Understanding the andromeda strain – The role of cytokine release, coagulopathy and antithrombin III in SARS-CoV2 critical illness

Mir, Nabiel; D'Amico, Alex; Dasher, John; Tolwani, Ashita J.; Valentine, Vincent G.

doi:10.1016/j.blre.2020.100731

Cited by 11 publications

(9 citation statements)

References 92 publications

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“…In our study, diabetes/stress hyperglycemia was associated with both inflammation and coagulopathy (elevated C reactive protein and D-dimer levels, mild prolongation of the prothrombin time and decreased antithrombin III), suggesting that an hyperglycaemia-related amplification of the pathobiological mechanisms of immunothrombosis [33] could be responsible of the increased thrombotic risk. The reduced activity of antithrombin III is of particular interest in this context [34]. In fact, antithrombin III is a powerful natural anticoagulant which is…”

Section: Discussionmentioning

confidence: 99%

Thromboembolism risk among patients with diabetes/stress hyperglycemia and COVID-19

et al. 2021

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This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Section: Discussionmentioning

confidence: 99%

Thromboembolism risk among patients with diabetes/stress hyperglycemia and COVID-19

et al. 2021

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“…Corticosteroids provide benefit in patients with hypoxia and more advanced lung disease but are only partially effective and are not recommended in early stages of COVID-19 (1)(2)(3)(4)23,24). Anticoagulants such as heparin have had variable benefit and there can be marked resistance in SARS-CoV-2 intensive care unit (ICU) admissions (25)(26)(27)(28). Targeted monoclonal antibodies against individual pro-inflammatory cytokines can also have limited therapeutic benefits.…”

Section: Introductionmentioning

confidence: 99%

Treatment with anti-inflammatory viral serpin modulates immuno-thrombotic responses and improves outcomes in SARS-CoV-2 infected mice

Zhang

Kibler

et al. 2022

Preprint

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Severe acute respiratory distress syndrome (ARDS) during SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2) infection, manifests as uncontrolled lung inflammation and systemic thrombosis with high mortality. Anti-viral drugs and monoclonal antibodies can reduce COVID-19 severity if administered in the early viremic phase, but treatments for later stage immuno-thrombotic syndrome and long COVID are limited. Serine protease inhibitors (SERPINS) regulate activated proteases during thrombotic, thrombolytic and immune responses. The myxoma poxvirus-derived Serp-1 protein is a secreted immunomodulatory serpin that targets activated coagulation and complement protease pathways as part of a self-defense strategy to combat viral clearance by the innate immune system. When purified and utilized as an anti-immune therapeutic, Serp-1 is effective as an anti-inflammatory drug in multiple animal models of inflammatory lung disease and vasculitis. Here, we describe systemic treatment with purified PEGylated Serp-1 (PEGSerp-1) as a therapy for immuno-thrombotic complications during ARDS. Treatment with PEGSerp-1 in two distinct mouse-adapted SARS-CoV-2 models in C57Bl/6 and BALB/c mice reduced lung and heart inflammation, with improved clinical outcomes. PEGSerp-1 significantly reduced M1 macrophage invasion in the lung and heart by modifying urokinase-type plasminogen activator receptor (uPAR) and complement membrane attack complex (MAC). Sequential changes in urokinase-type plasminogen activator receptor (uPAR) and serpin gene expression were observed in lung and heart with PEGSerp-1 treatment. PEGSerp-1 is a highly effective immune-modulator with therapeutic potential for treatment of severe viral ARDS with additional potential to reduce late SARS-CoV-2 complications related to immune-thrombotic events that persist during long COVID. Significance: Severe acute respiratory distress syndrome (ARDS) in SARS-CoV-2 infection manifests as uncontrolled tissue inflammation and systemic thrombosis with high mortality. Anti-viral drugs and monoclonal antibodies reduce COVID-19 severity if administered early, but treatments for later stage immuno-thrombosis are limited. Serine protease inhibitors (SERPINS) regulate thrombotic, thrombolytic and complement pathways. We investigate here systemic treatment with purified poxvirus-derived PEGSerp-1 as a therapeutic for immuno-thrombotic complications in viral ARDS. PEGSerp-1 treatment in two mouse-adapted SARS-CoV-2 models (C57Bl/6 and BALB/c) significantly reduced lung and heart inflammation and improved clinical outcomes, with sequential changes in thrombolytic (uPAR) and complement expression. PEGSerp-1 is a highly effective immune-modulator with therapeutic potential for immune-thrombotic complications in severe viral ARDS and has potential benefit for long COVID.

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“…In our study, diabetes was associated with both inflammation and coagulopathy (elevated C reactive protein and D-dimer levels, mild prolongation of the prothrombin time and decreased antithrombin III), suggesting that an hyperglycaemia-related amplification of the pathobiological mechanisms of immunothrombosis (32) could be responsible of the increased thrombotic risk. The reduced activity of antithrombin III is of particular interest in this context (33). In fact, antithrombin III is a powerful natural anticoagulant which is regulated by inflammation (34).…”

Section: Discussionmentioning

confidence: 99%

Thromboembolism risk among patients with diabetes/stress hyperglycemia and COVID-19

Stefania

Ramirez

Scavini

et al. 2021

Preprint

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Purpose. Individuals with diabetes carry an increased risk for adverse clinical outcome in case of SARS-CoV-2 infection. The purpose of this study was to evaluate whether this risk is, at least in part, modulated by an increase of thromboembolic complications. Methods. We prospectively followed 169 hospitalized patients with confirmed COVID-19 pneumonia admitted to the Internal Medicine Units of San Raffaele Hospital. We analysed inflammation and tissue damage biomarkers, hemostatic parameters, thrombotic events and clinical outcome according to the presence of hyperglycaemia or diagnosed diabetes. Results. Among 169 patients, 51 (30.2%) had diabetes. Diabetes and hyperglycemia were associated with increased inflammation and tissue damage circulating markers, higher D-dimer levels, increased prothrombin time and lower antithrombin III activity. Forty-eight venous and 10 arterial thrombotic events were identified in 49 (29%) patients. Diabetes (HR 2.71, p=0.001), fasting blood glucose (HR 4.32, p<0.001), glucose variability (HR 1.6, p < 0.009), presence of antiphospholipid antibodies (HR 4.18, p=0.033) and the positivity for virus spike protein antibodies (RBD IgG, HR 3.93, p=0.006; S1/S2 IgG, HR 3.36, p=0.027 and RBD IgA, HR 4.98, p=0.001) were all associated with an increased risk of thromboembolic complication. Thromboembolic complications significantly increased the risk for an adverse clinical outcome only in the presence of diabetes (HR 3.05, p=0.01) or hyperglycaemia (HR 3.07, p=0.015). Conclusions. Thromboembolism risk is higher among patients with diabetes and COVID-19 pneumonia and is associated to poor clinical outcome. In case of SARS-Cov-2 infection patients with diabetes could be considered for a more intensive prophylactic anticoagulation regimen.

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Understanding the andromeda strain – The role of cytokine release, coagulopathy and antithrombin III in SARS-CoV2 critical illness

Cited by 11 publications

References 92 publications

Thromboembolism risk among patients with diabetes/stress hyperglycemia and COVID-19

Thromboembolism risk among patients with diabetes/stress hyperglycemia and COVID-19

Treatment with anti-inflammatory viral serpin modulates immuno-thrombotic responses and improves outcomes in SARS-CoV-2 infected mice

Thromboembolism risk among patients with diabetes/stress hyperglycemia and COVID-19

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