Abstract
Abnormal coagulation and an increased risk of thrombosis are features of severe COVID-19, with parallels proposed with hemophagocytic lymphohistiocytosis (HLH), a life-threating condition associated with hyperinflammation. The presence of HLH was described in severely ill patients during the H1N1 influenza epidemic, presenting with pulmonary vascular thrombosis. We tested the hypothesis that genes causing primary HLH regulate pathways linking pulmonary thromboembolism to the presence of SARS-CoV-2 using novel network-informed computational algorithms. This approach led to the identification of Neutrophils Extracellular Traps (NETs) as plausible mediators of vascular thrombosis in severe COVID-19 in children and adults. Taken together, the network-informed analysis led us to propose the following model: the release of NETs in response to inflammatory signals acting in concert with SARS-CoV-2 damage the endothelium and direct platelet-activation promoting abnormal coagulation leading to serious complications of COVID-19. The underlying hypothesis is that genetic and/or environmental conditions that favor the release of NETs may predispose individuals to thrombotic complications of COVID-19 due to an increase risk of abnormal coagulation. This would be a common pathogenic mechanism in conditions including autoimmune/infectious diseases, hematologic and metabolic disorders.
Highlights
Reports from China [1, 2] and France [3, 4], have highlighted abnormal coagulation and a high risk of thrombosis in severe COVID-19
We have assembled a list of candidate genes responsible for primary hemophagocytic lymphohistiocytosis (HLH) and associated syndromes to explore their relationships with COVID-19[24, 25] (S1 Table)
To demonstrate that the method can assign significant connectivity scores to genes associated with COVID-19, we obtained a list of 10 confirmed COVID-19 related genes [26], which are differentially expressed in severe COVID19 patients (S1 Table)
Summary
Reports from China [1, 2] and France [3, 4], have highlighted abnormal coagulation and a high risk of thrombosis in severe COVID-19. A strong pro-inflammatory but ineffective anti-viral response contributes to COVID-19[7] This can lead to a hyperinflammatory state described in a subset of COVID-19 adult patients with severe and often deadly complications [8]. The post-mortem lungs from patients with COVID-19 showed severe endothelial injury associated with the presence of intracellular virus and alveolar capillary microthrombi. This was 9 times more prevalent in COVID-19 than H1N1 lungs analysed following autopsy [17]. Vascular injury resulting from hyperinflammation in the alveoli in response to SARS-CoV-2 may be an important pathophysiological mechanism of severe illness in children and adults
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