Abstract
Background Activated factor V (FVa) is a potent procoagulant cofactor in the prothrombinase
complex, whereas its precursor factor V (FV) stimulates the inhibition of factor Xa
(FXa) by tissue factor pathway inhibitor-α (TFPIα), presumably by promoting TFPIα
binding to phospholipids. Plasma FV comprises two glycosylation isoforms (FV1 and
FV2) with low and high phospholipid-binding affinity, respectively. The FV1/FV2 ratio
is increased in carriers of the FV R2 haplotype.
Objective This article demonstrates the TFPIα-cofactor function of FV in plasma and compares
FV1 and FV2.
Materials and Methods Thrombin generation at low TF concentration was measured in FV-depleted plasma reconstituted
with 0 to 100% FV, FV1 or FV2, and in 122 individuals genotyped for the R2 haplotype.
The TFPIα-cofactor activities of FV1 and FV2 were also investigated in a model system
of TFPIα-mediated FXa inhibition.
Results In the FV titration, thrombin generation first increased (up to 5% FV) and then progressively
decreased at higher FV concentrations. This anticoagulant effect of FV, which was
also observed with FV2 but not with FV1, was largely abolished by anti-TFPIα antibodies,
suggesting that it reflects TFPIα-cofactor activity of FV. In the model system of
TFPIα-mediated FXa inhibition, FV2 was a more potent TFPIα-cofactor than FV1, in line
with their respective phospholipid affinities. Accordingly, FV R2 carriers had higher
thrombin generation than non-carriers, even after correction for demographics and
plasma levels of coagulation factors and inhibitors.
Conclusion FV (and particularly its FV2 isoform) contributes to the TFPIα-dependent down-regulation
of thrombin generation in plasma triggered with low TF.
Keywords
factor V - tissue factor pathway inhibitor - R2 haplotype - thrombin generation -
phospholipids
