Severe thrombophilia in a factor V-deficient patient homozygous for the Ala2086Asp mutation (FV Besançon)

BACKGROUND: Coagulation factor V (FV), present in plasma and platelets, has both pro- and anticoagulant functions.OBJECTIVE: We investigated a FV-deficient patient (FV:C 3%, FV:Ag 4%) paradoxically presenting with recurrent venous thrombosis (11 events) instead of bleeding.METHODS/RESULTS: Thrombophilia screening revealed only heterozygosity for the F2 20210G>A mutation. While thrombin generation in the patient's platelet-poor plasma was suggestive of a hypocoagulable state, thrombin generation in the patient's platelet-rich plasma (PRP) was higher than in control PRP and extremely resistant to activated protein C (APC). This was partially attributable to the complete abolition of the APC-cofactor activity of FV and a marked reduction of plasma tissue factor pathway inhibitor antigen and activity. The patient was homozygous for a novel missense mutation (Ala2086Asp, FVBesançon ) that favours a "closed conformation" of the C2 domain, predicting impaired binding of FV(a) to phospholipids. Recombinant FVBesançon was hardly secreted, indicating that this mutation is responsible for the patient's FV deficiency. Model system experiments performed using highly diluted plasma as a source of FV showed that, compared to normal FVa, FVaBesançon has slightly (≤1.5-fold) unfavourable kinetic parameters (Km , Vmax ) of prothrombin activation, but also a lower rate of APC-catalysed inactivation in the presence of protein S.CONCLUSIONS: FVBesançon induces a hypercoagulable state via quantitative (markedly decreased FV level) and qualitative (phospholipid-binding defect) effects that impact anticoagulant pathways (anticoagulant activities of FV, FVa inactivation, TFPIα level) more strongly than the prothrombinase activity of FVa. A possible specific role of platelet FV cannot be excluded.