Severe COVID-19 Is a Microvascular Disease

Abstract

he range of clinical responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is extremely broad.Although most patients with coronavirus disease 2019 (COVID-19) present with a mild upper respiratory tract infection and then recover, some infected patients develop pneumonia, acute respiratory distress syndrome, multi-organ failure, and death.Clues to the pathogenesis of severe COVID-19 may lie in the systemic inflammation and thrombosis observed in infected patients.We propose that severe COVID-19 is a microvascular disease in which coronavirus infection activates endothelial cells, triggering exocytosis, a rapid vascular response that drives microvascular inflammation and thrombosis.Both arterial and venous thromboembolism are common in patients with severe COVID-19.The incidence of venous thromboembolic events in patients with COVID-19 admitted to intensive care units ranges from 20% to 35%, and deep venous thrombosis has been identified in 70% to 100% of patient who died from COVD-19. 1 Furthermore, arterial thrombosis resulting in stroke or myocardial infarction occurs in up to 4% of patients with COVID-19 hospitalized in intensive care units.Patients with severe COVID-19 often have laboratory findings consistent with a hypercoagulable state, suggesting widespread thrombosis and fibrinolysis, as well as elevated levels of D-dimer, von Willebrand factor (VWF), and factor VIII.These patients also manifest a hyperinflammatory state, or "cytokine storm," characterized by elevated levels of inflammatory markers such as C-reactive protein and interleukin-6, which have been linked to severity of pneumonia and mortality.Endothelial injury is an underlying mechanism that might link inflammation and thrombosis in severe COVID-19.Autopsy studies have suggested that both endothelial inflammation and microvascular thrombosis are prominent, with inflammatory cells attached to the endothelium of small vessels in lung, kidney, heart, and liver. 2 Moreover, VWF, which is released from endothelial cells after vascular injury, and P-selectin, which is also released from activated endothelial cells, are both markedly elevated in several series of patients with COVID-19. 3,4The combination of high VWF levels, elevated P-selectin levels, microvascular thrombosis, and microvascular inflammation all suggest that microvascular injury may be a common trigger for both the inflammatory and thrombotic complications of COVID-19. 5 We propose that the coronavirus SARS-CoV-2 triggers a unique endothelial response, endothelial exocytosis, which simultaneously activates 2 parallel pathways, microvascular inflammation and microvascular thrombosis, ultimately leading to hyperinflammation and diffuse thrombosis characteristic of severe COVID-19.Exocytosis is a rapid secretory response to injury in which diverse agonists bind to endothelial cell surface receptors, triggering endothelial granules to fuse with the endothelial membrane and release granule contents into the blood stream.

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