EF6265, a novel inhibitor of activated thrombin-activatable fibrinolysis inhibitor, protects against sepsis-induced organ dysfunction in rats*

Muto, Yuko; Suzuki, Koichi; Iida, Hiroyuki; Sakakibara, Shiro; Kato, Emiko; Itoh, Fumi; Kakui, Nobukazu; Ishii, Hidemi

doi:10.1097/ccm.0b013e31819ffc14

Cited by 26 publications

(21 citation statements)

References 33 publications

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“…Our results are consistent with the data from an E. coli challenge model in which there was less liver damage in Cpb2 À/À mice than in WT mice [15] and with a rat model of sepsis induced by Pseudomonas aeruginosa in which treatment with a CPB2 inhibitor improved outcomes [38].…”

Section: Discussionsupporting

confidence: 90%

Carboxypeptidase B2 deficiency reveals opposite effects of complement C3a and C5a in a murine polymicrobial sepsis model

Shao

Nishimura

Leung

et al. 2015

Journal of Thrombosis and Haemostasis

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Summary Background and Objectives Carboxypeptidase B2 (CPB2) is a basic carboxypeptidase with fibrin and complement C3a and C5a as physiological substrates. We hypothesized that in polymicrobial sepsis, CPB2-deficient mice would have sustained C5a activity, leading to disease exacerbation. Methods Polymicrobial sepsis was induced by cecal ligation and puncture (CLP). Results Contrary to our hypothesis, Cpb2−/− mice had significantly improved survival, with reduced lung edema, less liver and kidney damage, and less disseminated intravascular coagulation. Hepatic proCPB2 was induced by CLP leading to increase in proCPB2 levels. Thrombomodulin present on mesothelium supported thrombin activation of proCPB2. Both WT and Cpb2−/− animals treated with a C5a receptor antagonist had improved survival, demonstrating that C5a was detrimental in this model. Treatment with a fibrinolysis inhibitor, tranexamic acid, caused a decrease in survival in both genotypes, however, the Cpb2−/− animals still retained their survival advantage. Administration of a C3a receptor antagonist exacerbated the disease in both WT and Cpb2−/− mice, and eliminated the survival advantage of Cpb2−/− mice. C5a receptor is expressed in both peritoneal macrophages and neutrophils; in contrast, C3a receptor expression is restricted to peritoneal macrophages, and C3a induced signaling in macrophages but not neutrophils. Conclusions Thus while C5a exacerbates the peritonitis, resulting in a deleterious generalized inflammatory state, C3a activation of peritoneal macrophages may limit the initial infection following CLP, thereby playing a diametrically opposing protective role in this polymicrobial sepsis model.

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Section: Discussionsupporting

confidence: 90%

Carboxypeptidase B2 deficiency reveals opposite effects of complement C3a and C5a in a murine polymicrobial sepsis model

Shao

Nishimura

Leung

et al. 2015

Journal of Thrombosis and Haemostasis

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“…[20][21][22][23] Additionally, inhibition of TAFIa represents a potentially subtle adjustment of the clotting and lysis balance, without affecting the coagulation cascade. Ideally, this subtlety may reduce the risk of bleeding when using TAFIa inhibitor, compared with other potential mechanism for treating thrombotic disease.…”

Section: Discussionmentioning

confidence: 99%

Thrombin-Activatable Fibrinolysis Inhibitor Is Activated in an Instant Blood-Mediated Inflammatory Reaction After Intraportal Islet Transplant

Wang

Zhang²,

Cong³

et al. 2014

Exp Clin Transplant

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Objectives: Activated thrombin-activatable fibrinolysis inhibitor is a coagulation factor in some thrombotic diseases. However, available data on whether thrombin-activatable fibrinolysis inhibitor is activated in islet transplant are limited. In this study, changes of plasma-activated thrombinactivatable fibrinolysis inhibitor levels in instant blood-mediated inflammatory reaction after islet transplant were assessed. Materials and Methods: Plasma concentrations of thrombin-antithrombin complex, D-dimer, C-peptide, and activated thrombin-activatable fibrinolysis inhibitor were assessed at 0 minutes, 30 minutes, 1 hour, 6 hours, 12 hours, and 24 hours after an intraportal islet transplant using rats via an enzymelinked immunosorbent assay, or solid-phase, 2-site chemiluminescent immunometric assay. We recovered the liver at 1 hour after the transplant for histologic examination. Results: Thrombin-antithrombin complex, C-peptide, and activated thrombin-activatable fibrinolysis inhibitor levels increased immediately after we stopped islet infusion, and their peak levels occurred at 1 hour after islet infusion. D-dimer levels increased continually after islet infusion was stopped, and peaked 24 hours after infusion. Histologic examination of the liver 1 hour after islet infusion revealed frequent portal venous thrombi, with entrapped islets. The entrapped islets showed a disrupted morphology. Conclusions:Activated thrombin-activatable fibrinolysis inhibitor was generated and peaked 1 hour after islet transplant according with activating coagulation, indicating that thrombin-activatable fibrinolysis inhibitor is activated and accumulated at levels in instant blood-mediated inflammatory reaction was sufficient to affect fibrinolysis.

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“…11 Therefore, a decreased rate of TAFI activation contributes to enhanced fibrinolysis, and an increased rate of activation leads to thrombotic disorder. 11 Several in vivo experimental [44][45][46][47] and clinical [48][49][50][51][52][53] studies investigated the association between the levels of TAFI and endotoxemia, sepsis, or DIC, with conflicting results. These inconsistencies may be explained by the use of different methods for measuring TAFI or by the largely different dynamics of TAFI activators, such as thrombin, thrombomodulin, plasmin, and neutrophil elastase, in these diseases compared with those under normal physiologic conditions.…”

Section: Role Of Tafi In Fibrinolysismentioning

confidence: 99%

Role of Fibrinolysis in Sepsis

Gando

2013

Semin Thromb Hemost

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Sepsis, defined as infection-induced systemic inflammatory response syndrome, invariably leads to hemostatic abnormalities ranging from insignificant coagulopathy to disseminated intravascular coagulation (DIC). The inflammation-induced activation of coagulation, the downregulation of physiologic anticoagulant pathways, and impairment of fibrinolysis play a pivotal role in the pathogenesis of microvascular fibrin thrombosis and multiple organ dysfunction syndrome (MODS) in DIC associated with sepsis. The balance between tissue plasminogen activator and plasminogen activator inhibitor-1 mainly regulates fibrinolytic activity. Thrombin-activatable fibrinolysis inhibitor and neutrophil elastase also modulate fibrinolysis. Dynamic changes in these molecules are deeply involved in the pathomechanisms of the impairment of fibrinolysis, leading to MODS in DIC associated with sepsis. Evidence indicates that physical entrapment of bacteria by fibrin at the site of infection may limit their capacity to disseminate into nearby tissues, organs, and systemic circulation. Under this circumstance, impairment of fibrinolysis has protective role in the host defense. Given the protective and pathologic potential of fibrinolysis during sepsis, therapeutics that control DIC as a systemic syndrome, while maintaining the host defense at the infectious foci, are required for the protection against both the development of MODS and for the host defense mechanisms.

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EF6265, a novel inhibitor of activated thrombin-activatable fibrinolysis inhibitor, protects against sepsis-induced organ dysfunction in rats*

Abstract: These results clearly suggest that TAFI plays an important role in the deterioration of organ dysfunction in sepsis and the inhibitor of TAFIa protects against sepsis-induced tissue damage through regulation of fibrinolysis and inflammation.

Cited by 26 publications

References 33 publications

Carboxypeptidase B2 deficiency reveals opposite effects of complement C3a and C5a in a murine polymicrobial sepsis model

Carboxypeptidase B2 deficiency reveals opposite effects of complement C3a and C5a in a murine polymicrobial sepsis model

Thrombin-Activatable Fibrinolysis Inhibitor Is Activated in an Instant Blood-Mediated Inflammatory Reaction After Intraportal Islet Transplant

Role of Fibrinolysis in Sepsis

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