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

James T.B Crawley,Argita Zalli,James H Monkman,Anastasis Petri,David A Lane,Josefin Ahnstrӧm,Isabelle I Salles‐Crawley

doi:10.1111/jth.14593

James T.B Crawley, Argita Zalli + Show 5 more

Open Access

https://doi.org/10.1111/jth.14593

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Abstract

BackgroundBone 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. ObjectiveWe aimed to delineate how BAMBI influences endothelial function and thrombus stability. MethodsBambi‐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. ResultsThrombus 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. ConclusionsWe 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.

Highlights

Hemostatic plug formation after vessel injury serves to limit blood loss and maintain vascular integrity
We show that the thrombus formation/stability defect in Bambi‐deficient mice is associated with defective fibrin accumulation
Our data iden‐ tify the contributions of elevated tissue factor pathway inhibitor (TFPI) and thrombomodulin to the decreased thrombin generation and increased embolization seen in Bambi−/− mice

Summary

| INTRODUCTION

Hemostatic plug formation after vessel injury serves to limit blood loss and maintain vascular integrity. Many proteins expressed in the endothelium, plate‐ lets, and plasma influence both the formation and stabilization of a thrombus.[10]. Endothelial cells play a critical role in regulating hemostatic plug formation through production of a variety of thromboprotec‐ tive agents. These include vasodilators, such as nitric oxide and prostacyclin, that influence platelet function, as well as antico‐ agulant proteins such as TFPI and thrombomodulin. We define the mechanisms by which BAMBI in the endo‐ thelium (rather than in blood cells, platelets, or extravascular lo‐ cations) exerts its function and how these influence thrombus formation and stability

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Findings

CONFLICT OF INTEREST