Defective fibrin deposition and thrombus stability in Bambi‐/‐ mice is mediated by elevated anticoagulant function
File(s)
Author(s)
Type
Journal Article
Abstract
Background
BAMBI is a transmembrane protein related to the type I TGF‐β receptor family that is present on both platelets and endothelial cells (EC). 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 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 EC 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. EC 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, and also highlight the importance of these anticoagulant proteins in the laser‐induced thrombosis model.
BAMBI is a transmembrane protein related to the type I TGF‐β receptor family that is present on both platelets and endothelial cells (EC). 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 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 EC 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. EC 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, and also highlight the importance of these anticoagulant proteins in the laser‐induced thrombosis model.
Date Issued
2019-07-27
Date Acceptance
2019-07-22
Citation
Journal of Thrombosis and Haemostasis, 2019
ISSN
1538-7933
Publisher
Wiley
Journal / Book Title
Journal of Thrombosis and Haemostasis
Copyright Statement
© 2019 Owner. This is the accepted version of the following article: Crawley, J. T., Zalli, A. , Monkman, J. H., Petri, A. , Lane, D. A., Ahnstrӧm, J. and Salles‐Crawley, I. I. (2019), Defective fibrin deposition and thrombus stability in Bambi‐/‐ mice is mediated by elevated anticoagulant function. J Thromb Haemost. Accepted Author Manuscript. doi:10.1111/jth.14593, which has been published in final form at https://doi.org/10.1111/jth.14593.
Sponsor
British Heart Foundation
British Heart Foundation
British Heart Foundation
British Heart Foundation
Grant Number
PG/14/90/31219
FS/10/004/28165
FS/10/004/28165
PG/17/42/33039
Subjects
1102 Cardiorespiratory Medicine and Haematology
1103 Clinical Sciences
Cardiovascular System & Hematology
Publication Status
Published online
Article Number
jth.14593
Date Publish Online
2019-07-27