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A central role for amyloid fibrin microclots in long COVID/PASC: origins and therapeutic implications, Kell, Laubscher, Pretorius, 2022

Discussion in 'Long Covid research' started by SNT Gatchaman, Feb 23, 2022.

  1. SNT Gatchaman

    SNT Gatchaman Senior Member (Voting Rights)

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    A central role for amyloid fibrin microclots in long COVID/PASC: origins and therapeutic implications
    Douglas B. Kell, Gert Jacobus Laubscher and Etheresia Pretorius

    Post-acute sequelae of COVID (PASC), usually referred to as ‘Long COVID’ (a phenotype of COVID-19), is a relatively frequent consequence of SARS-CoV-2 infection, in which symptoms such as breathlessness, fatigue, ‘brain fog’, tissue damage, inflammation, and coagulopathies (dysfunctions of the blood coagulation system) persist long after the initial infection.

    It bears similarities to other post-viral syndromes, and to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Many regulatory health bodies still do not recognize this syndrome as a separate disease entity, and refer to it under the broad terminology of ‘COVID’, although its demographics are quite different from those of acute COVID-19.

    A few years ago, we discovered that fibrinogen in blood can clot into an anomalous ‘amyloid’ form of fibrin that (like other β-rich amyloids and prions) is relatively resistant to proteolysis (fibrinolysis). The result, as is strongly manifested in platelet-poor plasma (PPP) of individuals with Long COVID, is extensive fibrin amyloid microclots that can persist, can entrap other proteins, and that may lead to the production of various autoantibodies.

    These microclots are more-or-less easily measured in PPP with the stain thioflavin T and a simple fluorescence microscope.

    Although the symptoms of Long COVID are multifarious, we here argue that the ability of these fibrin amyloid microclots (fibrinaloids) to block up capillaries, and thus to limit the passage of red blood cells and hence O2 exchange, can actually underpin the majority of these symptoms.

    Consistent with this, in a preliminary report, it has been shown that suitable and closely monitored ‘triple’ anticoagulant therapy that leads to the removal of the microclots also removes the other symptoms. Fibrin amyloid microclots represent a novel and potentially important target for both the understanding and treatment of Long COVID and related disorders.

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    Edit: fixed full text link (removed expiring token)
     
    Last edited: Feb 24, 2022
  2. SNT Gatchaman

    SNT Gatchaman Senior Member (Voting Rights)

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    Selected quotes (minus refs)

     
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  3. SNT Gatchaman

    SNT Gatchaman Senior Member (Voting Rights)

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    However... as much as I like the hypothesis, it still remains to be proven that micro-clots are present in circulation (rather than being an in vitro artefact of hypercoagulation).
     
  4. Wyva

    Wyva Senior Member (Voting Rights)

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    I think someone asked about the conflict of interest a couple of weeks ago in another thread and what it really meant in this case, because it wasn't so clear. It seems clearer from this one:

    Competing Interests
    E.P. is a named inventor on a patent application covering the use of fluorescence methods for microclot detection in Long COVID.​
     
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  5. SNT Gatchaman

    SNT Gatchaman Senior Member (Voting Rights)

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    On the competing interests question: I don't personally see this as problematic. Surely it's simply a standard protective mechanism? I.e. to stop a bad actor coming along and patenting the technique and locking up its use by the inventors or any other scientist round the world.

    The authors seem very keen (to a fault on Twitter) that everyone use the technique to investigate Long Covid and there is no indication that there is any attempt to profit from this - currently or in the future.
     
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  6. cassava7

    cassava7 Senior Member (Voting Rights)

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    This may have been discussed elsewhere, but I do not understand why the symptoms of long Covid would not be observed in other diseases where the authors claim microclots have been found (bolding mine):
    More specifically, while the authors explain that SARS-CoV-2 is inductive to (micro)clotting, their proposed pathological mechanism for acute and long Covid does not seem specific to either condition. Wouldn’t it generally apply to other diseases in which microclots are found? (bolding mine)
    It should also be noted that their main hypothesis for the persistence of long Covid is two-fold:

    - viral persistence in immune-privileged reservoirs with occasional reactivation

    - continued release of inflammatory molecules and autoantibodies entrapped in microclots (see also Dr Pretorius’ tweet below)

    The authors cite Bruce Patterson’s findings on the persistence of the S1 spike protein in CD16+ monocytes in long Covid — the basis of his commercial “diagnostic” assay — as “highly relevant”, but these are from a small unreplicated study. (bolding mine)
    https://twitter.com/user/status/1546441544693174280


    Dr Pretorius’ tweet seems ambiguous with regards to the paper. The latter mentions that microclots preventing O2 supply to tissues is the cause of long Covid symptoms alone, but Dr Pretorius writes that the release of their contents as well as vascular pathology causes long Covid. I am not sure whether she meant that they cause the persistence of the condition or its symptoms.

    If the contents of the microclots explain the symptoms in part, and assuming that the said contents vary between diseases in which the microclots are found (e.g. type 2 diabetes and rheumatoid arthritis), this could presumably explain the differences with the symptoms of long Covid.

    However, in other diseases, microclots would still be blocking capillaries and causing some of the symptoms of LC unless their sizes and structures do not allow for it. These properties seem to vary among individuals and between diseases:
    But the authors argue that, in general, microclots are stiff and resistant and thus “strongly” prone to blocking capillaries:
    I am not sure what to make of all of this. Overall, the microclot theory is constituted of multiple hypotheses that are yet to be proven robustly. Independently, the diagnostic assay has been patented but no public and replicated data is available on its sensitivity and specificity for now. We will see what the ongoing research efforts from Dr Pretorius’ team yield.

    https://twitter.com/user/status/1546378184987475974
     
    Last edited: Jul 11, 2022
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  7. SNT Gatchaman

    SNT Gatchaman Senior Member (Voting Rights)

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  8. SNT Gatchaman

    SNT Gatchaman Senior Member (Voting Rights)

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    Now contradicted by —

    I guess it's possible the licence fee is merely nominal to maintain the patent, but yes that does rather overturn my initial claim.
     
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  9. cassava7

    cassava7 Senior Member (Voting Rights)

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  10. cassava7

    cassava7 Senior Member (Voting Rights)

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    Another question: if microclots are resistant to fibrinolysis, as Drs Pretorius and Kell argue, then they should forever persist in the body; how does fit in with the natural course of long Covid (and other post-viral syndromes), which in the vast majority of cases is self-remission after a few months or 1-2 year(s)?

    Going by Dr Pretorius’ tweet, a simple explanation would be that all of the “inflammatory molecules and antibodies” entrapped in microclots are eventually released and cleared. But the microclots themselves would still be present as they cannot be broken down. Depending on their sizes, they may still block capillaries and thus oxygen uptake in tissues, so some symptoms would persist (e.g. breathlessness) — this does not fit.

    It may be that the microclots lose some of their resistance over time and can eventually be broken down by fibrinolysis, but this raises the question of why some people do not recover from long Covid. Pretorius and Kell may counter-argue, based on the recent Harvard pre-print, that the spike protein of SARS-CoV-2 still circulates in the blood of some long-haulers and continuously drives the formation of new microclots. So it seems we are circling back to the start.

    Perhaps the conditions for long Covid recovery are the eventual clearances of:

    1) the spike protein from the blood, which may stop the formation of new microclots

    2) the remaining microclots — both their contents and the clots themselves, assuming they lose resistance over time and then get broken down by fibrinolysis.

    (Edit: I am referring two these two papers:

    https://www.s4me.info/threads/prepr...ute-covid-19-sequelae-2022-swank-et-al.28133/

    https://www.s4me.info/threads/amyloidogenesis-of-sars-cov-2-spike-protein-2022-nyström-hammarström.27708/)

    Once again, I am not sure what to make of it all.
     
    Last edited: Jul 17, 2022
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