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.