Complement inhibition: A possible therapeutic approach in the fight against Covid‐19

Deravi, Niloofar; Ahsan, Elahe; Fathi, Mobina; Hosseini, Parastoo; Yaghoobpoor, Shirin; Lotfi, Ramin; Pourbagheri‐Sigaroodi, Atieh; Bashash, Davood

doi:10.1002/rmv.2316

Cited by 6 publications

(8 citation statements)

References 163 publications

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“…These results have implications for the utilization of complement inhibition in the management of COVID-19 which has been trialed in observational studies with variable results as reviewed by Deravi et al. ( 46 ). Our findings support activation of the classical and alternative complement pathways on monocytes even in mild-moderate SARS-CoV-2 infection with a compensatory upregulation of CD55.…”

Section: Discussionmentioning

confidence: 94%

Activation of Complement Components on Circulating Blood Monocytes From COVID-19 Patients

et al. 2022

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The coronavirus disease-2019 (COVID-19) caused by the SARS-CoV-2 virus may vary from asymptomatic to severe infection with multi-organ failure and death. Increased levels of circulating complement biomarkers have been implicated in COVID-19-related hyperinflammation and coagulopathy. We characterized systemic complement activation at a cellular level in 49-patients with COVID-19. We found increases of the classical complement sentinel C1q and the downstream C3 component on circulating blood monocytes from COVID-19 patients when compared to healthy controls (HCs). Interestingly, the cell surface-bound complement inhibitor CD55 was also upregulated in COVID-19 patient monocytes in comparison with HC cells. Monocyte membrane-bound C1q, C3 and CD55 levels were associated with plasma inflammatory markers such as CRP and serum amyloid A during acute infection. Membrane-bounds C1q and C3 remained elevated even after a short recovery period. These results highlight systemic monocyte-associated complement activation over a broad range of COVID-19 disease severities, with a compensatory upregulation of CD55. Further evaluation of complement and its interaction with myeloid cells at the membrane level could improve understanding of its role in COVID-19 pathogenesis.

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Section: Discussionmentioning

confidence: 94%

Activation of Complement Components on Circulating Blood Monocytes From COVID-19 Patients

et al. 2022

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“…However, which target(s) is the most effective remains an open question. Equally important, the timing for intervention is crucial to abrogate hyper‐inflammation without impairing the immune response against the virus 9 . Thus, there is still an unmet need for controlled randomized clinical trials to answer these questions on the benefits of anticomplement therapy in COVID‐19.…”

Section: Discussionmentioning

confidence: 99%

“…High plasma levels of soluble C5b‐9 (sC5b‐9), C5a, and C4d are found in patients with severe disease and respiratory failure 4131,42 . In addition, decreased serum concentrations of C3 and C4 are associated with disease severity and mortality, probably reflecting complement consumption 9,43 . Pulmonary, skin, and autopsy samples of COVID‐19 patients showed C5b‐9, C4d, and MASP‐2 deposition associated with thrombotic microvascular injury.…”

Section: Complement Activation In Covid‐19mentioning

confidence: 99%

“…8 The complement system is an essential agent of immunity that acts as a bridge between innate and adaptive immune responses, protecting the host from infectious agents. 9 In viral infections, although complement activation promotes the neutralization of viral particles and the clearance of virus-infected cells, collateral damage may occur.…”

Section: Introductionmentioning

confidence: 99%

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Hyper‐inflammation and complement in COVID‐19

Pires

Calado

2023

American J Hematol

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COVID‐19 is a complex disease manifesting in a broad severity spectrum and involving distinct organs and systems. Hyperinflammation, including complement over‐activation, has a pivotal role in severe COVID‐19 pathobiology, stimulating the inflammatory response, causing microangiopathy, platelet–neutrophil activation, and hypercoagulability. SARS‐CoV‐2 can directly activate the complement system by the classic, alternative, and lectin pathways, and infected cells can produce intracellular complement (the complesome). COVID‐19 severity appears to be associated with the degree of complement activation, and it has been hypothesized that patients with COVID‐19 may benefit from therapeutic complement inhibition. Different complement cascade molecules may be targeted with potential advantages and disadvantages. Which target(s) is the most effective and when is the best timing for intervention remain open questions. Early phase I and phase II clinical trials have shown promising but conflicting results, warranting phase III controlled randomized trials. Upstream complement inhibition appears to better and more effectively block hyperinflammation with potential clinical significance. Understanding how SARS‐CoV‐2 exploits the complement system can add precious information about the pathogenesis of other infections, inflammatory, and autoimmune diseases beyond COVID‐19.

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“…Actually, C3a and C5a fragments are known to stimulate mast cell degranulation and endothelial cell activation, thus promoting prothrombotic events mainly by stimulating TF and VWF secretion, respectively [88]. Furthermore, C3a fragment, in particular, directly stimulates platelets, suggesting that the over-activation of the complement system in SARS-CoV-2-infected patients may contribute to exacerbating the risk of thrombosis [89] not only for the accumulation of inflammatory infiltrates in the pulmonary alveoli but also for leading to a fatal hypercoagulable state This could support a role for complement inhibition as potential therapeutic approach to treat patients SARS-CoV-2 infected [90].…”

Section: Platelets and Immunothrombosismentioning

confidence: 99%

Prothrombotic Phenotype in COVID-19: Focus on Platelets

Barale

Melchionda

Morotti

et al. 2021

IJMS

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COVID-19 infection is associated with a broad spectrum of presentations, but alveolar capillary microthrombi have been described as a common finding in COVID-19 patients, appearing as a consequence of a severe endothelial injury with endothelial cell membrane disruption. These observations clearly point to the identification of a COVID-19-associated coagulopathy, which may contribute to thrombosis, multi-organ damage, and cause of severity and fatality. One significant finding that emerges in prothrombotic abnormalities observed in COVID-19 patients is that the coagulation alterations are mainly mediated by the activation of platelets and intrinsically related to viral-mediated endothelial inflammation. Beyond the well-known role in hemostasis, the ability of platelets to also release various potent cytokines and chemokines has elevated these small cells from simple cell fragments to crucial modulators in the blood, including their inflammatory functions, that have a large influence on the immune response during infectious disease. Indeed, platelets are involved in the pathogenesis of acute lung injury also by promoting NET formation and affecting vascular permeability. Specifically, the deposition by activated platelets of the chemokine platelet factor 4 at sites of inflammation promotes adhesion of neutrophils on endothelial cells and thrombogenesis, and it seems deeply involved in the phenomenon of vaccine-induced thrombocytopenia and thrombosis. Importantly, the hyperactivated platelet phenotype along with evidence of cytokine storm, high levels of P-selectin, D-dimer, and, on the other hand, decreased levels of fibrinogen, von Willebrand factor, and thrombocytopenia may be considered suitable biomarkers that distinguish the late stage of COVID-19 progression in critically ill patients.

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Complement inhibition: A possible therapeutic approach in the fight against Covid‐19

Cited by 6 publications

References 163 publications

Activation of Complement Components on Circulating Blood Monocytes From COVID-19 Patients

Activation of Complement Components on Circulating Blood Monocytes From COVID-19 Patients

Hyper‐inflammation and complement in COVID‐19

Prothrombotic Phenotype in COVID-19: Focus on Platelets

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