Scientific Poster Session II - Case Reports

Abstract

Most genetic variants within the enzymes that metabolize warfarin result in increased sensitivity to warfarin necessitating decreases in warfarin dosing. Identification of new variants are leading to increased understanding of the genetic basis of warfarin resistance. One variant, the VKORC1 D36Y variant, is being reported more frequently in the literature. This case report defines warfarin resistance and details how the VKORC1 D36Y variant affects warfarin sensitivity.

Case:

A young North African woman with a mechanical mitral valve presented to the anticoagulation clinic in August 2019 to manage her warfarin therapy. Previously lost to follow-up, the patient restarted warfarin 20 mg daily and therapeutic enoxaparin injections. Persistent subtherapeutic INRs resulted in a referral to hematology and genetic testing. The testing results showed heterozygosity for the VKORC1 D36Y mutation. After testing, her weekly warfarin dose was titrated up to 630 mg/week.

Discussion:

Warfarin resistance is defined as the administration of warfarin doses greater than or equal to 80-140 mg/week. Recently discovered genetic variants in the VKORC1 enzyme has led to increased understanding of the mechanisms underscoring warfarin resistance. One particular variant, D36Y, reflects a change of aspartic acid to tyrosine at position 36 within the luminal loop.

First described in 2006, Loebstein, et al., later described the prevalence of the D36Y variant in a patient population with stable INRs. Seven out of fifteen patients deemed warfarin resistant had the variant, requiring more than 70 mg warfarin/week. Lastly, the D36Y variant frequently presents in individuals of Ethiopian, Ashkenazi Jewish, and North African descent.

Conclusion:

Within the last 20 years, the VKORC1 D36Y variant has demonstrated significance with respect to warfarin resistance, particularly in patients of Mediterranean descent. Clinicians should recommend testing for this variant when assessing patients deemed warfarin resistant. Further research is warranted to include this variant in future clinical pharmacogenomic guidelines.

Presenting Author

Authors