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Defective fibrin deposition and thrombus stability in Bambi-/- mice are mediated by elevated anticoagulant function.

Crawley, JTB; Zalli, A; Monkman, JH; Petri, A; Lane, DA; Ahnstrom, J; Salles-Crawley, II (2019) Defective fibrin deposition and thrombus stability in Bambi-/- mice are mediated by elevated anticoagulant function. J Thromb Haemost, 17 (11). pp. 1935-1949. ISSN 1538-7836 https://doi.org/10.1111/jth.14593
SGUL Authors: Salles-Crawley, Isabelle Irene

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Abstract

BACKGROUND: Bone morphogenetic and activin membrane-bound inhibitor (BAMBI) is a transmembrane protein related to the type I transforming growth factor- β (TGF-β) receptor family that is present on both platelets and endothelial cells (ECs). Bambi-deficient mice exhibit reduced hemostatic function and thrombus stability characterized by an increased embolization. OBJECTIVE: We aimed to delineate how BAMBI influences endothelial function and thrombus stability. METHODS: Bambi-deficient mice were subjected to the laser-induced thrombosis model where platelet and fibrin accumulation was evaluated. Expression of thrombomodulin and tissue factor pathway inhibitor (TFPI) was also assessed in these mice. RESULTS: Thrombus instability in Bambi-/- mice was associated with a profound defect in fibrin deposition. Injection of hirudin into Bambi+/+ mice prior to thrombus formation recapitulated the Bambi-/- thrombus instability phenotype. In contrast, hirudin had no additional effect upon thrombus formation in Bambi-/- mice. Deletion of Bambi in ECs resulted in mice with defective thrombus stability caused by decreased fibrin accumulation. Increased levels of the anticoagulant proteins TFPI and thrombomodulin were detected in Bambi-/- mouse lung homogenates. Endothelial cells isolated from Bambi-/- mouse lungs exhibited enhanced ability to activate protein C due to elevated thrombomodulin levels. Blocking thrombomodulin and TFPI in vivo fully restored fibrin accumulation and thrombus stability in Bambi-/- mice. CONCLUSIONS: We demonstrate that endothelial BAMBI influences fibrin generation and thrombus stability by modulating thrombomodulin and TFPI anticoagulant function of the endothelium; we also highlight the importance of these anticoagulant proteins in the laser-induced thrombosis model.

Item Type: Article
Additional Information: © 2019 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis This is an open access article under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Keywords: anticoagulants, endothelial cells, fibrin, mice, thrombomodulin, thrombosis, Animals, Anticoagulants, Blood Coagulation, Cells, Cultured, Disease Models, Animal, Endothelial Cells, Female, Fibrin, Hirudins, Lipoproteins, Lung, Male, Membrane Proteins, Mice, Inbred C57BL, Mice, Knockout, Thrombomodulin, Thrombosis, Lung, Cells, Cultured, Endothelial Cells, Animals, Mice, Inbred C57BL, Mice, Knockout, Thrombosis, Disease Models, Animal, Lipoproteins, Fibrin, Thrombomodulin, Membrane Proteins, Hirudins, Anticoagulants, Blood Coagulation, Female, Male, anticoagulants, endothelial cells, fibrin, mice, thrombomodulin, thrombosis, Cardiovascular System & Hematology, 1102 Cardiorespiratory Medicine and Haematology, 1103 Clinical Sciences
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Journal or Publication Title: J Thromb Haemost
ISSN: 1538-7836
Language: eng
Dates:
DateEvent
31 October 2019Published
26 August 2019Published Online
22 July 2019Accepted
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
FS/10/004/28165British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
FS/12/60/29874British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
PG/17/42/33039British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
RG/18/3/33405British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
PG/14/90/31219British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
PubMed ID: 31351019
Web of Science ID: WOS:000482610200001
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/114224
Publisher's version: https://doi.org/10.1111/jth.14593

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