Is me/cfs a blood disorder?

wabi-sabi

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I'm going to go with no.

Here's my reasoning. When people say "blood disorder" that means something wrong with your RBCs, like anemia, something wrong with your WBCs, like leukemia, or something wrong with your platelets (although those often get referred to as clotting disorders, rather than blood disorders. All of these things are fairly easy to diagnose and would be hard to miss on the common blood tests where most of us are normal. When you first went to the doc saying you were tired all the time, anemia was probably one of the first things s/he ruled out.

That's not to say that there's not something off with our blood, like the RBC deformability problems some studies show. But other studies haven't shown, I think? I am certainly not ready to say that ME/CFS is caused by RBC deformability issues, even if that is a component, since I don't think we know that yet. And again because calling it a blood disorder would imply that is both the case and the main treatment target, which I also don't think we know yet.

There is something clearly wrong with blood flow and perfusion, but those types of issues aren't necessarily not something categorized as (or caused by) a blood disorder. You could say I'm arguing semantics a bit, but I think it's more a problem of correct disease classification and identifying the underlying problem as opposed to all the downstream problems.

Prove me wrong, science!
 

SNT Gatchaman

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I'm going with "qualified yes" but also "no" i.e. "it's complicated". I think it is a blood and blood vessel disorder.

This concept is based on the idea that micro-clots are the "something in the blood" that Ron Davis found. Just a personal theory and I'm sure there are plenty of holes to pick!

Established and New Knowledge
  • Ron Davis showed abnormal impedance measurements in plasma containing peripheral blood mononuclear cells (PBMCs) that are stressed by hyperosmotic saline.
  • No false positives/negatives vs health controls
  • Ron Davis showed that filtering plasma by size significantly reduced but did not eliminate the effect
  • Effect assumed to relate to the stressed PBMCs
  • Resia Pretorius has shown micro-clots in long COVID patients that contain:
    • Von Willebrand Factor
    • C-reactive protein
    • Coagulation factor XIII A chain
    • Plasminogen
    • Fibrinogen alpha chain
    • a2 Antiplasmin (a2AP)
    • Serum Amyloid (SAA4)
    • Complement components C4b and C7
I wonder if Ron Davis was measuring the micro-clots themselves, could they eg aggregate and result in impedance changes after 60 minutes of exposure to hyperosmotic saline?
  • Long COVID has significant symptom overlap with ME/CFS. Post-exertional malaise is a defining feature of ME/CFS and a unique symptom, whose cause is not understood. It can follow physical, cognitive or emotional exertion that may be demanding or modest. There is typically a delay of up to 24-48 hours following exertion, before the symptoms of PEM manifest.
  • Early anecdotal experience is suggesting significant symptom reduction from long COVID symptoms, following removal of these micro-clots from the circulation via HELP-apheresis.
  • Long COVID patients also demonstrate significantly decreased SvO2 at least in their first 12 months. However, long-term ME/CFS patients show normal to high SvO2.
Micro-clots
  • Have been detected in circulating blood
  • Could tend to accumulate, adherent to capillary walls where their contents could induce endothelitis
  • May cause flow limitation, without being occlusive
  • Could be released from the capillaries into the venous circulation with increased blood flow of exertion or tend to aggregate more in capillaries
Red Blood Cells
  • RBCs have been shown to have abnormal morphology and reduced deformability
  • They need to fold from bi-concave disc to "taco" shape to pass through the smallest capillaries
  • Poor deformability and abnormal shape could slow capillary transit speeds
  • At rest, RBCs transit random capillaries, leaving some relatively free
  • More blood flow would recruit more capillaries for RBC transit
Theory of ME metabolic disruption
  • Due to endothelitis, micro-clots are impairing oxygen delivery at the micro-circulation level,
  • This results in metabolic adaptations, which may be adequate for at-rest requirements, but rely on operation at or near anaerobic threshold
  • The micro-clots cause associated platelet changes and RBC morphology/deformability changes that may result in impaired passage through capillaries
  • Increased capillary RBC transit time could promote increased oxygen extraction from RBCs which results in decreased venous oxygen saturation
  • This means that circulating white blood cells (in the venous blood pool) are in an oxygen-poor environment so also switch their metabolic pathways, which might cause multiple immune perturbations.
Theory of PEM
  • PEM is a generalised phenonomen that has a variable symptom range
  • It may vary according to the increased blood flow associated with demand in different organs: muscles, gut or brain
  • PEM might be explained by metabolic and/or immune exhaustion following exertion. Another possibility is that there is a vascular and/or haemodynamic component.
  • Increasing blood flow could result in involvement of more capillaries, which — at threshold — results in a "traffic jam" of slow-moving poorly deformable RBCs
  • Or higher blood flows may be associated with more RBC damage as they pass through capillaries with micro-clots
  • This might acutely lower venous oxygenation due to more opportunity for oxygen extraction, from tissues that usually receive less than normal and would like more
  • The more oxygen-poor venous blood pool may further metabolically impair circulating white blood cells causing increased immune perturbation
  • Reduced blood reaching the venous circulation and/or haemodynamic compensations may cause POTS symptoms, including reduced cerebral blood flow (neuroinflammation)
Low SvO2 in "early-phase" ME / Normal-high SvO2 in "late-phase" ME
  • Chronic ME patients could develop short AV shunts in the micro-circulation that bypass (even temporarily) compromised capillaries and lead to normalisation or elevation of SvO2
  • Does every episode of severe PEM cause functional impairment of more capillaries and result in more short AV shunts forming?
  • Does this mean that with more PEM, recovery takes longer and overall symptoms risk worsening?
Demographics and Disease Spectrum
  • May relate to genetics of immune and coagulation systems that fail to handle or promote micro-clot formation
  • Females have a stronger immune system - do the micro-clots form from immune over-response to infectious agents?
  • May be genetic variation in capillary diameters
  • Capillary diameters may be smaller in some organs only (muscle, brain, gut, nerve)
  • Might explain "fibromyalgia", "ME", "POTS" type profiles
  • Children have a higher recovery rate - capillary growth or remodelling?
  • Sex-variation in vascular performance (see NASA astronaut studies on return-to-gravity orthostatic Intolerance)
 

wabi-sabi

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This concept is based on the idea that micro-clots are the "something in the blood" that Ron Davis found. Just a personal theory and I'm sure there are plenty of holes to pick!
I see the argument mostly hanging on microclots are the right size to be the something and long COVID has microclots so probably ME/CFS does too. If these two premises are correct, everything else flows quite nicely and logically from them.

I'm not yet (totally) convinced that the microclots are the special something. I thought there was talk of extracellular vesciles being the something at one point?

More data! How would we show this one way or the other?
 
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Its an interesting theory that might explain why rons team wasn't able to isolate the compound responsible, maybe it isn't a specific compound... wouldn't micro clots show on a microscope though ? or are we talking about aggregations that are thousands of times smaller than the cells but are still able to slow blood flow ? I would have assumed that to be significant in obstructing the circulation these clots would have needed to be on a visible scale when compared to a red blood cell ? I may be misunderstanding the science of this. I feel like it might be hard to answer this without taking the question directly to those that ran the experiment as they would understand the intricate details of the design.
 
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I would have assumed that to be significant in obstructing the circulation these clots would have needed to be on a visible scale when compared to a red blood cell ?
a long covid paper showed images of a very large clot in a long haul person, but its unclear if we have seen actual stained clots in ME folks. (that is in a recent PR thread around here someplace)

I was recalling that the Something in the Blood is associated with Exosomes.
 

Shanti1

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I think microclots are too large to be the "something" Ron Davis found in the blood.
Here is an image of the resistant microclots found by Dr. Pretorius in Long-Covid patients:
1636146806182.png

Here is an infographic on sizes
1636146857760.png

Given the size of the clots and that clots contain platelets (which are visible with a microscope), I don't think they would have been missed as the "something".
 

Shanti1

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My thought is that ME/CFS is not a blood disorder per se, but something triggers altered blood flow, low RBC deformability, and hypercoagulability, which contributes to symptoms. But I think there are other mechanisms at work too, for example, vegas nerve inflammation, altered immune and cytokine response, mitochondrial dysfunction, and autoimmunity.
Resistant microclots like those found in long-covid, to my knowledge, have not been found in ME/CFS, but people are looking, so we should know soon.

What has been found in some studies is a higher incidence of the following clotting markers:
  • Prothrombin Fragment 1+2
  • Thrombin/ AntiThrombin Complexes
  • Soluble Fibrin Monomer
  • Cardiolipin Antibodies (IgA, IgG, IgM)
  • Beta-2-Glycoprotein I Antibodies (IgG, IgA, IgM)
https://pubmed.ncbi.nlm.nih.gov/10695770/
https://paolomaccallini.com/2016/07...e-anti-cardiolipin-antibodies-and-mast-cells/

I am planning on asking my Doc to check the factors above. For those in the US, the Quest Lab test codes that cover them are:

Thrombotic Marker Panel (11345)
Antiphospholipid Syndrome Diagnostic Panel (19872)
Fibrinogen (461)
 

drob31

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I tested weakly positive for APA on cyrex labs autoimmune panel but not in any of the "regular" lab Corp serum tests.
 

SNT Gatchaman

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wouldn't micro clots show on a microscope though ? or are we talking about aggregations that are thousands of times smaller than the cells but are still able to slow blood flow?
I think most of the micro-clots are very small (the dots in the images) but able to induce platelet activation which adhere to RBCs. RBCs carrying platelets around would slow their passage in capillaries.

The larger aggregates shown in the fluorescence studies might be an artefact of their preparation, rather than representing their in vivo state. Eg does adding the Thioflavin T that binds to the anomalous amyloid (fluorescence) cause clumping?

ETA: Of course even more likely, they may clump as a result of the spin-down to form the platelet-poor plasma.
 
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SNT Gatchaman

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What are your plans to test your hypothesis? It is interesting.
Well I'm leaving that part to the experts (Prof. Pretorius is visiting Germany in 1-2 weeks). She will look for the microclots pre- and post- apheresis.

For myself though, if the early evidence is compelling and we can get the HELP apheresis technique working here in NZ (I think it would be new for us), I might be able to submit myself. I'll let you know, but unlikely before next year I imagine. If I don't report back after then though, it didn't work... ;)
 

Shanti1

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I think most of the micro-clots are very small (the dots in the images) but able to induce platelet activation which adhere to RBCs. RBCs carrying platelets around would slow their passage in capillaries.

The larger aggregates shown in the fluorescence studies might be an artefact of their preparation, rather than representing their in vivo state. Eg does adding the Thioflavin T that binds to the anomalous amyloid (fluorescence) cause clumping?

ETA: Of course even more likely, they may clump as a result of the spin-down to form the platelet-poor plasma.
This is a good point, the microclots were elicited from the plasma in Dr. Pretorius's study by adding something to make them clot, so you wouldn't see microclots under the microscope if you drew blood and looked at it. It seems the formation/deposition of the microclots is actually in the microcirculation, so hard to visualize and access.

Microclots can be visualized on autopsy in COVID patients in the lungs and other organs. Their presence can be inferred by tissue perfusion MRI, CT, or SPEC scan and by altered venous blood gas readings. The tendency to microclot can be measured through a TEG test.

However, to distinguish typical microclots from Long-Covid type resistant microclots you have to use the method described by Dr. Pretorius in her paper or examine them after removal by HELP apheresis for the hallmarks of resistant microclots (altered-fibrinogen structure, high alpha-antiplasmin, high serum amyloid, and resistance to breakdown from trypsin).

I think microclots would also contain platelets since they are basically very small thrombi, but they didn't in Dr. Pretorius's study because she elicited the clotting in platelety poor plasma.
@SNT Gatchaman Is the above your understanding as well? Two brains are better than one :)

Still, when it comes to Ron Davis's "Something in the Blood", since that experiment was carried out measuring the ability of WBC in ME/CFS serum to produce energy (and not in a microvasculature environment), it seems the something would have been an exosome (with miRNA which can epigenetically modify other cells), or an unknown signaling molecule.

To me it seems that clots, serum amyloid A, or primed clotting factors would have been spotted and probably wouldn't have the direct impact on intracellular energy production seen in the experiment. Here is a nice summary: https://www.virology.ws/2019/12/16/...grath-on-ron-davis-on-something-in-the-blood/
 

SNT Gatchaman

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Still, when it comes to Ron Davis's "Something in the Blood", since that experiment was carried out measuring the ability of WBC in ME/CFS serum to produce energy (and not in a microvasculature environment), it seems the something would have been an exosome (with miRNA which can epigenetically modify other cells), or an unknown signaling molecule.
Yes, that's what was described, but what if they weren't measuring the impedance change in the cell (which is what they were looking to see), but instead after 60 minutes, what if they were measuring an impedance change brought about by the micro-clots themselves?

That's why I want to know if the impedance effect was ever tested without monocytes present. The theory of the test and the delay to effect occurring from 1-2 hours all imply it's a cell effect. But what if hyperosmotic saline and time induces a change in the microclots that alters impedance?

If I understand correctly, Prof Pretorius told us the microclots contain abnormally folded proteins — fibrin(ogen) — not in the alpha-helices they should be but beta pleated sheets. I'm pretty sure beta-pleated sheets have an effect on electrical impedance, but have little knowledge in this area.
 

SNT Gatchaman

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Although not talking about impedance, this paper describes the alpha-beta transition in clots.

The a-Helix to b-Sheet Transition in Stretched and Compressed Hydrated Fibrin Clots

It concludes:
First, the a-b transition may toughen fibrin at large deformations because b-sheets are more resistant to shear than a-helices, and clot stiffness has been known to correlate directly with the incidence of myocardial infarction and other cardiovascular diseases. Second, the ability of fibrin to undergo the a-b transition and aggregation may result in formation of tightly packed b-sheets, analogous to those of amyloid structures. Of importance, fibrin clots displayed amyloid-like features upon extension revealed by staining by Congo red, and accumulation of b-amyloid peptide makes fibrin clots more resistant to proteolytic degradation. There is also genetically determined fibrin(ogen)-related amyloidosis in some dysfibrinogenemias. Third, controlling the a-b transition could potentially lead to new strategies for elimination of thrombi by either stabilizing or destabilizing the coiled-coil, rendering clots more sensitive to treatment.
I think the reference to "genetically determined fibrin(ogen)-related amyloidosis in some dysfibrinogenemias" is also notable as perhaps that may play a role in micro-clot persistence.
 

Shanti1

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Yes, that's what was described, but what if they weren't measuring the impedance change in the cell (which is what they were looking to see), but instead after 60 minutes, what if they were measuring an impedance change brought about by the micro-clots themselves?

That's why I want to know if the impedance effect was ever tested without monocytes present. The theory of the test and the delay to effect occurring from 1-2 hours all imply it's a cell effect. But what if hyperosmotic saline and time induces a change in the microclots that alters impedance?

If I understand correctly, Prof Pretorius told us the microclots contain abnormally folded proteins — fibrin(ogen) — not in the alpha-helices they should be but beta pleated sheets. I'm pretty sure beta-pleated sheets have an effect on electrical impedance, but have little knowledge in this area.
I see what you are saying, and I don't think it is impossible, but it seems fibrin is something they would have been able to detect, being a known and common blood component. Additionally, if misfolded fibrin was causing impedance, it would seem that the impedance would have been present from the getgo, not just after adding the salt.