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The micro-clot finding in Long Covid — implications for the possible aetiology of ME/CFS
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Fizzlou
Senior Member (Voting Rights)
https://clinmedjournals.org/article...eletal-disorders-and-treatment-jmdt-7-090.pdf
@Arnie Pye
Heparin: a few blogs out there.
The paper above has a table of treatments reviewed for MECFS. I’m not sure about the data such as time for remission etc (to my untrained eye it makes omega 3 look pretty good but evidence levels based on Oxford criteria) but as a comparative against other treatments it’s an interesting list with Heparin showing 100% response rate. Data from 1998 paper by D Berg of the hyper coagulation hypothesis. (Can’t find it just now)
@Arnie Pye
Heparin: a few blogs out there.
The paper above has a table of treatments reviewed for MECFS. I’m not sure about the data such as time for remission etc (to my untrained eye it makes omega 3 look pretty good but evidence levels based on Oxford criteria) but as a comparative against other treatments it’s an interesting list with Heparin showing 100% response rate. Data from 1998 paper by D Berg of the hyper coagulation hypothesis. (Can’t find it just now)
I think that is correct (that they don't work in this scenario).
The micro-clots are a very new finding, so unlikely anyone has tried. I haven't (yet) come across reports from previous years of ME symptom improvement or resolution when tPA / streptokinase / urokinase etc has been given for other, standard reasons.
More importantly, though I don't think they'd help. As I understand it, the recent findings suggest that the micro-clots are forming around abnormal protein aggregates (amyloid beta-sheets). It's possible this abnormal protein makes the micro-clot unusually resistant to the clot-busters, but even if not, there's a more important consideration.
Breaking apart the micro-clots while they remain in the circulation would just expose the anomalous amyloid protein and the micro-clots would presumably reform quite quickly. I think that would be the case, as in people affected by long COVID (ME?) the scavenger systems would be overloaded (as opposed to people that don't get long COVID) — and would be unable to deal with the large volume of these newly released abnormal proteins.
I think the best strategy is for them to be removed from the circulation by the apheresis technique.
If it works, great, and then someone can come up with a drug that rips into these abnormal proteins. That may be a monoclonal antibody therapy. Not sure if you'd need to degrade the established micro-clots first with clot-busters in that scenario though.
ETA: thank you @Fizzlou, that's an interesting comment on the heparin experience. I can't find the Berg article either - it may no longer be hosted on the Solve M.E. site?
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Hoopoe
Senior Member (Voting Rights)
If the microclots are an explanation for PEM and other symptoms this would be a big step forward even if microclots are primarily associated with one subgroup of long covid.
It means that the other patients, those without microclots but very similar symptoms, must have a problem that affects the body in a similar way.
Maybe the microclots will be more associated with the POTS than the ME phenotype.
It means that the other patients, those without microclots but very similar symptoms, must have a problem that affects the body in a similar way.
Maybe the microclots will be more associated with the POTS than the ME phenotype.
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Mij
Senior Member (Voting Rights)
The head hematologist here that my doctor and I consulted said that Berg's theory is complete nonsense, and the head of virology agreed.
Fizzlou
Senior Member (Voting Rights)
Update from Dr Asad Khan (AK) who is a respiratory consultant in Manchester and he fits the MECFS criteria. He is in Germany undergoing HELP apheresis.
This YouTube channel is good and MECFS has featured a lot.
Rough timeline for video:
0-4 mins problem of identifying LC drivers
4-7.15 AK gives hypotheses as he understands it so far
7.15-8 outline of procedure
8-12 discussion on why microclots May drive LC inc PEM, waxing and waning symptoms etc
12-15.20 AK personal experience
15.20-18.26 microclots as driver of LC and MECFS (lots here on MECFS)
18.26-21.54 Microclot markers (none) and why standard clotting measurements are usually in normal range
21.54-25.48 venous oxygen saturation
25.48 where HELP apheresis available
29.44 Research agenda in next few weeks
39.32 way forward for LC then MECFS
39.44 conclusion
In the video I didn't see any reference to the potential role of reduced red cell deformability. The focus seems to be on the resulting endothelitis and impaired O2 tissue delivery. I think much more of the micro-clot effect could be happening due to the resulting changes in RBC morphology and capillary blood flow.
I know I'm banging on about this, but I really think we need to look into the haemorheology aspect and what happens to SvO2 in the days following PEM-inducing exertion.
ETA: changed O2 "transit" to "tissue delivery" to remove ambiguity.
I know I'm banging on about this, but I really think we need to look into the haemorheology aspect and what happens to SvO2 in the days following PEM-inducing exertion.
ETA: changed O2 "transit" to "tissue delivery" to remove ambiguity.
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Forbin
Senior Member (Voting Rights)
In the first three or four months of ME, I experienced a handful of occasions where it fairly suddenly and inexplicably felt like my symptoms had receded significantly. The change only took a minute or so and metaphorically it felt like the "boot had been taken off my neck." This feeling of "restoration" only lasted 10 to 15 minutes at best. I would then find myself slowly returning to my previous state in a similar time frame of 10 to 15 minutes. The "switch" to feeling nearly normal was quite quick, while the return to feeling ill was much more gradual.
I have no idea what this was or what brought it on. As I say, it was only a feature of the first couple of months.
JemPD
Senior Member (Voting Rights)
Although i must say i have wondered about a blood flow issue because of the numbness/pins & needles sensation i get in my arms/legs, which is exactly the same as the sensation you get when you have slept/sat funny & cut off your circulation... when you move & blood flow returns, there is a short while of the limb feeling like a heavy lump of wood which then turns to tingling/pins & needles, on the cusp of the change both sensations are present concurrently, which is exactly what i experience in PEM, except it lasts for hours/days on & off.
sorry thats probably totally irrelevant to microclotting
sorry thats probably totally irrelevant to microclotting
Excellent point
Hoopoe
Senior Member (Voting Rights)
When the pandemic started, it didn't take long for some people to notice that covid was associated with clotting problems. Later it also became apparent that clotting was an issue in long covid.
Clotting problems don't seem to be typically associated with ME/CFS.
Long covid patients describe an illness that is often identical to ME/CFS. A portion of patients have problems that don't fit ME/CFS (organ damage, clotting to name two). That suggests that something very similar is occurring in these two patient groups, but that there are also some additional problems in long covid patients that may be fairly SARS-2 specific. The clotting so far seems to be one of the SARS-2 specific things.
It might be that these microclots are there not because they're causing a ME/CFS-like illness (also called long covid) but because the ME/CFS was caused by SARS-2 which also has a tendency to cause these clotting problems.
Clotting problems don't seem to be typically associated with ME/CFS.
Long covid patients describe an illness that is often identical to ME/CFS. A portion of patients have problems that don't fit ME/CFS (organ damage, clotting to name two). That suggests that something very similar is occurring in these two patient groups, but that there are also some additional problems in long covid patients that may be fairly SARS-2 specific. The clotting so far seems to be one of the SARS-2 specific things.
It might be that these microclots are there not because they're causing a ME/CFS-like illness (also called long covid) but because the ME/CFS was caused by SARS-2 which also has a tendency to cause these clotting problems.
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Jonathan Edwards
Senior Member (Voting Rights)
I think that post sums things up very well.
I don't see any real likelihood that clotting is relevant to ME.
Fizzlou
Senior Member (Voting Rights)
https://www.tlcsessions.net/episodes/episode-18-professor-resia-pretorius-microclots
Podcast from The Long COVID Sessions
Episode 18 with Professor Resia Pretorius. She interviews well and explains many things from the research in a way I could understand.
Brief mention of MECFS and Amy Proal with study starting in January. (Abt 34 mins)
Lots of things that have been queried in this thread are covered in this episode.
Trypsinization, fibrinolysis , why coag tests come back normal, difference between these and clots, PEM, whether cycles of treatment needed, removing microclots by drugs or apheresis plus healing the vessels and possibly viral persistence in gut driving a continuing state etc
Podcast from The Long COVID Sessions
Episode 18 with Professor Resia Pretorius. She interviews well and explains many things from the research in a way I could understand.
Brief mention of MECFS and Amy Proal with study starting in January. (Abt 34 mins)
Lots of things that have been queried in this thread are covered in this episode.
Trypsinization, fibrinolysis , why coag tests come back normal, difference between these and clots, PEM, whether cycles of treatment needed, removing microclots by drugs or apheresis plus healing the vessels and possibly viral persistence in gut driving a continuing state etc
hibiscuswahine
Senior Member (Voting Rights)
Good talk by Prof Pretorius and how research shows some contribution by microclots to other autoimmune disease like RA, lupus, diabetes and Alzheimers but not to the same and even greater extent of having covid infection. She admits the association to ME is unknown but good to know there will be a study on this. She is clear that she does not know how many treatments are required and what type and dose of anticoagulant medication is recommended as she freely admits she doesn’t have the data and she would have to discuss this with Dr Jeager doing the apheresis in Germany.
I feel quite unsettled as a former medical professional by the level of advice Dr Khan is giving in his video (even though he gives caveats, the overwhelming theme is the microclotting process is causing all your long covid problems and possibly ME too) Thousands of people have signed up. It needs to be put through a sound scientific process with good pre and post outcome measures which he says is happening but is having to do it in a hurry, while being unwell (yikes!). They do need a control treatment arm of sham apheresis which he states no one will want to do because they are having to pay big bucks for it to hopefully relieve their illness. I think it would be quite easy to set one up to blind the patient, blinding the technician might be difficult but not impossible but early days and it’s a start. But this scientific evidence will be needed for doctors and healthcare providers to start looking at this being a treatment option.
As a clinician I would want a lot more information to help inform on the risks/benefits of anticoagulation to a patient as I think he really doesn’t state the risks of bleeding from falls causing brain injury etc. something you would not want to add to your illness.
I feel quite unsettled as a former medical professional by the level of advice Dr Khan is giving in his video (even though he gives caveats, the overwhelming theme is the microclotting process is causing all your long covid problems and possibly ME too) Thousands of people have signed up. It needs to be put through a sound scientific process with good pre and post outcome measures which he says is happening but is having to do it in a hurry, while being unwell (yikes!). They do need a control treatment arm of sham apheresis which he states no one will want to do because they are having to pay big bucks for it to hopefully relieve their illness. I think it would be quite easy to set one up to blind the patient, blinding the technician might be difficult but not impossible but early days and it’s a start. But this scientific evidence will be needed for doctors and healthcare providers to start looking at this being a treatment option.
As a clinician I would want a lot more information to help inform on the risks/benefits of anticoagulation to a patient as I think he really doesn’t state the risks of bleeding from falls causing brain injury etc. something you would not want to add to your illness.
I've listened to the talk with Professor Pretorius and it's intriguing. These microclots could well be real. But so far, I think we only have her lab saying they have seen them? The lab work to see them doesn't sound difficult, so I hope we get some independent studies soon.
Assuming they are real, I'm still left with the concern that they are just part of a post-infection mopping up, and that they would be cleared over time. And that they may have nothing to do with Long Covid symptoms. There was still no comment about comparisons between post-Covid-19 people with and without Long Covid symptoms, which I would have thought would be something to do early on.
Professor Pretorius said that the clots are different to normal thrombotic clots in that they are spongy and can squeeze through the capillaries. And so this is why people aren't getting thrombosis, or dying of stroke.
Her idea is that the clots do get stuck in the capillaries though and so reduce blood flow. When people with Long Covid exert themselves, their organs don't get enough oxygen, and so the PEM, the bad after effects, are due to that hypoxia. She said that the South African clinicians she works with have been administering anti-coagulants and this is having a good effect - so she didn't seem to think there is a problem with the molecules in the microclots suddenly being released and causing harm. But she did say that a particular combination of drugs was needed to manage both the microclots and the platelet activation together - so people shouldn't just try anticoagulants at home.
Professor Pretorius said something along the lines of 'these microclots should not be there, so we think if they are removed it will give the body a chance to heal'. And she suggested that doing that may not address all of the problems of Long Covid, such as brain fog, and something about psychological aspects perhaps remaining. And that the clinicians can clear the microclots, and then it might be that these people need other specialists to attend to their other problems. I found all that a bit worrying - a sort of lowering of the bar of what people can expect this treatment to do. Potentially the creation of an 'out' clause in terms of not actually curing people.
It is frustrating that the studies can't be done systematically from the beginning, with good controls and blinding. I guess they take time to do and everyone is in a rush to either be cured, or do the curing. And I guess there's lots of money at stake. If the German clinic can afford to fly Professor Pretorius out to Germany and pay for a study on the presence of microclots before and after the aphaeresis, it's hardly surprising that that is where the effort goes.
Assuming they are real, I'm still left with the concern that they are just part of a post-infection mopping up, and that they would be cleared over time. And that they may have nothing to do with Long Covid symptoms. There was still no comment about comparisons between post-Covid-19 people with and without Long Covid symptoms, which I would have thought would be something to do early on.
Professor Pretorius said that the clots are different to normal thrombotic clots in that they are spongy and can squeeze through the capillaries. And so this is why people aren't getting thrombosis, or dying of stroke.
Her idea is that the clots do get stuck in the capillaries though and so reduce blood flow. When people with Long Covid exert themselves, their organs don't get enough oxygen, and so the PEM, the bad after effects, are due to that hypoxia. She said that the South African clinicians she works with have been administering anti-coagulants and this is having a good effect - so she didn't seem to think there is a problem with the molecules in the microclots suddenly being released and causing harm. But she did say that a particular combination of drugs was needed to manage both the microclots and the platelet activation together - so people shouldn't just try anticoagulants at home.
Professor Pretorius said something along the lines of 'these microclots should not be there, so we think if they are removed it will give the body a chance to heal'. And she suggested that doing that may not address all of the problems of Long Covid, such as brain fog, and something about psychological aspects perhaps remaining. And that the clinicians can clear the microclots, and then it might be that these people need other specialists to attend to their other problems. I found all that a bit worrying - a sort of lowering of the bar of what people can expect this treatment to do. Potentially the creation of an 'out' clause in terms of not actually curing people.
It is frustrating that the studies can't be done systematically from the beginning, with good controls and blinding. I guess they take time to do and everyone is in a rush to either be cured, or do the curing. And I guess there's lots of money at stake. If the German clinic can afford to fly Professor Pretorius out to Germany and pay for a study on the presence of microclots before and after the aphaeresis, it's hardly surprising that that is where the effort goes.
Appreciate this thread is a very left-field exploration of a disease that has defied explanation for decades. Perhaps it should be left there for now until some useful reproducible data appears. I would like to try and capture my thinking and questions at this point, until that time.
I agree and think they are a post-infection manifestation. I think they are long-lived however (potentially very long-lived). They are said to be resistant to fibrinolysis — I think Prof Pretorius indicated due to the contained antiplasmin. In the paper they noted the unusual requirement for two rounds of digestion prior to content analysis.
I wonder if the majority of the micro-clots in vivo might be small, not the larger forms demonstrated in some of the pictures, which may have clumped due to the spin-down to make platelet-poor plasma or some other artefact of processing. I think that the micro-circulation is vulnerable due to the slow flow and increased chance for peripheral wall contact, allowing the inflammogens she describes the potential to take effect.
I think fatiguability, PEM etc has to be more complicated than simply hypoxia from clots blocking capillaries. If it applied to ME patients, then surely this would have been seen in post-mortem studies. I think what blocks the capillaries is RBCs, poorly deforming due to the effect of the micro-clots, plus the encumbrance of attached activated platelets. But I think this is a functional blockage, rather than purely mechanical.
I think this process is dynamic and variable. 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. 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 SvO2: is it increased from baseline after sleep due to reduced oxygen extraction; is it decreased from baseline in the days following exertion?
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?
No question proper science needs to happen here (as you, Jonathan Edwards and HibiscusWahine have commented above). The therapeutic side (apheresis) appears to have come about strangely. I assume it was a popular therapy in some parts of the world for various reasons. Perhaps reports of symptom help for LC patients was initially serendipitous and desperate patients are jumping the gun. A therapy would be great, but needs to be validated and safe.
First job is to work out the mechanism of LC/ME and develop a bio-marker. Maybe then precision-targeted therapeutics can be created that clear up what may be the long-lived deleterious result of immune overdrive.
In order to help, we're going to attempt to find some of these micro-clots in my blood, hopefully sometime in the next three days. (Also see if any evidence that I was a previous COVID, which would be important to know.) If we find them easily, then we can do some basic science and try and learn things. I will report back.
I agree and think they are a post-infection manifestation. I think they are long-lived however (potentially very long-lived). They are said to be resistant to fibrinolysis — I think Prof Pretorius indicated due to the contained antiplasmin. In the paper they noted the unusual requirement for two rounds of digestion prior to content analysis.
I wonder if the majority of the micro-clots in vivo might be small, not the larger forms demonstrated in some of the pictures, which may have clumped due to the spin-down to make platelet-poor plasma or some other artefact of processing. I think that the micro-circulation is vulnerable due to the slow flow and increased chance for peripheral wall contact, allowing the inflammogens she describes the potential to take effect.
I think fatiguability, PEM etc has to be more complicated than simply hypoxia from clots blocking capillaries. If it applied to ME patients, then surely this would have been seen in post-mortem studies. I think what blocks the capillaries is RBCs, poorly deforming due to the effect of the micro-clots, plus the encumbrance of attached activated platelets. But I think this is a functional blockage, rather than purely mechanical.
I think this process is dynamic and variable. 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. 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 SvO2: is it increased from baseline after sleep due to reduced oxygen extraction; is it decreased from baseline in the days following exertion?
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?
No question proper science needs to happen here (as you, Jonathan Edwards and HibiscusWahine have commented above). The therapeutic side (apheresis) appears to have come about strangely. I assume it was a popular therapy in some parts of the world for various reasons. Perhaps reports of symptom help for LC patients was initially serendipitous and desperate patients are jumping the gun. A therapy would be great, but needs to be validated and safe.
First job is to work out the mechanism of LC/ME and develop a bio-marker. Maybe then precision-targeted therapeutics can be created that clear up what may be the long-lived deleterious result of immune overdrive.
In order to help, we're going to attempt to find some of these micro-clots in my blood, hopefully sometime in the next three days. (Also see if any evidence that I was a previous COVID, which would be important to know.) If we find them easily, then we can do some basic science and try and learn things. I will report back.
Forbin
Senior Member (Voting Rights)
FWIW, this article in Science Daily refers to the "insolubility" of the micro clots and mentions a "pathological fibrinolytic system."
Could the clots themselves just be indicators of some other dysfunction that is more directly related to the effects seen in Long Covid?
Jonathan Edwards
Senior Member (Voting Rights)
I have not read published papers on this but my instinct is that it is a laboratory artefact, because:
1. The plasma samples appear to have undergone freezing and thawing, centrifugation and maybe 'trypsinisation', although that sounds like a confusion by a journalist. The clot shown is over 120 microns long (big enough to see with the naked eye). Even red cells have to squeeze through capillaries at 7 microns. No way would a clot, even if spongy, survive recirculation through capillaries. Objects of this size are normally cleared every cycle by lung capillary bed or spleen or just be embolising in tissues.
2. The original report of twenty LongCovid patients was a year ago. I have not yet seen any other lab replicate this.
3. All of 20 'LongCovid' cases had clots. Since LongCovid is a heterogeneous group that is surprising. We do not hear about controls.
4. A responsive scientist with an important new pathological finding does not start treating patients with anticoagulant cocktails outside trials and sending them to Germany for some special sort of apheresis. Germany seems to be a place where questionable haematological procedures are allowed. Why isn't this being done in S Africa if it is a well recognised procedure? Why not the USA or the UK?
5. If these clots exist in patients why are they not detectable with simple Coulter counter analysis? They ought to show up as highly characteristic I think.
1. The plasma samples appear to have undergone freezing and thawing, centrifugation and maybe 'trypsinisation', although that sounds like a confusion by a journalist. The clot shown is over 120 microns long (big enough to see with the naked eye). Even red cells have to squeeze through capillaries at 7 microns. No way would a clot, even if spongy, survive recirculation through capillaries. Objects of this size are normally cleared every cycle by lung capillary bed or spleen or just be embolising in tissues.
2. The original report of twenty LongCovid patients was a year ago. I have not yet seen any other lab replicate this.
3. All of 20 'LongCovid' cases had clots. Since LongCovid is a heterogeneous group that is surprising. We do not hear about controls.
4. A responsive scientist with an important new pathological finding does not start treating patients with anticoagulant cocktails outside trials and sending them to Germany for some special sort of apheresis. Germany seems to be a place where questionable haematological procedures are allowed. Why isn't this being done in S Africa if it is a well recognised procedure? Why not the USA or the UK?
5. If these clots exist in patients why are they not detectable with simple Coulter counter analysis? They ought to show up as highly characteristic I think.