Identification and functional characterization of a novel F5 mutation (Ala512Val, FVBonn) associated with activated protein C resistance

Abstract

See also Bernardi F. Better or worse than the original. This issue, pp 1350-2. Essentials• Activated protein C (APC) resistance is a prevalent risk factor for venous thrombosis.• A novel missense mutation (Ala512Val -FV Bonn ) was characterized in vitro and in silico.• FV Bonn is a new cause of APC resistance and venous thrombosis.• FV Bonn expresses additionally enhanced procoagulant activity in the absence of APC.Summary. Background: Activated protein C (APC) resistance is a prevalent risk factor for venous thrombosis. This phenotype is most commonly associated with the factor V Arg506Gln mutation (FV Leiden), which impairs the APC-mediated inactivation of both activated FV (FVa) and activated FVIII (FVIIIa Leiden). The APC-mediated inactivation of FVa Bonn was slower than that of WT FVa (mainly because of delayed cleavage at Arg506), but was greatly stimulated by protein S. The APC cofactor activity of FV Bonn in FVIIIa inactivation was~24% lower than that of WT FV. In line with these findings, an in silico analysis showed that the Ala512Val mutation is located in the same loop as the Arg506 APC cleavage site and might hamper its interaction with APC. Moreover, FV Bonn was more procoagulant than WT FV and FV Leiden in the absence of APC, because of an increased activation rate and, possibly, an enhanced interaction with activated FX. Conclusions: FV Bonn induces hypercoagulability via a combination of increased activation/procoagulant activity, decreased susceptibility to APC-mediated inactivation, and slightly reduced APC cofactor activity.

Emicizumab‐mediated haemostatic function in patients with haemophilia A is down‐regulated by activated protein C through inactivation of activated factor V

“…In this context, the concentrations of APC required for the anticoagulant effects in the present study were greater than had been previously published (Castoldi et al , ; Bos et al , ; Nogami et al , ; Pezeshkpoor et al , ). These discrepancies could have been due to the use of difference of trigger reagents.…”

“…Activated protein C‐regulated haemostasis is generally assessed using TF‐triggered TGA (Castoldi et al , ; Bos et al , ; Pezeshkpoor et al , ), and our results utilizing TF/Elg‐triggered TGA require further investigation. Nevertheless, emicizumab is known to mimic FVIIIa cofactor function rather than native FVIII, and the results of TF‐triggered TGA, reflecting the extrinsic coagulation pathway, have demonstrated low sensitivity to the enhancing effect of the bispecific antibody, whilst Elg‐triggered TGA, reflecting the intrinsic coagulation pathway, are likely to occur too rapidly for detecting emicizumab‐mediated TG (Muto et al , ).…”

Better or worse than the original

“…In this issue, Pezeshkpoor et al ., from the University Clinic of Bonn, Germany, and from Maastricht University, The Netherlands, report a novel and stimulating finding, i.e. the Ala512Val mutation (FV Bonn), detected in the heterozygous condition in six unrelated patients and their affected family members . APC resistance was described in plasma from the six probands.…”

Novel insights into the regulation of coagulation by factor V isoforms, tissue factor pathway inhibitorα, and protein S

“…Other rare F5 gene mutations resulting in APC resistance have been described. FV Nara (W1920R) causes APC resistance in a Japanese family [37], whereas FV Bonn (A512V) was found in six European patients with APC resistance [38]. For both FV Nara and FV Bonn, the F5 mutations were demonstrated to impart APC resistance.…”