NETosis and Nucleosome Biomarkers in Septic Shock and Critical COVID-19 Patients: An Observational Study

Morimont, Laure; Dechamps, Mélanie; David, Clara; Bouvy, Céline; Gillot, Constant; Haguet, Hélène; Favresse, Julien; Ronvaux, Lorian; Candiracci, Julie; Herzog, Mariëlle; Laterre, Pierre‐François; Poortere, Julien De; Horman, Sandrine; Beauloye, Christophe; Douxfils, Jonathan

doi:10.3390/biom12081038

Cited by 18 publications

(23 citation statements)

References 40 publications

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“…Plasma soluble nucleosomes in COVID-19 patients and controls: NETosis results in the release of neutrophil contents including histone-DNA complexes and cell-free DNA into plasma (8,50,55). To confirm the NETosis did occur in vivo, we determined the soluble plasma levels of nucleosomes or NET fragments using ELISA-based methods as described (50,57).…”

Section: Accepted Manuscriptmentioning

confidence: 99%

“…Neutrophils undergo NETosis following SARS-CoV-2 infection. [52][53][54] However, the extent of NETosis and its reserve (or vital NETosis) in patients with COVID-19 of different disease severities are not fully understood. Utilizing flow cytometric analysis, we were able to determine the percentage (%) of neutrophils undergoing NETosis on admission and its reserve or vital NETosis in response to external stimuli.…”

Section: Netosis and Its Reserve In Patients With Covid-19 And Controlsmentioning

confidence: 99%

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ADAMTS13 or Caplacizumab Reduces the Accumulation of Neutrophil Extracellular Traps and Thrombus in Whole Blood of COVID-19 Patients under Flow

Yada,

Zhang,

Bignotti

et al. 2024

Thromb Haemost

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Background. Neutrophil NETosis and neutrophil extracellular traps (NETs) play a critical role in pathogenesis of COVID-19 associated thrombosis. However, the extents and reserve of NETosis, and potential of thrombus formation under shear in whole blood of patients with COVID-19 are not fully elucidated. Neither has the role of recombinant ADAMTS13 or caplacizumab on the accumulation of NETs and thrombus in COVID-19 patients’ whole blood under shear been investigated. Methods. Flow cytometry and microfluidic assay, as well as immunoassays were employed for the study. Results. We demonstrated that the percentage of H3Cit+MPO+ neutrophils, indicative of NETosis, was dramatically increased in patients with severe but not critical COVID-19 compared with that in asymptomatic or mild disease controls. Upon stimulation with poly [I:C], a double strain DNA mimicking viral infection, or bacterial shigatoxin-2, the percentage of H3Cit+MPO+ neutrophils was not significantly increased in the whole blood of severe and critical COVID-19 patients compared with that of asymptomatic controls, suggesting the reduction in NETosis reserve in these patients. Microfluidic assay demonstrated that the accumulation of NETs and thrombus was significantly enhanced in the whole blood of severe/critical COVID-19 patients compared with that of asymptomatic controls. Like DNase I, recombinant ADAMTS13 or caplacizumab dramatically reduced the NET accumulation and thrombus formation under arterial shear. Conclusions. Significantly increased neutrophil NETosis, reduced NETosis reserve, and enhanced thrombus formation under arterial shear may play a crucial role in pathogenesis of COVID-19 associated coagulopathy. Recombinant ADAMTS13 or caplacizumab may be explored for the treatment of COVID-19 associated thrombosis.

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Section: Accepted Manuscriptmentioning

confidence: 99%

Section: Netosis and Its Reserve In Patients With Covid-19 And Controlsmentioning

confidence: 99%

ADAMTS13 or Caplacizumab Reduces the Accumulation of Neutrophil Extracellular Traps and Thrombus in Whole Blood of COVID-19 Patients under Flow

Yada,

Zhang,

Bignotti

et al. 2024

Thromb Haemost

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“…Nucleosomes are complexes formed of 147 base pairs of DNA wrapped around a protein core of histones [ 68 ]. Nucleosomes are released into circulation with apoptotic cell death [ 69 ].…”

Section: Nonconventional Hemostatic Tests and Markers In Sepsismentioning

confidence: 99%

Sepsis-Induced Coagulopathy: An Update on Pathophysiology, Biomarkers, and Current Guidelines

Tsantes

Parastatidou²,

Tsantes

et al. 2023

Life

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Significant cross talk occurs between inflammation and coagulation. Thus, coagulopathy is common in sepsis, potentially aggravating the prognosis. Initially, septic patients tend to exhibit a prothrombotic state through extrinsic pathway activation, cytokine-induced coagulation amplification, anticoagulant pathways suppression, and fibrinolysis impairment. In late sepsis stages, with the establishment of disseminated intravascular coagulation (DIC), hypocoagulability ensues. Traditional laboratory findings of sepsis, including thrombocytopenia, increased prothrombin time (PT) and fibrin degradation products (FDPs), and decreased fibrinogen, only present late in the course of sepsis. A recently introduced definition of sepsis-induced coagulopathy (SIC) aims to identify patients at an earlier stage when changes to coagulation status are still reversible. Nonconventional assays, such as the measurement of anticoagulant proteins and nuclear material levels, and viscoelastic studies, have shown promising sensitivity and specificity in detecting patients at risk for DIC, allowing for timely therapeutic interventions. This review outlines current insights into the pathophysiological mechanisms and diagnostic options of SIC.

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“…Extracellular histones have been described as DAMPs that play an important role in the pathogenesis of inflammatory diseases, such as in sepsis [21,44,45], SLE [31,46], myocardial infarction [27,47], and, as recently discovered, in COVID-19 [7,9,10,[48][49][50][51][52][53]. Extracellular histones exert cytotoxic effects through several mechanisms: (i) histone-mediated membrane disruption, (ii) histone-induced increase of intracellular calcium, (iii) histone-induced TLR-activation, (iv) histone-mediated NOD2/NLRP3 activation, and (v) complement activation.…”

Section: Histone-mediated Mechanisms Leading To Tissue Damagementioning

confidence: 99%

The role of extracellular histones in COVID‐19

et al. 2022

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The severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) had spread from China and, within 2 months, became a global pandemic. The infection from this disease can cause a diversity of symptoms ranging from asymptomatic to severe acute respiratory distress syndrome with an increased risk of vascular hyperpermeability, pulmonary inflammation, extensive lung damage, and thrombosis. One of the host defense systems against coronavirus disease 2019 (COVID‐19) is the formation of neutrophil extracellular traps (NETs). Numerous studies on this disease have revealed the presence of elevated levels of NET components, such as cell‐free DNA, extracellular histones, neutrophil elastase, and myeloperoxidase, in plasma, serum, and tracheal aspirates of severe COVID‐19 patients. Extracellular histones, a major component of NETs, are clinically very relevant as they represent promising biomarkers and drug targets, given that several studies have identified histones as key mediators in the onset and progression of various diseases, including COVID‐19. However, the role of extracellular histones in COVID‐19 per se remains relatively underexplored. Histones are nuclear proteins that can be released into the extracellular space via apoptosis, necrosis, or NET formation and are then regarded as cytotoxic damage‐associated molecular patterns that have the potential to damage tissues and impair organ function. This review will highlight the mechanisms of extracellular histone‐mediated cytotoxicity and focus on the role that histones play in COVID‐19. Thereby, this paper facilitates a bench‐to‐bedside view of extracellular histone‐mediated cytotoxicity, its role in COVID‐19, and histones as potential drug targets and biomarkers for future theranostics in the clinical treatment of COVID‐19 patients.

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NETosis and Nucleosome Biomarkers in Septic Shock and Critical COVID-19 Patients: An Observational Study

Cited by 18 publications

References 40 publications

ADAMTS13 or Caplacizumab Reduces the Accumulation of Neutrophil Extracellular Traps and Thrombus in Whole Blood of COVID-19 Patients under Flow

ADAMTS13 or Caplacizumab Reduces the Accumulation of Neutrophil Extracellular Traps and Thrombus in Whole Blood of COVID-19 Patients under Flow

Sepsis-Induced Coagulopathy: An Update on Pathophysiology, Biomarkers, and Current Guidelines

The role of extracellular histones in COVID‐19

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