TY - JOUR
T1 - Severe thrombophilia in a factor V-deficient patient homozygous for the Ala2086Asp mutation (FV Besançon)
AU - Castoldi, Elisabetta
AU - Hézard, Nathalie
AU - Mourey, Guillaume
AU - Wichapong, Kanin
AU - Poggi, Marjorie
AU - Ibrahim-Kosta, Manal
AU - Thomassen, M Christella L G D
AU - Fournel, Alexandra
AU - Hayward, Catherine P M
AU - Alessi, Marie-Christine
AU - Hackeng, Tilman M
AU - Rosing, Jan
AU - Morange, Pierre-Emmanuel
N1 - This article is protected by copyright. All rights reserved.
PY - 2021/5
Y1 - 2021/5
N2 - 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.
AB - 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.
KW - factor V
KW - factor V deficiency
KW - activated protein C resistance
KW - phospholipids
KW - venous thrombosis
U2 - 10.1111/jth.15274
DO - 10.1111/jth.15274
M3 - Article
C2 - 33605529
SN - 1538-7933
VL - 19
SP - 1186
EP - 1199
JO - Journal of Thrombosis and Haemostasis
JF - Journal of Thrombosis and Haemostasis
IS - 5
ER -