Thromboinflammation Supports Complement Activation in Cancer Patients With COVID-19

Abstract

BackgroundCOVID-19 pathology is associated with exuberant inflammation, vascular damage, and activation of coagulation. In addition, complement activation has been described and is linked to disease pathology. However, few studies have been conducted in cancer patients.ObjectiveThis study examined complement activation in response to COVID-19 in the setting of cancer associated thromboinflammation.MethodsMarkers of complement activation (C3a, C5a, sC5b-9) and complement inhibitors (Factor H, C1-Inhibitor) were evaluated in plasma of cancer patients with (n=43) and without (n=43) COVID-19 and stratified based on elevated plasma D-dimer levels (>1.0 μg/ml FEU). Markers of vascular endothelial cell dysfunction and platelet activation (ICAM-1, thrombomodulin, P-selectin) as well as systemic inflammation (pentraxin-3, serum amyloid A, soluble urokinase plasminogen activator receptor) were analyzed to further evaluate the inflammatory response.ResultsIncreases in circulating markers of endothelial cell dysfunction, platelet activation, and systemic inflammation were noted in cancer patients with COVID-19. In contrast, complement activation increased in cancer patients with COVID-19 and elevated D-dimers. This was accompanied by decreased C1-Inhibitor levels in patients with D-dimers > 5 ug/ml FEU.ConclusionComplement activation in cancer patients with COVID-19 is significantly increased in the setting of thromboinflammation. These findings support a link between coagulation and complement cascades in the setting of inflammation.

Targeting thromboinflammation in COVID-19 – A narrative review of the potential of C1 inhibitor to prevent disease progression

“…In line, modified (cleaved) C1-INH was previously identified in severe sepsis patients which rendered C1-INH inactive again promoting a relative C1-INH deficiency ( Nuijens et al, 1989 ). Consistent with this hypothesis, C1-INH activity correlated negatively with D-dimer levels in COVID-19 patients ( Peerschke et al, 2021 ). Given the formation of 1:1 complexes between C1-INH and respective proteases, C1-INH concentrations are insufficient to inhibit all target proteases in any of the plasmatic cascades even at a resting state ( Peoples and Strang, 2021 ).…”

“…C1-INH concentrations on admission correlated with inflammatory markers including their peak value but were also not associated with COVID-19 outcome ( Charitos et al, 2021 ). C1-INH activity was also elevated in hospitalized COVID-19 cancer patients compared to healthy controls ( Peerschke et al, 2021 ). In a proteomic analysis of sera, C1-INH expression was found to be significantly upregulated in severe vs. non-severe COVID-19 patients but also in COVID-19 compared to control individuals ( Hausburg et al, 2021 , Shen et al, 2020 ).…”

Prognostic significance of complement factors in severely ill patients with COVID-19

“…The association between complement activation and elevated D-dimer levels was reported in patients with COVID-19 and was related to the associated state of exaggerated thromboinflammation 22. Also, complement activation was associated with higher fibrinogen levels in those patients 23…”

Network Pharmacology and Bioinformatics Analysis Identifies Potential Therapeutic Targets of Paxlovid Against LUAD/COVID-19

“…By means of network pharmacology, The enrichment analysis of target genes showed that functions or pathways such as COVID-19, Complement and coagulation cascades, and IL-17 signaling pathway were more active. Evidence shows that patients with mild COVID-19 significantly increase complement activation and help control viral infection ( 45 ). But when it becomes severe, the massive activation of complement can exacerbate lung and systemic inflammation, and promote coagulation and thrombosis ( 46 ).…”