Persistent clotting protein pathology in Long COVID/PASC is accompanied by increased levels of antiplasmin, 2021, Pretorius et al

Discussion in 'Long Covid research' started by Sly Saint, Oct 5, 2021.

  1. Fizzlou

    Fizzlou Senior Member (Voting Rights)

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    MEAssociation Facebook have a thread and a few interesting comments coming up.
    As with all ME avenues it may work for some and not others but fed up of waiting for a universal (without risk) treatment.
     
  2. Fizzlou

    Fizzlou Senior Member (Voting Rights)

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    (Full tweet in image)

    Amy Proal (I assume that the ‘we’ means Polybio) is helping Professor Pretorius with a plan to look at hyper coagulation in MECFS and have submitted a grant. This was retweeted by Pretorius
     

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  3. SNT Gatchaman

    SNT Gatchaman Senior Member (Voting Rights)

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    I just looked back at my allegedly "normal" blood tests from my first hospital admission in Jan 2021. (This was probably my first POTS/ME crash after slowly going off from my usual healthy self over Nov/Dec 2020).

    The normal reference range for SvO2 is 60-80% (70% if it were taken from the internal jugular vein). Mine was from my right antecubital fossa.

    22%

    Dr. Asad Khan's was 33%. Pffft - those are amateur numbers... :cool:

    If this could be at least a bio-marker for a subset... We're going to see if we could run this test on all our long Covid and ME/CFS patients here in NZ. We don't have many LC yet (but Delta is uncontained now, so they're coming).

    Venous Blood Gas.jpeg
     
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  4. Hutan

    Hutan Moderator Staff Member

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    The Pretorius study is interesting - I'm trying to understand it. I haven't read the whole paper yet.

    They looked at the blood of
    • healthy volunteers (13)
    • people with acute Covid (15)
    • people with type 2 diabetes (10)
    • patients with Long Covid (11)
    The definition of Long Covid was
    2 months is a pretty short time, especially as some of these patients were very sick with acute Covid-19 (6 were hospitalised and given oxygen, one of those was on a ventilator). Maybe some of the symptoms attributed to Long Covid are really just the result of recovering from having a significant illness?

    And they did not look at the blood of people who recovered from Covid-19 and who do not have Long Covid symptoms. So, we can't be sure that anything that is found in the Long Covid patients would not also be found in other people who had Covid-19 not long ago and don't have ongoing symptoms.




    In the results section there is a section about
    Platelet poor plasma (PPP): Amyloid fibrin(ogen) protein and anomalous clotting in platelet poor plasma samples, before and after two trypsin digestion protocols

    They say that they have previously shown that platelet poor plasma from healthy controls and type 2 diabetes patients have significantly less 'anomalous Microclots' than that from people with Covid-19. They use a marker, thioflavin, to bind to the clots. And they say that they have found that people with Long Covid have a similar amount of microclots as the people with acute Covid-19.

    So in Figure 3, they are looking at platelet poor plasma (PPP) before trypsin was added to digest the microclots. Pictures A and B are from one individual who donated a blood sample when healthy, and then went on to get Covid-19 and developed Long Covid symptoms. And C is pictures from other Long Covid patients.

    Screen Shot 2021-10-28 at 6.59.43 PM.png

    Screen Shot 2021-10-28 at 7.00.09 PM.png


    Then, they add trypsin, to, they say, 'digest', the microclots. And that seems to work in the platelet poor serum of the controls and diabetes patients (Pictures A and B in Figure 4). But it doesn't work in platelet poor serum of the Covid-19 patients (Pictures C in Figure 4), or of the Long Covid patients (Figure 5).
    Screen Shot 2021-10-28 at 7.36.41 PM.png




    Screen Shot 2021-10-28 at 7.00.51 PM.png Screen Shot 2021-10-28 at 7.01.09 PM.png
     
    Last edited: Oct 28, 2021
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  5. Hutan

    Hutan Moderator Staff Member

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    So, then the authors go on to look at what is in these resistant clots. They applied trypsin again, this time successfully digesting the clots. And then they looked for proteins in the dissolved clot liquid. Table 1 is interesting - they certainly found significant differences between the proteins of the Covid-19, Long Covid and control samples. They reported the results as fold changes (so 1 means the same amount, 2 means twice the amount). All of the differences have p-values indicating very good significance.

    Between acute Covid -19 and control samples
    Von Willebrand Factor - 4.5 x control level
    Complement component C4b - 4.2 x control level
    C-reactive protein - 18.7 x control level

    Between Long Covid and Control samples
    Von Willebrand Factor - 10.2 x control level
    Complement component C4b - not in the table
    C-reactive protein - 11.2 x control level
    Coagulation factor XIII A chain - 6.9 x control level
    Plasminogen - 3 x control level
    Fibrinogen alpha chain - 4.1 x control level
    a2 Antiplasmin (a2AP) - 8.0 x control level
    Serum Amyloid (SAA4) - 17.5 x control level
    Complement component C7 - 20 x control level

    Between Long Covid and acute Covid-19 samples
    Plasminogen - 2.3 x acute Covid-19 level
    Fibrinogen beta chain - 2.8 x acute Covid-19 level
    Coagulation factor XIII B - 2.7 x acute Covid-19 level
    Fibrinogen alpha chain - 3.1 x acute Covid-19 level
    Complement component C6 - 7.5 x acute Covid-19 level
    a2 Antiplasmin (a2AP) - 9.2 x acute Covid-19 level
    Complement factor 1 - 25 x acute Covid-19 level

    This looks pretty interesting to me. It's not often we see really big, statistically valid differences. I really want to see this study replicated, looking at Long Covid (>6 months) versus controls who have had Covid-19 about the same number of months ago. And of course in ME/CFS too.
     

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  6. Hutan

    Hutan Moderator Staff Member

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    The other thing the authors talk about is
    Platelet pathology as viewed with fluorescence microscopy

    They say that they and others have found that platelets are hyperactivated in type 2 diabetes. And that they have recently found this hyperactivation in acute Covid-19.

    They say that they have found the same in Long Covid. Not only are the platelets activated, but they are also clumping.

    An activated platelet seems to be one that is doing what needs to be done when there is a wound: forming a clot to stop the bleeding. The authors used two different fluorescent markers that attach to the surface of the platelet when it is activated.

    Figure 2 gives some images. A and B are controls; C and D are Covid-19; E, F G and H are all Long Covid. all of the pictures are at the same level of magnification.


    Screen Shot 2021-10-28 at 11.41.51 PM.png

    In the discussion, the authors mention Von Willebrand Factor (VWF) as causing the activation. VWF seems to act specifically to cause the platelet to stick to the wall of a blood vessel.

    So, the authors suggest there are two things going on:
    1. the hyper-activation and clumping of the platelets, and
    2. as discussed in the previous two posts, the amyloid microclots
     
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  7. Fizzlou

    Fizzlou Senior Member (Voting Rights)

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    A Facebook group exists -Patient initiative Apheresis for long covid

    This group seems to be run by a successfully treated Long Hauler and has the purpose of sharing on the ground information from the clinic in Germany. Dr Asad Khan is a member of this group. They also use the Telegram Messenger App, link available through the group. PwME are on the group and are welcomed by admins.

    Lots of hype and with lots of self funders data is emerging fast. Excitement is high but I feel very cautious and suspicious of the positivity so early on, especially for a treatment that will cost patients 1300-18200 Euros (1-14 sessions depending on need). Papers and materials are all referenced through the page and their website but there's not a lot. This treatment is routinely used in other conditions including a form of sudden hearing loss and cardiac problems.

    That said there's a lot of papers out there on fibrinogen in neurological disease, microglial activation etc. The whole concept of hyper-coagulation makes sense to me so I'm just watching for now. (BTW: I was diagnosed with Von Willebrandts disease as a child, quite a common condition, so i didn't clot too well. Bleeding problems eased as an adult. My plasma viscosity is now in the very high range.)

    Imformation gleaned from the website, facebook page, videos and messenger app:

    • 3 centers (S Africa, San Francisco and Germany) have published papers on this.
    • Long haulers can email the German Clinic to go on a list (a clinic starting in Cyprus soon under the umbrella of the German one)
    • Around 150 patients have been treated.
    • "50-60% full recovery, 30-40% partial, 5-10% little response" (Approximation from admin)
    • No biomarker required to access facilities. Dr Khan had normal range Fibrinogen and D Dimer coagulation tests.
    • Venous O2 saturation and plasma viscosity may be better indicators
    • Professor Pretorius has a device patent for a biomarker.
    • Health insurers in Germany are starting to embrace funding for patients
    • 20 German health clinics are cooperating to the effort.

    Professor Carmen Scheibenbogen talked about this in a recent Solve ME webinar. Efforts in place to study MECFS too.
    Patients seem to go on heparin treatment or similar beforehand.
     
  8. Hubris

    Hubris Senior Member (Voting Rights)

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    I mean, this seems huge, compared to what we're used to seeing in ME/CFS research. 20 clinics just in Germany cooperating together administering expensive IV treatment is not something you see often. 50-60% full recovery out of 150 patients? Of course we don't know if it actually works until it gets replicated in a controlled environment but what does @Jonathan Edwards think of this HELP Apheresis treatment? Is this realistic/promising, is the theory sound (also applying to ME/CFS?) or are there red flags?
     
    Last edited: Oct 30, 2021
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  9. Perrier

    Perrier Senior Member (Voting Rights)

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    Would you be able to give a link to this Facebook page please. When I type in MEAssociation about 10 organisations turn up. Also, please include the one for Aphaeresis. Thank you.
     
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  10. Fizzlou

    Fizzlou Senior Member (Voting Rights)

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  11. Hoopoe

    Hoopoe Senior Member (Voting Rights)

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  12. Hoopoe

    Hoopoe Senior Member (Voting Rights)

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    @Jonathan Edwards what's your opinion on this study and on the idea that it could be applicable to ME?

    Are these microclots a possible explanation for the metabolic and blood flow abnormalities and the exertion intolerance?
     
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  13. Hutan

    Hutan Moderator Staff Member

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  14. SNT Gatchaman

    SNT Gatchaman Senior Member (Voting Rights)

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  15. Andy

    Andy Committee Member

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