Back to Search
Start Over
Deletion of tissue factor pathway inhibitor isoform beta or gamma, but not alpha, improves clotting in hemophilic mice.
- 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.)
- Subjects :
- Animals
Mice, Knockout
Thrombin metabolism
Hemostasis
Mice
Factor VIII genetics
Factor VIII metabolism
Disease Models, Animal
Hemorrhage blood
Hemorrhage genetics
Thrombosis genetics
Thrombosis blood
Gene Deletion
Bleeding Time
Blood Coagulation
Lipoproteins genetics
Lipoproteins blood
Hemophilia A blood
Hemophilia A genetics
Protein Isoforms
Mice, Inbred C57BL
Subjects
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