A Mutation in Vitamin K Epoxide Reductase Complex Subunit-1 (VKORC1) in a Patient with Vitamin K Antagonist Resistance

Abstract number: OR085

Bodin¹ L, Samama² MM, Horellou² MH, Parent³ F, Flaujac² C, Beaune¹ P, Loriot¹ MA, Conard² J

¹¹INSERM URMS 490, Rene Descartes University, Paris, France ²²Department of Biological Hematology, Hotel Dieu Hospital, Paris, France ²²Department of Biological Hematology, Hotel Dieu Hospital, Paris, France ³³Lung Department, Antoine Beclere Hospital, Clamart, France

Resistance to vitamin K antagonists is a rare disorder which until recently has not been associated to a genetic factor. Mutations in vitamin K epoxide reductase complex 1 (VKORC1) gene are responsible for both human and rat warfarin resistance. The patient is a 63-year old man with recurrent pulmonary embolism and deep vein thrombosis without known hereditary or acquired thrombophilia who was found resistant to warfarin (up to 45 mg/day), fluindione (up to 80 mg/day), acenocoumarol (up to 12 mg/day) and phenprocoumon (up to 30 mg/day). With phenprocoumon, a long-acting drug, the plasma concentration reached 85 mg/L (usual range 1–5 mg/L) but the INR remained about 1.0. Treatment with low molecular weight heparin (LMWH) was discontinued on 2 occasions and recurrent thrombotic episodes were observed. Careful biochemical investigation has demonstrated a deficiency in vitamin K-dependent carboxylation and absence of blockade of vitamin K epoxide reductase by phenprocoumon. We recently sequenced the three exons of VKORC1 in this patient and detected a heterozygous T383G transversion resulting in a leucine to arginine substitution (L128R). This mutation is most likely responsible for the so called warfarin resistance since it was not found in 259 control subjects that we tested. The mutation T383G of the VKORC gene has been reported in only one patient before this case. The patient we report is now receiving a single daily dose of LMWH (enoxaparin 67 IU/kg once a day) for the past 10 years without thrombotic or bleeding episodes. Bone density tests were normal after 9 years of treatment. Progress in genetics has been very useful in order to understand the mechanism of resistance to four different vitamin K antagonists and testing for mutation in VKORC1 could help in explaining some cases of resistance to vitamin K antagonists.