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.

A Review on the Neurological Manifestations of COVID-19 Infection: a Mechanistic View

“…The overactivation of the complement cascade in the process of the inflammatory response by SARS-CoV-2 can lead to thrombosis (Fig. 4) [92,93]. Besides, due to the reduction of ACE2 proteins and a further increase in Ang II, enhanced BP can raise the occurrence of stroke.…”

Is prostate infarction and acute urinary retention a possible complication of severe COVID-19 infection?

“…For patients compromised by the cytokine storm after COVID infection, the procoagulant state seems to be a common and important manifestation, affecting many organs, evolving to insufficiency of multiple organs. 2,3,6 As far as we know, this is the first report of prostate involvement in the context of COVID infection. SARS-CoV-2 was already found in semen, but which organ is affected by the infection is not yet clear.…”

The Influence of the Lectin Pathway of Complement Activation on Infections of the Respiratory System

“…Polycarpou et al (120) suggested that targeting complement might contribute to reducing COVID-19 systemic complications (multiorgan failure, coagulopathy), mediated by lectin pathway activation. Therefore, inhibition of the complement system at the levels of C3 or C5a/ C5aR is considered a possible therapeutic option (121,122).…”