SARS-CoV-2 cell entry receptor ACE2 mediated endothelial dysfunction leads to vascular thrombosis in COVID-19 patients

Abstract

Several studies have described unusually high incidence of vascular thrombosis in coronavirus disease-2019 (COVID-19) patients. Pathogenesis of the vascular thrombosis in COVID-19 is least understood for now and presents a challenge to the treating physicians. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative pathogen for COVID-19, has been shown to bind to angiotensin converting enzyme 2 (ACE2) protein in human epithelial cells which facilitates its entry in the organ and mediate tissue specific pathogenesis. For ACE2 mediated cell entry of the SARS-CoV-2, co-expression of one more protein-Transmembrane protease serine 2 (TMPRSS2) is essential. Existing studies suggested significant expression of ACE2 and TMPRSS2 in human vascular endothelium. Vascular endothelial dysfunction can potentially activate coagulation cascade eventually resulting in thrombosis. ACE2 has proven role in the maintenance of endothelial integrity inside the vessels. Existing in situ evidence for SARS-CoV-1 (the causative agent for SARS pandemic of 2002, which shared ACE2 as cell entry receptor) suggested that virus binding can downregulate ACE2, thus can induce endothelial dysfunction. Recently, in situ evidence has been presented that SARS-CoV-2 can infect cells in engineered human vascular endothelium, which can be effectively blocked by using clinical-grade recombinant human ACE2. Based on the circumstantial evidence present in the literature, we propose a SARS-CoV-2 cell entry receptor ACE2 based mechanism for vascular thrombosis in COVID-19 patients.

Keywords: ACE2; COVID-19; SARS-CoV-2; TMPRSS2; Thrombosis; Vascular endothelial dysfunction.

Fig. 1

Schema of ACE2 mediated mechanisms of vascular thrombosis in COVID-19 patients. (Binding of SARS-CoV-2 to ACE2 receptor present at the vascular endothelial cell surface leads internalization and replication of the virus inside the cell, and consequently cellular disintegration which activates prothrombotic cascade. Additionally, SARS-CoV-2 binding induces downregulation of ACE2 inturn imbalances ACE/ACE2 ratio favoring prothrombosis. Both of these stated mechanisms in consequence also induce activation and aggregation of the platelets, altogether culminating in intravascular thrombosis.)