SARS-CoV-2 is a vascular and coagulation disease
While respiratory damage and complications are the major clinical signs of severe COVID-19 many tissues and organs are affected often prior to, or independently of lung pathology for example Kawasaki-like vascular disease in children (93). Clinical, post-mortem studies and experimental animal models of SARS-CoV reveal infection of endothelial cells and the widespread damage of endothelial cells, vascular dysfunction and thrombosis (93,94) that are emerging as a common pathological feature of SARS-CoV-2 infection. The link between SARS-CoV-2 infection, vascular damage and thrombosis is evidenced by high levels of D-dimers in 20-40% critically ill patients likely produced in an attempt to dissolve thrombotic clots. The endothelial cell damage is supported by the finding that endothelial cells express ACE2 and are thus permissible to SARS-CoV-2 infection (93). Thus, infection not only leads to reduced ACE2 in endothelial cells, but also direct viral cytopathic damage and increased vascular permeability [figure 4], although more recent data challenge this view suggesting that pericytes and not endothelial cells are permissible to infection and viral induced damage (94,95). Damage of endothelial cells and pericytes leads to vascular permeability in severe COVID-19 that is likely amplified by activation of complement components widely expressed in tissues post-mortem tissues of COVID-19 cases (67,68). Disruption of the vascular barrier and endothelial cell exposure to IL-1β, TNFα and ROS increases expression of P-selectin, von Willebrand factor and fibrinogen, and attracting platelets that trigger expression of tissue factor [figure 4]. Together this sequence triggers the coagulation cascade and explains the finding of increased D-dimer and fibrin, abnormal clotting times in severe COVID-19 cases, and widespread disseminated thrombi in post-mortem tissues.