Aphaeresis/ Apheresis (for removal of microclots)

(I know I'm going to regret trying to answer Jo's questions! Realistically they're unanswerable at this time - which is, I guess, his point. Apologies for the rehashing, I think we've taken this subject about as far as we can until there are other publications that support or deafening silence refutes.)

I'm enthusiastic about the idea of amyloid-form clotting, with abnormal fibrinogen, small fibrin monomers and larger fibrin aggregates, being resistant to fibrinolysis. I'm not enthusiastic about apheresis, which does not appear to have usefully held up over time. I was more interested in it at the beginning, although thought it would be difficult to subject to an RCT. Many commentators here warned back then that it would not pass scrutiny.

As Jo says, no-one has yet reported these in living people. The closest related report I came across was descriptions of microvascular thrombosis appearing during clot-retrieval interventions. As I recall this was said to be a new phenomenon, not previously noted by experienced operators. I can't recall whether that was a Twitter post or elsewhere. Of course that only describes de novo observed microvascular clotting, it doesn't say they were due to microclots in circulation or that they were amyloid in nature.

Microclots have been described in postmortem studies, but needless to say, those patients are dead, so quite different and of limited study value. The other related data point I guess is the multiple reports from embalmers that postmortem clots, with which they are very experienced, had become very abnormal in extent and consistency. This was said to be a new finding, shown in people who had died of COVID-19 (or, more contentiously, following recent vaccination).

None of that is particularly helpful for the questions though.

How could apheresis help? (Or: how might it have helped?). The hypothesis is that the microclots they were seeing in vitro, were present in vivo. In their papers they have stated that the microclots they show must have already been in circulation, because no thrombin was subsequently added. The logic I presume being that thrombin is required to turn soluble fibrinogen into insoluble fibrin. I don't know that that follows exclusively. As far as I understand fibrin exists on a continuum that as a small fibrin monomer (that has not yet cross-linked) can still be soluble. I imagine there is opportunity for soluble or near-soluble fibrin to form larger aggregates in vitro, such that microclots could simply be an artefact (as Jo has always maintained).

Assuming they were circulating in vivo though, the hypothesis was that they were abnormally formed: not tightly compacted as clots should be, but instead nebulous and deformable enough to pass through small capillaries even if they were themselves quite large. (c.f. RBCs turning into tacos in small capillaries). In this way they would continue to circulate, not be filtered in lung or kidney and persist. The in vitro microclot analysis showed they contained a2-antiplasmin which would tip the balance away from fibrinolysis and help explain their longevity.

As Jo says, no-one appears to have replicated this in a publication. What has been shown recently is the mechanism for how spike protein causes amyloid fibrin(-ogen), again in vitro (also in silico). See this thread detailing that basic science work by an unrelated Swedish group. That demonstration goes lower level, whereas we need to go "up" and show circulating amyloid microclots. The Swedish group did demonstrate two PET tracers that tag the amyloid fibrin. They suggest this could be used in patient investigations.

Presumably if a patient had lots of amyloid fibrin (small) in blood, then the blood pool would be generally "hot" on PET. I'm surmising that if there were larger circulating microclots, then, notwithstanding the deformability mentioned above, they might be expected to pass much more slowly through some organs with obligate capillary networks, compared to organs with opportunity for arteriovenous anastomotic bypass, which could have the effect of appearing to accumulate tracer preferentially in eg lungs or kidney, despite not ultimately being filtered out there, as above.

 

I am afraid I don't buy the attempt to make the micro clots long lasting and yet troublesome.

The liver and spleen remove fine debris from blood all the time. Red cells, which pass nicely through capillaries are constantly being cleaned or 'pitted' to remove complement bound material stuck to CR1.

The clinical picture of chronic diffuse intravascular microcoagulation or other forms of micro-obstruction is well known in its various forms - with anti-phospholipid syndrome, polycythaemia rubs vera, chronic myeloid leukaemia, Felty's syndrome etc etc. You get micro infarction or sludging haemodynamic problems. You see characteristic things on ophthalmoscopy where you can see blood going through tiny vessels directly. If micro clots were important in LongCovid at least a few cases of splinter haemorrhage or DVT or TIA would have been noted. Clotting problems are obviously a major issue during severe acute Covid but that is not relevant.

 

So just to clarify, according to the research theory and investigation, as yet published, this small amyloid-fibrin protein, that does not get cleared by the liver, then causes problems in the micro-circulation throughout the body as well as travelling into the cerebrovascular microcirculation to do what it does, yet unknown.

Do you know if this protein then passes through the blood brain barrier and then has effects on cerebral tissue or related interactions?

What is the current radiological investigation being done within the PASC literature to narrow this down to this protein?

Is there any pathological investigation of post-mortem tissues showing elevated amyloid-fibrin within cerebral tissue?

Would you envisage people might (big might) need a one-off HELP apheresis to remove excess clots after having had a course of platelet stabilisation/anticoagulant treatment?

Do we know the efficacy and safety of the anticoagulant treatment on stabilising this?

Have any harms been recorded and reported for HELP-apheresis (I guess will have to wait on that one)

I appreciate you probably don’t have PET scans to work any of this out with locally but what would be your radiological plan? (in an ideal world with lots of money or just available here, private or public)

Obviously this research is in its infancy but would be interested to read how various researchers/clinicians are contributing to this theory.

 

Yes, agree (including your point about liver, spleen etc). I'm pretty keen on the possibility of abnormal (small) fibrin, but would like replication. I don't see proof of circulating microclots, but think it remains a possibility worth exploring.

Isn't that what's being shown? Retinal changes. Covid toes/nails. Higher thromboembolic risk. Often young, previously healthy/fit people down the line from Covid having the later thromboembolic events of DVT, PE, MI and stroke.

• Retinal Microcirculation as a Correlate of a Systemic Capillary Impairment After [SARS-CoV-2] Infection (2021)
• Retinal vessels modifications in acute and post-COVID-19 (Nature, 2021)
• A review of nail findings associated with COVID-19 infection (2021)
• Long-term cardiovascular outcomes of COVID-19 (Nature, Feb 22)
• EDIT: See also today's CDC figures to Nov 2021

Also common to see individual reports on Twitter.

https://twitter.com/user/status/1489221020837888005

https://twitter.com/user/status/1502994935326388226


Additionally, V/Q scans appear to be coming back into vogue to assess for subsegmental PE, which is below the resolution of CT pulmonary angiography.
https://twitter.com/user/status/1528016436135964672

 

Does plasma viscosity show this

 

Yes, the theory is a combination of platelet hyperactivation, endotheliitis and amyloid long-lasting fibrin(-ogen) are interacting with each other to perpetuate both all of these pathological processes and also downstream pathology.

I don't, but endotheliitis / endothelial dysfunction would likely be associated with degradation of BBB integrity.

Standard and even advanced neuroimaging by MRI has been limited. The Xenon MRI lung studies were definitely an advance. I think a promising line is specific PET tracers. These might be able to assess for amyloid fibrin in the same way that Aβ is assessed in Alzheimer's. (I appreciate the amyloid in AD is probably a secondary phenomenon.)

I don't know, but there's always the problem that postmortem studies have limitations. By definition, the patient died so has had a more severe disease pathway than living patients. But I guess more importantly blood likes to clot once it's out of circulation (or not circulating). So would be prone to artefact.

I'm not keen on HELP apheresis, until it can be shown to be effective, following good replicating evidence that this is the mechanism at play. But possibly a use case would be a one-off for severe symptoms, and then proceed with medical therapy. Also, that medical therapy may not be anticoagulation, but MAbs or some other more tightly targeted approach. Unclear if the coagulation pathology is a specific, additional feature of this virus which is unrelated or obliquely related to more typical postviral ME pathogenesis.

Paucity of publications so far. Anecdotally, people maintain they have not had adverse bleeding events, but the researchers are at pains to demand this is only attempted under proper medical supervision, with demonstrated hypercoagulability (and the doctor has to agree this is reasonable). Asad Khan maintains that 3x anticoagulation is much safer than you might think, because it brings the patient down from hypercoagulable to normal, rather than making a normal patient hypocoagulable and prone to adverse bleeding events. For what it's worth, I haven't seen any Twitter reports of bleeding.

Those advocating claim it is very safe with a 40 year track record. Unclear if 1 or 2 treatments have the same risk profile as 8+ for this LC treatment. I would have concerns that it's removing lots of good stuff on the way, and this could be harmful. I would prefer that we can understood the potential mechanisms and could then target with RCT-able drugs.

We have good quality PET scanners, but the trick is to be able to manufacture the novel tracers. They may be challenging and expensive to make and often only available to research institutes. Also, if the half-life is short it needs to be made close to the scanner, just before the patient appointment. In NZ standard 18FDG is made in Wellington and flown up or down, which is fine given its 2hr half-life. We can even fly it in from Oz at times.

 

There seems to be good evidence for microvascular damage during acute Covid but I don't think it adds up as a basis for LongCovid. There is a report of cotton wool spots in retinae during acute Covid but not as far as I can see later. The nailbed lesions reported are mostly not what one expects with micro infarcts (i.e. splinters) and again seem to be during acute phase or left over from (transverse bands).

I agree that there is an increase in reported PE and stroke - which I guess is reminiscent of anti-phospholipid syndrome and I think that points more towards formation of large clots (as in APS) rather than micro clots. Also as far as I know the MIs and strokes are not necessarily in people who are otherwise considered to have LongCovid. Moreover, from what I can see from the relative incidence chart posted the late incidence is not that great - a statistical doubling maybe.

Basically I find it implausible that people who have a symptom complex similar to ME after Covid are suffering fro micro clot problems.

 

We had a UCL Grand Round on 'Covid Toes' today. The speaker confirmed (and showed pictures to show) that the pathology of Covid Toes does not look thrombotic - more a dermal lymphocytic infiltrate suggesting diffuse vascular injury perhaps.

They also indicated that Covid toes are not a feature of LongCovid judging by the evidence available. They seem to be associated with the first six weeks after onset.

Nobody had heard of Pretorius.

 

Thank you, I very much appreciate your review. Yes absolutely agree with your point that PE etc implies large thrombo-emboli and wouldn't be explained by "microclots". Given these ongoing increased T-E reports, to me that supports the idea that there's persisting hypercoagulability in many people. It's something I've subjectively observed in myself (frequently clotting tubing to the surprise and lack-of-delight of phlebotomists).

I had thought that Covid toes were a more prolonged phenomenon (per patients' postings on Twitter) but interesting to see that reported evidence indicates a shorter timeframe in reality.

Does seem a shame that no-one has read the Pretorius publications. While this current work may ultimately not amount to anything, I still think the underlying ideas warrant a second look by other groups. Appreciate this was likely a Medical Grand Round, but I imagine her co-author, Prof. Doug Kell would be known to one or two researchers at UCL, though perhaps they wouldn't be audience members.

He has commented on Twitter that previously there was a clear distinction between their in vitro micro-clot finding being present in 100% of LC and not (or minimally) in healthy controls. Now they observe that it's no longer quite so minimal in HCs and that even commercial plasma shows more activity than previously. He ascribed this to the fact that many more donors have been exposed to spike protein (virus and/or vaccine). I wonder if this could be regarded as representative of a dose-response relationship.

https://twitter.com/user/status/1523802460258816002

 

From what I can see on the net Kell is a retired basic scientist who has wandered into a clinical area that he may not have any practical knowledge of.

 

My hematologist said pretty much the same thing when I talked to her last month.

 

Sure, but let's not lose sight that it's very likely that the underlying cause will contradict current theory. Not that this is it, but "contradicts current medical knowledge" is not a compelling argument in research, it's literally the whole point to do research.

Frankly if the underlying cause is identified to a high degree of accuracy and does not upturn a lot of medical "common wisdom", at least to the same degree as "bacteria cannot possibly survive long enough in the stomach to cause ulcers", I would be very surprised. It's very likely to be more baffling than familiar, at least at first.

 

There is a difference between contradicting current theory - which is the name of the game - and contradicting empirical findings replicated tens of thousands of times in routine laboratories throughout the world. Science is not about showing that what was found to be the case empirically wasn't.

The problem with the micro clot stuff is that it isn't consistent with what has been found clinically or in labs. It is a bit like having a theory that the sun comes up twice each day - it doesn't.

 

I think that Dr. Scheibenbogen has said that apheresis might help; I believe I saw her name on the
Apheresis Facebook page. She provided a list of what might help. But there are not many reports from ME patients at all, at this point. I wrote to Dr. Pretorius and asked her when her paper was coming out, and she said they are writing it up at this time.

 

Apheresis covers a lot of different things - it just means cleaning plasma of something by filtration or absorption. Carmen Scheibenbogen has suggested Apheresis to remove antibodies, which is a different technique from clot removal. I don't think we have much reason to think that either would help. Apheresis for antibodies has largely been abandoned in clinical immunology except for acute conditions like encephalitis from anti-neuronal antibodies.

 

Thank you for refining this; you see, the Facebook apheresis page simply indicated Scheibenbogen recommends apheresis, without specifying. At any rate, the ME situation for patients is just interminable suffering, and for their kin, unrelenting heartbreak.

 

Just to follow on this part of the discussion as it relates to acute COVID disease, there is a new publication: Sex Differences in Clinical Characteristics, Management Strategies, and Outcomes of STEMI With COVID-19: NACMI Registry, looking at MI in acute C19 patients.

It discusses the findings in ST segment elevation myocardial infarction (STEMI) in those hospitalised for this, who are also recently positive for SARS-CoV-2 (out to four weeks). They also include those having MIs while in hospital for any other reason, who are similarly recently C19 +ve. It notes a 30% in-hospital mortality rate and found a relatively high rate of no identifiable coronary artery lesion, moreso in women. 585 patients.

In women, chest pain presentations without angiographically demonstrated obstructive coronary artery lesions have been challenging. Women have often been treated as if the chest pain is non-cardiac. This is despite heart disease being the leading cause of death in women across all ages. Discussed more in Gender and Microvascular Angina (2011).

 

Copied from the Long Covid in the media thread here

Thousands seeking unproven long Covid blood treatments abroad

"Apheresis, a blood filtering treatment normally used for lipid disorders, involves needles being put into each arm and the blood passing over a filter, separating red blood cells from the plasma. The plasma is then recombined with red blood cells and returned to the body via a different vein.

Gitte Boumeester, a trainee psychiatrist in Almelo, the Netherlands, tried it after developing severe long Covid symptoms.

After undergoing treatment at The Long Covid Center in Cyprus at a cost of more than €50,000 (£42,376), she returned home with no improvement to her symptoms. She received six rounds of apheresis, as well as nine rounds of hyperbaric oxygen therapy and an intravenous vitamin drip at the Poseidonia clinic next door to the clinic."

......

"Chris Witham, a 45-year-old long Covid patient from Bournemouth, England, spent about £7,000 on apheresis treatment (including travel and accommodation costs) in Kempten, Germany, last year. “I’d have sold my house and given it away to get better, without a second thought,” he said. The treatment did not improve his long Covid symptoms, the BMJ reported."

https://www.theguardian.com/society...g-unproven-long-covid-blood-treatments-abroad


The BMJ article, 'Long covid patients travel abroad for expensive and experimental “blood washing”'

"Patients with long covid are travelling to private clinics in Cyprus, Germany, and Switzerland for blood filtering apheresis and anticoagulation drugs. Experts question whether these invasive treatments should be offered without sufficient evidence. Madlen Davies reports

Gitte Boumeester, a trainee psychiatrist in Almelo, the Netherlands, was infected with SARS-CoV-2 in November 2020. She was tired for weeks afterwards but chalked it up to the virus. Soon, she was experiencing such extreme fatigue that it took her two hours to walk to the kitchen to make breakfast. She had brain fog and heart palpitations, was short of breath, often felt sick, and woke up in the night with chest pain. A battery of tests found nothing wrong with her heart or lungs, and she was sent back to her GP. She left her job in November 2021, after two failed attempts to go back to work.

She joined a Facebook group for patients with long covid, many of whom discussed travel to Germany for apheresis, what some of them call a “blood washing” treatment. Apheresis, in which large needles are inserted into the veins and the blood is filtered, removing lipids and inflammatory proteins, is recommended by the German Society of Nephrology as a standard last resort in the country for lipid disorders. A new clinic offering apheresis for long covid patients, called the Long Covid Center, was opening in Cyprus, and she could be treated there in March. “I thought, what’s the worst thing I’ve got to lose?” she said. “Money was the only thing. I thought, OK, well, why not give it a try?”

Two months later she was back home in the Netherlands, having spent nearly all her savings—more than €50 000 (£42 400; $60 000)—with no improvement in her symptoms."

https://www.bmj.com/content/378/bmj.o1671

 

The most important part of the article, in my opinion, is the one about the consent form. According to the BMJ and one patient, it fails to inform patients of the experimental nature and risks of the treatment, and instead promotes unproven benefits. Worryingly, it also asks them to waive any legal liability from the apheresis clinic should they be injured.

This is absolutely unethical. Experimental treatments can be expensive, so be it, but patients must be correctly informed and have a legal recourse if they are injured (no matter how hard it may be to apply if needed).