations in the CYP2C9 and VKORC1 genes, have been identified that affect warfarin dose requirements, prompting the expectation that gene-based dosing strategies may maximize therapeutic efficacy while minimizing the risks associated with dosing errors. While the association between variation in these genes and differences in warfarin dose requirements has been identified, the specific contribution of allelic variation to the response to warfarin administration has not been thoroughly identified. The investigators therefore seek to assess the impact of allelic variation on warfarin dose-response relationships in a group of healthy subjects. The investigators hypothesize that genetic variation in the CYP2C9 and VKORC1 enzymes will result in differences in the warfarin dose-response relationships when accounting for non-genetic factors that can affect the pharmacokinetics of warfarin and its effect on coagulation.

Inclusion criteria

• Healthy adult (> 18 years old.) subjects not taking warfarin
• Willing and able to grant written informed consent
• Available in proximity to the Medical Center for the anticipated duration of data collection (approximately 3 weeks).
• Pre-menopausal women required negative pregnancy test at study onset and willingness to abstain from sexual activity or use barrier contraception; oral contraceptives interfere with coumadin.

Exclusion criteria

• Daily prescribed medications including (1) a medication known to interact with warfarin, based on interactions listed in Micromedex as moderate or severe, and probable or definite (as of study start date, Appendix A) (2) aspirin or clopidogrel, which may increase bleeding risk in combination with warfarin.
• Recent therapy (within two weeks) with a medication known to interact with warfarin based on medication interactions listed in Micromedex
• History of thrombotic disorder requiring anticoagulant therapy
• Thrombophilia or coagulopathy, by history or screening coagulation profile with INR or PTT level > 2x the upper limit of normal
• Family history of thrombophilia or coagulopathy; prisoners or wards of the state; scheduled elective surgery within one month
• Active liver disease based on clinical history or serum transaminase levels > 2x the upper limit of normal
• Protein C or S Deficiency assessed on screening protein C and S activity profile
• Age ≥ 75
• Pre-menopausal women on oral contraception
• Non-English speaking individuals