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

Background: Fibrin(ogen) amyloid microclots and platelet hyperactivation are key pathological findings in patients with acute COVID-19 infection and also in those with Long COVID/Post-Acute Sequelae of COVID-19 (PASC). These pathologies may represent a suitable target for pharmacological treatment of Long COVID.

Methods: Here we report on the symptoms displayed by a cohort of 91 South African Long COVID patients at baseline and after a clinician-initiated anticoagulant regime was completed. For laboratory analysis, patients provided a blood sample before and after treatment. Fibrinaloid microclot presence was studied by adding thioflavin T to platelet poor plasma (PPP), whilst platelet hyperactivation was studied using two platelet markers- PAC1 and CD62P (P-selectin). The anticoagulant regime included dual antiplatelet therapy (DAPT- Clopidogrel 75mg + Aspirin 75mg) once a day, and a direct oral anticoagulant (DOAC- Apixaban) 5mg twice a day. A proton pump inhibitor (PPI) pantoprazole 40 mg/day was also prescribed for gastric protection. Each of the treated cases reported their main Long COVID symptoms, and whether their symptoms resolved following treatment or not.

Results: In our cohort a most participants did not report any comorbidities before acute COVID-19 infection. Hypertension and dyslipidaemia were the commonest underlying illnesses, whilst the most commonly reported Long COVID symptoms included fatigue, cognitive dysfunction, shortness of breath, and joint and muscle pains. Following completion of treatment, each of the different symptoms resolved in the majority of patients. This was also reflected in the laboratory analysis, where a decrease in the severity of fibrin amyloid microclotting and the degree of platelet pathology was noted. No serious adverse bleeding events were reported.

Conclusions: Fibrin amyloid microclots, platelet hyperactivation/ aggregation, and widespread endothelialitis inhibit the transport of oxygen at a capillary/cellular level. This provides a ready explanation for the symptoms of Long COVID. By normalizing the failed clotting physiology and reversal of the endothelialitis, triple anticoagulant therapy represents a promising treatment option that appears to be highly efficacious, and warrants controlled clinical studies. We caution that such a regime must only be followed under expert medical supervision in view of the risk of bleeding.

https://www.researchsquare.com/article/rs-2697680/v1

 

Self-reported symptoms, no control group.

 

I would like to see a properly conducted scientific survey of PwME who have been on long-term anticoagulant therapy (due to risk of stroke, etc) and see if there's any difference in their level of function since they began it. Also would like to see if those with antiphospholipid syndrome (and seronegative APS) who also have ME have seen a change in their level of function since they began anticoagulant treatment.

 

Symptoms can only be self-reported, but they did validate reduction in the clots. However accurate this method is at identifying and measuring them, the method is seeing that reduction.

Lack of controls is an issue but the numbers are massively above even natural outcomes for remission and recovery, and this is preliminary research supporting a controlled study.

Jumping to RCTs is a terrible, wasteful idea. They are very expensive, slow and unreliable as any effective treatment would light up like a 1kW Christmas tree anyway. It's supposed to be a stepped process. I hope this pans out. Let's see if it does.

However what we need is a turbocharged approach on the scale of the AIDS initiative, rapidly trialing and testing out hypotheses. This is the first promising anything in 3 years from a hypothesis that was identified early on, and there isn't any other. And I'm sick beyond all reason to hear about how this is going quicker than usual, because all it means is the usual speed is excessively slow. It's basically geological pace.

However I think this is likely to stop there. Healthcare services won't want to touch this. I'm coming around to the very real possibility that medicine will want nothing to do with any effective treatment. Ever. We'll have to do it ourselves and work entirely around the system for the most part. Embarrassment is a powerful force.

 

You can do without a control group for a very well documented disease at times.
But for this situation a study without a control is worthless.
There is no justification in recruiting numbers like this if the study tells us nothing and the treatment is potentially hazardous.

I still do not understand how endothelialitis and clotting are supposed to be causing symptoms if nobody has seen any clinical evidence of such changes. Why are there no spinner haemorrhages or palpable purpura? Why don't ordinary clotting studies like fibrin degradation products show anything? Why haven't UK and US haematologists taken interest?

 

I'm talking about the subjective outcome measure + no control group combo, which we would never accept from a BPS study as convincing or promising. It should be the same standards for everyone. We have actimetry, a 6-minute walk test, it doesn't need to be self-reported improvement. Maybe these patients really did get that much better but we need to be cautious with a theory like this widely hyped by patients.

And if they really get better, we still need a control group and later follow up as others have said to see if the effect can indeed be attributed to the therapy or how well it holds up.

 

Dr. Marc Carrier, senior scientist and Chief of the Division of Hematology here at The Ottawa Hospital did mention seeing increased blood clots during an interview a couple of years ago in acute Covid patients in hospital, but I have not heard or read anything on his twitter that says much about Long Covid patients and clots.

 

Can anyone give some context for understanding the Patient Global Impressions of Change scale used (attached below)? I find the wording confusing to the point that my answers as a patient would be a little arbitrary. I also find it strange the way it’s weighted and that it doesn’t measure worsening. I don’t have the function to research how common this scale is.

My wife (an LC & ME patient) has been trialing Nattokinase supplements for some time and feels they have been significantly helpful with chest pain she gets, but not to any other symptoms. She’s gone off and on them a few times and the pains recur each time she discontinues. I asked how she would rate the effect on this scale and she would rate it between a 4 and 5, though it’s one symptom of a great many and the improvement of that symptom produces no change in day to day function. Asked to focus on different items in the prompt, her answers move up and down the scale.

 

I had unprovoked multiple bilateral pulmonary emboli in 2006. The hematologist did a thorough work up but could not find a reason for why I had the clots. As it was my second episode of a pulmonary embolism (the first combined with DVT following knee & ankle surgery in 1998), he recommended life-long anticoagulation and I've been on blood thinners since then (warfarin from 2006-2016 when I was then switched to ribovaraxin). Not only have I had NO improvement in my ME/CFS symptoms, my condition steadily declined over the years.

The one proviso to this: I was discharged from the hospital in 2006 with a ten day cycle of low-dose heparin (they did this in 1998 also) in addition to warfarin. I had a puzzling improvement in my symptoms starting the day after I was admitted that lasted about 10 days. And I know there have been patients over the years who swear heparin makes them feel better. I've always been skeptical of this but have no way to say with certainty this wasn't the reason. A more likely explanation for my brief improvement may be that they needed to do a second CT so they started pumping me full of fluids so that I would pee out the radioactive dye from the previous day's CT scan so they could give me more radioactive dye without harming my kidneys. IV fluids have long been known to improve symptoms in ME/CFS patients.

 

Dr. David Berg's hypercoagulation hypothesis has been discussed before on this Forum:


https://me-pedia.org/wiki/Hypercoagulation_hypothesis#:~:text=Dr.,genetic variations related to coagulation.

Additional info on Dr. Berg's theory:

https://www.anapsid.org/cnd/diffdx/hypercoagulation.html

 

I have not seen a scale like that before. As you say it looks vague and confusing. I cannot think that the 7 grades are justified. More commonly people use about 3-4 - same, a bit better, much better, and yes should include worse.

 

I have tried to make sense of the figures giving the results. Other than the fact that they seem to show lots of people improving over time I cannot make anything of them. This seems like a study done by people who think they are doing a trial but have no understanding of how trials are done.

As @Wyva points out, this is at least as bad as PACE and Co. - in fact far worse.

 

Correction, David Berg is not a doctor, but he plays one in real life. My understanding is that his wife owned HEMEX lab.

He immediately told my doctor when he met him that I had active HHV6 infection and was in a hypercoagulative state based on minor "high" level fragmin lab tests.

 

Ah yes, my recall was that he is not a doctor, but one or maybe more websites said "Dr.", so I went with that.

Thanks for noting your experience with this...

 

The investigators recruited enough participants to have both an active intervention group and a placebo control one of adequate sizes for statistical purposes. It is disappointing that they did not do so, especially as it would have been easy to provide placebos since the drugs were in tablet form.

 

When i saw the #teamClots stuff on Twitter and the way they were marketing this whole thing, i would have bet money that it would turn out to be a scam with garbage tier science. It is unfair and dystopian that patients keep getting exploited like this, and nobody cares. Almost nobody is even aware of this. It's the same tune for decades, the same thing happening over and over and nothing ever changes.

 

Some fair criticism but the economics of jumping to RCTs will never work, this is not how to do research. Research is a process. No one starts a research process with a massively expensive later phase methodology.

Actual research is different from the BS "pragmatic" approach of "let's try random stuff that we imagined". This is the test phase of observe-hypothesize-test, it follows the observe and hypothesize phase of finding clots, accurately or not.

There is no successful trial that will not show a reduction in symptoms, so that's not valid criticism. PACE was like the 10th phase of a 2 decades-long process with dozens of identical trials before it. I don't even understand comparisons here, not even in the same universe. There is a theoretical basis here, correct or not. Testing a hypothesis is how research works and it works in phases.

 

I don't know about you, but I've tried about 50 drugs/supplements from trials like this one and none of them worked. Trials like these are literally worthless. Yes, they should jump to RCT right away, if not simply just do nothing, it's better than luring patients into trying stuff that doesn't work.

 

Have you ever been involved in this process @rvallee?
As you know, I have. I have done pilot studies and larger follow-on studies.
At each stage you have to do a study that is capable of producing a meaningful result.
This study, much like PACE, was incapable of producing a meaningful result.
So this is not how you do research.

You need controls and you need randomisation in this situation. That was done in the trial that identified dexamethasone as useful for acute Covid right from the start. It need not be significantly more expensive than an open study with no controls. I have myself done a randomised controlled trial of steroids in lupus with no funding other than routine health service resources.

Everyone is entitled to their opinion but the idea that this sort of study is the way to do research simply makes no sense to me.

A pilot study of 5 patients would have been fair for this anti-clotting treatment - just to see if there was a dramatic change within an implausibly short time for natural recovery. But that is not what was done here.