Abstract Number: PB2187
Meeting: ISTH 2020 Congress
Theme: Venous Thromboembolism and Cardioembolism » Genetic Risk Factors of Thrombosis
Background: Coagulation factor V (FV), present in plasma and platelets, has multiple pro- and anticoagulant functions. FV deficiency is usually associated with a bleeding diathesis.
Aims: We investigated a 37-year-old male with FV deficiency (FV:C 3%, FV:Ag 4%) and recurrent venous thrombosis (11 events).
Methods: The patient provided informed consent to blood sampling for the purpose of this study. Thrombin generation in frozen-thawed platelet-rich (PRP) and platelet-poor plasma (PPP) was measured by Calibrated Automated Thrombography. The cofactor activity of FV for activated protein C (APC) in factor VIIIa inactivation was determined with the Immunochrom assay. The mutant FV C2 domain structure was analysed by molecular dynamics simulation. The functional properties of FV(a)Besançon were studied by kinetic assays using highly diluted patient’s PPP as a source of FVBesançon.
Results: The patient carried no thrombophilic defects, except for the F2 20210G>A mutation. Thrombin generation showed a hypocoagulable state in the patient’s PPP, but a hypercoagulable state in the patient’s PRP. The APC-response was impaired in both PPP and PRP, partly due to the absence of APC-cofactor activity of FV (Immunochrom APCsr 1.44 vs.2.04 in normal plasma) and to the low tissue factor pathway inhibitor level (24%). The patient’s FV deficiency was attributable to a novel missense mutation (Ala2114Asp, FVBesançon) that favours a “closed conformation” of the C2 domain and interferes with FV(a) binding to phospholipids. Compared to normal FVa, FVaBesançon had 2-fold lower affinity for factor Xa, slightly (< 1.5-fold) unfavourable kinetic parameters
(Km, Vmax) of prothrombinase, but a considerably 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 the anticoagulant reactions (anticoagulant activities of FV, FVa inactivation) more strongly than the procoagulant reactions (prothrombinase). A possible specific role of platelet FV is still under investigation.
To cite this abstract in AMA style:
Castoldi E, Hézard N, Mourey G, Wichapong K, Ibrahim-Kosta M, Thomassen MCLGD, Fournel A, Alessi M-, Hackeng TM, Rosing J, Morange P-. Characterisation of a Novel F5 Gene Mutation (Ala2114Asp, Factor V Besançon) Associated with Factor V Deficiency and Recurrent Venous Thrombosis [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/characterisation-of-a-novel-f5-gene-mutation-ala2114asp-factor-v-besancon-associated-with-factor-v-deficiency-and-recurrent-venous-thrombosis/. Accessed March 22, 2024.« Back to ISTH 2020 Congress
ISTH Congress Abstracts - https://abstracts.isth.org/abstract/characterisation-of-a-novel-f5-gene-mutation-ala2114asp-factor-v-besancon-associated-with-factor-v-deficiency-and-recurrent-venous-thrombosis/