The roles and potential therapeutic implications of C5a in the pathogenesis of COVID-19-associated coagulopathy

Li, Jing; Liu, Bin

doi:10.1016/j.cytogfr.2020.12.001

Cited by 11 publications

(10 citation statements)

References 72 publications

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“…110 In the end, the interplay between the inflammatory, coagulation, complement and endothelial systems in COVID-19 may account for the ensuing CV complications. 111,112 COVID-19induced inflammation may involve primary vessel inflammation, possible sepsis and a secondary reaction to tissue damage caused by the virus, leading to generation and release of inflammatory mediators. 113 In addition to acute lung injury and multi-organ failure, a cytokine storm, typically associated with concurrent serum ferritin rises and hemodynamic instability, may also lead to vascular damage.…”

Section: Acute Cardiac Injurymentioning

confidence: 99%

COVID-19 and Acute Myocardial Injury and Infarction: Related Mechanisms and Emerging Challenges

Manolis¹,

Manolis

et al. 2021

J Cardiovasc Pharmacol Ther

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In the era of the coronavirus disease 2019 (COVID-19) pandemic, acute cardiac injury (ACI), as reflected by elevated cardiac troponin above the 99th percentile, has been observed in 8%-62% of patients with COVID-19 infection with highest incidence and mortality recorded in patients with severe infection. Apart from the clinically and electrocardiographically discernible causes of ACI, such as acute myocardial infarction (MI), other cardiac causes need to be considered such as myocarditis, Takotsubo syndrome, and direct injury from COVID-19, together with noncardiac conditions, such as pulmonary embolism, critical illness, and sepsis. Acute coronary syndromes (ACS) with normal or near-normal coronary arteries (ACS-NNOCA) appear to have a higher prevalence in both COVID-19 positive and negative patients in the pandemic compared to the pre-pandemic era. Echocardiography, coronary angiography, chest computed tomography and/or cardiac magnetic resonance imaging may render a correct diagnosis, obviating the need for endomyocardial biopsy. Importantly, a significant delay has been recorded in patients with ACS seeking advice for their symptoms, while their routine care has been sharply disrupted with fewer urgent coronary angiographies and/or primary percutaneous coronary interventions performed in the case of ST-elevation MI (STEMI) with an inappropriate shift toward thrombolysis, all contributing to a higher complication rate in these patients. Thus, new challenges have emerged in rendering a diagnosis and delivering treatment in patients with ACI/ACS in the pandemic era. These issues, the various mechanisms involved in the development of ACI/ACS, and relevant current guidelines are herein reviewed.

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Section: Acute Cardiac Injurymentioning

confidence: 99%

COVID-19 and Acute Myocardial Injury and Infarction: Related Mechanisms and Emerging Challenges

Manolis¹,

Manolis

et al. 2021

J Cardiovasc Pharmacol Ther

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“…9 Thus, complement and complement-regulated pathways have immense potential and pharmacological value for therapeutic intervention. 10 Therapeutic intervention of the C5a−C5aR1 system 11 usually involves the following strategies: (i) block the ECS of C5aR1, (ii) block the generation of C5a, and (iii) block or neutralize the C5a. 12−15 Large-scale mutagenesis and biomolecular signaling data evidence that the nanomolar to picomolar potency of C5a toward C5aR1 16 is due to the recruitment of two distal sites with large surface areas, respectively, engaging (i) the NT-peptide (Site1) and (ii) ECS of C5aR1 (Site2) with the core and the C-terminus (CT) peptide of C5a through a specific protein−protein interaction.…”

Section: Introductionmentioning

confidence: 99%

“…Dysregulated complement accentuates the C5a–C5aR1 interaction in several tissues leading to several chronic inflammation-induced diseases, such as asthma, lung injury, kidney failure, rheumatoid arthritis, cardiovascular complications, multiorgan failure, and sepsis, including the most recent pandemic COVID-19 . Thus, complement and complement-regulated pathways have immense potential and pharmacological value for therapeutic intervention …”

Section: Introductionmentioning

confidence: 99%

Interaction of Human C5a with the Major Peptide Fragments of C5aR1: Direct Evidence in Support of “Two-Site” Binding Paradigm

2021

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The C5a receptor’s (C5aR1) physiological function in various tissues depends on its high-affinity binding to the cationic proinflammatory glycoprotein C5a, produced during the activation of the complement system. However, an overstimulated complement can quickly alter the C5a–C5aR1 function from physiological to pathological, as has been noted in the case of several chronic inflammation-induced diseases like asthma, lung injury, multiorgan failure, sepsis, and now COVID-19. In the absence of the structural data, the current study provides the confirmatory biophysical validation of the hypothesized “two-site” binding interactions of C5a, involving (i) the N-terminus (NT) peptide (“Site1”) and (ii) the extracellular loop 2 (ECL2) peptide of the extracellular surface (ECS) of the C5aR1 (“Site2”), as illustrated earlier in the reported model structural complex of C5a–C5aR1. The biophysical and computational data elaborated in the study provides an improved understanding of the C5a–C5aR1 interaction at an atomistic resolution, highlighting the energetic importance of the aspartic acids on the NT-peptide of C5aR1 toward binding of C5a. The current study can potentially advance the search and optimization of new-generation alternative “antibodies” as well as “neutraligands” targeting the C5a to modulate its interaction with C5aR1.

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“…C5a-mediated activation of endothelial C5aR1 induces TF production [239] . Three clinical trials have been registered for eculizumab, a complement C5 inhibitor, as a treatment for patients with COVID-19 ( ClinicalTrials.gov Identifiers: NCT04288713 , NCT04346797 , and NCT04355494 ) [240] , [241] . Recently, a combination of ruxolitinib (a JAK1/2 inhibitor) and eculizumab was administered to severely ill COVID-19 patients with a hypercoagulable state and ARDS.…”

Section: Complement Activation and Tf In Covid-19mentioning

confidence: 99%

Tissue factor in COVID-19-associated coagulopathy

Subramaniam

Kothari²,

Bosmann³

2022

Thrombosis Research

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The roles and potential therapeutic implications of C5a in the pathogenesis of COVID-19-associated coagulopathy

Cited by 11 publications

References 72 publications

COVID-19 and Acute Myocardial Injury and Infarction: Related Mechanisms and Emerging Challenges

COVID-19 and Acute Myocardial Injury and Infarction: Related Mechanisms and Emerging Challenges

Interaction of Human C5a with the Major Peptide Fragments of C5aR1: Direct Evidence in Support of “Two-Site” Binding Paradigm

Tissue factor in COVID-19-associated coagulopathy

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