Is me/cfs a blood disorder?

SNT Gatchaman

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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.
Maybe, but as Resia Pretorius was pointing out, our "blood tests" evaluate plasma, but the micro-clots are sequestering their contents, which might be why they don't show up. Unaware of their existence or potential, we may not have been testing the micro-clots and their contents at all.
 

Wishful

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Put me down for 'no, I don't think it's a blood disorder'. I don't feel that it fits my observations of my ME, which has very rapid changes in symptoms, and an insensitivity to things that I would expect to alter blood flow, oxygen levels, etc.

My take on microclots: if they are more abundant in PWME, it may be the result of a malfunctioning immune system. Researchers are finding high levels of autoantibodies being involved, and maybe ME's immune system malfunctions might allow for greater autoantibody production. The microclots might produce some symptoms in some people, but while it may be possible for microclots to cause some ME-like symptoms, I don't think they are actually responsible for ME symptoms in most people. I consider most if not all of my symptoms to be neurological in origin.

Question for the experts: if the symptoms of 'fatigue' and brainfog were due to inadequate oxygen getting to brain cells due to poor blood flow, shouldn't the symptoms change if you're doing something strenuous enough to boost your heart rate and breathing, or get worse if you are resting? Shouldn't they change if you use HBOT or other oxygen boosting or blood flow boosting techniques which a number of members here have experimented with and not gotten dramatic improvements from? Microclots might look like a good fit for ME symptoms if you microfocus on some technical aspects of them, but do they really fit well when you consider the whole body and a wider range of timeframes and treatments that people have tried which haven't worked?
 

Shanti1

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Here is the original paper:
https://www.pnas.org/content/116/21/10250
I think that if there was impedance from fibrin or microclots, it would have been seen at baseline in ME/CFS Patients vs controls. The researchers tested baseline for 20mins. It was only after NACL was added that the impedance changed between baseline and controls.

I can see fibrinogen or fibrin being small enough to miss, but I think an actual microclot likely contains platelets, like other types of clots, and would be spun down and land with the platelets in the spun down tube. Dr. Pretorius used platelet-poor plasma, which I believe is why her images don't contain platelets. She also had to artificially activate the clots to form from circulation with a factor derived from platelets (so I think they tend to form in the microcirulation as opposed to floating around in abundance in the circulation).

Even without platelets, her images of COVID microclots are 40uM across, and even more lengthwise. I can see the size possibly being an artifact of the dye to a degree, but doubtful that it is to extent of turning something invisible into something 10x the size of a platelet.
 

Shanti1

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if the symptoms of 'fatigue' and brainfog were due to inadequate oxygen getting to brain cells due to poor blood flow, shouldn't the symptoms change if you're doing something strenuous enough to boost your heart rate and breathing, or get worse if you are resting? Shouldn't they change if you use HBOT or other oxygen boosting or blood flow boosting techniques which a number of members here have experimented with and not gotten dramatic improvements from? Microclots might look like a good fit for ME symptoms if you microfocus on some technical aspects of them, but do they really fit well when you consider the whole body and a wider range of timeframes and treatments that people have tried which haven't worked?
I tend to agree. My own take is that altered blood flow, due to multiple possible causes, is one of many factors that can cause symptoms in ME/CFS. I do think most of us have some sort of blood flow or oxygen extraction issue (like mitochondrial dysfunction) as part of our condition, but it probably varies from person to person and there are many other dysregulated systems. I know for me, using a few breaths of 90% O2 in the morning makes a big difference for my brain, but others seem to have no benefit, even from HBOT.
 

SNT Gatchaman

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if the symptoms of 'fatigue' and brainfog were due to inadequate oxygen getting to brain cells due to poor blood flow, shouldn't the symptoms change if you're doing something strenuous enough to boost your heart rate and breathing, or get worse if you are resting? Shouldn't they change if you use HBOT or other oxygen boosting or blood flow boosting techniques which a number of members here have experimented with and not gotten dramatic improvements from?
The neurological symptoms might not be due directly to oxygen reduction with reduced blood flow in the brain. There may be an intermediate step in the form of neuro-inflammation. That would take longer to set up and retreat, so likely wouldn't respond to acute manoeuvres.

Neuroinflammation may also be partly a mirror effect of generalised low grade inflammation in the body, per Van Elzakker's vagus work.
 

SNT Gatchaman

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From notes of the Sept 2021 Stanford Working Group Meeting as summarised in this post.

We heard an update on red cell deformability. In previous work, some labs have found a difference in red cell deformability between patients and healthy controls, and one lab found no difference. However, it was recently discovered that oxygen levels in the blood have a major impact on deformability. New instruments are being developed to measure deformability under controlled oxygen levels. There is a clear difference in deformability between patients and healthy controls under low blood oxygen levels. Thus, this continues to provide promise for a fast and inexpensive biomarker and diagnostic test.
 
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crashing at least at first feels more like some sort of metabolic / biochemistry switch rather than blood flow failure to be honest, the reason I say that is I can feel fine all day and then can feel a crash beginning and it seems to come on within a 10 minute time frame where I start to feel unnaturally tired.
 

Wishful

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crashing at least at first feels more like some sort of metabolic / biochemistry switch rather than blood flow failure to be honest,
I think the flare-up of my symptoms (since I've never 'crashed') is more likely neurological: something altering neural functioning. I had the same flare-up from quickly digested carbs, which increase TRP transport into the brain, and the flare-up was blocked by BCAAs, so it appears that the kynurenine pathway in brain cells is involved, at least for me.
 

Wishful

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I noticed that the recent OMF report mentioned the finding that autoantibodies are increased in PWME, due to immune systeme dysfunction. The Covid research points to autoantibodies being responsible for the microclots. What's missing is evidence that the microclots are the cause of neurological symptoms, rather than just another asymptomatic downstream effect of the immune dysfunction.
 

Shanti1

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The Covid research points to autoantibodies being responsible for the microclots.
Thanks @Wishful I didn't know that. Interesting because some of the same autoantibodies have been found in some studies to be present in a higher percentage in pwME.

Prothrombotic autoantibodies in serum from patients hospitalized with COVID-19
https://www.science.org/doi/full/10.1126/scitranslmed.abd3876

Abstract
Patients with COVID-19 are at high risk for thrombotic arterial and venous occlusions. Lung histopathology often reveals fibrin-based blockages in the small blood vessels of patients who succumb to the disease. Antiphospholipid syndrome is an acquired and potentially life-threatening thrombophilia in which patients develop pathogenic autoantibodies targeting phospholipids and phospholipid-binding proteins (aPL antibodies). Case series have recently detected aPL antibodies in patients with COVID-19.

Here, we measured eight types of aPL antibodies in serum samples from 172 patients hospitalized with COVID-19. These aPL antibodies included anticardiolipin IgG, IgM, and IgA; anti–β2 glycoprotein I IgG, IgM, and IgA; and anti-phosphatidylserine/prothrombin (aPS/PT) IgG and IgM. We detected aPS/PT IgG in 24% of serum samples, anticardiolipin IgM in 23% of samples, and aPS/PT IgM in 18% of samples.

Antiphospholipid autoantibodies were present in 52% of serum samples using the manufacturer’s threshold and in 30% using a more stringent cutoff (≥40 ELISA-specific units). Higher titers of aPL antibodies were associated with neutrophil hyperactivity, including the release of neutrophil extracellular traps (NETs), higher platelet counts, more severe respiratory disease, and lower clinical estimated glomerular filtration rate. Similar to IgG from patients with antiphospholipid syndrome, IgG fractions isolated from patients with COVID-19 promoted NET release from neutrophils isolated from healthy individuals. Furthermore, injection of IgG purified from COVID-19 patient serum into mice accelerated venous thrombosis in two mouse models. These findings suggest that half of patients hospitalized with COVID-19 become at least transiently positive for aPL antibodies and that these autoantibodies are potentially pathogenic.
 
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There is a clear difference in deformability between patients and healthy controls under low blood oxygen levels. Thus, this continues to provide promise for a fast and inexpensive biomarker and diagnostic test.
I hope they look a bit further than just this. As defects in deformability can have a profound effect. Here's a bit and the whole lot is in the file-it's a long one.
 

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SNT Gatchaman

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To cut to the chase, these defects can effect vasoregulation. Would that be enough to cause the wide range of symptoms in me/cfs? Taking into account the lack of evidence for other causes I'm saying yes.
I'm saying a strong yes too. I don't think we have to pin down all the varying ME symptoms. Many of those can be considered secondary and could be put into a default basket of "neuroinflammation" for now. What we need is to prove the mechanisms of exercise intolerance and PEM. They are the hallmark features of this disease. Everything else follows in my view.
 

SNT Gatchaman

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@andyguitar this is how I'm currently formulating the concept of PEM vs fatiguability...

While fatiguability is reasonably quick to take its effects, PEM is characterised by delayed onset and slow recovery.

Perhaps the difference might be in relation to the low-demand vs high-demand states. Low flows under low demand might promote more endothelial inflammatory changes from contact with micro-clots and their inflammagens. Although this might be relatively modest inflammation if you were to look under the microscope, the physiological effect could be large over the entire capillary bed. It could act to impair oxygen diffusion to tissues and perhaps keep us at a generally low anaerobic threshold.

Perhaps also this effect cycles up to maximum when we have low cardiac output and little movement and that that is why we have "unrefreshing sleep".

High demand might push more RBCs through the capillary bed, faster. If their transit is impaired by even mild inflammation, they might be subject to damage from shear forces. Poorly deformable, slow-to-transit RBCs may get more oxygen extracted, which while maybe helping the tissues, could reduce venous blood pool saturation. PEM might then start with white blood cell hypoxia and RBC damage, manifesting with symptoms after 1-2 days.

That's why I want to know if (maybe only in early onset) ME patients show variation with venous oxygen saturation: is it increased from baseline after sleep due to reduced oxygen extraction; is it decreased from baseline in the days following exertion with increased oxygen extraction?

Could constant cycling between normal and hypoxic environments stress white cells and tissues, leading to all the metabolic adaptations? Similarly could the dynamic impairment of the micro-circulation overcome the cardiovascular homeostatic mechanisms that are trying to stabilise venous-side volumes and explain POTS type symptoms?
 

Inara

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Shouldn't they change if you use HBOT or other oxygen boosting or blood flow boosting techniques
I tried using an oxygen machine. It helped slightly, but not really, and in the long run the effects subsided. I wondered the same: If oxygen played a role, shouldn't extra oxygen help? On the other hand: If "transport systems" are affected, extra oxygen wouldn't help that much I think. In POTS, e.g., I would say "oxygen transport" is somehow affected, and I think that little extra oxygen won't really change sth.
 

Shanti1

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I tried using an oxygen machine. It helped slightly, but not really, and in the long run the effects subsided.
I have had good results with a few inhalations of 90% oxygen, when I take a "hit" I get an immediate lift in brain-fog and a sensation of warmth through my head and ears. But I have noticed that I need more and more to get the same effect. I started only needing 1 inhalation, and now I need 4-5. Its almost like the body is purposely shutting down pathways and when I find a way to improve them, it finds a way to shut them down again, so I am wondering how much mileage I will get out of the 02.

I have "sticky platelet syndrome". I have no idea what this is and it was not followed up. I also don't know if this is relevant.
Wiki has a nice writeup, it looks like a genetic condition that makes you more prone to clotting. Looks like people are often advised to take a baby aspirin, but if they have a clotting event, they are put on something stronger. https://en.wikipedia.org/wiki/Sticky_platelet_syndrome
 
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Although this might be relatively modest inflammation if you were to look under the microscope, the physiological effect could be large over the entire capillary bed. It could act to impair oxygen diffusion to tissues and perhaps keep us at a generally low anaerobic threshold.
If that is whats going on then anti inflammatory drugs might be the way out of PEM. What should show up is an increase in inflammatory substances during PEM.
Could constant cycling between normal and hypoxic environments stress white cells and tissues, leading to all the metabolic adaptations?
My guess would be yes. So crashing needs to be avoided. Have you heard of "aggressive resting" as a treatment?
 

Wishful

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What we need is to prove the mechanisms of exercise intolerance and PEM. They are the hallmark features of this disease.
I don't consider exercise intolerance to be a hallmark feature, since I never had it, and others seem to not have it either.

PEM is characterised by delayed onset and slow recovery.
My PEM had different delays for physically and cognitively induction: the former was a consistent 24 hrs, while the latter was more variable and more in the 1 hour range. I think my delay from physical induction was due to IFN-g, which rises 24 hrs after exertion, which in turn triggers the neurological mechanism of PEM that cognitive exertion can trigger more directly.

My recovery time from PEM was a bit more difficult to identify, but I think it was generally <24hrs. I don't recall it ever lasting much longer than that. I think cognitively-induced PEM cleared up within hours.