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

Peter van Doorn, Jan Rosing, Connie Duckers, Tilman M. Hackeng, Paolo Simioni, Elisabetta Castoldi*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

15 Citations (Web of Science)

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-alpha (TFPI alpha), presumably by promoting TFPI alpha 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 TFPI alpha-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 TFPI-cofactor activities of FV1 and FV2 were also investigated in a model system of TFPI alpha-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-TFPI alpha antibodies, suggesting that it reflects TFPI alpha-cofactor activity of FV. In the model system of TFPI alpha-mediated FXa inhibition, FV2 was a more potent TFPI alpha-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 TFPI alpha-dependent down-regulation of thrombin generation in plasma triggered with low TF.
Original languageEnglish
Pages (from-to)1194-1202
Number of pages9
JournalThrombosis and Haemostasis
Volume118
Issue number7
DOIs
Publication statusPublished - 1 Jul 2018

Keywords

  • factor V
  • tissue factor pathway inhibitor
  • R2 haplotype
  • thrombin generation
  • phospholipids
  • FACTOR PATHWAY INHIBITOR
  • TISSUE FACTOR PATHWAY
  • ACTIVATED PROTEIN-C
  • VENOUS THROMBOSIS
  • FACTOR-XA
  • COFACTOR ACTIVITY
  • COAGULATION
  • ALPHA
  • PROTHROMBINASE
  • RISK

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