Accumulated clinical evidence during the evolving coronavirus 2019 (COVID-19) pandemic indicates that severe acute respiratory syndrome coronavirus 2 (SARS–CoV-2) infection triggers thrombotic complications that affect multiple vital organs, increasing the mortality burden in patients with COVID-19 (1, 2). The pathological process of coagulopathy in COVID-19 is commonly characterized as an immunothrombosis, since it is related to a maladaptive host immune response fueled by excessive activation of innate immune pathways, deregulated thromboinflammation, and endothelial dysfunction (1, 2). Understanding the immunothrombotic mechanisms in COVID-19 constitutes a significant medical challenge.

Increased neutrophil counts have been associated with disease severity and poor prognosis in COVID-19, and extensive neutrophil infiltration of pulmonary capillaries has been described in autopsy specimens (3–7). In several inflammatory disorders (8), neutrophil extracellular traps (NETs) have been shown to exert thrombogenic activity through the expression of functionally active tissue factor (TF). NETs appear to be involved in COVID-19 as well (9).

Complement activation has been implicated as driver of the maladaptive inflammatory response in COVID-19. Complement can enhance neutrophil/monocyte activation and recruitment to the infected lungs, and several complement effectors, acting in concert with platelets, can fuel thromboinflammation, microvascular thrombosis, and endothelial dysfunction (thrombotic microangiopathy) (7, 10, 11). Therefore, early clinical data have prompted the initiation of trials to evaluate various complement therapeutics in patients with COVID-19 (12).

The well-established crosstalk between complement and neutrophils in human immunothrombosis (13–15) led us to hypothesize that the collaboration of these innate immune systems may mediate early events leading to coagulopathy in COVID-19. Here, we investigated the role of neutrophils in COVID-19 thromboinflammation and provide evidence that complement activation potentiates the platelet/NETs/TF/thrombin axis during SARS–CoV-2 infection.

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