Preprint: Treatment of Long COVID symptoms with triple anticoagulant therapy 2023 Laubshder, Pretorius et al

This process you are describing has yielded exactly nothing in decades. So I don't think much of it. Hasn't even produced a single bit of useful data in basically dozens of similar conditions and barely delivers anything in general. Medical breakthroughs are made in labs, not because of a perfect study that pleases bureaucrats.

No need to be involved in a failed process to see it has failed, just as you don't need to be a programmer to notice when software doesn't work. The failure is visible for all to see.

The idea that research should begin at a later phase makes as much sense as public testing of software that isn't even in an alpha phase, doesn't even have a user interface. This could go on for a millennia and it wouldn't even amount to anything.

It's good to be critical but seeing this makes it pretty clear how many of you would have dismissed work like Barry Marshall's. Or in fact any work that isn't mostly bureaucratic checkboxing. Maybe rightfully so, but breakthrough research never looks like previous research. That's the breaking through part. It breaks textbooks and conventions.

I understand this slow process is the norm. And it has failed us miserably and hundreds of millions more. We need to move fast and break things, and it's going to have to happen because none of this damn system is capable of actually delivering squat. It's likely going to happen anyway, precisely because of how inept the whole system is revealing itself to be.

 

I'm pretty sure that hypercoagulability is going to be shown to be an important factor in LC, and likely ME. There are just too many signals and indeed we had a decent paper that had good evidence of this in LC (Analysis of thrombogenicity under flow reveals new insights into the prothrombotic state of patients with post-COVID syndrome, 2022).

I suspect that this work on microclotting will be developed and ultimately could be shown to be happening in vivo — but we're a long way from it being merely an artefact of hypercoagulability as Jo has said from the outset. The team's hypothesis includes the idea that fibrin degradation products aren't high (#alltestsarenormal) because fibrinolysis is impaired, so fibrin is not being degraded; and microclots persist when conventional thinking says they should degrade or simply be filtered. We do have potentially supportive secondary evidence in vivo, eg the hyperpolarised Xenon MRI studies.

If so, then yes that would be a paradigm shift in understanding thrombosis and the prothrombotic state and this could be a Marshall moment: "why would anyone treat a stress ulcer with antibiotics?" -> "why would anyone treat fatigue or brain fog with anticoagulants?". Similarly, as the team points out in their paper: using anticoagulants not to make people hypocoagulable, with inherent risks of major bleeding events, but instead to return people from hypercoagulable to normal. If that's able to be monitored and confirmed then treated patients would have similar risks of bleeding as a normal healthy person.

Apart from the major problems in study design as outlined up-thread (it's a case series not a trial), I think one of the other main problems is pushing too hard for this to be The Explanation. This preprint shows a subgroup of patients who didn't improve and who still had hyperactivated platelets and microclots. I suspect at best this would be a symptomatic treatment, while some people naturally recover, but that eg upstream immunometabolic dysregulation still needs to be addressed in the non-spontaneous recoverers.

There's handwaving, eg "widespread endothelialitis inhibit the transport of oxygen at a capillary/cellular level. This provides a ready explanation for the symptoms of Long COVID." It's going to be much more complex than that. Perhaps it might contribute and from my own experience of "vascular/blood weirdness" I'm suspicious that it does — but it's a long way from the whole picture. I recall Resia Pretorius did recently tweet that they thought microclotting was downstream.

I would like to see demonstration of microclots in vivo, eg Martin Kräter's microfluidics studies or maybe via flow cytometry which I believe this team is also looking at. Studying responses with such objective markers to correlate subjective symptoms against (controlled) triple therapy might then be able show something useful — whether effective or ineffective.

 

I think maybe we're just not seeing this from the same perspective. I don't see this as an evidence-based type trial for this particular treatment. That process is generally worthless and frankly I wrote if off entirely as likely to produce anything useful.

Simply asking about symptoms is also useless in itself, it's the correlation that matters. It's not the treatment that is being tested, it's the hypothesis.

That's probably a product of the fact that we're trying to figure out the pathophysiology, whereas normally it is known and the EBM process is about trying to target it. But the pathophysiology here can only be figured out from large numbers, whereas distinct diseases can often do much of this phase with a few validated patients. We don't even know how to really validate patients.

This study tells us very little about this particular treatment, and even if it had been a 1,000-strong quantum-randomized double-blinded controlled trial, no MD worth their license would prescribe this treatment.

Research is a process. Maybe we're too used to having one shot only and that's it, but there are supposed to be subsequent steps. It's not supposed to be THE one trial, it's the first one. No effective treatment will ever be found from a single trial, nor would a single one tell us much about whether it is really effective.

The only reason the trial is worth anything is because of the observed effect on the microclots detection and correlation with symptoms. If valid, it tells us that it is a viable research path. I don't know if it's valid, and there is no textbook for this because it's not previously known. Medicine is still finding entire new organs, though small ones, so I think people should chill a bit on this.

I'm not comparing the two studies or saying this is it for us but it's a lot like how bacteria could not possibly survive in the stomach lining. Science is a process and anything new will, by definition, be controversial as not being textbook. That's normal.

It's like Ron Davis said about his difficulty getting funded from the NIH: they don't do exploratory research. This is normally done at universities from tenured budgets, which is what then leads to grants for formal studies.

We have to do the academic stuff using the grant model because no one can get tenured working on any of this. It's terrible but this study is in the observe-hypothesize-test model of scientific research, not an evidence-based paradigm.

I don't know if that's really how the researchers intend it, but that's where I see its value. We have to work with the wrong tools because we are denied the standard ones. It's bound to be messy.

But it's really clear that the current model only works as well as the overall level of technological progress. So any breakthrough will likely involve a new piece or method of technology.

It's not so much about method as getting a clear signal, and whatever the method used, once the technology needed to understand this is figured out, it will be pretty obvious.

 

Maybe I'm not understanding, but this is completely wrong. RCT is often the only way to know if a treatment works and if the trial is large enough and the results significant you can trust that it does work. You can try asking anyone who works at a hedge fund and analyses pharma stocks for a living and they will tell you this.

Why did i pick this example? Because it's a job where you have to perform well if you want to earn your salary - pick the wrong companies and you are fired. So you have to develop a reality based approach. You have to know what actually works and what doesn't. It's not like medical researchers where you can spend your entire life publishing poor studies, contribute absolutely nothing to the science and still get paid.

 

A possible counter-example might be the findings in the metformin vs fluvoxamine vs ivermectin study There they did a decent attempt at an RCT (admittedly as an add-on to the original acute study) with good attempts at blinding and look to be showing a significant preventative effect against Long Covid with a short 14 day course) of metformin instituted within 3 days of infection. That might give us a treatment (or at least a partial preventative) first and then secondarily possibly tell us something about the pathophysiology of LC.

The trick in that case though is we don't know enough about how metformin works to answer immediately what the pathophysiological mechanism might be. Metformin's effects are pleiotropic, just some of them being effects on metabolism/mitochondria/respiratory chain, as well as the microcirculation, NO signalling and vascular permeability. As a partial structural analog, it also reduces serum ADMA, which is one of the (not) excreted metabolites that was significantly different in Maureen Hanson's recent urinary study.

 

Despite what we might be accused of, I, and others on this thread, are perfectly capable of holding two thoughts. One, that the idea of microclots is worth investigating, even if just to rule it out, and two, that in order to do so it will actually need more than just a series of case reports. And as SNTG highlights, the authors of this paper acknowledge this as well.

Declaring that research is broken and and demanding that therefore things should be done in a different way doesn't achieve anything in the real world. We have collectively worked for a long time to highlight how BPS research into ME/CFS, and other areas, does not follow existing best research practices and therefore is fatally flawed; to then argue that biomedical research should not need to follow the same existing best research practices because the "process is generally worthless" undermines all of that effort.

 

They may not be able to gain ethics at this stage. They do have ethics to do an observational study, where a clinician has already independently decided to offer treatment with informed consent, but it might be viewed differently when the committee would be giving permission for this treatment (or placebo) - which everyone would naturally be wary of, because it sounds inherently dangerous. The calculation should weigh the dire state of the patients as well as the mechanistic principles being proposed.

It does seem from the tweets that other international centres are going ahead. Hopefully the level of evidence will rise over the year - RCTs will take time to enrol and report - but maybe we'll see something relating to newer/different fundamental science investigations before then.

 

Have the ethical boards considered that maybe, just maybe, spewing out one unblinded study after another for decades, luring desperate patients into trying dozens of harmful drugs that don't work, might in fact be more unethical than doing proper RCT studies? If the researchers have limited funds (and also time but nevermind that, nobody cares if patients have to wait 40 years for a treatment) why not let them do a RCT right away?

As absurd as this sounds, i can believe it. I've had personal experience with researchers struggling to get ethical approval for a stool microbiome study (which they had already done many times in other illnesses), which literally poses no risk to the patient (you just poop and mail it to them). What reason could you possibly have for denying approval? Oh, i know - someone on the ethics board thinks ME is a fake illness so any biomedical research is inherently immoral and a waste of money.

My question:
Is there anyone who is supposed to oversee and correct these blatant issues with ethics boards or is it another case of "don't worry, we police ourselves because we can never be wrong" kind of deal? Well, we are talking about medicine after all so i guess there is no accountability as usual.

Sometimes i understand why nobody wants to study ME. You find so many roadblocks ahead of you, get treated like shit by every colleague, at a certain point you just choose something else.

 

I think that the last few years have made it clear that pragmatic trials without a theoretical foundation are completely useless, and probably harmful because of the huge wasted opportunity cost (decades wasted on CBT-GET means having given up on real research all this time).

RCTs are useless here because they need to be large and extremely rigorous to be useful. And that's extremely expensive so trials are usually a 3-step process. Only a full process is valuable, same as the process to validate vaccines. It's massively expensive to do this, it's not a working model for trial-and-error.

This model only works when the pathophysiology is understood and treatments are being compared for their effect on the pathophysiology. And even then, unless the effect is massive, it's probably worthless.

Nothing matters other than understanding the biology. The rest is just noise. Finding any treatment that has an effect is only significant if it leads to understanding the pathophysiology. I mean it when I say this paradigm is useless, said it many times before. It's not just for when I like the outcome. I'd likely be more suspicious of any treatment that only has preliminary EBM "evidence", frankly. This paradigm is basically like a reverse-seer: it's almost perfectly wrong all the time.

And here as far as I'm concerned is not an outcome, merely a step. This is indeed evidence for nothing, it's a process of figuring out the cause and that's many complicated steps.

If there's anything to any part of the evidence found so far, whether to do with something in the blood, or something with the vascular/endothelial system, it all has to be figured out before it can help patients. The process of trying random treatments in typical BPS/EMB fashion is the worst idea ever, and that's not at all how I see it here.

When it comes to asking for controls, there is no evidence that the clots disappear naturally. So no need for controls here. I said trial a few times but this really is a basic science study that simply has to rely on awkward tools out of necessity.

 

It's a massively expensive process that only works in some contexts. I don't think it works outside of drug development at all.

We can even look at examples where it technically went though the process, but the evidence is very unreliable, in the form of SSRIs. The biology isn't known, either for the problem or the solution, so the evidence is all over the place and generally poor or conflicted.

Medicine has made everything to be about pathophysiology or bust, they demand it. It's not the system we deserve but it's the one we have to work with. Or ideally around, soon enough.