Complement activation and endothelial perturbation parallel COVID-19 severity and activity

Abstract

Background: Animal models and few clinical reports suggest the involvement of the complement system in the onset of severe manifestations of coronavirus disease-2019 (COVID-19). However, complement contribution to endotheliopathy and hypercoagulability has not been elucidated yet.

Objective: To evaluate the association among complement activation, endothelial damage and disease severity or activity in COVID-19 patients.

Methods: In this single-centre cohort study, 148 patients with COVID-19 of different severity were evaluated upon hospital admission and 30 days later. Markers of complement activation (SC5b-9 and C5a) and endothelial perturbation (von Willebrand factor [vWF], tissue-type plasminogen activator [t-PA], plasminogen activator inhibitor-1 [PAI-1], soluble thrombomodulin [sTM], and soluble endothelial selectin [sE-selectin]) were measured in plasma.

Results: The patients had high plasma levels of SC5b-9 and C5a (p = 0.0001 for both) and vWF, t-PA and PAI-1 (p = 0.0001 for all). Their SC5b-9 levels correlated with those of vWF (r = 0.517, p = 0.0001) and paralleled disease severity (severe vs mild p = 0.0001, severe vs moderate p = 0.026 and moderate vs mild p = 0.001). The levels of sE-selectin were significantly increased only in the patients with severe disease. After 30 days, plasma SC5b-9, C5a and vWF levels had significantly decreased (p = 0.0001 for all), and 43% of the evaluated patients had normal levels.

Conclusions: Complement activation is boosted during the progression of COVID-19 and dampened during remission, thus indicating its role in the pathophysiology of the disease. The association between complement activation and the biomarkers of endothelial damage suggests that complement may contribute to tissue injury and could be the target of specific therapy.

Keywords: C5a; COVID-19; Complement; Endothelium; SC5b-9; von Willebrand factor.

Fig. 1

Plasma levels of soluble complement terminal complex (SC5b-9) (1a) and activated complement component 5 (C5a) (1b) in 58 COVID-19 patients kept under observation and receiving low-intensity care (mild), 44 patients requiring intermediate care with non-invasive ventilation (moderate), 46 patients admitted to an intensive care unit for mechanical ventilation (severe), and 27 healthy controls.

Fig. 2

a) Plasma levels of von Willebrand factor (vWF) in 58 COVID-19 patients kept under observation and receiving low-intensity care (mild), 44 patients requiring intermediate care with non-invasive ventilation (moderate), 46 patients admitted to an intensive care unit for mechanical ventilation (severe), and 27 healthy controls; b) Correlation between the plasma levels of vWF and soluble complement terminal complex (SC5b-9) in 148 COVID-19 patients.

Fig. 3

Plasma levels of tissue-type plasminogen activator (t-PA) (3a), plasminogen activator inhibitor-1 (PAI-1) (3b), soluble thrombomodulin (sTM) (3c), and soluble E-selectin (sE-selectin) (3d) in 13 COVID-19 patients kept under observation and receiving low-intensity care (mild), 21 patients requiring intermediate care with non-invasive ventilation (moderate), 16 patients admitted to an intensive care unit for mechanical ventilation (severe), and 20 healthy controls.

Fig. 4

Plasma levels of soluble complement terminal complex (SC5b-9) (4a) and von Willebrand factor (vWF) (4b) upon admission and 30 days later in 30 patients who developed COVID-19 of different severity: 20 patients who had been kept under observation and received low-intensity care (mild); eight patients who had required intermediate care with non-invasive ventilation (moderate); and two patients who had been admitted to an intensive care unit for mechanical ventilation (severe). The dotted lines represent the lower and upper limits of normal.