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Copyright ©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Exp Med. Jul 20, 2022; 12(4): 53-67
Published online Jul 20, 2022. doi: 10.5493/wjem.v12.i4.53
Complement-mediated microvascular injury and thrombosis in the pathogenesis of severe COVID-19: A review
Panagiota Gianni, Mark Goldin, Sam Ngu, Stefanos Zafeiropoulos, Georgios Geropoulos, Dimitrios Giannis
Panagiota Gianni, Department of Internal Medicine III, Hematology, Oncology, Palliative Medicine, Rheumatology and Infectious Diseases, University Hospital Ulm, Ulm 89070, Germany
Mark Goldin, Sam Ngu, Dimitrios Giannis, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Northwell Health, New York, NY 11549, United States
Mark Goldin, Feinstein Institutes for Medical Research at Northwell Health, Feinstein Institutes , New York, NY 11030, United States
Stefanos Zafeiropoulos, Elmezzi Graduate School of Molecular Medicine, Northwell Health, New York, NY 11030, United States
Georgios Geropoulos, Department of General Surgery, University College London Hospitals, London NW12BU, United Kingdom
Dimitrios Giannis, North Shore/Long Island Jewish General Surgery, Northwell Health, New York, NY 11021, United States
Author contributions: Gianni P, and Giannis D led the study including review of the literature, data analysis, and drafted the manuscript; Goldin M, Ngu S, Geropoulos G and Zafeiropoulos S contributed to the editing, data analysis and critical review of the manuscript; all authors are agreeable to be accountable for all aspects of the work and gave final approval of the version to be published.
Conflict-of-interest statement: All the authors declare no conflict of interests for this article.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Dimitrios Giannis, MD, MSc, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Northwell Health, 500 Hofstra Blvd, Hempstead, NY 11549, United States. dimitrisgiannhs@gmail.com
Received: February 9, 2022
Peer-review started: February 9, 2022
First decision: April 13, 2022
Revised: April 27, 2022
Accepted: June 13, 2022
Article in press: June 13, 2022
Published online: July 20, 2022
Processing time: 160 Days and 1 Hours
Abstract

Coronavirus disease 2019 (COVID-19) causes acute microvascular thrombosis in both venous and arterial structures which is highly associated with increased mortality. The mechanisms leading to thromboembolism are still under investigation. Current evidence suggests that excessive complement activation with severe amplification of the inflammatory response (cytokine storm) hastens disease progression and initiates complement-dependent cytotoxic tissue damage with resultant prothrombotic complications. The concept of thromboinflammation, involving overt inflammation and activation of the coagulation cascade causing thrombotic microangiopathy and end-organ damage, has emerged as one of the core components of COVID-19 pathogenesis. The complement system is a major mediator of the innate immune response and inflammation and thus an appealing treatment target. In this review, we discuss the role of complement in the development of thrombotic microangiopathy and summarize the current data on complement inhibitors as COVID-19 therapeutics.

Keywords: COVID-19; Complement; Microvascular injury; Thromboembolism; Cytokine storm; Thrombotic microangiopathy

Core Tip: Current evidence supports the role of excessive complement activation with subsequent illness progression and development of a complement-dependent cytotoxic tissue damage with detrimental effects in coronavirus disease 2019 (COVID-19) patients, including thromboembolic complications. Based on its role in the development of the cytokine storm and thrombogenesis in COVID-19, the complement system is an appealing treatment target with promising results from preliminary reports. Whether inhibition of upstream (C3, C1) or terminal (C5, C5a, or C5aR) components is of equal importance remains to be elucidated, however, preliminary results from several ongoing clinical trials show benefit in terms of 28-d mortality and pulmonary embolism.