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

[Peter T]

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.

I suppose with Long Covid there are more people to get excited and also more people who have not had time to get jaded with great new potential game changers prematurely launched coming every two years or so.

 

[BruceInOz]

This possibility of a link to the deformability of red blood cells has been around for a while beginning with Leslie Simpson in the 1980's. I remember in 1995, soon after my diagnosis, being given a photocopy of a photocopy of an article from the local Adelaide newspaper about Simpson's ideas around RBC's and CFS. Always wondered if nothing came of it because there was nothing there or because Simpson died and nobody else took it up.

 

[Mij]

I've had a few friends in real life with FM over the years that never experienced PEM, and didn't understand what it was when I explained it to them. I don't understand why Dr. Khad is making all these assumptions and connections to POTS, FM etc.

 

[SNT Gatchaman]

I've had a few friends in real life with FM over the years that never experienced PEM, and didn't understand what it was when I explained it to them. I don't understand why Dr. Khad is making all these assumptions and connections to POTS, FM etc.

I think it's running with the idea that these different disease labels could refer to symptoms on a range, with variable overlap.

For example I have a diagnosis of POTS but I have sufficient other symptoms for "Atypical ME" per ICC or "ME/CFS" per IOM. I don't get cognitive impairment — in any meaningful way — certainly compared with others' descriptions of this. And I don't get pain, apart from the mild lactic acid burn. But I went to a cardiologist and was told "POTS".

We also now know that 90% of ME patients have orthostatic intolerance, demonstrating reduced cerebral blood flow, but many of those don't have pulse/BP changes. They would never go to a cardiologist and are much more likely to be given a diagnosis of "ME/CFS". Suspect there's a group who are pain-predominant and some of those may not display some features of ME so they may be labelled "fibromyalgia".

For your friends @Mij, perhaps there's a mechanism of the disease process or the body's adaptations to it, that makes them relatively resistant to PEM or elevates its threshold particularly high. Maybe there are two aspects to the fundamental ME pathogenesis and they are minimal on one side of it. So, perhaps, they have more generalised oxygen diffusion issues and are more lactic acidotic, but have less problems with their red cell deformability.

For me, perhaps I'm more about the red cell deformability and less about the hypoxic tissues.

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.

I suppose with Long Covid there are more people to get excited and also more people who have not had time to get jaded with great new potential game changers prematurely launched coming every two years or so.

There are enough clues to make this finding worth pursuing and as you can tell from the number of posts I've made already in this discussion, I think the next few months could be very interesting for us, even if it were found to be a Covid-specific phenomenon.

If it turns out to be another of the many over-hyped theories (and I've read back around a few of them), well I'll just have to take it on the chin and chalk up this newbie's first hype disappointment.

PS I am assuming the exploration of potential disease mechanisms in this and other threads is widely welcomed and enjoyed and not distressing for other members.

 

[Andy]

If it turns out to be another of the many over-hyped theories (and I've read back around a few of them), well I'll just have to take it on the chin and chalk up this newbie's first hype disappointment.

My comment wasn't meant to be aimed at you, or intended to discourage balanced discussion of the topic here, so apologies if it came across that way. It would be wonderful if this is THE explanation for ME but all the previous explanations proposed, and particularly the ones based on very small numbers, that didn't pan out have left me wary of getting my hopes up too soon.

 

[hibiscuswahine]

I think it is good to discuss the issues. ME/CFS is a multisystem illness and so much discovery is going on at the moment. There is a lot of homeostatic pathways, e.g. neural, hormonal, immunological etc, (both centrally and peripherally), that science is still working out as well as the oxidative stress one. ME/CFS comes in many shapes and forms which makes it difficult for clinicians and pwME/CFS. It also has an array of different precipitants, like anaesthetics, trauma, infections and is frustratingly elusive on many levels to get my head around. The RBC deformity is interesting and it would be good to see what comes out of further investigation.

 

[Fizzlou]

The problem I have with MECFS is that nothing gets done because there’s supposedly not enough evidence to warrant it.

The new guideline recommendations for research is telling. No biomedical just cost effective self management tools.

All we can expect is clinic’s insisting we are to stabilise our levels and then ‘build tolerance’.

I am seeing unnecessary and unhelpful hype by admins on the FB group, matched equally with a desire from many for reassurance of data to make informed choices. I think Dr Khan is quite balanced overall judging by his interviews.

However I am pleased that as momentum builds to deal with LC that people might just pull out all the stops and throw huge resources at it. Great! We might just get some answers.

 

[SNT Gatchaman]

Thanks @Andy I didn't take your comment negatively in the slightest - just reflecting on a number of the measured and/or disquiet posts from all the experienced commenters and not wishing to be risking irritating spam!

I do find myself in an unusual position of near-front row access for this particular set of investigations at the moment, potentially bridging the worlds of patient and researcher.

One other interesting point that I'm sure many will relate to is the difficulty of communicating symptoms to doctors and researchers. Arguably I should be well placed to articulate things, and yet I'm not. I struggle to define many things that make me feel "bad", "fuzzy in the head", "not right" etc. However, over the last couple of weeks I've been thinking a lot about possible mechanisms and how they might relate to my illness experiences over the year and even trying little manoeuvres to see their effects. I haven't had to worry about encapsulating a formal response into a researcher's sheet - I've just known that "yep, that makes me feel better". All really minor stuff obviously and subjective for now, but encouraging me to think more and try for some objective scientific assessments that could mirror my subjective observations.

Fingers-crossed, I have three such investigations lining up over the next couple of weeks. One kicked off today and is in the hands of others (I'm just watching with interest). The other two are not directly related to the micro-clot stuff, though I got the idea by thinking about them. The second will have a trial run tomorrow and the third maybe on the weekend.

Again, this is an unusually happy set of circumstances (not common for these parts I grant you). I'm an early-onset ME patient, currently well enough to contemplate this. I kinda still part-own a one-year old well-specced 3T MRI scanner and I have access to some of the advanced toys found in a cardiac intensive care unit and liver transplant theatre (and smart friends in high places!). That offers the intriguing possibility of some in-depth assessments in a single patient to complement the usual large number population studies, which are limited by: access to none of the above, various other practicalities and of course ethics!

Eg I don't mind being stabbed for blood multiple times or even having modest invasive monitoring - you generally couldn't do that to patients (excepting the Systrom CPET studies). Also this is homegrown and not dependent on external fund-raising (I can cover any consumable cost and there's no penalty to patient access to consider).

If any of this looks feasible, I'll post later in a new thread and I imagine people may have some very helpful ideas to contribute. If it flops, nothing lost.

 

[JES]

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.

Yeah, I think the deformability is probably a consequence of something else. I trialed pentoxifylline, which supposedly aids in deformability, but it didn't help me much. What helped me temporarily was supplementing with fibrinolytic enzymes like bromelain or nattokinase. I felt a massive decrease in brain fog a couple of hours later, it was as if I had been cured for a while. Unfortunately, this improvement only lasted for a day or so, after which I began to feel worse, with increased flu-like symptoms and POTS. The longer I continued with these supplements, the worse I got.

I don't believe you can cure this just by removing the micro-clots, supposed that they are present. Otherwise you could just try the supplements like I did or more powerful blood thinning medications. If I understood correctly, apheresis is not just about removing the clots, but filtering out other things as well, so it would be one step closer to the cause perhaps.

 

[sea]

With the Dubbo study, it seemed possible that a delay in assessing the illness severity may have skewed the rating of severity to those who were already experiencing a post-infection reaction (rather than an accurate assessment of the acute illness itself).

It’s been a while since I read the Dubbo studies but from memory the patients were followed from the time of diagnosis of the original illness. I don’t think there was any delay in assessing illness severity.

 

[Hutan]

I found this previous post of mine, which starts to answer the question of illness severity ratings in the Dubbo study.

I'm not sure how reliable that Dubbo finding was. From memory, the baseline testing was done after the onset of the acute illness. In some cases, it was quite a long time after the onset. So, rather than measuring how bad the acute infection was, they may have measured how people were feeling some weeks afterwards, possibly with a retrospective bias on that as well. As I said, that's from memory, but I did make a mental note that the study structure may have made the assessment of acute illness severity a bit dodgy.

I think the idea of a more severe illness increasing the risk seemed quite attractive, both to the BPS people who wanted to support a deconditioning hypothesis and to those of us who favour an immune system perturbation cause. But it may not be true.

I think Jason's prospective study may have found something about severity of illness and likelihood of ME/CFS, although I'm remembering the numbers actually developing ME/CFS as being quite low.

People were referred to the team; they had to fill out a battery of surveys including a self-reported severity of acute illness. I got the impression the time between illness and survey filling could actually be weeks and even months. I can't recall if this information came from the 2019 paper that gave more information about what was done, or if it was the original paper.

 

[Hoopoe]

In my opinion it's reasonable to think that two illnesses that look similar might have the same underlying disease process. Therefore it's reasonable to suspect that microclots could be relevant for ME/CFS, POTS, chronic Lyme, etc (assuming they are important in LC). If we look at it from the perspective of what is known about ME/CFS then it doesn't seem likely that microclots would have much to do with ME/CFS.

That said we don't know much about microclots in long covid. Maybe they don't play a big role in symptoms and aren't the main problem. The main problem could be in the central nervous system and hard to measure.

 

[Fizzlou]

https://portlandpress.com/bioscirep...RS-CoV-2-spike-protein-S1-induces-fibrin-ogen


[URL]https://www.google.co.uk/amp/s/www.the-scientist.com/sponsored-article/trapped-inflammatory-molecules-contribute-to-long-covid-69391/amp[/URL]

The Scientist from 8 Nov (2nd link and easy read): Research done by Professor Pretorius and Professor Douglas Kell from Liverpool uni over the past few years on ‘Trapped inflammatory molecules’. He is the Research Chair in Systems Biology with impressive looking resumé.
Scanning the (long) paper it’s focused on the acute stage of Covid-19 but there’s a lot of diagrams and images that I found helpful.

 

[Sly Saint]

 

[Slamdancin]

@JES I had almost the exact same reaction to NatTokinase/Bromelain. A hopeful start but definitely worse after a few days. The flu like symptoms went away as soon as I ceased the regimen. Do you have any speculation on what may be the reason for this worsening caused by fibrinolytic enzymes?

 

[JES]

@JES I had almost the exact same reaction to NatTokinase/Bromelain. A hopeful start but definitely worse after a few days. The flu like symptoms went away as soon as I ceased the regimen. Do you have any speculation on what may be the reason for this worsening caused by fibrinolytic enzymes?

It is very curious indeed. One hypothesis often speculated about in Lyme communities and elsewhere was that those blood thinning supplements exposed pathogens that were hiding and forming biofilms and as a result you got a Herxheimer reaction.

But like you, I never got better either. One would think weakening the defenses of pathogens would eventually result in improvement. I feel like there is more going wrong than just bacteria hiding, which would be more in line with Ron Davis' observations and the long COVID ones.

 

[Ariel]

 

[SNT Gatchaman]

BTW @SNT Gatchaman, I know it must be feeling that we are relentlessly negative. I do appreciate you posting about what people are reporting about this issue.

Thanks @Hutan, it has been a little rough lately.

I find this a very unusual situation for all the reasons we've discussed above. This will (I hope) be my last post on this subject until formal scientific reporting occurs. It appears this thread has not been helpful. I think I have not done a good job with my part in this discussion and I regret that. I started this thread as an offshoot from these new findings related to long COVID. I wanted to explore what the implications for the micro-clot finding could be, in terms of a potential disease mechanism in ME. This was fascinating to me and I could see how it might all hang together, based on what I had learned and my own (admittedly short term) disease experiences.

However, it's been too easy to keep wondering what on earth is happening with the apheresis treatments. Unfortunately, so much of that story is opaque at the moment. I have tried to summarise what is being described elsewhere and draw inferences about the situation, assuming best intention from those inexperienced in LC (and ME) who suddenly found themselves deep in it. These were clinicians with (presumably) no pre-conceived notions of what LC/ME was and they weren't massaging data to support some flawed disease model - psychogenic or biological. There also appear to be significant difficulties in blinding for this type of treatment.

Given that this was so fast-moving I thought it was also good to report what was being said/written - though again, through a frosted glass. It might have been better if I had not tried to defend the situation as it appeared to me.

Regardless, if this did subsequently turn out to be an inflexion point in ME research, this forum's summaries and comments might help historians/authors to review the timeline of events.

I would prefer to get the horse back in front of the cart. For my part, I am pleased to now be involved in supporting the basic scientific research into the cells and proteins associated with inflammation and coagulation in LC/ME (all needing rapid upskilling for me, of course). In my own area, if my situation allows, I would also like to arrange for some targeted imaging studies to try and answer some fundamental questions on fatigue and PEM, and potentially how they might relate to red cells and vessels. Perhaps one day you might even discuss a short paper and I will excuse myself from the room.

In closing, the micro-clot finding from the South Africa / Liverpool team and the apheresis finding from the German clinic have drawn in new researchers into LC (and presumably by extension ME). New researcher blood seems a good thing and perhaps old ideas that were inappropriately left unloved will now have their time in the sun. Leaving aside the many unknowns of the apheresis, I maintain confidence that the biological science researchers are approaching things methodically and appropriately. I would also expect that drug therapies will be similarly evaluated on the clinical side.

[The moderators may wish to consider closing this thread and starting afresh with published data when / if it appears.]

Moderation note: A thread on the topic of the Apheresis treatment has been split off this thread. Some of the responses to this post are there.

 

[Ariel]

@SNT Gatchaman I have appreciated your posts on this x

 

[Trish]

It appears this thread has not been helpful. I think I have not done a good job with my part in this discussion and I regret that. I started this thread as an offshoot from these new findings related to long COVID. I wanted to explore what the implications for the micro-clot finding could be, in terms of a potential disease mechanism in ME. This was fascinating to me and I could see how it might all hang together, based on what I had learned and my own (admittedly short term) disease experiences.

I think it has been a useful thread, and I appreciate your contributions to it. I hope very much you will continue to contribute your experiences and hypotheses.

Inevitably, after experiences over the last few years, some of us are feeling a bit world weary with doctors who offer treatments and patients who publicise them on social media before the research necessary to see whether there is a sound foundation to the treatment. And inevitably this will look like we are pouring cold water on the efforts of new researchers exploring new avenues.

We are just cautious. That doesn't mean we want to shut down discussion or are unwilling to hear about new developments. It just means we will look closely at what is supported by evidence. I hope the apheresis doctors will be able to publish more soon about their findings. And I'm fascinated to hear more about your and anyone else's ideas and research. Please don't stay away.