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

ABSTRACT: BACKGROUND:Bone morphogenetic and activin membrane-bound inhibitor (BAMBI) is a transmembrane protein related to the type I transforming growth factor- ? (TGF-?) 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.

SUBMITTER: Crawley JTB

PROVIDER: S-EPMC6899896 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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

Crawley James T B JTB Zalli Argita A Monkman James H JH Petri Anastasis A Lane David A DA Ahnstrom Josefin J Salles-Crawley Isabelle I II

Journal of thrombosis and haemostasis : JTH 20190826 11

<h4>Background</h4>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.<h4>Objective</h4>We aimed to delineate how BAMBI influences endothelial function and thrombus stability.<h4>Methods</h4>Bambi-d ...[more]

PMID: 31351019

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Project description:Platelets play a pivotal role in stimulating liver regeneration after partial hepatectomy in rodents and humans. Liver regeneration in rodents is delayed when platelets are inhibited. However, the exact mechanisms whereby platelets accumulate and promote liver regeneration remain uncertain. Thrombin-dependent intrahepatic fibrin(ogen) deposition was recently reported after partial hepatectomy (PHx) in mice, but the role of fibrin(ogen) deposits in liver regeneration has not been investigated. We tested the hypothesis that fibrin(ogen) contributes to liver regeneration by promoting intrahepatic platelet accumulation and identified the trigger of rapid intrahepatic coagulation after PHx. PHx in wild-type mice triggered rapid intrahepatic coagulation, evidenced by intrahepatic fibrin(ogen) deposition. Intrahepatic fibrin(ogen) deposition was abolished in mice with liver-specific tissue factor deficiency, pinpointing the trigger of coagulation after PHx. Direct thrombin activation of platelets through protease-activated receptor-4 did not contribute to hepatocyte proliferation after PHx, indicating that thrombin contributes to liver regeneration primarily by driving intrahepatic fibrin(ogen) deposition. Fibrinogen depletion with ancrod reduced both intrahepatic platelet accumulation and hepatocyte proliferation after PHx, indicating that fibrin(ogen) contributes to liver regeneration after PHx by promoting intrahepatic platelet accumulation. Consistent with the protective function of fibrin(ogen) in mice, low postoperative plasma fibrinogen levels were associated with liver dysfunction and mortality in patients undergoing liver resection. Moreover, increased intrahepatic fibrin(ogen) deposition was evident in livers of patients after liver resection but was remarkably absent in patients displaying hepatic dysfunction postresection. The results suggest a novel mechanism whereby coagulation-dependent intrahepatic fibrin(ogen) deposition drives platelet accumulation and liver regeneration after PHx.

Dataset Information

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

Publications

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

Similar Datasets

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