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

You might be unique in this. Most people have fluctuations, yes, but I'm not sure they vacillate so quickly and clearly.

 

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.

 

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! 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!

 

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.

 

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.

 

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.

 

Has anyone looked though? I had massive clots (severe bilateral deep vein thrombosis) a few years after onset, but before diagnosis of ME/CFS.

 

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.

 

To me the key point is that if clots were big enough to explain any of the features of ME they would have been found by now.

I also think that considering that a lot of people with severe ME are bed bound if there was an issue with clotting it would have come to light.

 

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)

 

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!