Abstract
Based on Chinese CDCP report on COVID-19, 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, at autopsy also, 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. It has been shown that SARS-CoV-2 infection of alveolar cells is driven by the S-protein by engaging ACE2 and TMPRSS2 cell receptors. Whose activation depends on the activity of various host proteases. Full inhibition of SARS-CoV-2 entry was observed when serine proteases inhibitor camostat mesylate was coupled with Cathepsin B/L inhibitor E-64d. In addition multiple proteases are involved in host immune response against viral invasion and immunopathology related to imbalanced immune activation. In this paper it’s hypothesized that the severity of Covid-19 is induced by recruitment of innate responder neutrophils, which release proteases and NETs inducing endothelial damage 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 vWFVIII multimers presence, due to loss of ADAMTS13, contributes to hypercoagulability state. Human plasma or serine protease inhibitors like aprotinin can help to control neutrophil induced “proteolytic storm”. The goal of this paper is to support the view that, in SARS-CoV-2 infection, proteases have a key role and exceeding imbalanced neutrophil innate “unfriendly fire” response can be identified as the trigger of a “proteolytic storm”, responsible for subsequent well known hyper coagulation and “cytokine storm” and human plasma, in adequate volumes, together with serine proteases inhibitors can be an effective therapeutic strategy.
Highlights
According to the largest current report from the Chinese Center for Disease Control and Prevention with 72 314 cases, 58 574 patients (81%) were classified as mild, 10 124 (14%) were classified as severe, and 3616 (5%) were considered critical [1]
The goal of this paper is to support the view that, in Severe Acute Respiratory Syndrome (SARS)-CoV-2 infection, proteases have a key role and exceeding imbalanced neutrophil innate “unfriendly fire” response can be identified as the trigger of a “proteolytic storm”, responsible for subsequent well known hyper coagulation and “cytokine storm” and human plasma, in adequate volumes, together with serine proteases inhibitors can be an effective therapeutic strategy
The conclusions of the review are uncertain whether convalescent plasma decreases all‐cause mortality at hospital discharge (Risk Ratio (RR) 0.55, 95% confidence interval (CI) 0.22 to 1.34; 1 RCT, 86 participants; low‐certainty evidence) and whether convalescent plasma decreases mortality (Hazard Ratio (HR) 0.64, 95% CI 0.33 to 1.25; 2 RCTs, 189 participants; low‐certainty evidence)
Summary
According to the largest current report from the Chinese Center for Disease Control and Prevention with 72 314 cases, 58 574 patients (81%) were classified as mild, 10 124 (14%) were classified as severe, and 3616 (5%) were considered critical (respiratory failure, septic shock, and/or multiple organ failure) [1]. Among 201 patients in Wuhan, Wu, et al [2] reported that risk factors associated with development of acute respiratory distress syndrome and death included older age, neutrophilia, organ dysfunction, coagulopathy and elevated D-dimer levels. ACE2, the viral receptor, and one of its entry-associated proteases, TMPRSS2, are expressed in nasal goblet cells, in lung goblet, multiciliated and AT2 cells and gut epithelial enterocytes, in pancreatic ductal cells, bladder, testis, prostate and kidney epithelial cells, cholangiocytes, oligodendrocytes in the brain, inhibitory enteric neurons, heart fibroblasts/pericytes, and fibroblasts
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