Complement and neutrophil-mediated immunothrombosis: lessons from COVID-19

Panagiotis Skendros, MD, PhD,

University Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, Greece

Complement and neutrophil-mediated immunothrombosis: lessons from COVID-19.

During inflammation and infection coagulation and immunity are tightly interconnected using common molecular pathways and mechanisms, in a process known as immunothrombosis. A growing body of clinical evidence today indicates that complement and neutrophils participate in the maladaptive host immune response that triggers hyper-inflammation and thrombotic microangiopathy, increasing substantially the mortality rate in COVID-19 pandemic; however possible underlying mechanisms that can explain these clinical phenotypes are still elusive. Here, we propose a novel mechanistic basis that describes how the complex crosstalk between key humoral and cellular components of the innate immune response and vascular barrier system, including complement, platelets, neutrophils and the endothelium, shapes the thromboinflammatory milieu that impacts many vital organs in COVID-19 patients. We investigated the role of neutrophils as key drivers of COVID-19 pathogenesis, providing evidence that complement activation is a major inflammatory mediator in the activation of the platelet/neutrophil extracellular traps (NETs)/thrombin axis leading to endothelial dysfunction during SARS-CoV-2 infection. Our findings support the evaluation of therapeutic strategies against COVID-19, which target complement activation or/and NET formation. We suggest that COVID-19 constitutes an emerging clinical model of immunothrombosis with substantial translational impact for several thromboinflammatory diseases.