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

摘要

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 ( EC s). 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 EC s 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.