The hyperfibrinolytic state of mice with combined thrombin‐activatable fibrinolysis inhibitor (TAFI) and plasminogen activator inhibitor‐1 gene deficiency is critically dependent on TAFI deficiency

Vercauteren, Ellen; Peeters, Miet; Hoylaerts, Marc; Lijnen, H.R.; Meijers, Joost C. M.; Declerck, Paul; Gils, Ann

doi:10.1111/jth.12036

Cited by 23 publications

(19 citation statements)

References 45 publications

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“…Further, we show that the thrombus formation/stability defect in Bambi-deficient mice is associated with defective fibrin accumulation. Our data also identify the contributions of elevated TFPI and thrombomodulin to the [51][52][53][54] Moreover, in order for fibrinolysis to occur, fibrin needs to be deposited first at the site of injury before fibrinolysis is efficiently activated.…”

Section: Discussionmentioning

confidence: 72%

“…Thrombin activatable fibrinolysis inhibitor, plasminogen activator inhibitor‐1, tissue plasminogen activator), based on the literature, it is unlikely they could be major contributors to the phenotype that we observed in Bambi −/− mice. Indeed, full deficiencies in these markers have not always been reported to protect against thrombosis depending on the model chosen in the study (arterial or venous thrombosis) and the vascular bed (carotid, mesenterium, femoral) . Moreover, in order for fibrinolysis to occur, fibrin needs to be deposited first at the site of injury before fibrinolysis is efficiently activated.…”

Section: Discussionmentioning

confidence: 99%

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

Crawley

Zalli

Monkman

et al. 2019

Journal of Thrombosis and Haemostasis

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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.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.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.

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Section: Discussionmentioning

confidence: 72%

Section: Discussionmentioning

confidence: 99%

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

Crawley

Zalli

Monkman

et al. 2019

Journal of Thrombosis and Haemostasis

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“…PAI-1 suppresses the activation of plasmin, the primary mediator of fibrinolysis (55), whereas TAFI cleaves lysine residues from fibrin, thereby decreasing fibrinolysis by removing binding sites for plasmin (56, 57). Prior studies established that genetic depletion of both PAI-1 and TAFI decreases fibrin levels more than depletion of either one alone (33, 58). Control mice largely survived infection with D27-pLpxL, whereas significantly fewer PAI-1/TAFI-deficient mice survived (Figure 8E).…”

Section: Resultsmentioning

confidence: 99%

Fibrin Facilitates Both Innate and T Cell–Mediated Defense againstYersinia pestis

Luo

Lin

Parent

et al. 2013

The Journal of Immunology

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The gram-negative bacterium Yersinia pestis causes plague, a rapidly progressing and often fatal disease. The formation of fibrin at sites of Y. pestis infection supports innate host defense against plague, perhaps by providing a non-diffusible spatial cue that promotes the accumulation of inflammatory cells expressing fibrin-binding integrins. This report demonstrates that fibrin is an essential component of T cell-mediated defense against plague but can be dispensable for antibody-mediated defense. Genetic or pharmacologic depletion of fibrin abrogated innate and T cell-mediated defense in mice challenged intranasally with Y. pestis. The fibrin-deficient mice displayed reduced survival, increased bacterial burden, and exacerbated hemorrhagic pathology. They also showed fewer neutrophils within infected lung tissue and reduced neutrophil viability at sites of liver infection. Depletion of neutrophils from wild type mice weakened T cell-mediated defense against plague. The data suggest that T cells combat plague in conjunction with neutrophils, which require help from fibrin in order to withstand Y. pestis encounters and effectively clear bacteria.

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“…In a stroke model induced by transient middle cerebral artery occlusion, Cpb2 − / − mice had similar outcomes to WT mice determined as functional outcomes, infarct volume, and fibrin(ogen) levels . Mice with a double deficiency in both CPB2 and plasminogen activator inhibitor‐1 were hyperfibrinolytic as measured by thromboelastometry on blood, but did not show any differences in tail bleeding times, mesenteric thrombosis or thromboembolism from single‐deficient or WT mice . Therefore, these new data have not increased the evidence that Cpb2 − / − mice have a deficit in thrombosis or fibrinolysis in acute models, even though the mice have the expected changes biochemically ex vivo .…”

Section: Roles For Cpb2 Explored In Cpb2−/− Micementioning

confidence: 92%

Carboxypeptidase B2 and carboxypeptidase N in the crosstalk between coagulation, thrombosis, inflammation, and innate immunity

Leung

Morser

2018

Journal of Thrombosis and Haemostasis

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Two basic carboxypeptidases, carboxypeptidase B2 (CPB2) and carboxypeptidase N (CPN) are present in plasma. CPN is constitutively active, whereas CPB2 circulates as a precursor, procarboxypeptidase B2 (proCPB2), that needs to be activated by the thrombin-thrombomodulin complex or plasmin bound to glycosaminoglycans. The substrate specificities of CPB2 and CPN are similar; they both remove C-terminal basic amino acids from bioactive peptides and proteins, thereby inactivating them. The complement cascade is a cascade of proteases and cofactors activated by pathogens or dead cells, divided into two phases, with the second phase only being triggered if sufficient C3b is present. Complement activation generates anaphylatoxins: C3a, which stimulates macrophages; and C5a, which is an activator and attractant for neutrophils. Pharmacological intervention with inhibitors has shown that CPB2 delays fibrinolysis, whereas CPN is responsible for systemic inactivation of C3a and C5a. Among mice genetically deficient in either CPB2 or CPN, in a model of hemolytic-uremic syndrome, Cpb2 mice had the worst disease, followed by Cpn mice, with wild-type (WT) mice being the most protected. This model is driven by C5a, and shows that CPB2 is important in inactivating C5a. In contrast, when mice were challenged acutely with cobra venom factor, the reverse phenotype was observed; Cpn mice had markedly worse disease than Cpb2 mice, and WT mice were resistant. These observations need to be confirmed in humans. Therefore, CPB2 and CPN have different roles. CPN inactivates C3a and C5a generated spontaneously, whereas proCPB2 is activated at specific sites, where it inactivates bioactive peptides that would overwhelm CPN.

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The hyperfibrinolytic state of mice with combined thrombin‐activatable fibrinolysis inhibitor (TAFI) and plasminogen activator inhibitor‐1 gene deficiency is critically dependent on TAFI deficiency

Cited by 23 publications

References 45 publications

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

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

Fibrin Facilitates Both Innate and T Cell–Mediated Defense againstYersinia pestis

Carboxypeptidase B2 and carboxypeptidase N in the crosstalk between coagulation, thrombosis, inflammation, and innate immunity

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