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      SARS-CoV-2 spike protein S1 induces fibrin(ogen) resistant to fibrinolysis: implications for microclot formation in COVID-19


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          Severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2)-induced infection, the cause of coronavirus disease 2019 (COVID-19), is characterized by unprecedented clinical pathologies. One of the most important pathologies, is hypercoagulation and microclots in the lungs of patients. Here we study the effect of isolated SARS-CoV-2 spike protein S1 subunit as potential inflammagen sui generis. Using scanning electron and fluorescence microscopy as well as mass spectrometry, we investigate the potential of this inflammagen to interact with platelets and fibrin(ogen) directly to cause blood hypercoagulation. Using platelet-poor plasma (PPP), we show that spike protein may interfere with blood flow. Mass spectrometry also showed that when spike protein S1 is added to healthy PPP, it results in structural changes to β and γ fibrin(ogen), complement 3, and prothrombin. These proteins were substantially resistant to trypsinization, in the presence of spike protein S1. Here we suggest that, in part, the presence of spike protein in circulation may contribute to the hypercoagulation in COVID-19 positive patients and may cause substantial impairment of fibrinolysis. Such lytic impairment may result in the persistent large microclots we have noted here and previously in plasma samples of COVID-19 patients. This observation may have important clinical relevance in the treatment of hypercoagulability in COVID-19 patients.

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          Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein

          Summary The emergence of SARS-CoV-2 has resulted in >90,000 infections and >3,000 deaths. Coronavirus spike (S) glycoproteins promote entry into cells and are the main target of antibodies. We show that SARS-CoV-2 S uses ACE2 to enter cells and that the receptor-binding domains of SARS-CoV-2 S and SARS-CoV S bind with similar affinities to human ACE2, correlating with the efficient spread of SARS-CoV-2 among humans. We found that the SARS-CoV-2 S glycoprotein harbors a furin cleavage site at the boundary between the S1/S2 subunits, which is processed during biogenesis and sets this virus apart from SARS-CoV and SARS-related CoVs. We determined cryo-EM structures of the SARS-CoV-2 S ectodomain trimer, providing a blueprint for the design of vaccines and inhibitors of viral entry. Finally, we demonstrate that SARS-CoV S murine polyclonal antibodies potently inhibited SARS-CoV-2 S mediated entry into cells, indicating that cross-neutralizing antibodies targeting conserved S epitopes can be elicited upon vaccination.
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            Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19

            Progressive respiratory failure is the primary cause of death in the coronavirus disease 2019 (Covid-19) pandemic. Despite widespread interest in the pathophysiology of the disease, relatively little is known about the associated morphologic and molecular changes in the peripheral lung of patients who die from Covid-19.
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              Extrapulmonary manifestations of COVID-19

              Although COVID-19 is most well known for causing substantial respiratory pathology, it can also result in several extrapulmonary manifestations. These conditions include thrombotic complications, myocardial dysfunction and arrhythmia, acute coronary syndromes, acute kidney injury, gastrointestinal symptoms, hepatocellular injury, hyperglycemia and ketosis, neurologic illnesses, ocular symptoms, and dermatologic complications. Given that ACE2, the entry receptor for the causative coronavirus SARS-CoV-2, is expressed in multiple extrapulmonary tissues, direct viral tissue damage is a plausible mechanism of injury. In addition, endothelial damage and thromboinflammation, dysregulation of immune responses, and maladaptation of ACE2-related pathways might all contribute to these extrapulmonary manifestations of COVID-19. Here we review the extrapulmonary organ-specific pathophysiology, presentations and management considerations for patients with COVID-19 to aid clinicians and scientists in recognizing and monitoring the spectrum of manifestations, and in developing research priorities and therapeutic strategies for all organ systems involved.

                Author and article information

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                Role: Data curationRole: Project administration
                Role: SoftwareRole: Formal analysisRole: Investigation
                Role: Methodology
                Role: Writing—review and editing
                Role: Writing—review and editing
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                Biosci Rep
                Biosci Rep
                Bioscience Reports
                Portland Press Ltd.
                27 August 2021
                20 August 2021
                : 41
                : 8
                : BSR20210611
                [1 ]Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Stellenbosch, Private Bag X1, Matieland 7602, South Africa
                [2 ]Central Analytical Facility: Mass Spectrometry Stellenbosch University, Tygerberg Campus, Room 6054, Clinical Building, Francie van Zijl Drive, Tygerberg, Cape Town 7505, South Africa
                [3 ]Department of Mechanical Engineering, Faculty of Engineering and the Built Environment, University of Cape Town, Cape Town, Rondebosch 7701, South Africa
                [4 ]Stellenbosch Institute for Advanced Study, Wallenberg Research Centre, Stellenbosch University, Stellenbosch, South Africa
                [5 ]Private practice clinician, Mediclinic Stellenbosch, Stellenbosch 7600, South Africa
                [6 ]PathCare Laboratories, PathCare Business Centre, PathCare Park, Neels Bothma Street, N1 City 7460, South Africa
                [7 ]Department of Biochemistry and Systems Biology, Institute of Systems, Molecular and Integrative Biology, Faculty of Health and Life Sciences, University of Liverpool, Liverpool L69 7ZB, U.K.
                [8 ]The Novo Nordisk Foundation Centre for Biosustainability, Technical University of Denmark, Kemitorvet 200, Kgs Lyngby 2800, Denmark
                Author notes
                Correspondence: Etheresia Pretorius ( resiap@ 123456sun.ac.za ) or Douglas B. Kell ( dbk@ 123456liv.ac.uk )
                Author information
                © 2021 The Author(s).

                This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY). Open access for this article was enabled by the participation of University of Liverpool in an all-inclusive Read & Publish pilot with Portland Press and the Biochemical Society under a transformative agreement with JISC.

                : 12 March 2021
                : 13 July 2021
                : 29 July 2021
                : 30 July 2021
                Page count
                Pages: 17
                Diagnostics & Biomarkers
                Immunology & Inflammation
                Molecular Interactions
                Research Articles

                Life sciences
                covid-19,electron microscopy,fibrin(ogen),fluorescence microscopy,microclot,spike protein sa


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