Use of oral anti-Xa inhibitor in prosthetic mechanical aortic valve with warfarin hypersensitivity due to the FIX p.(Ala37Thr) pro peptide variant: case report and literature review.

Abstract

Bleeding is the most common side effect during treatment with vitamin K antagonists (VKAs). Sometimes, VKA use causes bleeding episodes due to rare variants in the factor IX (FIX) pro peptide that modify the affinity of FIX pro peptide to the binding of γ-glutamyl carboxylase. We report on a 51-year-old patient who presented with recurrent spontaneous and severe intramuscular and cutaneous bleedings during VKA (warfarin) treatment for the presence of prosthetic mechanical aortic valve. Laboratory evaluation revealed INR within the therapeutic range with markedly prolonged aPTT and large reduction of FIX levels. Laboratory parameters significantly improved when warfarin was switched with low-molecular-weight heparin. Next generation sequencing analysis revealed the variant p.(Ala37Thr) in the F9 gene, which has been previously associated with VKA sensitivity. As an alternative to warfarin, apixaban 5 mg twice daily and aspirin 100 mg daily was started, with no thrombosis or recurrence of hemorrhage and normalization of INR, aPTT and FIX levels, at 12-months follow-up. We also performed a literature search across PubMed and Scopus, until January 2025. The analysis evidenced 5 case reports and 2 case series. The mechanisms of this rare VKA hypersensitivity have also been reviewed. In conclusion, while VKA hypersensitivity is a rare phenomenon, awareness towards this complication and the current accessibility to molecular testing make it important to identify patients at risk. The efficacy/safety of direct thrombin or factor Xa inhibitors in patients with mechanical heart valve and VKA hypersensitivity due to F9 p.(Ala37Thr) variant deserves more attention and further investigations.