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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.
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Publication History

09 January 2018

19 April 2018

Publication Date:
04 June 2018 (online)

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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

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