Is Apheresis an effective treatment for Long Covid and ME?

[andyguitar]

It's not just that they're "clots" it's that the clots contain protected inflammatory mediators that cause endothelial, platelet and blood cell dysfunction.

This is a problem for me in all this. I dont see how those inflammatory mediators could cause symptoms if they are inside a clot.

 

[wabi-sabi]

I dont see how those inflammatory mediators could cause symptoms if they are inside a clot.

Yes, I'm having trouble picturing that too. Probably need to study up on it more.

I guess I don't understand why the body's normal anticlotting mechanisms aren't working- I mean specifically, not just chronic illness! inflammation! all normal physiology broken!

 

[Shanti1]

Yes, I think we need to ensure that those low and high SvO2 findings is correct. I know I had an extremely low value when I first presented and that Asad Khan was not quite as low at his (I think) 12 month mark. I want to re-check mine next week...

If it's true that long-term ME have normalised or high SvO2, then that could indicate the difference between "early-phase" ME and "late-phase" ME. The micro-circulation is dynamic and as more of the capillary bed gets compromised, short AV shunts might form, allowing RBCs to bypass and so not get held up and over de-oxygenated. The anaerobic-favouring metabolic pathways may de-oxygenate less also.

If this is all true, I don't know what the implication is for long-term / severe patients, but it's entirely possible that on resolution of that underlying pathological process, the micro-circulation could recover, along with the metabolic pathways. (The metabolism may need assistance).

See for example Systemic microvascular shunting through hyperdynamic capillaries after acute physiological disturbances following cardiopulmonary bypass.

So here are the two studies showing the normal and high SvO2 in ME/CFS:
https://forums.phoenixrising.me/thr...-long-covid-and-me.85939/page-12#post-2374037
https://forums.phoenixrising.me/thr...-long-covid-and-me.85939/page-13#post-2374076

I think that these are pretty confirmatory given the number of participants and the consistency of the findings such that an ME/CFS patient with low SvO2 would be an outlier. I know that you had a very low SpVO2, but that it was taken during hospitalization for a POTS crisis, so it will be interesting to see what yours is like when you don't have such altered physiology. Is your arterial oxygen saturation typically normal on an oxpulse?

I haven't found any published studies showing that Long-COVID patients have low SvO2, but we have the testimony of some respected doctors. SvO2 can be low in acute COVID, but this could also be due to the decreased uptake of oxygen from the lungs (SvO2 needs to be put into perspective by looking at arterial blood gases or oxygen saturation from an oxpulse meeter to determine if it is low due to compromised lungs or low tissue perfusion, or other factors such as altered blood pH).

If this is all true, I don't know what the implication is for long-term / severe patients, but it's entirely possible that on resolution of that underlying pathological process, the micro-circulation could recover, along with the metabolic pathways. (The metabolism may need assistance).

My thought is that much of capillary/blood flow dysfunction is functional instead of a permanent pathological change, and this helps to account for the fact that we see remissions, good days, bad days, good hours, bad hours.... meaning the dysfunction is dynamic and related to the degree dysautonomia, RBC perturbance, possibly other factors too.

 

[GlassCannonLife]

Just dropping in to say thank you all for such an interesting and in-depth discussion!

 

[SNT Gatchaman]

This is a problem for me in all this. I dont see how those inflammatory mediators could cause symptoms if they are inside a clot.

I guess I don't understand why the body's normal anticlotting mechanisms aren't working- I mean specifically, not just chronic illness! inflammation! all normal physiology broken!

Yes, that is a key piece of information to understand. Two possibilities spring to mind.

I know the clot is not a cell (obvs!) but is there some functional equivalence? Whereby a reservoir of abnormal protein, bound to inflammatory mediators and anti-coagulation factors "cycles" from the centre of the clot to its surface where it can interact physiologically and return to the centre where it's temporarily physiologically inert.

Or, more likely:

No need for any such cycling. Some of the mediators are held deep in the clot and some are "surface expressed" as it were. A bit like viral surface proteins. Still the adjacent clot - because it has formed around abnormal amyloid protein - is able to hold on strongly to (even) surface mediators, preventing their degradation by normal processes.

 

[andyguitar]

My thought is that much of capillary/blood flow dysfunction is functional instead of a permanent pathological change,

Having met a fair few people who have recovered from severe ME I'd say that if this is a blood disorder it is reversible. So a functional disorder. You just need the right treatment. And avoid the wrong treatment.

 

[wabi-sabi]

Yes, that is a key piece of information to understand.

Inflammation and clotting do seem to be intimately tied together, although my brain is in no shape to try to sort out the connections tonight. Seems some clotting factors double as inflammatory mediators. Makes sense the immune system would want to get in on any injury severe enough to require blood clotting functionality.

I was thinking of the main problem with clots as cutting off the flow of blood and therefore oxygen, with all the problems in the body that would cause. In the impaired perfusion sense, the problems cells have in the nanoneedle doesn't seem to fit. I can't picture how a cell in media is having its oxygen supply cut off by a clot floating around in the same broth. The idea of that being a clot problem only seems to work if the clot is also some sort of cell signaling thingy that's causing the cell to downregulate some metabolic something.

 

[dylemmaz]

I know that you had a very low SpVO2, but that it was taken during hospitalization for a POTS crisis, so it will be interesting to see what yours is like when you don't have such altered physiology. Is your arterial oxygen saturation typically normal on an oxpulse?

i likewise had a very low SpVO2. i admitted myself to the hospital because i was experiencing severe PEM when i was undiagnosed. frankly, i thought i was dying at the time but it was really just a very bad crash. this was 3 and a half years in to my me/cfs when the venous blood gas test was performed that showed low central venous oxygen saturation

i have a pulse oximeter that i regularly use. it’s always normal, and i have no reason to believe i have any lung problems whatsoever that would cause such a low SpVO2 (36%).

i am not sure what to make of this information, and the studies you linked. they are much more objective than my own personal labs. and yet my results are consistent with the anecdotes of low SpVO2 that we have heard from in some long covid patients. i’m very confused and unsure of what to make of all of this

 

[SNT Gatchaman]

Is your arterial oxygen saturation typically normal on an oxpulse?

Yes SpO2 is always 98-100%, on medical grade sat meters and commercial wearable (Apple Watch 6). I haven't done a formal arterial stab to confirm physiological SaO2.

I should also give a bit more context to that hospital admission. Cardio-respiratory exam and obs were normal (slightly hypertensive). This was seated in a cubicle bed, no standing P/BPs etc as POTS wasn't even on the diagnostic horizon, for them or me at the time.

I had done the typical doctor self-caring thing and rode out four days of feeling like the proverbial (at anchor, in paradise, not that I could enjoy it) thinking "must be just a virus, she'll be right". I presented at day 6 because things just weren't right and there was a possibility this was a PE, but I was nowhere near as bad. I.e. what everyone here has learnt to do as a routine. All this is to say I wasn't badly ill at the time I was assessed in hospital, so probably not in the middle of a POTS crisis then. My GP was very concerned about the story and some (ultimately spurious) ECG findings.

 

[wabi-sabi]

i’m very confused and unsure of what to make of all of this

It is hard to say. Maybe it's something to do with how long someone has had the disease. Or if you're in a crash or not.

It's also possible that while long COVID and ME/CFS look very much the same on the outside, they aren't the same on the inside. Kind of like ME/CFS and Gulf War syndrome. I don't get the impression that ME/CFS comes with lung problems in the way that long COVID might come with lung damage.

That's partly why I'm hesitant about that inspiritol thing. We're not (mostly) short of breath of oxygen due to the lungs. We're short of breath because we're hyopvolemic and have impaired tissue perfusion (I think).

 

[Shanti1]

i likewise had a very low SpVO2. i admitted myself to the hospital because i was experiencing severe PEM when i was undiagnosed. frankly, i thought i was dying at the time but it was really just a very bad crash. this was 3 and a half years in to my me/cfs when the venous blood gas test was performed that showed low central venous oxygen saturation

i have a pulse oximeter that i regularly use. it’s always normal, and i have no reason to believe i have any lung problems whatsoever that would cause such a low SpVO2 (36%).

i am not sure what to make of this information, and the studies you linked. they are much more objective than my own personal labs. and yet my results are consistent with the anecdotes of low SpVO2 that we have heard from in some long covid patients. i’m very confused and unsure of what to make of all of this

I am not sure what it means, but I think it would be worth doing a repeat SpVO2 as an outpatient, if possible, and if it is still low, consider other causes, microclots among them.

 

[andyguitar]

I was thinking of the main problem with clots as cutting off the flow of blood and therefore oxygen, with all the problems in the body that would cause.

Yes, in my opinion the micro clots are enough on their own to cause disease. The other findings being background noise.

i’m very confused and unsure of what to make of all of this

Dont sweat about it @dylemmaz this is all very new and we are all a bit in the dark at the moment.

 

[SNT Gatchaman]

i likewise had a very low SpVO2. i admitted myself to the hospital because i was experiencing severe PEM when i was undiagnosed. frankly, i thought i was dying at the time but it was really just a very bad crash. this was 3 and a half years in to my me/cfs when the venous blood gas test was performed that showed low central venous oxygen saturation

i have a pulse oximeter that i regularly use. it’s always normal, and i have no reason to believe i have any lung problems whatsoever that would cause such a low SpVO2 (36%).

Thank you for adding another data point !

We've just ordered a point of care SvO2 analyser here in Auckland. Intention is to do (at rest) sampling of our enrolled Long Covid patient cohort, and we need to enrol our ME group to compare. (Both groups will all be very keen).

Also, I am prepared to induce (mild) PEM and track what happens to SvO2 over days (expect it to reduce and then recover to whatever my current baseline is). This on top of looking for micro-clots and impedance changes of course.

Lots of action. I think the next two months might be an exiting time - let's hope this all doesn't fizzle like all the past disappointments (looking at you XMRV)!

For those following along on Twitter, watch the tag #teamclots

 

[Shanti1]

We've just ordered a point of care SvO2 analyser here in Auckland. Intention is to do (at rest) sampling of our enrolled Long Covid patient cohort, and we need to enrol our ME group to compare. (Both groups will all be very keen).

Also, I am prepared to induce (mild) PEM and track what happens to SvO2 over days (expect it to reduce and then recover to whatever my current baseline is). This on top of looking for micro-clots and impedance changes of course.

Lots of action. I think the next two months might be an exiting time - let's hope this all doesn't fizzle like all the past disappointments (looking at you XMRV)!

For those following along on Twitter, watch the tag #teamclots

Thank you @SNT Gatchaman, this is great that you have the opportunity to get this valuable data for us! I will be very interested in the results.
You may be interested in this study on the differences in SvO2 readings when taken peripherally compared to from a picc line or pulmonary artery: https://forums.phoenixrising.me/thr...-long-covid-and-me.85939/page-11#post-2373891 The SpVO2 tends to be lower from the periphery and with more variation.
But what would be best is if you also have some healthy controls so you can have the ME/CFS and Long-COVID readings calibrated with healthy controls on your specific machine.
Would you mind linking to the machine you purchased?

 

[Shanti1]

@SNT Gatchaman I think you may be aware, but something else to keep in mind is that Sv02 will drop significantly lower than baseline during exercise in both healthy and pwME, so one can't use the same reference range for exercise SvO2. I believe the poor oxygen extraction in pwME was determined using calculations with SvO2 and arterial gas. I'm on my phone right now but tomorrow I will pull the studies and post more detail.

 

[Martin aka paused||M.E.]

Amy Proal thinks HELP APHERESIS could be beneficial for ME/CFS patients?

I think so. She posted it under a post about successful apheresis in ME. But I haven’t talked to her.

Then the question becomes: what is driving the body to make these micro clots, assuming this thesis is correct.

the same question remains for LC. Let’s wait for Jaeger's paper.

The clots are resistant to breakdown but the mediators presumably still take effect, causing inflammation in the micro-circulation,

Yes!

The notable feature of PEM is variation in delay to symptom, post-exertion. This could be a direct result of time to effect of further RBC damage or capillary occlusion (remembering that the tissues have compensated to some degree, by shifting metabolic pathways).

That’s my working theory now. The only problem I have is that low pyruvate has been shown in some ME patients (me included) …does not fit and points towards failure in glycolysis. There are also hints of a dysfunctional ADP translocater protein in my mind.

ME and long COVID are the same disease, both an amyloid pathology that affects the blood and causes coagulation, immune and inflammatory derangement centred at the micro-circulation level.

Downstream symptoms are all secondary

Yes, I think so too. But i would add: if the cause for the clots isn’t removed, they’ll come back…

that we see remissions, good days, bad days, good hours, bad hours.... meaning the dysfunction is dynamic

You see the same in LC

It's also possible that while long COVID and ME/CFS look very much the same on the outside, they aren't the same on the inside. Kind of like ME/CFS and Gulf War syndrome. I don't get the impression that ME/CFS comes with lung problems in the way that long COVID might come with lung damage.

That’s because it’s caused by another virus. SARS-Cov-2 infects lung cells and has it’s reservoirs there (and seemingly in the gut.) EV infect epithelial cells of the mucosa.

it’s all very preliminary stuff. But keep in mind that Jaeger has successfully treated a ME patient from bedridden to up on her feet.

She is very interested in my case bec Asad told her about me. But I couldn’t call her back bec atm I have a bad crash and have no voice. I will ask her the problems discussed in this thread.

 

[SNT Gatchaman]

@Shanti1 thank you for the advice above re: peripheral SvO2 readings. I was thinking analysis in days following an exercise event, where I would assume normal controls would have returned to normal — for the modest exercising I had in mind, like a 10-15 minute gentle walk. As you say for proper study design though it would be sensible to confirm on the same gear, particularly with the variability of peripheral readings.

Would you mind linking to the machine you purchased?

Not at all, though order not yet submitted. It's the i-STAT Allinity, which is a cartridge based system. We had the CG4+ cartridge in mind. It may be prudent to include Hb and Hct also though. Please let me know if you think we should include other parameters.

 

[SWAlexander]

When considering all the info in this thread, I see similarities between Long-COVID and ME/CFS, but also places where they differ and my read is that persistent micro-clots may be a difference. I base this on the reported finding that Long-COVID patents have low SvO2, presumably due to microclots. In contrast, ME/CFS patients have normal SvO2 at rest and HIGH SvO2 during exercise (see earlier studies posted).

So in one condition, we have the inability to extract oxygen (ME/CFS) and in the other we have hyper-extraction of oxygen due to poor tissue perfusion secondary to micro-clots (Long-COVID). Based on these findings, how can the same pathology be occurring?

In addition, the SARS-COV-2 is very tightly linked with severe clotting pathology while viruses like EBV, HHV-6 and Enteroviruses are not known to cause this type of severe clotting with active infection.

The low ESR found in ME/CFS also points away from clotting as the primary pathology as you would typically find a high ESR in hypercoagulation syndromes.

I think it is more likely the in ME/CFS we are seeing some hypercoagulation due to inflammation and autoantibodies associated with a variation of anti-phospholipid syndrome. However, if it were clotting alone causing the issue, I think we would see a low SvO2, and we don't.

This makes me think we are also seeing dysautonomia impacting the capillary blood flow (as described in the paper posted by @Pyrrhus earlier), mitochondrial dysfunction (causing inability to utilize oxygen), and possibly poor release of O2 from RBC due to their altered deformability. All of these factors would be consistent with the high SvO2 (low oxygen extraction) which has been observed.

This isn't to say that HELP Apheresis wouldn't be useful, perhaps even greatly so, but in my opinion, it would be for other reasons than the type of micro-clot occurring in Long-COVID.

Can allergies fit in picture of blood clotting - hypercoagulation and inflammation? Like dust mites and peanut can cause respiratory symptoms?

 

[SWAlexander]

@SNT Gatchaman I think you may be aware, but something else to keep in mind is that Sv02 will drop significantly lower than baseline during exercise in both healthy and pwME, so one can't use the same reference range for exercise SvO2. I believe the poor oxygen extraction in pwME was determined using calculations with SvO2 and arterial gas. I'm on my phone right now but tomorrow I will pull the studies and post more detail.

May I suggest this article:
Mixed venous oxygen saturation (SvO2) monitoring: https://litfl.com/mixed-venous-oxygen-saturation-svo2-monitoring/

 

[SNT Gatchaman]

Thank you very much again @Shanti1. I believe the most accurate studies to date on this are the invasive CPET tests done by Systrom and team which were all on-the-day evaluations, sampling directly from the pulmonary artery (just prior to the lungs) and used controlled exercise on a cycle. This would have moved the lower body, but spared upper body movement.

Although the most accurate, it's too risky to keep a Swan-Ganz pulmonary artery catheter in over days in an awake and mobile patient. Even a short internal jugular central venous line would be too much infection risk for patients and controls, so that to follow the hypothesised descent and recovery over days post-exertion that I'm interested in trying to show, I think we're obliged to go with simple intermittent upper limb sampling. I suspect the swings would be quite marked in patients vs controls (though that remains to be shown).

For the wider group's interest:
Even if I were game to volunteer myself for a trans-cardiac catheter (via my friends in ICU), we'd never get past ethics and/or probably all get metaphorically shot by management! And the likelihood of a pulmonary artery dissection would be non-zero, unless I was doing my best impression of an intubated/paralysed ICU patient over those following days. As they say on BGT: "that's a no from me."