The micro-clot finding in Long Covid — implications for the possible aetiology of ME/CFS

Another interview with Prof. Pretorius (by Dr. Amy Proal). Probably from ~2 weeks ago, as discusses Omicron. Focuses on LC, but does discuss ME.

YouTube link

A few points made in this interview, complementing prior discussions —

• Spike protein is forming a unique type of micro-clot, in very large numbers in patients
• Spike protein forms micro-clots in healthy blood, in vitro (e.g. using spike purchased from Sigma)
• No difference in wild-type -> delta spikes (omicron spike not yet evaluated)

• Concern that omicron "mild" disease could still lead to significant LC
• Those going on to LC are probably not clearing the micro-clots [that form in many/all?]

• Thioflavin-T binds to the micro-clot misfolded fibrinogen (cheap marker, not just Alzheimer-type amyloid of its original usage)
• LC micro-clots are spongy, likely able to squeeze through fine blood vessels

• Describes a healthy friend who had Covid (initially asymptomatic, found on random test, then mild illness). Formed micro-clots and hyperactivated platelets, which cleared after a few weeks during observation
• Apheresis made many patients "healthy again"
• Apheresis significantly reduces micro-clot load (18 patients: pre, 6hrs, 24hrs post)
• Emphasises urgent need for controlled trials of pharmaceutical regimens

• Children's LC under-recognised and under-studied (makes economic argument to complement the moral imperative)
• ME under-studied - affirms not psychological, just the marker hasn't been shown yet
• Want to evaluate ME with proteomics
• Implores ME and LC patients to not give up: the researchers are working as hard as possible and think they are on to something

 

That could be anything. It could be any cause of fatigue or even anhedonia. Did they have a control group where healthy human blood was donated to the mice?

 

The main problem with the "micro-clot" hypothesis is that it doesn't explain long-term symptoms (when there is no longer any spike protein) at all.

 

Nor the phenomenon where some people appear to recover well from acute Covid, but then develop hard-hitting chronic symptoms weeks or even months later. I've seen numerous reports of that over the last year or so.

 

Two potential mechanisms I guess:

1. Ongoing micro-clot formation in the absence of spike protein
2. Symptom maintainance / progression despite clearance of micro-clots

Ongoing clot formation
Spike protein causes micro-clotting in healthy blood (in vitro). The implication is that all people could produce micro-clots in response to spike protein. The micro-clots are persistent and resistant to fibrinolysis, as they have been shown to be formed of anomalous fibrin(ogen) and also contain mediators such as alpha-2 antiplasmin.

The balance of fibrinolysis is upset. Most people clear the micro-clots and return to health, but in some it's over-threshold and they are not adequately cleared.

In long COVID the overall mechanism is suggested to be due to the inter-relationship between: platelet hyperactivation, micro-clot formation, endothelial dysfunction and alteration of RBC deformability. This pathological situation could promote ongoing micro-clot formation, despite monocyte clearance of the initiating spike-containing micro-clots over time.

Anomalous amyloid clotting is seen in conditions other than COVID, so the process is presumably not spike-dependent. Eg DM2. See Substantial fibrin amyloidogenesis in type 2 diabetes assessed using amyloid-selective fluorescent stains.

Symptoms despite clearance of micro-clots
People may eventually clear micro-clots as their fibrinolytic balance returns to normal. However, symptoms could persist or even progress by a number of different pathways.

Auto-antibodies may have formed, eg the GPCR AAbs treated with BC007, or more specifically the ß2-AdR AAbs per Wirth/Scheibenbogen.

Metabolic and other physiological compensations will have occurred in the meantime and some of these may be fixed. This could be a second or third stage - potentially a metabolic trap such as tryptophan/kynurenine (per Phair, Davis). This could match a step-wise descent of illness severity following repeated crashes.

Initially as an attempt to compensate for poor micro-vascular performance, POTS-type pathophysiology might persist in some in the absence of a reset. See this recent case report of stellate ganglion block which reversed the symptoms.

That could tie in as the initial relatively small burden of spike-induced micro-clots slowly induces the production of more until symptoms become apparent. In hindsight I was becoming sick for around six weeks before I personally noticed any symptoms (others could see my deterioration/loss of form though). I then had six months of mild fluctuating symptoms before a severe crash.

Apparently, I'm now the "gold standard" for demonstrating micro-clots — that's an informal comment not a robust scientific appraisal!.

 

This seems rather vague. At this point if we are pushing out vague hypotheses, we may as well propose that the micro-clots induce some sort of persistent endothelial dysfunction similar to ME/CFS.

 

The whole thing looks complicated to me, too. The immune system clears the virus quite quickly in most healthy younger people, so the theory seems to rely on fragments of a particular protein being able to hang around for an extended period to set off, and then sustain, this kind of havoc.

Maybe that's possible, or at least plausible...but I'm not sure what Friar William would have thought of it. I guess we'll have to see what the trials say.

 

I am afraid it all sounds very much like a BPS theory:

It's this, but not quite, it is more this, but not quite it's this, but not quite it's ...

Maybe it just isn't.

 

Perhaps...

https://www.researchsquare.com/article/rs-1139035/v1

Keeping in mind this is in severely ill patients who died - I would not assume the same is true for mild-moderate COVID cases, where it has generally been shown that the brain is not infected.

 

Fabulous! Is that because you have not had anticoagulant or aspirin treatment? And unadulterated blood i.e. not had apheresis treatment? Or have had your blood examined in a different research lab?

Thanks for all this explanation, I only worked out the other day that the long covid microclots originally started as MicroCLOTS ( Microvascular COVID-19 lung vessels obstructive thromboinflammatory syndrome) and appears the term has been expanded to beyond the lung. I often still think of clots as having RBC involvement (macroclots) rather than just platelet and inflammatory proteins which is what is being discovered. And I can entertain some of the theories for some people with ME who have known autoantibodies to adrenergic receptors.

I don’t have a problem with the disjointed pathological processes being proposed, ME has a lot too, been trying for a unified theory for years.

That stellate ganglion blockade is very interesting and it maybe a useful treatment even if not curative for some.

 

That is what is being proposed, yes. I don't know what the specific cytokine etc profile will be - that work is underway. So, yes, in that sense it is still vague.

To be fair, I have put myself on over-the-counter aspirin, but would only go further as part of a study that can advance understanding. My blood (and others) is being / will be assessed by multiple modalities. Early work appears promising.

Yes, the explanation for ME has evaded our understanding for decades. By definition then, the mechanism will involve newly recognised elements or old elements "re-purposed" in ways not previously considered. I don't see this (particular core LC explanation) as being particularly disjointed - basically thrombo-inflammatory cross-talk (which is an accepted concept). It all seems quite elegant and relatively simple, but perhaps I just don't know what I don't know.

I think people's major objection is the concept of micro-clot persistence. I don't think they are cleared in seconds or need to be made daily - they are uniquely persistent.

So part of the explanation that is elegant is "how can blood tests be normal when there is profound physiological derangement?" The answer being that we are not doing "blood tests" we are doing "serum tests" and the micro-clots represent a separated compartment. Elevated markers of abnormal inflammation and coagulation are sequestered within the micro-clots and invisible to our serum tests.

Spike protein induces micro-clot formation in vitro. I think demonstrating spike protein in micro-clots ought to be good evidence for their presence in vivo; and also their persistence (although granted, persistent virus could keep producing micro-clots).

I would encourage people to keep an open mind on this and not simply dismiss because "if this were real we would have seen it before". Whatever the ultimate explanation(s) for ME in general, we won't have seen it before - or at least not recognised it as such.

 

Can these micro clots effect the erythrocyte sedimentation rate? There has been speculation in the past that ME is associated with low values. Mine has always tested less than 5, sometimes 1. Of course that is still within range and I gather doctors are only interested in high values. But is there anything to such low values of ESR?

 

So what would make them so unusual in this respect?
Presumably, to persist, they would have to not release any activating components or get stuck in vessels. In other words they would need to be inert and cause nothing?

As far as I can see the 'compartment' these clots are found in is an artifactual one in processed blood. Why do they not show up on Coulter Counter analysis of whole blood in the FBC?

 

Thank you! I'd like to continue this exploration, but perhaps with Christmas very nearly here (which I very much hope you'll be thoroughly enjoying) I should park my questions until the new year.

 

I have read about two successful replications of finding these microclots with microscopy. Apologies if I can't provide links at the moment.

 

https://www.itv.com/news/meridian/2...-6000-and-left-me-close-to-taking-my-own-life

 

Very sad. I think it's wrong that clinics are taking people's money for treatments at this point. They may not be intending to make money out of people's desperation but that doesn't make it ok. We've seen this scenario so many times. Proper research is the only way!

 

Yes @Tia this is upsetting. So many potential treatments, but without rigorous testing we don’t know who or whether they help.

 

I took bromelain as a potential anticoagulant (on empty an stomach) twenty years ago when hypercoagulation was a theory for pwME. I took the supplement for 3 months before my blood panel was finalized and it really thinned my blood, I cut my finger and it wouldn't stop bleeding- kind of scary at the time. When my ISAC panel was finalized it was determined that I didn't have hypercoagulation. The head Hematologist here advised not to assume when taking blood thinners.

Just a caution for everyone reading this thread in case they want to 'explore' on their own.