Thromb Haemost 2018; 118(07): 1194-1202
DOI: 10.1055/s-0038-1656549
Coagulation and Fibrinolysis
Georg Thieme Verlag KG Stuttgart · New York

Factor V Has Anticoagulant Activity in Plasma in the Presence of TFPIα: Difference between FV1 and FV2

Peter van Doorn
1  Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, The Netherlands
,
Jan Rosing
1  Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, The Netherlands
,
Connie Duckers
1  Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, The Netherlands
,
Tilman M. Hackeng
1  Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, The Netherlands
,
Paolo Simioni
2  Thrombotic and Hemorrhagic Diseases Unit, Department of Medicine, University of Padua Medical School, Padua, Italy
,
Elisabetta Castoldi
1  Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, The Netherlands
› Author Affiliations
Funding This work was supported by grant 2014–1 from the Dutch Thrombosis Foundation. Prof. Jan Rosing is Van de Laar Professor of Coagulation Enzymology.
Further Information

Publication History

09 January 2018

19 April 2018

Publication Date:
04 June 2018 (eFirst)

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.

Supplementary Material