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

Agree with your disquiet - much of this scenario is less than ideal, best practice or the way we would wish things.

However, for your point 4 I don't think that's what happened. I believe the patients were taking themselves to Germany, possibly because word of mouth suggested that this technique was found to be helping Long COVID patients.

The LC community have been very active in sharing information online, so this info would spread quickly. Like us they've struggled to be believed, been forced to self-advocate and, with no offered treatments beyond BPS, have been sharing ideas on what they thought helped them. Their community has formed rapidly and with big numbers in an era of easy transmission of information (valid and invalid).

As I understand it, the South African team have been invited to analyse the blood before and after treatment to see if there are micro-clots present and whether they reduce. Nothing more than that, I believe. Prof Pretorius has indicated plans for a blood study of her regional ME patients starting in 3 months, so no rush there.

This may have been serendipitous. Eg a patient that was having routine treatment for, say, severe familial dyslipidaemia happened to get long COVID and may have reported improvement in their LC symptoms following scheduled treatments. Similar to what kicked off the rituximab trial I believe.

I think HELP apheresis is not commonly used outside of a few countries. Entirely possible it's not available in the US and UK at all.

I completely agree, first order of the day is to see if the micro-clot finding is real / repeatable and what its specificity is. Then work out how it might induce symptoms. Then start evaluating treatments with properly designed trials.

At the moment a lot of this remains opaque. If I'm presented with an opportunity to communicate directly with the relevant parties, I will share anything appropriate for an open forum.

 

Could you expand on what you mean here please?

 

Sorry Keela Too, I probably could have worded that concept better.

I'm trying to draw the distinction between the sort of fixed flow limitation you would see with, e.g. atherosclerosis, where the arterial lumen is narrowed by a plaque. Here I envisage a more dynamic form of flow limitation, where the vessel itself is less the problem and more its contents. At times you might have a modest load of textbook biconcave disc red blood cells that flow freely. At other times there may be a larger number of abnormal morphology and/or poorly deformable red cells, some of which may have platelets stuck to them. These would pass through small capillaries much slower I would presume.

As we've subsequently learned today there is apparently new knowledge (unpublished) from the global ME researchers (we haven't heard which specific ones), that shows ME patients have poorly deformable RBCs when they are hypoxic. This is the sort of scenario I was imagining could create dynamic flow limitation — which in this example could also be self-reinforcing .

Poorly deformable RBCs -> slow capillary flow -> increased oxygen extraction -> low venous oxygen saturation -> more poorly deformable RBCs

 

I do like the idea of a positive feedback loop causing PEM. They are suggesting the RBCs are deformable in normal O2 conditions though, so perhaps this could read instead like:

Exertion -> lower local [O2] -> decreased RBC deformability -> lower local [O2] etc

Will be cool to see if this is published and reproduced. Would be nice to know if this is a problem with the RBCs themselves or something in the plasma causing the change in deformability.

More generally, why would RBCs change deformability? Is there a normal physiological role here? This would have to involve a change in the cytoskeleton I presume. Perhaps there could be an interesting application for proteomics here to look for post translational modifications of actin or spectrin in these cells.

 

Thank you! Your explanation makes sense.
I think I got stuck on the BPS interpretation of the word “functional” and couldn’t see past it!

 

Re: Fatiguability - might a means of maintaining blood pressure reduce the fatiguability?

Would it help keep capillaries perfusing even with the increased resistance of poorly deforming RBCs and potentially sticky microclots?

Personal observation:

I do agility with my dogs and this involves about 50s of fairly intense concentration and activity. (I use distance handling, so I’m walking, hollering and arm waving, and not running like normal handlers).

A recent conversation on compression wear has led me to start using an abdominal binder (corset!) as well as my usual compression socks & leggings. This has been a game changer.

Previously, I almost always exited the ring like a drunk, with poor coordination, inability to form words, and a need to get my head between my knees. Friends told me I lost colour to my face as well. After 5-10 minutes, I would be able to walk and talk normally again.

With the binder on, I can walk normally out of the agility ring and even talk to friends at once and not look or feel distressed!

Of course, I still need to allow myself recovery time etc, and this doesn’t make my ME dissappear, but in terms of coping in the moment, it allows me to do something I love.

And maybe the observation adds to this conversation?

 

I think the explanation starts to get too complicated. William of Ockham would disapprove.

If sagging blood pressure is important, which it might be, we don't really need to suggest clots or slow red cells as well If there are clots then sagging blood pressure probably wouldn't make much difference.

 

Okay. Each on their own can be sufficient I guess.

As you were!

 

I'm much more interested in this, since it seems at least to be a real phenomenon. We don't all have it, but it does seem to be a feature in some of us. There are a lot of potential explanations for it, but I'm not sure anyone's really pinned it down yet.

The effects of it on patients aren't really appreciated, as doctors don't see it as problematic—especially as the worst effects can be relieved by simply changing position. It might not present the serious risks that sustained high blood pressure does, but not being able to stand or sit up for long is quite miserable enough!

 

I was thinking how poorly I am able to explain the drops in blood pressure to clinicians. It's not just brief episodes of low blood pressure, it's really a constant problem that also happens to occasionally become severe enough to cause falls.

I just don't have the language to describe the problem in other terms than "sometimes my circulation doesn't adjust fast enough to standing up and so I fall down because the blood drains away from the head and I can't control my body well enough anymore to remain standing".

It's there all the time in milder form because it's associated with a distinct sensation in the head which I associate with the "fall down from low blood pressure" episodes.

It's not just episodes. It's there all the time in a milder but still impactful form, causing a vague malaise and difficulty functioning and who knows what else.

This is also the problem my mother has and my grandmother had. Perhaps one of the risk factors for ME/CFS.

 

This would be analogous to traffic jams, that can result from structural problems, ie road works, or from traffic issues, ie the behaviour, number or type of vehicles on the road

 

This 2010 review ( https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2998922/ ) suggests RBCs use ATP to regulate deformability, becoming more rigid in low ATP conditions when tested in vitro. Given there's been various pieces of evidence suggesting metabolic problems in ME/CFS, it could also be that RBC rigidity - if present - is a downstream effect of the disease pathology, rather than causative of symptoms itself.

It would be nice to ascertain whether the problem is caused by a (metabolic) problem of the RBCs themselves, or an upstream signal that is telling the otherwise healthy RBCs to behave weirdly.

Could be another nice application for a plasma swap experiment: Do patient RBCs behave like controls when they are suspended in control plasma? Do control RBCs behave like patients when suspended in patient plasma?

 

The "something in the blood" had the effect of lowering intracellular oxygen levels in cells exposed to it in an unpublished experiment by Karl Morten.

I wonder if the NK cell function that is sometimes found abnormal sometimes found normal could also just be the effect of this something in the blood, which depending on the methods used to study the NK cells, is sometimes present and sometimes absent, giving confusingly contradictory results.

 

https://www.omfcanada.ngo/study-of-thrombospondin-1/

Just adding for information. A cluster of pwME have elevated TSP 1, another reduced and another no change after provocation.

 

https://www.researchgate.net/public..._ENDOTHELIAL_DYSFUNCTION_AND_PERSISTENT_CLOTS

Preprint posted today

Forum thread here:ME/CFS, FM: Mitochondrial dysfunction ... cellular hypoxia, hypoperfusion, endothelial dysfunction, persistent clots, 2021, Chang, Figueredo

 

https://twitter.com/user/status/1457732417545019395

 

Something about the hashtag #TeamClots makes me laugh. I think it's that it sounds like they're on the side of the clots rather than against them

 

Hmmm. I can't speak to the science but this is very much looking like the next over hyped theory that gets lots of people excited and doesn't amount to anything.