Complement and COVID-19: Three years on, what we know, what we don't know, and what we ought to know

Zelek, Wioleta M.; Harrison, Richard A.

doi:10.1016/j.imbio.2023.152393

Cited by 21 publications

(7 citation statements)

References 289 publications

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“…Supportive care, antivirals/antibiotics. [7,9,10] DIC: disseminated intravascular coagulation; SIC: sepsis-induced coagulopathy; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; PCR: polymerase chain reaction; ARDS: acute respiratory distress syndrome; ACE2: angiotensin-converting enzyme 2; PT: prothrombin time; aPTT: activated partial thromboplastin time.…”

Section: Introductionmentioning

confidence: 99%

Pathophysiology of Disseminated Intravascular Coagulation in Sepsis: A Clinically Focused Overview

Unar,

Bertolino,

Patauner

et al. 2023

Cells

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Sepsis is a major global health problem that results from a dysregulated and uncontrolled host response to infection, causing organ failure. Despite effective anti-infective therapy and supportive treatments, the mortality rate of sepsis remains high. Approximately 30–80% of patients with sepsis may develop disseminated intravascular coagulation (DIC), which can double the mortality rate. There is currently no definitive treatment approach for sepsis, with etiologic treatment being the cornerstone of therapy for sepsis-associated DIC. Early detection, diagnosis, and treatment are critical factors that impact the prognosis of sepsis-related DIC. Over the past several decades, researchers have made continuous efforts to better understand the mechanisms of DIC in sepsis, as well as improve its quantitative diagnosis and treatment. This article aims to provide a comprehensive overview of the current understanding of sepsis-related DIC, focusing on common causes and diagnoses, with the goal of guiding healthcare providers in the care of patients with sepsis.

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Section: Introductionmentioning

confidence: 99%

Pathophysiology of Disseminated Intravascular Coagulation in Sepsis: A Clinically Focused Overview

Unar,

Bertolino,

Patauner

et al. 2023

Cells

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“…Here, the circulating mortalin should be regarded as a stress reporter rather than a tissue damage marker. Activation of the complement system has been described in COVID-19 patients and even implicated in the tissue damage evident in severely ill patients (7)(8)(9)(10). It is possible that some of the mortalin that is released from complementattacked cells in the patients' body reflects the affected tissue's attempt to repair the lytic damage and some is released from dying cells.…”

Section: Discussionmentioning

confidence: 99%

“…To date, several markers have been proposed for early detection of severe COVID-19. SARS-CoV-2 virus activates the complement system of the patients, leading to the accumulation of cleaved fragments of complement C3 and C5, C3a, and C5a in the patients' blood (7)(8)(9). Apparently, C3a and C5a play a significant role in triggering the cytokine storm and ARDS in the patients (8,(10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

“…Apparently, C3a and C5a play a significant role in triggering the cytokine storm and ARDS in the patients (8,(10)(11)(12). This has led to clinical trials targeting, for example, complement C5 with Ravulizumab and testing its effect on COVID-19-associated lung injuries and distress (7,13). Moreover, complement activation as well as increased levels of C3a and C5a were found to be associated with advanced disease severity (8,14).…”

Section: Introductionmentioning

confidence: 99%

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Circulating mortalin in blood and activation of the alternative complement pathway as risk indicators in COVID-19 infection

Avraham,

Sinkovits,

Hurler

et al. 2024

Front. Immunol.

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BackgroundMortalin/GRP75 is a ubiquitous mitochondrial chaperone related to the cytosolic heat shock protein 70. It protects cells from various types of damages and from senescence. Our goal was to determine whether COVID-19 patients have circulating mortalin in their blood and to assess its prognostic value in anticipating disease severity.MethodsMortalin was determined by ELISA in the sera of 83 COVID-19 patients enrolled in the study. Patients were categorized into 4 groups: critical patients who died (FATAL) or required intensive care and survived (ICU), patients of mild severity (hospitalized but not critical) who required nasal oxygen support (HOSP+O2), and patients who did not need oxygen therapy (HOSP).ResultsThe mortalin concentration in the serum of all COVID-19 patients in the cohort was 194-2324 pg/mL. A comparison of the mortalin levels by peak severity among the various patient groups showed a highly significant difference between the HOSP and FATAL groups and a significant difference between the HOSP and the ICU groups. COVID-19 patients who eventually failed to survive had at hospitalization a markedly higher level of mortalin in their sera. Cox regression analysis revealed a high mortality hazard (HR=3.96, p<0.01) in patients with high mortalin circulating levels (above the median, ≥651 pg/mL). This was confirmed in survival curve analysis (Kaplan-Meier; p=0.0032, log-rank test). Mortalin remained an independent predictor of mortality even after adjusting for age and sex or various complement activation products. Complement activation data collected in an earlier study in the same cohort was compared regarding the mortalin levels. Patients with higher circulating mortalin levels also had higher levels of complement C3a but reduced levels of properdin.DiscussionThis is the first report on circulating mortalin in COVID-19 patients. Higher mortalin levels were associated with more severe illnesses and a higher risk of death. We claim that quantifying the blood levels of mortalin and activated complement proteins will provide important information on the prognosis of COVID-19 patients and will serve as a useful tool for guiding their clinical management and treatment.

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“…PE has been reported in 26% of CAPS cases [101]. Dysregulation of complement activity has also been described in other autoimmune diseases, such as ANCA-associated vasculitides, and in non-autoimmune pathologies, such as severe COVID-19 and unprovoked VTE [102][103][104][105][106].…”

Section: Inhibition Of Complement Activationmentioning

confidence: 98%

Cutting-Edge Techniques and Drugs for the Treatment of Pulmonary Embolism: Current Knowledge and Future Perspectives

Falsetti,

Guerrieri,

Zaccone

et al. 2024

JCM

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Pulmonary embolism (PE) is a potentially life-threatening condition requiring prompt diagnosis and treatment. Recent advances have led to the development of newer techniques and drugs aimed at improving PE management, reducing its associated morbidity and mortality and the complications related to anticoagulation. This review provides an overview of the current knowledge and future perspectives on PE treatment. Anticoagulation represents the first-line treatment of hemodynamically stable PE, direct oral anticoagulants being a safe and effective alternative to traditional anticoagulation: these drugs have a rapid onset of action, predictable pharmacokinetics, and low bleeding risk. Systemic fibrinolysis is suggested in patients with cardiac arrest, refractory hypotension, or shock due to PE. With this narrative review, we aim to assess the state of the art of newer techniques and drugs that could radically improve PE management in the near future: (i) mechanical thrombectomy and pulmonary embolectomy are promising techniques reserved to patients with massive PE and contraindications or failure to systemic thrombolysis; (ii) catheter-directed thrombolysis is a minimally invasive approach that can be suggested for the treatment of massive or submassive PE, but the lack of large, randomized controlled trials represents a limitation to widespread use; (iii) novel pharmacological approaches, by agents inhibiting thrombin-activatable fibrinolysis inhibitor, factor Xia, and the complement cascade, are currently under investigation to improve PE-related outcomes in specific settings.

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Complement and COVID-19: Three years on, what we know, what we don't know, and what we ought to know

Cited by 21 publications

References 289 publications

Pathophysiology of Disseminated Intravascular Coagulation in Sepsis: A Clinically Focused Overview

Pathophysiology of Disseminated Intravascular Coagulation in Sepsis: A Clinically Focused Overview

Circulating mortalin in blood and activation of the alternative complement pathway as risk indicators in COVID-19 infection

Cutting-Edge Techniques and Drugs for the Treatment of Pulmonary Embolism: Current Knowledge and Future Perspectives

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