Thromboinflammation in coronavirus disease 2019: The clot thickens

Abstract

Since the start of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, a disease that has become one of the world's greatest global health challenges, the role of the immune system has been at the forefront of scientific studies. The pathophysiology of coronavirus disease 2019 (COVID-19) is complex, which is evident in those at higher risk for poor outcome. Multiple systems contribute to thrombosis and inflammation seen in COVID-19 patients, including neutrophil and platelet activation, and endothelial dysfunction. Understanding how the immune system functions in different patient cohorts (particularly given recent emerging events with the Oxford/AstraZeneca vaccine) is vital to understanding the pathophysiology of this devastating disease and for the subsequent development of novel therapeutic targets and to facilitate possible drug repurposing strategies that could benefit society on a global scale. LINKED ARTICLES: This article is part of a themed issue on The second wave: are we any closer to efficacious pharmacotherapy for COVID 19? (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.10/issuetoc.

Keywords: inflammation; neutrophils; platelets; resolution pharmacology; thromboinflammation; thrombosis.

FIGURE 1

Thromboinflammation in coronavirus disease 2019 (COVID‐19). (1) Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) binds via the ACE2 expressed on the endothelial surface. The virus activates monocytes releasing a cytokine storm (including IL‐6, IL‐1β, IL‐2, IL‐6, IL‐7, IL‐8, IL‐10, IL‐17, TNF‐α, CCL2, CCL3, and CXCL10 , all of which correlate with adverse clinical outcomes). (2) The inflammatory effects of cytokines also activate vascular endothelial cells (ECs), disrupting endothelial function and integrity, which leads to increased platelet and neutrophil recruitment. (3) Increased neutrophil at inflammatory site results in increased expression of adhesion molecules such as L‐selectin, P‐selectin and intercellular adhesion molecule‐1 on ECs. Activated neutrophils release their neutrophil extracellular traps (NETs, which contain a backbone of DNA and citrullinated histone [H3Cit], cathepsin G and neutrophil elastase [NE]), which trap platelets, increasing their activation and aggregation; this in turn further activates neutrophils to produce more NETs. (4) This cycle of events triggers coagulation cascade activation, which in turn increases fibrin formation and thrombosis. CAMs, cellular adhesion molecules; RBC, red blood cell; vWF, von Willebrand factorIFFAHANDGAVINS3