Preprint Concept Paper Version 1 This version is not peer-reviewed

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

Version 1 : Received: 21 May 2020 / Approved: 23 May 2020 / Online: 23 May 2020 (10:42:38 CEST)

How to cite: Fornasari, P.M. COVID-19: Neutrophils “Unfriendly Fire” Imbalance Proteolytic Cascades Triggering Clinical Worsening and Viral Sepsis. Potential Role Explanation for Convalescent Plasma as “Fire Hose”. Preprints 2020, 2020050373 (doi: 10.20944/preprints202005.0373.v1). Fornasari, P.M. COVID-19: Neutrophils “Unfriendly Fire” Imbalance Proteolytic Cascades Triggering Clinical Worsening and Viral Sepsis. Potential Role Explanation for Convalescent Plasma as “Fire Hose”. Preprints 2020, 2020050373 (doi: 10.20944/preprints202005.0373.v1).

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, 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. In this paper, it’s hypothesised 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, contributes 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”. The hypothesis explains also the pathology of recently described systemic “Kawasaki Disease like” vasculitis cases in Covid-19 young ill patients.

Subject Areas

COVID-19; proteolytic cascades; thrombosis; viral sepsis

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