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

Moved from Six-month sequelae of post-vaccination SARS-CoV-2 infection: a retrospective cohort study of 10,024 breakthrough infections, 2021, Taquet et al



@Hutan thank you, I believe it's all coming together and Long Covid will have been instrumental.

The Pretorius micro-clot finding is key:

• Ron Davis found "something in the blood" that was reasonably large (< cell size, but > molecule).
• He found abnormal impedance in the blood of ME/CFS patients
• Filtering plasma by size removed most of the abnormal impedance effect
• Transferring ME plasma to normal (mice) causes ME/fibromyalgia type symptomatology
• Resia Pretorius found serum amyloid (SAA4) - 17.5 x control level in the microclots
• Amyloid is formed of abnormal beta-pleated sheets and causes abnormal impedance
• Amyloid tends to induce further protein misfolding

The implications are massive:

ME and long COVID are the same disease, both an amyloid pathology that affects the blood and causes coagulation, immune and inflammatory derangement centred at the micro-circulation level. Downstream symptoms are all secondary (haemodynamic, neuroinflammation, gut wall permeability). There is an element of the virus that kicks this amyloid formation process off (and I think we can guess what element that is).

 

Thanks - this is very interesting. If there are forum members with medical knowledge/experience (I personally have none) who are also interested in this angle, it would be great to hear their thoughts on what the most useful next steps might be to explore this further.

 

The authors are already working on confirming this in ME/CFS.

 

[QUOTE="SNT Gatchaman, post: 388199, There is an element of the virus that kicks this amyloid formation process off (and I think we can guess what element that is).[/QUOTE]

We guess it is?

 

https://twitter.com/user/status/1455637199949467651

 

Don't want to get my hopes up, but it reads like a smoking gun type scenario. I'm gonna close my pc now and wait until tomorrow to get kicked of cloud 9 .

 

I'm not sure I'd draw that parallel - never seen any evidence of any increased incidence of coagulopathies in ME/CFS, although there are many such reports post COVID (e.g. there was a podcast featuring a doctor who thought he had ME but turned out to have a nonocclusive CVST featured on S4ME a while back, IIRC). That's not a pattern that's seen with other viruses thought to be triggers of ME, such as Epstein-Barr. Also, if it's true that incidence of long COVID is unaffected by vaccination, it would follow that it's independent of the severity of the acute infection, and that would interestingly be at odds with one of the few prospective studies in ME/CFS, the Dubbo study (Hickie et al., 2006).

Haven't read the Pretorius study yet (or any of the COVID coagulopathy papers, too busy reading NICE documents), but on the impedance findings I'm equally cautious. I know Ron Davis is something of a folk hero in the ME community, but what's been presented to date is clearly not definitive. Esfandyarpour et al. (2019) used a sample size of 20 cases and 20 controls, only 5 of which were age/sex matched controls, and impedance was measured in plasma which had a NaCl concentration increased to 200 mmol/L, which obviously has no correlate in vivo. I'd certainly like to see these results replicated in a study with a larger sample size and demographically well-matched controls before drawing any conclusions about impedance.

 

Advancing the discussion points further if we were to accept the above premise as valid.

Why might some people be pre-disposed to ME? Why female predominance?
It might be genetic variation in the ability to clear the amyloid/micro-clot aggregates. E.g. heterogeneity in one part of the coagulation cascade or a relative immune tolerance and reduced monocyte scavenging.

We know that there are sex differences at the blood vessel level. Perhaps in order to propagate beyond the body's ability to handle, they are privileged when located in (for example) smaller-than-average diameter capillaries.

This could explain why children have a higher recovery rate, with smaller capillaries at disease onset and then out-growing the imbalance and allowing the fibrinolysis balance to normalise and clear.

Why could people go for years with multiple infections with no problem, but one day come down with ME?
May be dependent on the particular pathogen having the ability to form the abnormal amyloid, and doing it in sufficient numbers to overcome the body's ability to handle in any given infection event. Maybe a step-wise immune perturbation, following sufficient viral infections (e.g. starting with EBV).

Recovering the ability to clear the micro-clots might explain the stories of some people's recovery being slow, slow, slow and then rapid. Perhaps this is the bi-stable state OMF were theorising, rather than a metabolic trap in neurons.

We know that acute COVID causes very abnormal thrombosis events in the severely affected (multi-organ). The experience at the start of the pandemic also showed that initial "dose" of the virus was important. Unprotected healthcare workers exposed to large aerosolised loads did very badly.

COVID also had this unusual behaviour where people looked to be recovering and then rapidly deteriorated. I wonder if that's a clue too.

It also seems possible to me that there might be acute and chronic forms of this pathology. Severe SARS 1/2, MERS, Ebola etc disease might actually be "acute fatal ME".

 

Is there a source for where he reports on the size of the "something in the blood"? I think this is very interesting. When you say bigger than a molecule do you know if he means a small molecule (a metabolite eg glucose/amino acids etc) or a protein (which are gigantic biomolecules).

You're referring to the Goebells and Anderson JCI paper right? This is specifically IgG antibodies that is causing the symptoms in mice and not anything else in the serum according to their results.

So I think these pieces of evidence are not pointing towards the same thing.

I do think the search for this "factor" in the blood is one of the most promising avenues of exploration though. The microclots are also interesting in their own right.

 

I've been wondering about that, whether it could account for it. Stuff that gets stuck in clots and breaks down over time, maybe reigniting the process. I don't know, pure speculation since this is way out of my league but interesting to think about.

This could actually explain some of the things, including worsening of symptoms around menstruation. Clotting is a big part of this process, as far as I know anyway.

 

I've been wondering whether microclots could explain PEM and be somehow related to the unknown blood factor in ME.

Dr Bateman believed that PEM results from lack of oxygen in certain tissues.

Dr Fluge and colleagues "We believe that the clinical symptoms in ME/CFS suggest inadequate autoregulation of blood flow according to the demands of tissues, resulting in tissue hypoxia."

Maybe the dysregulation is in the balance of clotting and anticlotting factors and autonomic system is trying to deal with the consequences while not getting adequate oxygen.

 

There's a post on PR where Janet Dafoe says: "Big = larger than 10,000 molecular weight. Proteins, protein groups or antibodies (including autoantibodies). Amino acids are smaller, around 300 molecular weight."

Ah OK, I thought there had been an earlier form of those plasma transfer studies that was less specific than IgG and might allow for disease transfer via "some blood factor". I might have been conflating demonstrations of normal blood cells acting like ME blood cells after exposure to ME plasma, rather than showing in vivo symptoms.

There's so much to try and assimilate, apologies if I am mis-stating and thank you for correcting.

 

Could be inadequate regulation. I was thinking simplistically that there might be the pathological situation of impaired capillary transit, which is adequate at rest due to compensating metabolic shifts. With increased tissue demand there is early fatiguability as the compensations are out-done, but delayed PEM occurs as more capillaries were recruited into the blood flow, forming a "traffic jam" of poorly deformable RBCs, such that fewer capillaries are "empty" and available for relatively-unencumbered random RBC transits, as in the at-rest situation.

 

Yes, long-term LC patients need to be looked at, along with long term ME patients. I believe there are studies into the former being discussed as we speak. Comparisons with recovering/recovered acute Covid are needed with that exactly as you have said. I think the established ME and LC researchers need to get together in a global moon-short and grab some of that 1.15 billion NIH fund. It's no use doing surveys of symptoms in LC patients...

Yes, that's why I think it may be a paradigm shift in medicine. We've known about venous thrombotic disease and arterial occlusive disease, but the micro-circulation level is mysterious. There is a lot that is not understood about the potential for disease at this level. e.g. could a similar process explain pre-eclampsia in pregnancy? It may be that the microclots in the larger vessels circulate but do no harm (i.e. don't generally cause venous thrombosis), but when stuck in the capillaries their inflammatory action may be privileged, prolonged and pathogenic.

 

I'm unconvinced that this hypothesis fits with the rapid switching between full ME symptoms and full temporary remission. This switch of state takes place over a scale of minutes rather than hours. I triggered remissions via three different chemicals: prednisone, cumin, and T2. I don't see all three of those suddenly making microclots stop impeding blood flow. Also, if ME was simply poor blood flow, wouldn't the various treatments that affect blood flow have produced many more PWME reporting such correlation?