Abnormal coagulation and an increased risk of thrombosis MESHD are features of severe COVID-19, with parallels proposed with hemophagocytic lymphohistiocytosis MESHD (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 MESHD. We tested the hypothesis that genes causing primary HLH regulate pathways linking pulmonary thromboembolism MESHD thromboembolism HP 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 MESHD in severe COVID-19 in children TRANS and adults TRANS. 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 MESHD and metabolic disorders.