Mechanisms by which SARS-CoV-2 induces the prothrombotic transformation of the endothelium. (A) In severe systemic SARS-CoV-2 infection, endothelilal cytoprotective mechanisms are lost. The glycocalyx is degraded by metalloproteases (MMPs) and heparanases (panel 1). Several cytoprotective signaling pathways are downregulated. Featured in panel 2 is loss of Tie2 signaling, which occurs following the release of angiopoietin-2 from endothelial stores. High concentrations of angiopoietin-2 displace angiopoietin-1, with loss of clustering and decreased Tie2 phosphorylation resulting in loss of cytoprotective signaling. The spike protein of SARS-CoV-2 binds to ACE2, resulting in its endocytosis and loss from the cell surface. This prevents the cleavage of angiotensin II into Ang(1-7). The cytoprotective signaling of Ang(1-7) is therefore lost, and instead, proinflammatory signaling through the angiotensin II type 1 receptor prevails (panel 3). Complement deposition in the setting of COVID-19 results in assembly of the MAC, which permeabilizes the endothelial cell membrane (panel 4). (B) SARS-CoV-2 contains (1) S protein, which binds ACE2 facilitating endocytosis, (2) membrane protein (M protein) and envelope protein (E protein), which reside in the viral membrane and (3) nucleocaspid protein that encapsulates SARS-CoV-2 single stranded RNA (ssRNA). SARS-CoV-2 elicits a prothrombotic transformation of the endothelium that results in occlusion of microcirculation by several mechanisms: (1) Loss of glycocalyx integrity provides SARS-CoV-2 better access to endothelial cell receptors. (2) Decreased cytoprotective signaling results in loss of barrier fortification and increased endothelial damage, dysfunction, and phosphatidylserine exposure (yellow outline). (3) Neutrophil-platelet aggregates are found in the circulation in COVID-19 and facilitate the release of NETs from neutrophils. (4) Activation of platelets and vWF release results in formation of platelet-rich thrombi. (5) Fibrin formation on the endothelium results from activation of both the intrinsic and extrinsic pathways. (6) Generation of TF-bearing microparticles (small purple circles) from activated macrophages also contributes to fibrin formation. (7) Endothelial-leukocyte interactions and loss of barrier function enable arrest and transmigration of leukocytes from the endothelium. (8) Permeabilization of membranes by complement deposition results in endothelial cell damage. (C) Several molecular processes contribute to the prothrombotic transformation of the endothelium. Upregulation of tissue factor in activated endothelium along with downregulation of TM and EPCR results in the activation of factor X to factor Xa (panel 1). Externalization of plasma membrane phosphatidylserine (yellow) facilitates assembly of the prothrombinase complex, resulting in the generation of thrombin from prothrombin (panel 2). Upregulation of leukocyte adhesion molecules including VCAM, ICAM, E-selectin, and P-selectin promotes the association of leukocytes with endothelium and facilitates their transmigration into surrounding tissue (panel 3). Endothelial dysfunction interferes with production of NO and PGI₂, and secretion of vWF from Weibel-Palade bodies (WPB, blue) facilitates recruitment of platelets to the endothelial surface. Platelets bind to vWF primarily via GPIbα of the GPIbα-GPIbβ-IX-V complex. Platelet-platelet aggregation is mediated largely through the binding of fibrinogen by integrin α_IIbβ₃ (panel 4). vWF, von Willebrand factor; NETs, neutrophil extracellular traps.