Aphaeresis/ Apheresis (for removal of microclots)

I do not see any reason to think that. Why should they not do a tight double-blinded randomised controlled trial as Fluge and Mella did? Why would they have to break early?

The question I would like the answer to is why the scientific community as a whole is showing no interest. What if every competent coagulation haematologist in the world thinks, like I do, that this does not add up clinically and the 'biology' looks pretty unconventional?

Real breakthroughs have been made with Covid-19 - the identification of dexamethasone as a useful drug, the studies on monoclonals against spike protein. If this was a real breakthrough I do not understand why haematological friends of mine are not appearing on the news giving an account of how promising this is.

 

One way would be to find funding for a trial in a country where this treatment is not currently being offered, but which has the capability to do it—most European and Scandinavian countries would probably fit the bill, as would the UK. Those potential recruits wouldn't be missing out by being allocated to a placebo arm, since they're unlikely to be able to access treatment in Germany anyway due to the very high costs.

Unless it's shown to work, of course, in which case the healthcare system in their own country might well approve it.

 

@SNT Gatchaman, I listened to the tlc.sessions interview with Asad that was posted earlier and have followed his journey on other sites.

And with respect to the Dr William Weir comment you just referenced. For the sake of science (or just my understanding) and the possible improvements with ME/CFS, I wish to get your opinion on a possibility that some of Asad’s treatment effects may be due to him having hereditary hypercholesterolaemia (he has publicly stated this) and the possibility he has some aspects of ischaemic heart disease that we have not been made aware of. Dr Weir is saying there could be lipid globules running around as well as micro-clots. So it does make me wonder if people with ME that get benefit may have some sort of dyslipidaemia - perhaps undiagnosed or not meeting the normal criteria of treatment.

I personally think this is a promising treatment for pwLC due to the known hypercoagulability due to covid. Interestingly, Asad said that the apheresis may not be required, it is $1300 euros/per session…but that existing medication of aspirin, heparin and what sounds like warfarin, (he states “older anticoagulants”) maybe all that is needed on pwLC to reduce platelet hyperactivity and the clotting problems.

I totally understand his wish for clinicians to take a leap of faith. Gee if I had a machine and LC I might try it on myself but Asad knows this is a very difficult thing for clinicians to do. There are medicolegal ramifications and there has been no discussion of harms. He intimated there was harms to apheresis but has not expanded on them.

Disappointing Dr Pretorius has not been able to get her work into journals. There are a lot of medical politics that go on around publishing.

ETA: Sorry, I mean vascular disease from atherosclerotic plaques rather than ischaemic heart disease

 

Not saying they would have to break early, just that I can envisage the scenario where they might. This is assuming that these anecdotes we are hearing will be shown to be reflective of reality, when the rituximab findings were carefully shown not to be. Won't know til it's tried, but I was highlighting that enrolment could potentially be a problem the longer such studies are deferred and the more noise the anecdotes generate. Of course I would hope that this and my other worries about blinding are the silly/trivial concerns of the inexperienced and @Hutan's points would all hold. (I knew I'd get in trouble again!)

I can't answer why the scientific community as a whole is dismissive at this time. Yes! it is unconventional. But there must be an answer to these diseases that has eluded us til now. In the past new knowledge has been firmly resisted at the outset, as inconsistent with what we know. E.g. the concept of auto-immunity as proposed by Prof Noel Rose in the 50s (after Erlich) was roundly discounted for years, but is now fully accepted.

I'm certainly no expert in this and Prof. Edwards absolutely is! But, from where I'm sitting, the role of platelets in the innate immune system and their potential for dysfunction leading to auto-inflammation*, as opposed to the auto-immunity of the adaptive system, sounds like a potentially fruitful avenue of research that could have wide implications.

If that were new knowledge then it would be at odds with established community wisdom. To me there seem to pointers in support from multiple directions (Pretorius/Jaeger, even Bruce Patterson although he is attributing his findings to another mechanism). Now Dr. Blair Grubb at Toledo is leading a study into classical POTS and LC-POTS patients, looking at this role of platelets as an explanation for the observed immune dysfunction.

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*For others reading, the idea (if I've got the concept right) is as follows:

The immune system is in two parts - innate and adaptive. Innate is what you're born with and uses eg eosinophils, mast cells and interleukins to control parasites, bacteria etc. It seems to be considered more of a blunt instrument. Adaptive is what we develop over time from specific exposure and uses T cells, B cells and antibodies to control eg specific viruses. It seems to viewed as a more fine-grained response.

Auto-immune diseases result from disorders of the adaptive immune system.
Auto-inflammatory diseases would result from disorders of the innate system.

Some diseases could start with one and lead to the other: perhaps rheumatoid arthritis.

The role of platelets as part of the innate system is now being considered, esp. as a first responder with degranulation. Their persistent hyperactivation could be a mechanism that leads to auto-inflammatory diseases. Maybe that's what is driving LC and ME.

ETA: dysfunction centred on the innate immune system would tie in to the observed heritability.

 

Hard to know what the relative contributions might be for him and a good question all round. I don't know much more than the suggestion that lipids could be behaving in a related way to micro-clots in some ME patients. I would hope there aren't too many different fundamental mechanisms at play. For that to work in this type of model, presumably lipids would be promoting endothelial dysfunction (esp. in the capillaries) and perpetuating platelet activation (and dyslipdiaemia). We need to see what is published about micro-clot burden and lipid profile pre/post treatment (apheresis and anti-platelet).

I would note that Dr. Bruce Patterson (IncellDx) has been claiming great success in LC, with deep analysis of immune panels for diagnostics and monitoring and using a CCR5 antagonist (Maraviroc) and statins for treatment.

You bet! I can imagine there are also medicolegal ramifications in the other direction - possibly directed at the BPS contingent, but also to those in charge of the inadequate LC response. He's pushing very hard of course - but there is a risk, that we have highlighted here before, that loss of momentum could see BPS regaining the upper hand and consigning LC to the long term disaster of ME.

From what I've read, HELP apheresis is claimed to have been used in Germany for 40 years with no serious adverse events. Unsure if "no" is entirely realistic - surely someone has lost more than a bit of circulating blood volume or developed a canulation-related sepsis over the years.

No, that was Dr. Jaeger. I would hope that Distinguished Prof. Resia Pretorius does not have such difficulties!

 

yes, ME and cognitive problems

It is very unfortunate that Dr Patterson’s work has been overshadowed by politics because he is doing very good work in the field for ME/CFS, much as he did for HIV and hopefully will get his papers published.

 

I'll offer a hypothetical example that is at the sort of level I'm suggesting (per anecdotes).

The RCT is to look at effectiveness of a single oral medication course. The proposal is for a month of daily medication vs identical placebo. It's randomised and double-blinded as usual.

Patient A is a young man who was at a European university when he developed ME. He was previously fit and active and spoke four languages fluently. For the last five years he has been severely ill and bed-bound. For the last two of those, he has been intolerant of light and sound and barely able to mumble words and only in his native language.

He takes the first pill. After six hours he is still confined to bed, but now he's smiling and speaking fluent conversational English.

Of course I really want DB-RCTs too. I'm just flagging that this could well be more challenging than usual. Perhaps you can isolate the patient from the researchers for self-administered pills, but it seems to me it would be a lot harder for a physical technique like apheresis vs sham apheresis that needs active involvement. Harder, hopefully not impossible.

On apheresis: a sham apheresis would presumably do everything the HELP apheresis does, but without the heparin phase. Hopefully sham is genuinely ineffective in this context. It would have to be in an isolated room, patient physically blinded from the machine's filters, and the technicians would have to change the filters regardless (which may be an unacceptable risk). The filters would have to be opaque so that the technician doesn't know they've actually filled with fibrin. But, they can't be opaque because they need to monitor them continuously, to make sure they're not filling with fibrin, as that is a risk if the circuit occludes, ruptures and the patient then loses a fifth of their blood volume. (Air embolism is another potential risk)

As you say, hopefully they can think of a way around the difficulties. Maybe it's just as straightforward as comparing a single therapeutic vs sham dose, if you can't maintain the blind over a course. If they look at the objective blood markers as well as clinical response, maybe that's all that's needed to proceed to the next step of therapeutic evaluation.

Will be interesting to see how they try to solve this.

 

I can try to explain a bit more why I don't think there is any reason to think this is an undervalued breakthrough and that historical analogies are invalid but just one thing for now

Long Covid goes on for months and for some more than a year already. ME much longer.
If there are micro clots circulating they must be being produced on a daily basis over that time.
what is the point of trying to clear them away for a few hours a few times over a month or so?
As soon as you are back home the problem is just the same. It is a bit like treating diabetes with short courses of insulin injections. It makes no sense at all.

 

That’s what I thought.

I have LC + ME. I would love to find the answer but I am really worried by this one.

One or both illnesses could possibly be haematological. But if so they would still be illnesses with an ongoing pathological process. Chronic illness. Not an acute transitory attack. So surely there would be a more sophisticated appropriate way to treat, than sieving your blood however often you can afford it.

 

I find it very interesting although I don't allow myself to get my hopes up about anything anymore - not since Rituximab. To my mind there have been too many researchers that seem to think that something is wrong with blood or blood vessels in ME -Ron Davis, Fluge and Mella who thought there was some sort of endothelial dysfunction, and I think Van Spence at ME Research.

As well as Rituximab, I seem to remember Fluge and Mella did trials on L-Arginine, L-Citruline and nitroglycerin to see if improving vasodilation would eleviate symptoms unsuccessfully unfortunately. I've also a vague recollection of someone making a comment at a conference (Invest In ME?) around the time when Fluge and Mella were doing this work that perhaps blood being stickier in a morning, (hence more heart attack and strokes occuring in the early hours), might explain why PWME often feel worse in a morning.

 

Yeah and my blood ‘feels’ like it flows too slowly and all my tissues hurt and they all need lovely healthy blood. So the Bad Blood theory is quite acceptable to me on an intuitive level.

I am not sure about the treatment and have some concerns over unintended consequences that might arise when the origin of the cascade is known.

If looking to treat experimentally I feel that this should be framed as the shot in the dark that it really is.

I don’t think it is safe to leave people with LC untreated. People are dying from this neglect, many complications. So taking a risk with your own body or patients is different in the context of this condition than it would be otherwise.

Still I think it is best to be honest and to present this treatment as the risky and rather desperate endeavour that it is.

 

I think in a way this illustrates why 'LongCovid' may be an unhelpful concept.

1. Some people who have had Covid go on feeling terrible for months (maybe a bit like ME).

2. Some people who have had Covid have strokes and pulmonary embolism and die.

but
3. As far as I am aware: 1. has nothing to do with 2. So calling them LongCovid can only do harm.

In conditions where repeated clot formation causes stroke or PE etc. there is no clear association with feeling ill in between.

In other words if you have had Covid and feel terrible there seems to be no reason to think that having anti-clot therapy is of any use to you.

 

@SNT Gatchaman I suspect you have seen Blair Grubb's intro to this study broadcast last night? If not & for the benefit of others, it can be watched here:
https://fb.watch/9Mrloo28E-/

The prior study showing the platelet storage pool deficiency & abnormal cytokine findings in a subset of POTS patients was posted here:
https://www.s4me.info/threads/infla...utoantibodies-2021-gunning-grubb-et-al.19055/

 

My theory is: microclots = micro immune complexes

During viral infection the B cells of the adaptive immunity produce vast amounts of different antigens that some are autoreactive to various self proteins in the blood. This has been shown by Akikio at Yale.

These autoantigens towards small proteins create extremly small immune complexes when they bind in contrast to the larger immune complexes create when antigen binds to a cell or virus.

The process of constantly clearing those immune complexes activates the inate immune system and that is what is causing symptoms in both ME/CFS and Long Covid.

Therefor my next research question would be to analyse what these microclots actually contain.
.

 

I don't think that is possible.

Once immune complexes include more than a handful of antibody (not antigen) molecules they activate C1q and the resulting complement activation triggers binding to red cell complement receptors.

The 'micro-clots' described by Praetorius are about 100microns across - billions of protein molecules. She has described what is in them, I think including fibrin, platelet factors and an amyloid component. I don't think these have anything to do with immune complexes.

And I am not aware of evidence for autoantibodies to soluble plasma proteins?

 

This was covered on this thread: https://www.s4me.info/threads/reap-...-the-human-exoproteome-2021-wang-et-al.20747/

But I agree that if the microclots are 100microns across then it is even larger than a cell and my theory might not stand completely but I still think there is some truth there.

But if the microclots are so large why do they not clot up in membranes like the kidney?