TFPIα inhibition by Andexanet alfa is partially restored by protein S and factor V-short
File(s)
Published version
Author(s)
Crossette-Thambiah, Christina Keshini
Bamberg, Krister
Laffan, Mike A
Ahnstrom, Josefin
Type
Journal Article
Abstract
Andexanet alfa (AndA) is a modified, inactive form of coagulation factor (F)Xa, and is the only selective reversal agent for direct oral anti FXa inhibitors. Due to its similarity to FXa, AndA binds the endogenous anticoagulant, tissue factor pathway inhibitor alpha (TFPIα). We determined how AndA impacts TFPIα function and enhancement by its cofactors, protein S and FV-short. AndA reversed rivaroxaban-mediated suppression of thrombin generation in plasma. In the absence of rivaroxaban, AndA (0.25-4μM) increased peak thrombin ~22-fold, but had no impact in the presence of anti-TFPIα antibodies, suggesting AndA inhibited TFPIα anticoagulant function. However, AndA did not fully block TFPIα, with ~20-30% function remaining at 2-4μM AndA. This preserved TFPIα function was fully inhibited by anti-protein S antibodies, suggesting partial protection of TFPIα function by its cofactors. In pure-component FXa inhibition assays, AndA fully blocked TFPIα-mediated FXa inhibition, both in the presence and absence of protein S and FV-short. Similarly, AndA-bound TFPIα was unable to inhibit FIXa and FXa generation by tissue factor (TF)-FVIIa in the absence of protein S and FV-short. However, in their presence, AndA-TFPIα inhibited FIXa generation with an IC50 of 0.14nM compared to 0.05nM for FXa-TFPIα. Similarly, assays of FXa generation showed inhibition of TF-FVIIa-mediated FX activation at saturating concentrations of AndA in the presence of protein S and FV-short. Whilst AndA reduces TFPIα function by competing with FXa for TFPIα interactions, it does not fully block TFPIα. Protein S and FV-short enable AndA-bound TFPIα to locate at the membrane surface to inhibit TF-FVIIa.
Date Issued
2026-06-02
Date Acceptance
2026-03-21
Citation
Blood Advances, 2026, 10 (11), pp.4028-4040
ISSN
2473-9529
Publisher
American Society of Hematology
Start Page
4028
End Page
4040
Journal / Book Title
Blood Advances
Volume
10
Issue
11
Copyright Statement
© 2026 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribu- tion. All other rights reserved.
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/41962001
Source
65th Annual Scientific Meeting of the British-Society-for-Haematology
Subjects
Science & Technology
Life Sciences & Biomedicine
Hematology
Publication Status
Published
Start Date
2025-04-27
Finish Date
2025-04-29
Coverage Spatial
SCOTLAND, Glasgow
Date Publish Online
2026-04-10