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Deletion of tissue factor pathway inhibitor isoform beta or gamma, but not alpha, improves clotting in hemophilic mice.

Authors :
Eldem I
Antunes-Heck L
Subramanian R
Lasky NM
Ashworth K
Di Paola J
Girard TJ
Source :
Journal of thrombosis and haemostasis : JTH [J Thromb Haemost] 2024 Oct; Vol. 22 (10), pp. 2681-2691. Date of Electronic Publication: 2024 Jun 24.
Publication Year :
2024

Abstract

Background: Tissue factor pathway inhibitor (TFPI) regulates tissue factor-triggered coagulation. Humans and mice express transcripts encoding for multidistributed (endothelial, platelet, and plasma) 3-Kunitz domain TFPIα and endothelial membrane-anchored 2-Kunitz TFPIβ. Mice express a third transcript, γ, that encodes plasma lipoprotein-associated 2-Kunitz TFPI. In humans, proteolysis of α and/or β produces plasma lipoprotein-associated 2-Kunitz TFPI at lower levels. In clinical trials, monoclonal antibodies that target all TFPI isoforms extend coagulation and correct bleeding in hemophilic patients but with some thrombosis risks.<br />Objectives: To determine the impact of TFPI isoform-specific deletions on promoting clotting in hemophilic mice.<br />Methods: Engineered TFPI isoform-specific, hemophilic (factor VIII-null) mice were evaluated for clotting.<br />Results: Mice expressing any single TFPI isoform were healthy. Thrombin generation assays identified TFPIγ as the dominant anticoagulation isoform in mouse plasma. Hemostasis was assessed by serial bleeding times from a tail vein laceration. Repeatedly, after a clot forms, it was manually disrupted; the number of clots/disruptions occurring over a 15-minute period were reported. C57BL/6 and hemophilic mice clot on average 25.6 vs 5.4 times, respectively. On a hemophilia background, TFPIβ or TFPIγ-specific deletion improved clotting to 14.6 and 15.2 times, respectively (P < .0001). TFPIα-specific deletion was without impact, clotting 5.1 times. Heterozygous deletion of TFPIβ was effective, clotting 11.8 times (P < .0001). Heterozygous deletion of TFPIα or TFPIγ alone was ineffective, clotting 3.0 and 6.1 times, respectively, but heterozygous TFPIαγ deletion improved clotting to 11.2 times (P < .001).<br />Conclusion: In hemophilic mice, endothelial TFPIβ and plasma γ-derived 2-Kunitz TFPI individually contribute more to bleeding than total TFPIα.<br />Competing Interests: Declaration of competing interests All authors have no competing interests to disclose.<br /> (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Details

Language :
English
ISSN :
1538-7836
Volume :
22
Issue :
10
Database :
MEDLINE
Journal :
Journal of thrombosis and haemostasis : JTH
Publication Type :
Academic Journal
Accession number :
38925489
Full Text :
https://doi.org/10.1016/j.jtha.2024.06.006