Vascular occlusion by neutrophil extracellular traps in COVID-19

Abstract

Background Coronavirus induced disease 2019 (COVID-19) can be complicated by severe organ damage leading to dysfunction of the lungs and other organs. The processes that trigger organ damage in COVID-19 are incompletely understood. Methods Samples were donated from hospitalized patients. Sera, plasma, and autopsy-derived tissue sections were examined employing flow cytometry, enzyme-linked immunosorbent assays, and immunohistochemistry. Patient findings Here, we show that severe COVID-19 is characterized by a highly pronounced formation of neutrophil extracellular traps (NETs) inside the micro-vessels. Intravascular aggregation of NETs leads to rapid occlusion of the affected vessels, disturbed microcirculation, and organ damage. In severe COVID-19, neutrophil granulocytes are strongly activated and adopt a so-called low-density phenotype, prone to spontaneously form NETs. In accordance, markers indicating NET turnover are consistently increased in COVID-19 and linked to disease severity. Histopathology of the lungs and other organs from COVID-19 patients showed congestions of numerous micro-vessels by aggregated NETs associated with endothelial damage. Interpretation These data suggest that organ dysfunction in severe COVID-19 is associated with excessive NET formation and vascular damage. Funding Deutsche Forschungsgemeinschaft (DFG), EU, Volkswagen-Stiftung

The Role of DNA in the Extracellular Environment: A Focus on NETs, RETs and Biofilms

“…Confirming its positive role against NET-mediated pathologies, DNase 1 has been proposed as an enzyme able to attenuate them in mice (Németh et al, 2020). Consistent with the observation in mice, the persistence of NETs can have serious negative consequences in humans, leading to pathologies such as cardiovascular, lung and eye diseases, atherosclerosis, rheumatoid arthritis, thrombosis, diabetes, cancer, and severe COVID-19 (Demers et al, 2012;Arazna et al, 2013;Brinkmann, 2018;Daniel et al, 2019;Erpenbeck et al, 2019;Leppkes et al, 2020).…”

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Inflammation and intussusceptive angiogenesis in COVID-19: everything in and out of flow

“…Although the SARS-CoV-2 detection of SARS-CoV-2 in post mortem tissue by transmission electron microscopy is a challenging task (4), replicated virus-like particles were observed enveloped in endothelial cells (1,5), lymphatic cells (6) , but also in type 2 and 1 pneumocytes (6,7). (8,9). Viral-associated thrombotic microangiopathies have been described in numerous inflammatory cardiorespiratory diseases (e.g.…”

“NETs and EETs, a Whole Web of Mess”

“…In fact, higher levels of NETs have been correlated with an increased death rate in COVID-19 patients, in which an overreactive neutrophilic response leads to a general multi-organ failure [97]. Neutrophils appear to be decorated with thrombocytes in severe cases of COVID-19, the number of NETs identified in the circulation is significantly increased in these patients [100][101][102] and this correlates with the evidence of increased platelet factor 4 detected in these patients [101]. This increased NET formation has also been associated with COVID-19-related acute respiratory distress syndrome and is a potential biomarker for disease severity [101].…”