COVID-19: the role of excessive cytokine release and potential ACE2 down-regulation in promoting hypercoagulable state associated with severe illness

Abstract

The novel coronavirus disease (COVID-19) has become a universally prevalent infectious disease. The causative virus of COVID-19 is severe acute respiratory syndrome coronavirus type 2. Recent retrospective clinical studies have established a significant association between the incidence of vascular thrombotic events and the severity of COVID-19. The enhancement in serum levels of markers that reflect a hypercoagulable state has been suggested to indicate a poor prognosis. Therefore, at present, it is crucial to understand the mechanisms that foster the hypercoagulable state in COVID-19. Over-activated inflammatory response, which is manifested as excessive cytokine release in COVID-19 patients, is also associated with COVID-19 severity. This review discusses the immuno-pathological basis of the excessive cytokine release in COVID-19. Besides, this article reviews the role of pro-inflammatory or anti-inflammatory cytokines, whose significant elevations in their serum levels have been consistently detected in multiple different clinical studies, in promoting the hypercoagulable state. Since the expression of angiotensin-converting enzyme 2 (ACE2) is potentially down-regulated in COVID-19, as proposed by a recent bio-informatic analysis, mechanisms through which reduced ACE2 expressions promote vascular thrombosis are summarized. In addition, the reciprocal-enhancing effects of the excessive cytokine release and the downregulated ACE2 expression on their pro-thrombotic activities are further discussed. Here, based on currently available evidence, we review the pathogenic mechanisms of the hypercoagulable state associated with severe cases of COVID-19 to give insights into prevention and treatment of the vascular thrombotic events in COVID-19.

COVID-19 as the cause of thrombosis: recognising COVID-19 infection in apparently asymptomatic patients

“…It is also worth noting that a potential paradigm for the cause of COVID-19-related thrombus has been proposed, which may explain the development of thrombus in critically ill patients. 6 Once again, however, the case described here is clearly different in that the patient seemed to be asymptomatic on initial presentation, only developed mild respiratory failure after presentation and had no typical evidence of a hypercoagulable state. We propose that high-quality clinical trials are urgently needed to assess anticoagulation strategies for both treatment and prevention of these complications in patients with COVID-19 infection, as the problem may extend even to non-hospitalised and non-critically ill patients.…”

Target-Centered Drug Repurposing Predictions of Human Angiotensin-Converting Enzyme 2 (ACE2) and Transmembrane Protease Serine Subtype 2 (TMPRSS2) Interacting Approved Drugs for Coronavirus Disease 2019 (COVID-19) Treatment through a Drug-Target Interaction Deep Learning Model

“…Furthermore, the MT-DTI prediction resulted that ACE inhibitors, including enalaprilat, zofenopril, lisinopril, benazepril, trandolapril, cilazapril, perindopril, ramipril, fosinopril, moexipril, spirapril, have a strong binding affinity of less than K d 70 nM for ACE2 ( Table S1 ). Although there is concern that inhibition of ACE2 activity may promote an excessive inflammatory response resulting from an increase in Ang II [ 40 ], ACE inhibitors can be considered as a treatment option for COVID-19 in two respects. First of all, inhibition of ACE function that elicits an immune response via Ang II may alleviate the side effects of loss of ACE2 function by ACE inhibitors.…”

<p>Inflammatory Cytokine: IL-17A Signaling Pathway in Patients Present with COVID-19 and Current Treatment Strategy</p>

“…9 Taking this a step further, severely infected patients with ARDS have elevated serum levels of IL-1B, IL1RA, IL-6, IL-7, IL-8, IL-17, IL-9, IL-10, fibroblast growth factor (FGF), granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon-γ (IFNγ), granulocyte colony-stimulating factor (G-CSF), interferonγ-inducible protein (IP10), monocyte chemoattractant protein (MCP1), macrophage inflammatory protein-1α (MIP1α), platelet-derived growth factor (PDGF), tumor necrosis factor (TNFα), and vascular endothelial growth factor (VEGF) ( Table 1). 9,[14][15][16][17] Because there is no specific antiviral therapy for COVID-19, understanding of the cytokine storm mechanisms in this disease could help to reveal possible therapeutic interventions. Therefore, among several inflammatory cells and cytokines, T-helper (Th)-17 cells are a unique subset of a cluster of differentiation 4 (CD4 + ) T-helper cells characterized by the production of pro-inflammatory cytokines such as IL-17A, IL-17F, and IL-22.…”