COVID-19: Neutrophils “Unfriendly Fire” Imbalances Proteolytic Cascades Triggering Clinical Worsening and Viral Sepsis. Potential Role Explanation for Convalescent Plasma as “Firehose”

Based on COVID-19 Chinese CDCP report on, 14% of patients presented severe disease and 5% critical conditions. The average case-fatality rate was 2,3%, but mortality was as high as 49% in patients with critical illness. Serious life threatening thromboembolic complications have been found in 71,4% of non-survivors and micro/macro angiopathic coagulopathy has been found, also at autopsy, with highly increased neutrophil number, fibrinogen, concentrations of D-dimer and FDPs and NETs, ATIII decrease and normal number of platelets. A cytokine storm and interaction between inflammation and coagulation has been advocated as explanation of hypercoagulability. The paper shows that SARS-CoV-2 infection of alveolar cells induces recruitment of innate responder neutrophils, which release proteases and NETs inducing endothelial damage/ endotheliopathy and imbalance of the four major proteolytic cascades (coagulation, complement, fibrinolysis and kallikrein) with prevalence of activators over inhibitors and consequent thrombotic complications. Platelets adhesion to damaged endothelium and the presence of ULVWF multimers, due to decreased ADAMTS13, contribute to the state of hypercoagulability. Neutrophil innate unfriendly fire response can be identified as the trigger of a proteolytic storm, responsible for subsequent well known prothrombotic condition and cytokine storm, explaining also the pathology of recently described systemic Kawasaki Disease like vasculitis in Covid-19 young ill patients.