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

Creekside said:
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?
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You might be unique in this. Most people have fluctuations, yes, but I'm not sure they vacillate so quickly and clearly.
 
Trish said:
I have not come across any other pwME who describe such switching. I think it very likely that there are subgroups with different biological processes happening that lead to different symptom experiences, while still all experiencing versions of PEM.
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I did experience a handful of episodes that subjectively felt like my ME switching on or off in the first five plus years, mainly when I was oscillating between mild and moderate, but have not experienced them since in the last twenty years plus when on average my ME has moved between moderate and severe much more slowly.

[added - These episodes may just have been in my first spell of EBV triggered ME, which I did believe at the time I had recovered from after some four? years, but I don’t think I have experienced them in my second influenza triggered ME.]

I was mainly aware of it in relation cognitive function where suddenly my ‘brain function’ was what I felt should be normal. It is harder to be clear about ME switching on, as how do you distinguish between that and a fatigue threshold of some sort. But on the rare occasions when it felt like it was switching off it literally felt like a light was switched on inside my head.
 
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I guess we'll find out if this pans out in time, although of course it's fun to speculate. (And this just is speculation; I'm not feeling great and can't do something more useful so am just googling.)

I'm wondering if microclots might cause the fatiguability during activity, due to the increased oxygen demand causing traffic jams in capillaries causing localised hypoxia due to reduced blood flow. And then the subsequent and slow cleaning up of the microclot jams causes the release of substances that make us feel unwell (i.e. PEM).

Something has to cause the microclots.

Looking at what Pretorious et al found in the clots - there was a lot of a2AP(anti-plasmin) and complement component 7.

This study suggests that a2AP levels increase during an infection. Maybe the pathogen does something to disable it in clots; or maybe it's part of the body's clean-up system to fold unneeded a2AP into a clot for later breakdown.
Endogenous α2-antiplasmin is protective during severe gram-negative sepsis (melioidosis) (2013)
Patients with melioidosis showed elevated A2AP plasma levels.
This study is the first to identify A2AP as a protective mediator during gram-negative (pneumo)sepsis by limiting bacterial growth, inflammation, tissue injury, and coagulation.
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and complement component 7 is also part of a pathogen response.
Complement component 7 is a protein involved in the complement system of the innate immune system. C7 is part of the membrane attack complex (MAC) which creates a hole on pathogensurfaces, leading to cell lysis and death.
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So, it makes sense that people who have just dealt with a significant pathogen attack like Covid-19 might have the microclots as the body goes about recycling the weapons. Yeah, I really want to know if this process is still happening months after the infection.
 
Peter Trewhitt said:
I did experience a handful of episodes that subjectively felt like my ME switching on or off in the first five plus years, mainly when I was oscillating between mild and moderate, but have not experienced them since in the last twenty years plus
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Yes, I've had spontaneous recoveries that occurred pretty much overnight in the early part of my illness. The first was after seven years, and there have been two others subsequently, but nothing like them in the last 25.

For me, it was simply a case of waking up knowing that something major had shifted. Suddenly my muscles could produce power properly, my brain cleared, and my body felt reliable in a way that it usually doesn't. I think it might be similar to what Paul Garner experienced when he suddenly knew he could exercise again; that is exactly how it felt to me, it's just that I didn't attribute it to some woo-woo 'therapy'.

The only comparable sensations in more recent years is during a few viral infections, and most effective of all, the AZ Covid vaccine. The effects only lasted a few days, but it was fantastic to have working legs again for a little while.

Because of the rapid nature of the change, I can only make sense of it as some kind of immune or hormonal shift. I certainly always had a big energy boost at the end of the luteal phase of my cycle that lasted a single day, so I know that hormones can affect the way I feel, but the immune effects I've experienced seem much stronger and improve muscle function in a way that hormone shifts never did.

Coincidentally (and probably somewhat off-topic—apologies), I realised today that I've accidentally captured a graph of the way steroids affect my ME. In July I got asthma for the first time in many years, and was prescribed an inhaler. I'd completely forgotten that the treatment is much worse than the asthma, and duly started using it. Through the resting heart rate graph on the left, you can see the effect building up and then tailing off again when I threw the wretched thing in the bin! :laugh: The right-hand graph is the trace since then, which as usual is pretty stable because I haven't had any severe PEM.

ETA: it's not the asthma itself that caused the shift in the RHR, that's still as bad as ever!

RHR.png
 
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Would this sort of thing cause veins/capillaries in the hands to burst? At my very severe ME onset I was getting that bee sting type pain in my hands and would look at hands and see a burst blood capillary/vein under the skin. It happened often. I rarely get it now.
 
SNT Gatchaman said:
Why might some people be pre-disposed to ME? Why female predominance?
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I would have thought that the differences in the functioning of the immune systems in males and females must be part of the explanation, even if I can't take that thought any further (I have no medical training).

When women get pregnant their bodies must not reject the foreign body inside them or else the human race would effectively die out within a century. But the immune system of a man with something organic and foreign inside them would presumably try to destroy it with their immune system, or would attempt to encapsulate the foreign body, or digest it, or eject it via vomiting, urination, or defecation.

I know this is rather crude, but women are not just sad, dickless men with squishy bits on the chest. Our bodies have different functions to that of men. Society has concentrated on different aspects of that difference depending on what was convenient to them at the time. So, there have been times that women have been considered to be inferior to men because they are generally smaller and weaker than men. At other times society has decided the most important difference is that women are stupider than men after making sure that females were denied an education.

The difference in the functioning of immune systems in male and female bodies rarely gets a mention. But the fact that women get autoimmune diseases at a far greater rate than men must be related to that difference, I would have thought. Autoimmune diseases have been assumed (by society) to be due to psychological and physical weakness for millennia, even before the concept of an autoimmune disease was a twinkle in anyone's eye.
 
There was brief talk about looking at nailfold capillaroscopy as a diagnostic tool by Ron Davis but I haven't heard anything more about it. I was interested at the time because at one point I was assessed for systemic sclerosis because of my abnormal nailfold capillaries but in the end they put them down to Raynaud's instead (phew!). But I wonder what happened to OMF looking at capillaroscopy?

https://www.s4me.info/threads/lives...-columbia-university.12407/page-3#post-221191
 
@Arnie Pye I agree with everything you say above. Women have a stronger immune system, though this is something of a double-edged sword, with risk of autoimmune disease. As you note this is down-regulated in pregnancy.

I could have included that in the paragraph, but this is thread is tending long and I wanted to discuss new concepts. I was taking it as read that the female immune system difference was well appreciated.

The reports of ME remissions with pregnancy could easily be due to temporary immune tolerance, but they could also relate to the profound vascular changes that occur with the necessary hyperdynamic circulation. Does anyone know if ME in pregnancy has been adequately studied and whether remissions tend to occur in the later part of pregnancy when the circulation changes would take effect?
 
Thank you again @Hutan. A Comparison of Pregnancies That Occur Before and After the Onset of Chronic Fatigue Syndrome by Schacterle and Komaroff showed variable effects: some improvements, some stable, some deteriorations.

There were at least a couple of anecdotal descriptions by patients on PR (I won't quote as in members-only section) but both had significant improvement or remission starting in mid-second trimester. Understandably most discussion has been around the hormonal and immune changes. Not sure if the cardiovascular changes have been considered yet.

ETA: according to ME-pedia, Nancy Klimas raised the possibility of increased intravascular volume.
 
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Hutan said:
And yet, there doesn't seem to be evidence for people with ME/CFS suffering from thrombosis (as we would normally think of it) at unusual rates.? If these microclots are a problem, why don't they increase the incidence of bigger clots?
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Yes, I think for all hypotheses like this we need to stand back and ask if it fits in any way with what we already know.

There are a number of micro-clotting as well as macro-clotting diseases. They include sickle cell disease, TTP, anti-phospholipid syndrome, polycythaemia rubra vera and so on. None of these obviously produces anything like ME. By the time there is vascular insufficiency it is usually easy enough to pick up structural changes.

The only exception here is anti-phospholipid syndrome, which can overlap with lupus and can be associated with fatigue. Venables found anti-phospholipid antibodies in a group of PWME in the 1980s but I haven't seen anything much on that since. Moreover, I doubt the fatigue in APS has much to do with microvascular thrombosis.

People with ME are very disabled. It is hard to explain that with a vascular problem that is so hidden nobody has found it yet.
 
Hutan said:
And yet, there doesn't seem to be evidence for people with ME/CFS suffering from thrombosis (as we would normally think of it) at unusual rates.? If these microclots are a problem, why don't they increase the incidence of bigger clots?
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Has anyone looked though? I had massive clots (severe bilateral deep vein thrombosis) a few years after onset, but before diagnosis of ME/CFS.
 
SNT Gatchaman said:
As you note this is down-regulated in pregnancy.
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I didn't actually say that. I don't know if the immune system of women is only different to the immune system of men during pregnancy. I would find it much more believable that the immune system of women is different to that of men all during their fertile years, and possibly even before and after a woman's fertile years.
 
Jonathan Edwards said:
People with ME are very disabled. It is hard to explain that with a vascular problem that is so hidden nobody has found it yet.
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Thank you and I appreciate that this is all far from my medical wheelhouse and firmly in yours! I'm taking three pieces of new information demonstrated with long COVID: microclots containing abnormal proteins and inflammatory mediators; dramatically low venous oxygen saturation - shown at presentation and up to 12 months in Asad Khan; and anecdotal significant symptom improvement with apheresis removing the micro-clots. In the background, we note long-term ME patients have normal to high SvO2.

I'm trying to propose a model where the inflammatory mediators in the micro-clots cause tissue dysfunction primarily by causing an endothelitis, but only in the micro-circulation and that this causes the majority of symptoms. The occlusive aspect if present might be partial and only in the micro-circulation, sufficient to impede RBC transit and allow for PEM with increased blood flow and low SvO2 (at least in early-phase). An oxygen poor environment in the blood pool could affect circulating white blood cells and cause further immune perturbation.

Perhaps the micro-clots do not induce thrombosis beyond maintaining their own integrity, but their presence induces disruption of RBC deformability — and then slowed capillary transit.

(Time for bed down in this part of the world)
 
In idle googling, I did come across 'microparticles' which appear to be associated with many of the substances that were found in the microclots by Pretorius. And it was interesting to see that healthy neutrophils put in serum from patients with ANCA associated vasculitis released the microparticles and also the NETs we have looked at before. And there's mention of RBC shear forces and impacts on endothelium in the literature. But, yeah, it's making it hang together with what we actually see in ME/CFS that's a problem. Yes, time to call it a night in this part of the world.
e.g.
Tissue factor expression in neutrophil extracellular traps and neutrophil derived microparticles in antineutrophil cytoplasmic antibody associated vasculitis may promote thromboinflammation and the thrombophilic state associated with the disease
Abstract
Objectives: Antineutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) is characterised by neutrophil activation. An elevated prevalence of venous thromboembolic events has been reported in AAV. Because of the critical role of neutrophils in inflammation associated thrombosis, we asked whether neutrophil tissue factor (TF) may be implicated in the thrombotic diathesis in AAV.

Methods: Neutrophils from four patients and sera from 17 patients with ANCA associated vasculitis with active disease and remission were studied. TF expression was assessed by immunoblotting and confocal microscopy. Circulating DNA levels were evaluated. TF expressing microparticles (MPs) were measured by flow cytometry and thrombin-antithrombin complex levels by ELISA.

Results: Peripheral blood neutrophils from four patients with active disease expressed elevated TF levels and released TF expressing neutrophil extracellular traps (NETs) and MPs. TF positive NETs were released by neutrophils isolated from the bronchoalveolar lavage and were detected in nasal and renal biopsy specimens. Elevated levels of circulating DNA and TF expressing neutrophil derived MPs were further observed in sera from patients with active disease. Induction of remission attenuated the aforementioned effects. Control neutrophils treated with sera from patients with active disease released TF bearing NETs and MPs which were abolished after IgG depletion. Treatment of control neutrophils with isolated IgG from sera from patients with active disease also resulted in the release of TF bearing NETs. TF implication in MP dependent thrombin generation was demonstrated by antibody neutralisation studies.

Conclusions: Expression of TF in NETs and neutrophil derived MPs proposes a novel mechanism for the induction of thrombosis and inflammation in active AAV.
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This subject makes me think of MS, not that microcirculation has been implicated, just that reduced cerebral blood flow has been. I don’t follow the research but I know it’s been questioned as part of the pathology of symptoms like fatigue.

There was a proof of concept trial https://pubmed.ncbi.nlm.nih.gov/32765401/ looking at lowering Endothelian 1 in the brain (to decrease vasoconstriction) with a negative result but it turned out that the treated MS patients (just 11 of them) had normal cerebral blood flow, so not everyone with MS has this issue.

I just wonder if microcirculation is a missing piece of the puzzle. If perhaps multiple issues with blood flow in people with ME, MS, and long covid contribute to why there’s such a wide range of fatigue severity in each illness?

I was told by my doctor that pregnancy improvements occur at about the same rate in MS as ME and I think she was basing the ME numbers on this Harvard study https://dash.harvard.edu/handle/1/37168988
 
I see ME as a multifactorial end pathway with genetic predisposition. The problem I have with microclots being part of the causation of ME is currently the lack of evidence in the ME population and I can’t recall any evidence of the long term sequalae of having microclots, which should show up in a autopsy pathology slide of tissues, a muscle biopsy or in brain imaging. The covid virus is known to cause major thrombotic events and so microclots may be occurring within the brain (triggering ME symptoms) and periphery causing ischaemia and then presumably infarction. The “something in the blood” and transferable, to me, suggests a protein/inflammatory something.
 
Yes, it may turn out that long Covid only has symptom overlap with ME but it's a different pathway, as you say @hibiscuswahine. Might still shed light one might hope.

But, maybe autopsy / biopsy studies in the past have not done the required preparation to demonstrate the micro-clots?

Persistent Endotheliopathy in the Pathogenesis of Long COVID Syndrome

ETA: Whoops I copied the URL from the wrong browser tab. I'll leave it up in case anyone wants to cross the streams. Thanks @Hutan!
 
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