Thrombomodulin alfa attenuates the procoagulant effect and cytotoxicity of extracellular histones through the promotion of protein C activation

Osada, K.; Minami, Tatsuro; Arioka, Takashi; Sakai, Takumi; Tawara, Shunsuke; Kawasaki, Koh; Fareed, Jawed; Matsuzaki, Osamu

doi:10.1016/j.thromres.2017.10.019

Cited by 10 publications

(6 citation statements)

References 27 publications

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“…13,15 APC cleaves histones, thereby reducing their cytotoxicity, 14 an effect that can be potentiated via thrombomodulin alfa-mediated increase of APC generation. 66 To circumvent the potential bleeding risk associated with the anticoagulant properties of heparin and APC, non-anticoagulant variants could become of high interest. [67][68][69] Recurrent thrombosis is a concern in both arterial and venous thrombosis.…”

Section: Neutrophil Extracellular Traps: a New Therapeutic Target?mentioning

confidence: 99%

Neutrophil Extracellular Traps in Arterial and Venous Thrombosis

Laridan

Martinod

Meyer

2019

Semin Thromb Hemost

208

192

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Thrombotic complications are still a major health risk worldwide. Our view on the pathophysiology of thrombosis has significantly changed since the discovery of neutrophil extracellular traps (NETs) and their prothrombotic characteristics. Generated by neutrophils that release their decondensed chromatin as a network of extracellular fibers, NETs promote thrombus formation by serving as a scaffold that activates platelets and coagulation. The thrombogenic involvement of NETs has been described in various settings of thrombosis, including stroke, myocardial infarction, and deep vein thrombosis. The aim of this review is to summarize existing evidence showing the presence of NETs in human thrombus material. Following an introduction on NETs and their role in thrombus formation, the authors address studies showing the presence of NETs in arterial or venous thrombi. In addition, they focus on potential novel therapeutic opportunities to resolve or prevent thrombosis by targeting NETs.

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Section: Neutrophil Extracellular Traps: a New Therapeutic Target?mentioning

confidence: 99%

Neutrophil Extracellular Traps in Arterial and Venous Thrombosis

Laridan

Martinod

Meyer

2019

Semin Thromb Hemost

208

192

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“…Histones in NETs can attract platelet aggregation and activation through the interaction of fibrinogen, TLR2 and TLR4 and promote an increase in thrombin generation. In addition to the inhibition of activated protein C (APC), histones can also promote the expression of tissue factor on vascular endothelium and macrophages and promote coagulation ( Yang et al., 2016 ; Noubouossie et al., 2017 ; Osada et al., 2017 ). NE and cathepsin G can promote the coagulation pathway induced by tissue factor and coagulation factor XII by hydrolyzing tissue factor pathway inhibitor (TFPI).…”

Section: Nets and Thrombosis Formationmentioning

confidence: 99%

“…However, whether the degradation of NETs by DNase I will lead to the dispersion of components such as histones with procoagulant activity and increase the risk of thrombosis needs further study. Since APC can cleave NETs by cleaving histones, the strategy of using recombinant TMα to promote APC generation has also attracted researchers’ attention ( Osada et al., 2017 ). Recent studies have also shown that the NE inhibitor can effectively reduce the generation of NETs in mice with endotoxic shock, providing another potential method for NETs-related antithrombotic therapy ( Okeke et al., 2020 ).…”

Section: Potential Therapeutic Targets For Netsmentioning

confidence: 99%

Impact of Neutrophil Extracellular Traps on Thrombosis Formation: New Findings and Future Perspective

Zhou

Liu

2022

Front. Cell. Infect. Microbiol.

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Thrombotic diseases seriously endanger human health, neutrophils and neutrophil extracellular traps (NETs) play an important role in abnormal thrombus formation. NETs are extracellular structures released by neutrophils upon stimulation by pathogens. NETs include neutrophil elastase (NE), myeloperoxidase (MPO), cathepsin G and other active substances. The network structure provided by NETs can prevent the spread of pathogens and effectively kill and eliminate pathogens. However, the components of NETs can also abnormally activate the coagulation pathway and participate in the formation of pathological thrombi. This review aims to summarize the mechanisms of NETs formation in detail; the research progress of NETs in venous thrombosis, arterial thrombosis, acquired disease-associated thrombosis, sepsis coagulation disorder; as well as the strategies to target NETs in thrombosis prevention and treatment.

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“…In human sepsis, plasma histone concentrations are inversely related to endogenous aPC activity, 44 and several studies suggest that aPC reduces the toxicity of histones 179,226 and inhibits NETosis. 69 Similarly, thrombomodulin attenuates histone-induced thrombin generation and endothelial cell death in vitro, likely through its ability to activate protein C. 154 Thrombomodulin also reduces NETosis and blunts the prothrombotic state resulting from cecal-ligation and puncture-induced peritonitis in rats. 72 Recombinant human thrombomodulin is used successfully in humans with sepsis-induced DIC in Japan, 68,228 and Phase III clinical trials are ongoing in the USA (NCT01598831, NCT03517501).…”

Section: Nets As Therapeutic Targetsmentioning

confidence: 99%

Neutrophil-Extracellular Traps, Cell-Free DNA, and Immunothrombosis in Companion Animals: A Review

et al. 2019

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Immunothrombosis is a potentially beneficial physiological process that aids innate immunity and host defense against pathogen invasion. However, this process can also be damaging when it occurs to excess or in critical blood vessels. Formation of extracellular traps by leukocytes, particularly neutrophils, is central to our understanding of immunothrombosis. In addition to degranulation and phagocytosis, extracellular traps are the third mechanism by which neutrophils combat potential pathogens. These traps consist of extracellular DNA decorated with bactericidal cellular proteins, including elastase, myeloperoxidase, and cathepsins. Neutrophils can release these structures as part of a controlled cell-death process or via a process termed vital NETosis that enables the cells to extrude DNA but remain viable. There is accumulating evidence that NETosis occurs in companion animals, including dogs, horses, and cats, and that it actively contributes to pathogenesis. Numerous studies have been published detailing various methods for identification and quantification of extracellular trap formation, including cell-free DNA, measurements of histones and proteins such as high-mobility group box–1, and techniques involving microscopy and flow cytometry. Here, we outline the present understanding of these phenomena and the mechanisms of extracellular trap formation. We critically review the data regarding measurement of NETosis in companion animals, summarize the existing literature on NETosis in veterinary species, and speculate on what therapeutic options these insights might present to clinicians in the future.

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Thrombomodulin alfa attenuates the procoagulant effect and cytotoxicity of extracellular histones through the promotion of protein C activation

Cited by 10 publications

References 27 publications

Neutrophil Extracellular Traps in Arterial and Venous Thrombosis

Neutrophil Extracellular Traps in Arterial and Venous Thrombosis

Impact of Neutrophil Extracellular Traps on Thrombosis Formation: New Findings and Future Perspective

Neutrophil-Extracellular Traps, Cell-Free DNA, and Immunothrombosis in Companion Animals: A Review

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