Heparin induces neutrophil elastase-dependent vital and lytic NET formation

Lelliott, Patrick M.; Momota, Masatoshi; Shibahara, Takayuki; Lee, Michelle Sue Jann; Smith, Nicholas I.; Ishii, Ken J.; Coban, Cevayir

doi:10.1093/intimm/dxz084

Cited by 32 publications

(27 citation statements)

References 36 publications

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“…A large amount of heparin will produce antibodies against platelet factor 4 (PF4) and heparin complexes, leading to excessive activation of coagulation to activate platelets and promote thrombosis (Pouplard et al, 1999). In addition, heparin can directly induce the formation of NETs, but NETs cannot be induced by low molecular weight heparin, heparin analogs or heparin sulfate [low molecular weight heparin (LMWH), heparin mimetics or heparan sulfate] (Lelliott et al, 2020). However, there are also reports in the literature that heparin and heparin-derived drugs (including unfractionated heparin, LMWH and occasionally fondaparinux) can induce immune responses, leading to HIT (Perdomo et al, 2019).…”

Section: Heparinmentioning

confidence: 99%

Review: The Emerging Role of Neutrophil Extracellular Traps in Sepsis and Sepsis-Associated Thrombosis

Chen

Zhang

et al. 2021

Front. Cell. Infect. Microbiol.

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Patients with sepsis commonly suffer from coagulation dysfunction and lead to the formation of thrombus. During the development of sepsis, neutrophils migrate from the circulating blood to infected tissues and mediate the formation of neutrophil extracellular traps (NETs) that kill pathogens. However, the overactivation of neutrophils can promote the formation of immunothrombosis and even cause disseminated intravascular coagulation (DIC), which damages microcirculation. The outcome of sepsis depends on early recognition and intervention, so clinical evaluation of NETs function may be a valuable biomarker for early diagnosis of sepsis. The interaction of NETs with platelets, complement, and endothelium mediates the formation of immunothrombosis in sepsis. Inhibiting the formation of NETs is also considered to be one of the potential treatments for sepsis. In this review, we will discuss the key role of neutrophils and NETs in sepsis and septic thrombosis, in order to reveal new mechanisms for thrombosis treatment of sepsis.

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Section: Heparinmentioning

confidence: 99%

Review: The Emerging Role of Neutrophil Extracellular Traps in Sepsis and Sepsis-Associated Thrombosis

Chen

Zhang

et al. 2021

Front. Cell. Infect. Microbiol.

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“…Heparin also replaces histones from the chromatin backbone of NETs, thereby destroying the stability of NETs ( 87 ). However, recent studies have shown that heparin stimulates NET formation in vitro , and the ability of enoxaparin to induce NET production is much lower than that of heparin, while pentosan sodium (fondaparinux) does not induce the formation of NETs ( 101 ). The hypothesis of the potential benefits of heparin therapy for patients with PE in real life requires further verification.…”

Section: The Role Of Nets In Venous Thrombosismentioning

confidence: 99%

The Emerging Role of Neutrophil Extracellular Traps in Arterial, Venous and Cancer-Associated Thrombosis

Zhou

Tao

Shen

et al. 2021

Front. Cardiovasc. Med.

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Neutrophils play a vital role in the formation of arterial, venous and cancer-related thrombosis. Recent studies have shown that in a process known as NETosis, neutrophils release proteins and enzymes complexed to DNA fibers, collectively called neutrophil extracellular traps (NETs). Although NETs were originally described as a way for the host to capture and kill bacteria, current knowledge indicates that NETs also play an important role in thrombosis. According to recent studies, the destruction of vascular microenvironmental homeostasis and excessive NET formation lead to pathological thrombosis. In vitro experiments have found that NETs provide skeletal support for platelets, red blood cells and procoagulant molecules to promote thrombosis. The protein components contained in NETs activate the endogenous coagulation pathway to promote thrombosis. Therefore, NETs play an important role in the formation of arterial thrombosis, venous thrombosis and cancer-related thrombosis. This review will systematically summarize and explain the study of NETs in thrombosis in animal models and in vivo experiments to provide new targets for thrombosis prevention and treatment.

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“…These vesicles containing DNA are delivered through the cytoplasm and released extracellularly ( 31 ) ( Figure 1B ). This rapid NETosis is also reported when neutrophils are stimulated by Candida albicans ( 33 ), Leishmania parasites ( 34 ), heparin ( 35 ), and LPS-stimulated platelets ( 36 ). Unlike in suicidal NETosis, neutrophils releasing NETs rapidly do not undergo cell lysis and remain functional, thus this process is termed as vital NETosis ( 37 ).…”

Section: The Mesh-like Neutrophil Extracellular Trapmentioning

confidence: 67%

Insights Into Immunothrombosis: The Interplay Among Neutrophil Extracellular Trap, von Willebrand Factor, and ADAMTS13

Yang

Long

et al. 2020

Front. Immunol.

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Both neutrophil extracellular traps (NETs) and von Willebrand factor (VWF) are essential for thrombosis and inflammation. During these processes, a complex series of events, including endothelial activation, NET formation, VWF secretion, and blood cell adhesion, aggregation and activation, occurs in an ordered manner in the vasculature. The adhesive activity of VWF multimers is regulated by a specific metalloprotease ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motifs, member 13). Increasing evidence indicates that the interaction between NETs and VWF contributes to arterial and venous thrombosis as well as inflammation. Furthermore, contents released from activated neutrophils or NETs induce the reduction of ADAMTS13 activity, which may occur in both thrombotic microangiopathies (TMAs) and acute ischemic stroke (AIS). Recently, NET is considered as a driver of endothelial damage and immunothrombosis in COVID-19. In addition, the levels of VWF and ADAMTS13 can predict the mortality of COVID-19. In this review, we summarize the biological characteristics and interactions of NETs, VWF, and ADAMTS13, and discuss their roles in TMAs, AIS, and COVID-19. Targeting the NET-VWF axis may be a novel therapeutic strategy for inflammation-associated TMAs, AIS, and COVID-19.

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Heparin induces neutrophil elastase-dependent vital and lytic NET formation

Cited by 32 publications

References 36 publications

Review: The Emerging Role of Neutrophil Extracellular Traps in Sepsis and Sepsis-Associated Thrombosis

Review: The Emerging Role of Neutrophil Extracellular Traps in Sepsis and Sepsis-Associated Thrombosis

The Emerging Role of Neutrophil Extracellular Traps in Arterial, Venous and Cancer-Associated Thrombosis

Insights Into Immunothrombosis: The Interplay Among Neutrophil Extracellular Trap, von Willebrand Factor, and ADAMTS13

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