The Role of NETosis and Complement Activation in COVID-19-Associated Coagulopathies

Abstract

Inflammation-induced coagulopathy is a common complication associated with coronavirus disease 2019 (COVID-19). We aim to evaluate the association of NETosis and complement markers with each other as well as their association with thrombogenicity and disease severity in COVID-19. The study included hospitalized patients with an acute respiratory infection: patients with SARS-CoV2 infection (COVpos, n = 47) or either pneumonia or infection-triggered acute exacerbated COPD (COVneg, n = 36). Our results show that NETosis, coagulation, and platelets, as well as complement markers, were significantly increased in COVpos patients, especially in severely ill COVpos patients. NETosis marker MPO/DNA complexes correlated with coagulation, platelet, and complement markers only in COVpos. Severely ill COVpos patients showed an association between complement C3 and SOFA (R = 0.48; p ≤ 0.028), C5 and SOFA (R = 0.46; p ≤ 0.038), and C5b-9 and SOFA (R = 0.44; p ≤ 0.046). This study provides further evidence that NETosis and the complement system are key players in COVID-19 inflammation and clinical severity. Unlike previous studies that found NETosis and complement markers to be elevated in COVID-19 patients compared to healthy controls, our findings show that this characteristic distinguishes COVID-19 from other pulmonary infectious diseases. Based on our results, we propose that COVID-19 patients at high risk for immunothrombosis could be identified via elevated complement markers such as C5.

Symmetrical peripheral gangrene: potential mechanisms and therapeutic approaches in severe COVID-19

“…The amount of Circulating NET-forming neutrophil subset (immunotype DEspR+CD11b+) and NETosis induction levels are positively related with the progression, severity, and duration of acute COVID-19 ( 46 – 48 ). The levels of NETosis initiation showed a significant correlation with platelet activation indicators and blood clotting-related factors ( 47 , 49 ). NETs components cause the degradation of TFPI via neutrophil elastase during thrombotic complications ( 49 ), thus activating the coagulation cascade TF pathway ( 50 ).…”

“…The levels of NETosis initiation showed a significant correlation with platelet activation indicators and blood clotting-related factors ( 47 , 49 ). NETs components cause the degradation of TFPI via neutrophil elastase during thrombotic complications ( 49 ), thus activating the coagulation cascade TF pathway ( 50 ). The initiation of the intrinsic blood clotting mechanism occurs when NETs carrying a negative charge form a direct association with, and set into action, the coagulation factor FXII.…”

“…The initiation of the intrinsic blood clotting mechanism occurs when NETs carrying a negative charge form a direct association with, and set into action, the coagulation factor FXII. NETs additionally adhere to the Von Willebrand Factor (vWF), offering a foundation for platelets to attach ( 49 ). Complexes formed by NETs and platelets serve as frameworks that facilitate the attachment of other molecules promoting coagulation, like fibronectin and fibrinogen.…”

Coronavirus disease 2019 (COVID-19) pandemic and autoimmune rheumatic diseases: Outcomes and prospects

“…Однако данные, касающиеся генетических дефектов системы комплемента при COVID-19, пока отсутствуют. В то же время отмечена корреляция между формированием NЕTs (комплекс миелопероксидаза -ДНК), активацией комплемента и маркерами гиперкоагуляции при COVID-19 [216], а также с образованием циркулирующих иммунных комплексов (ЦИК) [217][218][219]. ЦИК, вызывающие FcγRIIIA/ CD16A активацию моноцитов, выявлены в сыворотках 80% пациентов с тяжелым COVID-19, а их уровень сопоставим с таковым при СКВ.…”

The Roles of Neutrophil-Derived Myeloperoxidase (MPO) in Diseases: The New Progress

“…In this review, we focus on the basic information of MPO and integrate extensive information about the relationship between MPO and its active reaction products and multiple diseases, hoping to provide a reference for the development of MPO-related biological targets. In addition, MPO was found to be relevant to the COVID-19 pandemic in the past three years [21][22][23][24]; therefore, the most recent information on the role of MPO in COVID-19 has also been included and discussed in detail in this review.…”