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The following case study focuses on the considerations for determining the appropriate dosing for individuals requiring anticoagulation with warfarin. Test your knowledge by reading the background information below and making the proper selection.

A 66-year-old woman had a left-sided deep-vein thrombosis, and oral warfarin dosing was recommended, while bridging with unfractionated heparin. Based on recent studies, which genetic changes(s) affect(s) the pharmacokinetics of warfarin dosing in patients?

1. P450 2C9 (CYP2C9) polymorphism
2. VKORC1 polymorphism/mutation
3. JAK 2 V617F mutation
4. No pharmacogenetic information has been associated with warfarin dosing and anticoagulation. Starting dosing should be based on algorithms, which apply similarly to all populations.
5. VKORC1 polymorphism/mutation and P450 2C9 (CYP2C9) polymorphism

Answer

5. VKORC1 and P450 2C9 (CYP2C9)

Explanation

Historically, warfarin dosing has been based on an empiric starting dose, often based on algorithms with dosing adjustments made based on individual, closely monitored International Normalized Ratio (IRN) results. It is well recognized that drug interactions of the P450 enzyme contribute to the variability of warfarin metabolism and influence INR results. Despite this, some patients are outliers, meaning that they have marked variation to the response of typical warfarin dosing, either by marked “sensitivity” or “resistance” to typical doses.

Recent advances to our understanding of the critical enzymes involved in the coagulation pathway affected by warfarin dosing has led to elucidation of genetic variants and clinically significant polymorphisms, which are associated with alterations in warfarin dose requirements to achieve therapeutic INRs.

The P450 CYP2C9 hepatic microsomal enzyme system is primarily responsible for the metabolism of the enantiomer S-warfarin, which is the more potent form of warfarin (compared to the R-warfarin enantiomer). Polymorphisms in CYP2C9*2 and CYP2C9*3 result in decreased metabolism of warfarin and have been associated with alterations in the clinical response to warfarin dosages, resulting in decreased warfarin dose requirements, increased INR levels, and a higher risk for bleeding during warfarin therapy.^1,2

The target of action for warfarin is the vitamin K epoxide reductase (VKOR) complex, which is responsible for normal recycling of vitamin K. Missense mutations of VKORC1 have been associated with warfarin resistance, and polymorphisms have been associated with inter-individual variability in the dose-anticoagulant effect of warfarin.^3,4,5

In 2007, the FDA added information to the warfarin packaging based on  these recent findings of the pharmacogenetic effects on warfarin dosing and provided information and approval of genetic testing for the polymorphisms in the VKORC1 and P450 2C9 (CYP2C9) genes in individuals receiving warfarin therapy.¹ To date, however, few studies have demonstrated a clinically significant benefit of genetic testing as frequent INR monitoring is still recommended in most patients initiating warfarin therapy.

The international warfarin pharmacogenetics consortium recently tested a pharmacogenetic algorithm and applied it to a validation cohort.⁶ The validation cohort consisted of 1,009 patients, and the algorithm accurately identified more patients who required less than 21 mg or more than 49 mg warfarin a week when compared to a traditional clinical algorithm. Further prospective studies of large numbers of patients are planned to determine whether warfarin pharmacogenetic testing translates into significantly decreased risks of adverse clinical outcomes including complications of bleeding or thromboses.

References

1. Wadelius M, Chen LY, Lindh JD, et al.. Blood. 2009;113:784-92.
2. Higashi MK, Veenstra DL, Kondo LM, et al. . JAMA. 2002;287:1690-98.
3. Wang D, Chen H, Momary KM, et al. . Blood. 2008;112:1013-21. Erratum in: Blood. 2009;113:1393-94.
4. Rost S, Fregin A, Ivaskevicius V, et al. . Nature. 2004;427:537-41.
5. D’Andrea G, D’Ambrosio RL, Di Perna P, et al. .Blood. 2005;105:645-649.
6. The International Warfarin Pharmacogenetics Consortium. .N Engl J Med. 2009;360:753-64.

Case study submitted by Anita Schwandt, MD, of the MetroHealth Medical Center/University Hospitals of Cleveland, Case Western University School of Medicine.