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[Preprint] SARS-CoV-2 spike protein induces abnormal inflammatory blood clots neutralized by fibrin immunotherapy, Ryu et al, 2021

Discussion in 'Long Covid research' started by SNT Gatchaman, May 5, 2022.

  1. SNT Gatchaman

    SNT Gatchaman Senior Member (Voting Rights)

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    SARS-CoV-2 spike protein induces abnormal inflammatory blood clots neutralized by fibrin immunotherapy (Non peer-reviewed)
    Jae Kyu Ryu, Elif G Sozmen, Karuna Dixit, Mauricio Montano, Yusuke Matsui, Yixin Liu, Ekram Helmy, Thomas J Deerinck, Zhaoqi Yan, Renaud Schuck, Rosa Meza Acevedo, Collin M Spencer, Reuben Thomas, Alexander R Pico, Scott S Zamvil, Kara L Lynch, Mark H Ellisman, Warner C Greene, Katerina Akassoglou

    Abstract
    Blood clots are a central feature of coronavirus disease-2019 (COVID-19) and can culminate in pulmonary embolism, stroke, and sudden death. However, it is not known how abnormal blood clots form in COVID-19 or why they occur even in asymptomatic and convalescent patients. Here we report that the Spike protein from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to the blood coagulation factor fibrinogen and induces structurally abnormal blood clots with heightened proinflammatory activity. SARS-CoV-2 Spike virions enhanced fibrin-mediated microglia activation and induced fibrinogen-dependent lung pathology. COVID-19 patients had fibrin autoantibodies that persisted long after acute infection. Monoclonal antibody 5B8, targeting the cryptic inflammatory fibrin epitope, inhibited thromboinflammation. Our results reveal a procoagulant role for the SARS-CoV-2 Spike and propose fibrin-targeting interventions as a treatment for thromboinflammation in COVID-19.

    One-sentence summary
    SARS-CoV-2 spike induces structurally abnormal blood clots and thromboinflammation neutralized by a fibrin-targeting antibody.

    Link | PDF
     
  2. SNT Gatchaman

    SNT Gatchaman Senior Member (Voting Rights)

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    This paper does not relate to the amyloid fibrin(-ogen) / microclot findings, and in fact does not reference those papers.

    Selected quotes —

    Background

    Findings

    Conclusions

     
  3. Trish

    Trish Moderator Staff Member

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    Assuming this research is accurate, this seems like a pretty significant finding.
    What I don't understand is why it causes major, even deadly, clotting in some individuals, and seemingly has no ongoing ill effect in others.
     
  4. SNT Gatchaman

    SNT Gatchaman Senior Member (Voting Rights)

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    It could be a matter of degree of fibrinolytic imbalance. Alternatively or additionally other factors such as the degree of endothelitis and platelet activation may come to bear.

    From my personal experience, I've observed that I have been clearly hypercoagulable: either by clotting blood tubing during phlebotomy or looking at thromboelastography (or in vitro fluorescing microclots). However, routine coagulation tests have remained steadfastly normal. <touches wood, non-scientifically> Despite this I haven't had any observable macrothrombotic issues.

    Related to "all tests are normal", one thing I've been considering is the possibility that clinical fibrinogen assays are reading incorrectly in me and other LC (±ME) patients. The assay indirectly quantifies fibrinogen by seeing how long it takes for fibrinogen to form a fibrin clot (the Clauss method).

    We know that glycated fibrinogen makes poorer clots and hyperglycaemic patients will read erroneously low on this test.

    If fibrinogen in LC is similarly defective and/or abnormally glycated due to associated metabolic derangements, then it might too read artificially low.

    This might be a more accurate indicator of hyperfibrinoginaemia and would complement (pun intended) this paper's and others' findings.

    See:
    1. Fibrinogen Glycation and Presence of Glucose Impair Fibrin Polymerization—An In Vitro Study of Isolated Fibrinogen and Plasma from Patients with Diabetes Mellitus (2020)
    2. Glucose Concentration Affects Fibrin Clot Structure and Morphology as Evidenced by Fluorescence Imaging and Molecular Simulations (2018)
    3. Determinants of Increased Fibrinogen in COVID-19 Patients With and Without Diabetes and Impaired Fasting Glucose (2021)
     
  5. SNT Gatchaman

    SNT Gatchaman Senior Member (Voting Rights)

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    Just to note that despite this paper being in pre-print, the same authors published in Nature in 2018 where they covered some of the same (non spike-related) ground:
    Fibrin-targeting immunotherapy protects against neuroinflammation and neurodegeneration

    Abstract
    Activation of innate immunity and deposition of blood-derived fibrin in the central nervous system (CNS) occur in autoimmune and neurodegenerative diseases, including multiple sclerosis (MS) and Alzheimer’s disease (AD). However, the mechanisms that link disruption of the blood–brain barrier (BBB) to neurodegeneration are poorly understood, and exploration of fibrin as a therapeutic target has been limited by its beneficial clotting functions.

    Here we report the generation of monoclonal antibody 5B8, targeted against the cryptic fibrin epitope γ377–395, to selectively inhibit fibrin-induced inflammation and oxidative stress without interfering with clotting. 5B8 suppressed fibrin-induced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation and the expression of proinflammatory genes. In animal models of MS and AD, 5B8 entered the CNS and bound to parenchymal fibrin, and its therapeutic administration reduced the activation of innate immunity and neurodegeneration.

    Thus, fibrin-targeting immunotherapy inhibited autoimmunity- and amyloid-driven neurotoxicity and might have clinical benefit without globally suppressing innate immunity or interfering with coagulation in diverse neurological diseases.
     
  6. Boba

    Boba Established Member

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  7. SNT Gatchaman

    SNT Gatchaman Senior Member (Voting Rights)

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    I'm with you on this question. The IBS biopsy findings certainly found remnant viral elements that included spike protein.

    These aren't replication-competent whole virions that they have found. But the cells contain spike protein - which could be exocytosed. More importantly if there is RNA and RNA polymerase, the cell could make more RNA and more spike protein (cf mRNA vaccines which - in theory - make a limited amount of spike).

    SARS-CoV-2 is a positive-sense, single-stranded RNA virus. Being positive-sense, its RNA acts like mRNA and can directly interact with a cell's ribosomes to make proteins. So I'm assuming it could make spike protein which could be discharged from the cell and enter blood vessels.

    So could gut mucosal cells continue to produce spike proteins, which reach the blood vessels and pathologically interact with fibrinogen? How long would this last? Surely not indefinitely, as the mucosal cells will be turned over eventually.

    Nevertheless, from the Austrian IBD biopsy paper —

     
  8. Snow Leopard

    Snow Leopard Senior Member (Voting Rights)

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    Because in some people, the virus gets a much stronger foothold before the adaptive immune response kicks in. The big spill-over of all of the virion/spike protein doesn't occur until things are already very bad.

    Some of which were suggested from the very start (due to research on SARS and other Coronaviruses). Namely the suppression of type I interferon responses of infected cells and syncitia of the cells lining the respiratory tract. This evasion of the immune system is likely the reason why the virus is more deadly for older men in particular.
     
  9. SNT Gatchaman

    SNT Gatchaman Senior Member (Voting Rights)

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    That presumably relates to acute, severe disease — in esp older men. But then there are those previously young and fit, esp female, with truly mild or even asymptomatic infection, who weeks or months down the line are going on to massive PE, stroke, MI etc. However, many (like me) are not having those severe post-acute venous or arterial thrombotic outcomes.

    If glycated fibrinogen makes poor clots [1, 2] then perhaps fibrinogen+spike might also be less effective and macrothrombogenic. Perhaps from a purely coagulation viewpoint, it's "OK" to have this abnormal fibrinogen circulating around for most people. However it may be doing bad things to inflammation, autoantibodies, metabolism etc while only causing major thromboembolic disease in a minority.

    1. Fibrinogen Glycation and Presence of Glucose Impair Fibrin Polymerization—An In Vitro Study of Isolated Fibrinogen and Plasma from Patients with Diabetes Mellitus (2020)
    2. Glucose Concentration Affects Fibrin Clot Structure and Morphology as Evidenced by Fluorescence Imaging and Molecular Simulations (2018)
    3. Determinants of Increased Fibrinogen in COVID-19 Patients With and Without Diabetes and Impaired Fasting Glucose (2021)
     
  10. Snow Leopard

    Snow Leopard Senior Member (Voting Rights)

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    The mechanism for that is likely different (autoimmunity, or unknown pre-conditions) and also cannot be explained simply by a generic pro-thombotic mechanism like that described in the pre-print.
     
    FMMM1 likes this.
  11. SNT Gatchaman

    SNT Gatchaman Senior Member (Voting Rights)

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    Peter Trewhitt and Trish like this.

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