COVID-19: A collision of complement, coagulation and inflammatory pathways

Abstract

COVID-19 is frequently accompanied by a hypercoagulable inflammatory state with microangiopathic pulmonary changes that can precede the diffuse alveolar damage characteristic of typical acute respiratory distress syndrome (ARDS) seen in other severe pathogenic infections. Parallels with systemic inflammatory disorders such as atypical hemolytic uremic syndrome (aHUS) have implicated the complement pathway in the pathogenesis of COVID-19, and particularly the anaphylatoxins C3a and C5a released from cleavage of C3 and C5, respectively. C5a is a potent cell signalling protein that activates a cytokine storm-a hyper-inflammatory phenomenon-within hours of infection and the innate immune response. However, excess C5a can result in a pro-inflammatory environment orchestrated through a plethora of mechanisms that propagate lung injury, lymphocyte exhaustion, and an immune paresis. Furthermore, disruption of the homeostatic interactions between complement and extrinsic and intrinsic coagulation pathways contributes to a net pro-coagulant state in the microvasculature of critical organs. Fatal COVID-19 has been associated with a systemic inflammatory response accompanied by a pro-coagulant state and organ damage, particularly microvascular thrombi in the lungs and kidneys. Pathologic studies report strong evidence of complement activation. C5 blockade reduces inflammatory cytokines and their manifestations in animal studies, and has shown benefits in patients with aHUS, prompting investigation of this approach in the treatment of COVID-19. This review describes the role of the complement pathway and particularly C5a and its aberrations in highly pathogenic virus infections, and therefore its potential as a therapeutic target in COVID-19.

Keywords: COVID-19; complement C5; cytokines; leukotriene B4; thrombin.

FIGURE 1

Interactions among the complement, coagulation, and inflammatory pathways following COVID‐19 infection, based on knowledge of previous highly pathogenic virus infections. Complement is activated through three different pathways following virus infection, eventually leading to increased levels of the critical anaphylatoxins C3a and C5a, which have central roles in the innate immune response; C5a in particular influences chemotaxis, and cell signaling and activation. This contributes to the release of pro‐inflammatory cytokines from effector cells, with a parallel reduction in anti‐viral cytokines and lymphocyte reduction. C5a also impairs fibrinolysis by increasing the release of PAI1 from cellular sources including mast cells and basophils. C5a activation of tissue factor leads to a pro‐coagulant activity, and critical clotting factors such as factors VIIa, IXa, and XIa complex cleave the parent C3 and C5 molecules into the anaphylatoxins C3a and C5a. C5a activity causes NETs to release pro‐coagulant mediators, contributing to microvascular thrombosis and endothelial damage. C, complement (a suffix indicates activated complement); F, factor; FDP, fibrinogen degradation products; IFN, interferon; IL, interleukin; MAC, membrane attack complex; PAI1, plasminogen activator inhibitor 1; tPA, tissue plasminogen activator; TNF, tumour necrosis factor; uPA, urokinase