The Occurrence of Hyperactivated Platelets and Fibrinaloid Microclots in ME/CFS, 2022, Nunes, Pretorius et al

Haven't read the paper, but I wonder about this and the other co-morbid diagnoses: Were these self-reported or tested in the study? If the latter, which tests did they use? Were the healthy controls also tested?

 

Since RA is not generally associated with PEM that suggests these microclots are not causing PEM (at least not alone).

If we ignore that for moment, would it be plausible for PEM to be roughly this sequence of events?

1. A person that was resting begins an activity.
2. The activity also causes a gradually increasing immune activity that favors formation of microclots, but this is initially not noticable due to the physiological changes occurring during activity (blood is being pumped faster and harder, changes in vasodilation, etc).
3. Once the person stops the activity and the cardiovascular system attempts to return to normal, the problems become more noticable. Exhausted cells are now being starved of nutrients and can't recover properly.
4. After some time, the most stressed cells die off and this unusual wave of cells dying triggers alarm signals that result in particular kind of sickness response that looks like PEM. Or maybe merely the signals sent out by these stressed cells is enough to trigger a PEM response which has the purpose of suppressing unnecessary activity.
5. Sleep quality is disrupted, making it even more difficult to properly recover.

 

There are a number of things about the paper that seem peculiar.

The abstract ends with 'The discovery of these biomarkers pointing to significant and systemic endothelial inflammation, represents an important development in ME/CFS research. It also points at novel treatment strategies using known drugs and/or nutraceuticals that target systemic vascular pathology and endothelial inflammation.'

I don't know what endothelial inflammation means. Inflammation is the process of white cells passing though endothelium to the tissues. The endothelium itself cannot be 'inflamed'.

Whether or not this is an important development is surely for readers to decide.

Why are nutraceuticals mentioned?

In the results it says that 3 out of 25 patients had rheumatoid arthritis. This suggests very strange recruitment since RA occurs in about 0.5% of the population. Moreover, surely a study of ME should exclude patients with RA since the findings might be due to RA. And the patients had all sorts of other diseases too. I am not sure what gut dysbiosis is supposed to be - who diagnosed this?

The results seem to consist of some rather vague statements, some pictures of blobs that I find pretty hard to make much of, and a dramatic histogram showing '% amyloid area' - maybe a measure of the blobs.

I am left a bit bewildered.

 

I think the problem is that if PEM was due to dying cells we would expect a rise in CRP and platelet count etc..

ME might not follow the usual rules but we can only get the plausibility of sequence like the by the rules from other conditions.

Poor blood supply muscle is a well known clinical problem and it produces claudication - pain of sudden onset relieved by rest.

Microclots from platelets produce transient loss of vision (amaurosis fugax) and transient stroke (TIA).

These are not feature of ME.

 

Since we're all happily speculating here, I'll add another idea to the mix (haven't read the study either, just to be certain I don't know what I'm talking about)

If only a subgroup is affected, could this be because the weird clotting is a corona-specific effect and that the affected ME subgroup just happens to have "very long covid" from one of the common cold coronaviruses circulating?

N=1 Thick, black blood, needles blocking up (that's the big ones like the ones they use for blood donations) and even having the nurses literally pull blood clots out of my veins when removing the needle used to be a regular occurrence for me. The doctor wasn't keen on blood thinners but didn't object to me trying supplements with blood-thinning effect (possibly because he thought they'd be useless?). Anyway, that's what I've been doing since. It's very effective for avoiding the blocked needles, my blood runs much better. Makes no difference to my ME though. And little if any (not sure on this one, definitely not a big effect) to my various symptoms related to capillaries doing strange things.

So I have a sneaky feeling that the whole blood clotting thing may turn out to be a sideshow. But prompt and rigorous replication would be much appreciated

 

Except that the common cold is the one infection nobody seems to have linked to ME?
Nobody much says 'well blow me down, I just had an ordinary cold with a runny nose and ever since I have been unable to do anything'.

 

One thing that perhaps worried me most is that the method section of the paper says nothing about blinding. It indicates that samples were viewed under a microscope and areas selected for image analysis. I am afraid that this is the perfect scenario for observer bias. I used to do this sort of microscopic analysis and it is almost impossible not to be biased if you know what you are supposed to be looking at.

 

Not any old cold, specifically the common cold caused by corona viruses. I'm speculating (wildly!) that they could be the ones responsible for the supposedly non-infectious ME onsets. Asymptomatic infection or very mild acute infection followed by a gap of apparent recovery before ME symptoms set in. This is a pattern frequently reported by Long Haulers, so it could be a general corona pattern for all we know and don't know.

I readily admit I'm mostly speculating for my own amusement and because for the time being, with the evidence we have or rather don't have, nobody can conclusively prove me wrong (since no one has bothered with large prospective population studies testing for all the viruses under the sun)

 

Supplementary table 2 presents the results of the Thrombelastograph (TEG)


This is what the values mean, after a brief online search:

R: Time to initial clot formation

K: Time from initial clot formation until reaching 20 mm in amplitude

Alpha angle (α): Angle between the baseline at initial clot formation, and a tangent line that intersects the tracing curve.

Maximum amplitude: Maximum deviation of tracing to baseline.

MRTG: maximum rate of thrombus generation

TMRTG: time to maximum rate of thrombus generation

TTG: Total Thrombus Generation​

I find it a bit strange that most values showed no significant difference while two (alpha angle and MRTG) showed major differences. From my limited understanding, these values should be related to each other. If I understand correctly, there was mostly an abnormality in the (steep) rate of clot formation (alpha and MRTG) in ME patients with no significant differences in maximum amplitude or total trombus generation.

 

The authors also write:

"it is important to note that the fibrinaloid burden in ME/CFS seems to be less than that present in LongCovid/PASC, thus caution is required when therapy in ME/CFS."​

 

In this sample of 25 ME patients, 12% had rheumatoid arthritis, which seems like quite a lot.

Here's a related Twitter reply from one of Doug Kell the authors of the paper indicating he believes it to be present in other conditions as well:
https://twitter.com/user/status/1534625939631525888

 

I'm having trouble reading the paper. Do these pwME have normal platelet counts?

What happens if you have perpetually low platelet counts, and have some issues with clotting? I have ME/CFS and PEM, but I have low platelets, usually out of range low. I wonder if this matters.

I am about to find out. My ME/CFS doctor is also a leader in Covid and LC research, and that doctor/researcher has me getting tested for all sorts of LC coagulant/microclot stuff. Mast cell tests, too, which evidently are employed in LC research.

I will try to pass on my results, although I'm told some could take weeks.

 

I also have trouble connecting these results to their previous paper on long covid. Seems like the results are hard to compare because other measures and techniques were used. Don't think they did a TEG in the long covid paper?
https://cardiab.biomedcentral.com/articles/10.1186/s12933-021-01359-7

 

The results of that figure look like a major difference but the authors reported even larger differences for diabetes type 2 and covid-19 in a 2020 paper:

The 2022 results on 25 ME patients and 15 controls:


2020 results of 10 healthy controls, 10 diabetes patients and 20 covid-19 patients

Reported here:
https://cardiab.biomedcentral.com/track/pdf/10.1186/s12933-020-01165-7.pdf

 

These microclots can't be the cause of PEM if they're found in other diseases not associated with PEM.

 

The term "endotheliitis" is being used a lot in relation to Covid. Authors generally seem to indicate direct viral infection (acutely) of endothelial cells, separation of ECs from basement membranes and pericytes, as well as an ongoing pathological interaction with platelets and mediators at the vessel/lumen interface.

The problem as you identify is the single cell endothelial layer has the function of directing the vascular component of the inflammatory response. Tight junctions loosen and then leukocytes migrate from blood to injured tissues. I guess this classic definition presupposes that the endothelial layer is healthy and behaving appropriately. Perhaps this is a necessary term for the edge-case for what happens as a damage limiting/repair response, when the target tissue is that endothelial cell layer.

Search on PubMed for review articles on "endotheliitis", gives 110 results with a graph that looks to match the pandemic.



The best/most recent I could come up with was in Endotheliitis, Shunts, and Ventilation–Perfusion Mismatch in Coronavirus Disease 2019: A Literature Review of Disease Mechanisms (Jun 2022).

I wondered if that was supposed to read "by subendothelial lymphocytes". I asked a paediatric pathologist friend (who is a tumour guru but doesn't do transplants).

So perhaps we could view it as an abbreviated form of inflammation. The vascular changes only need to go so far as lymphocytes don't need to pass through the basement membrane to deeper tissue layers, as they're not in need of attention.

 

Are there any conflicts of interest?

 

Yes, I think it is basically a reflection of the fact that nowadays people who work on these things have no basic histological training, or indeed basic pathological training on inflammation. So the terminology is garbage.

'Endotheliitis' as a component of graft rejection seems fair enough as a meaningful if aberrant technical term for evidence of lymphocyte attack on endothelial cells. That is something very specific to graft rejection though and I don't think the present paper talks of endothliitis - just endothelial inflammation, and it doesn't seem to bear any relation to the graft situation?

 

If they have found abnormal micro clots in RA then including three cases of RA in the ME series is just incompetent.

I looked up Kell. His background seems unusual. The paper on RA is revealing. It makes a lot of the work of my old colleague, Alan Ebringer, which nobody much has taken seriously and which to my mind is baseless. It includes the statement:

The present systems biology analysis benefits from the philosophical idea of "coherence," that reflects the principle that if a series of ostensibly unrelated findings are brought together into a self-consistent narrative, that narrative is thereby strengthened.

I think Kell is missing the fact that the scientific idea of coherence is that when you bring together lots of ostensibly unrelated findings none of them refute your hypothesis. In science we always look for the 'no' evidence' not for the 'yes' evidence. Kell's statement looks to me very much like the yes evidence approach. All series of ostensibly unrelated findings can be cobbled together into a self-consistent narrative - as long as you don't mention the ones that don't fit that is.

There are rather a lot of things in this story that don't fit, one being that they seem to get positive results with every known disease!