From angiotensin-converting enzyme 2 disruption to thromboinflammatory microvascular disease: A paradigm drawn from COVID-19

Abstract

We concisely review clinical, autopsy, experimental and molecular data of 2019 coronavirus disease (COVID-19). Angiotensin-converting enzyme 2 disruption and thromboinflammatory microangiopathy emerge as distinctive features. Briefly, entry of the virus into microvessels can profoundly disrupt the local renin-angiotensin system, cause endothelial injury, activate the complement cascade and induce powerful thromboinflammatory reactions, involving, in particular, von Willebrand factor, that, if widespread, may lead to microvascular plugging, ischemia and, ultimately, organ failure. We believe the current COVID-19 data consolidate a widely unrecognised paradigm of potentially fatal thromboinflammatory microvascular disease.

Keywords: 2019 coronavirus; Complement; Renin-angiotensin system; Thromboinflammatory microangiopathy; von Willebrand factor.

Fig. 1

Thromboinflammatory microangiopathy secondary to SARS-CoV-2 endotheliitis. Lower left: In normal microvascular endothelium, ACE2 cleaves Ang II to Ang(1–7) and, less efficiently, Ang I to Ang(1–9) which can further generate Ang(1–7); Ang(1–7), through the endothelial membrane G-protein-coupled Mas receptor (MAS-R), exerts antithrombotic, vasorelaxing and anti-inflammatory effects mediated by NO, t-PA and bradykinin. Top left and middle: SARS-CoV-2 enters the bloodstream – e.g., after crossing the alveolar-capillary membrane - and binds to endothelial ACE2, causing infectious endotheliitis, viral replication, cytokine secretion (purple circles) and VWF release. Functional ACE2 loss, induced by SARS-CoV-2, additionally inhibits the antithrombotic and anti-inflammatory properties of Ang(1–7). Chemotaxis by viral antigens, cytokines and VWF multimers all trigger complement activation culminating in cell lysis through the MAC C5b-9. Complement can induce lymphopenia and further prothrombotic, proinflammatory, chemotactic and anaphylotoxic effects. Lymphopenia may also be caused by direct viral infection of lymphocytes. Right: endothelial cell lysis, TF expression, release of VWF and PAI-1 from activated endothelium (green circles) contribute to leukocyte influx and to microthrombosis through platelet adhesion, aggregation and coagulation. Thrombocytopenia may signal widespread thrombosis. (For a colour version of this figure, the reader is referred to the web version of this article.)