Am J Blood Rev | Volume 1, Issue 1 | Review Article | Open Access

SARS-CoV-2 and Proteolytic Storm: Neutrophils and Proteolytic Enzymes are the “Prima Donna” in Severe COVID-19. Serine Proteases Inhibitors are Valuable Treatment Options

Pier Maria Fornasari*

Regen Health Solutions Research Unit, Bologna, Italy

*Correspondance to: Pier Maria Fornasari 

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Abstract

SARS-CoV-2 is a coronavirus responsible for COVID-19, resulting in over 115 million cases worldwide at the end of February 2021. While about 81% of COVID-19 patients are pauci/ asymptomatic, the remaining 19% present severe disease with pneumonia and ARDS, accounting for over 2.5 million deaths globally. Up to day, the reason of symptoms severity has remained unexplained. Severe COVID-19 disease has been associated with lymphopenia, cytokines increase, neutrophilia and high Neutrophil to Lymphocyte Ratio (NLR). Based on Chinese CDCP report on COVID-19, severe disease was present in 14% of patients and 5% were in critical conditions. The average death rate was 2.3%, but in critical patients’ mortality was as high as 49%. In 71%, 4% of deaths, at autopsies, were found serious thromboembolic and micro/ macro angiopathic coagulopathy complications, with high levels of neutrophils, fibrinogen, D-dimer and FDPs and NETs, with ATIII decrease and normal number of platelets. Hypercoagulability conditions have been explained as a result of the cytokine storm and of inflammatory state on coagulation. SARS-CoV-2 S-protein drives infection of alveolar cells by engaging ACE2 cell receptors and following TMPRSS2 activation depends on the activity of host proteases. Camostat mesylate, a serine protease inhibitor, coupled with Cathepsin B/L inhibitor E-64d, resulted in full inhibition of SARS-CoV-2 cell entry. Other proteases fight bacterial and viral invasion, with imbalanced immune activation. In this paper it’s hypothesized that the severity of COVID-19 is sustained by a “proteolytic storm” induced by recruited neutrophils proteases and NETs, which cause endothelial damage and unbalance of the four major proteolytic cascades (coagulation, complement, fibrinolysis and kallikrein) and consequent immunothrombosis. Hypercoagulability is worsened by platelets adhesion to damaged endothelium and vWFVIII multimers presence, due to loss of ADAMTS13. Serine protease inhibitors, like aprotinin, camostat or nafamostat mesylate and human plasma can be used to treat COVID-19 unbalanced proteolysis. This paper supports the hypothesis that, in severe COVID-19, neutrophil proteases are the “prima donna” and excessively unbalanced neutrophil innate “unfriendly fire” triggers a “proteolytic storm”, responsible for hypercoagulability and “cytokine storm”. Serine proteases inhibitors or human plasma, in adequate volumes, can help in severe COVID-19 therapy

Keywords:

Covid-19; Covid; Corona Virus; Coronavirus disease 2019; SARS-CoV-2

Citation:

Fornasari PM. SARS-CoV-2 and Proteolytic Storm: Neutrophils and Proteolytic Enzymes are the “Prima Donna” in Severe COVID-19. Serine Proteases Inhibitors are Valuable Treatment Options. Am J Blood Rev. 2021; 1(1): 1001..

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