33 - Resia Pretorius & Douglas Kell - Microclots

Episode 33 of the Long Covid Podcast is a chat with Professors Resia Pretorius & Douglas Kell about their discovery of microclots & hyperactive platelets in the blood of people with Long Covid, what this means and more about their research into this.

We cover a whole load of amazing stuff from causes to possible treatments - I hope you enjoy listening as much as I enjoyed speaking to them!

Links:
Doug's Clots website: http://dbkgroup.org/longcovid/
Resia's article in the Guardian HERE
The hashtag #TeamClots on Twitter 

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(music - Brock Hewitt, Rule of Life)

Transcript

Welcome to the long COVID podcast with me, Jackie Baxter. I'm really excited to bring you today's episode. Please check out the podcast website, longCOVIDpodcast.com, where there's a collection of resources, as well as a link to the Facebook support group. If you're able to, please consider supporting the show using the link in the show notes. If social media is your thing, you can follow me on Facebook @LongCOVIDpodcast, or on Twitter and Instagram, both @LongCOVIDpod. I'm really keen to hear from you. If there's anyone you'd like to hear on the podcast, or if you've got any other feedback, please do get in touch through any of the social media channels, or email LongCOVIDpodcast@gmail.com. I really hope you enjoyed this episode. So here we go.

Jackie Baxter  0:00  
Hello and welcome to this episode of the long COVID Podcast. I am absolutely delighted to be joined today by professors Resia Pretorius and Douglas Kell, who have been working together into researching micro clots and long COVID. So welcome both of you to the podcast. 

Doug Kell  0:19  
Thankyou 

Resia Pretorius  0:20  
Thank you. 

Jackie Baxter  0:21  
So to start with, would you mind both briefly introducing yourselves and just what it is that you do?

Resia Pretorius  0:29  
I'm Resia Pretorius. I'm from Stellenbosch University. I do work on long COVID and all of the other types of inflammatory conditions where we have been looking at clotting pathologies, platelets and microclot formation for a very long time. And Doug has been my collaborator for the past just over 10 years, I think. And we have looked at various conditions from Diabetes to Parkinson's to Alzheimer's to rheumatoid arthritis and lately long COVID and acute COVID.

Doug Kell  1:00  
I'm Doug Kell. I'm currently at the University of Liverpool. And as Resia says, we've been working together on a variety of things, starting with iron metabolism, actually, which we may come to, but fell into the discovery of amyloid micro clots, which turned out to be very important in long COVID and quite a few other chronic inflammatory diseases.

Jackie Baxter  1:23  
Fantastic. So how did you guys actually kind of meet and start working together?

Doug Kell  1:28  
I'll start by answering that because it was it was through me being slightly cheeky, having read one of Resia's papers about iron metabolism, which didn't cite my big review. So I took the opportunity to draw Resia's attention to this review, which does have two and a half thousand references in it. Unlike most people who just ignore snotty emails like that, Resia was very friendly and said, Oh, my goodness, this is really good stuff. Let's work together or words to that effect. So I'll now let Resia give her version of the same story!

Resia Pretorius  2:02  
Yes, Doug, emailed me and he said, Shall we Skype? And I thought, well, who is this person? And then I read the paper. And then I thought, well, let me not ignore him and let us have a Skype - at that stage we were still using Skype. And then well, I think immediately  we just thought that we have got some things to share and in common, and I have at the lab and Doug suggested a few experiments. And that is how it started. And it just snowballed from there. And we just never stopped working together.

Jackie Baxter  2:42  
That's so awesome. 

Doug Kell  2:43  
And the thing that makes such collaborations work is A obviously getting on with each other but B complementary skills. And they very much are the case - I mean what Resia does, I'm never going to do and to a lesser extent, but to some extent the converse is true.

Resia Pretorius  2:58  
Very true! Doug is obviously the chemist biochemist mind, and the mathematician all in one and the systems biologist, so he keeps me in check and checks all this stuff that we do.

Jackie Baxter  3:14  
Fantastic. So let's talk about micro clots. We've been hearing about these micro clots for a wee bit now. So what are they? And I guess, how did you discover them? Because so many of us with long COVID, we've had our tests come back clear, every blood test, every test - oh you're fine. So what led you to run this specific test that actually found them?

Resia Pretorius  3:39  
Perhaps I can start and then Doug can fill in, in 2020, quite early on in the disease progression and when we first discovered COVID I was contacted by one of my clinical collaborators that we have been working together with him Dr. Jaco Laubscher for quite a long time on diabetes. And he was basically looking at patients with acute COVID. And he said he noted clotting pathologies in his patient sample, but obviously not just you know, not on a research basis, but just the clinical presentation of the patients. So we immediately thought that while we have been focused in clotting for a while now for many years, now, let us look at the patient sample. 

So we got ethical clearance to work with him and with the hospital group that he actually works with and where his practice is. And quite soon after we received the first blood samples, we realized that there are a significant microclot presence and also platelet hyper activation in the sample. And we were just doing what we do. It's - we weren't looking for it. We were just simply doing what we have been doing 14 years or longer. And that was in acute sample, and it probably December of 2020, the January of last year, we started getting reports of patients with long COVID. But not Dr. Jaco Laubscher's patients, he treated clotting pathologies in his acute group of patients, and they didn't seem to go into long COVID. 

So I got hold of some of the patient samples dealing with ethics. And then we realized that the persistent system symptoms that these patients are complaining about might be linked to persistent clots that were present in the sample. And that's how we basically discovered it. And before we published, I thought, well, this might be a nice diagnostic. And we filed a provisional patent to use it as a diagnostic. Hindsight, perhaps that was a good or, sometimes, you one could argue not so good thing, because you would like to make the discovery available for for many people, but hopefully, we will be able to do that via various licensing agreements. 

And then we also looked at the content of the micro clots, I thought, last year, February, I thought let's do proteomics, and we had some funding. But to our surprise, we could not digest the micro clots. And then it all started, we had a double digestion step, we couldn't digest the samples with just a single one. And then we found all of these trapped inflammatory molecules inside the micro clots, and perhaps Doug can then perhaps just fill in about the fibrin and the amyloid nature of these clots.

Doug Kell  6:47  
So the backstory going back quite some time to when Resia and I first started corresponding and working together, is that she had discovered that under a variety of conditions, looking in the electron microscope, or an optical microscope, and the fibrinogen, when it clots into fibrin, would clot into what were then called dense matter deposits, ie. just a sort of scruffy looking mass of crap. And we didn't really quite know what this was, although we then studied it and found that it was the case and could be induced by various things such as the iron metabolism, where we started off actually including estrogen, which may be relevant to the large fraction of females who have long COVID. And then that occurred in rheumatoid, Alzheimer's, type two diabetes, and Parkinson's, all of which are chronic inflammatory diseases. 

And then we had long recognized that the probable cause of all of these things are bacterial infections, which leave behind dormant cells and other things which don't show up by conventional microbiology. But things like polysaccharide which is a bacterial cell wall component of grand negatives, are highly inflammagenic. Nobody doubts that - once you accept that there's that's around everybody will accept that it's inflammomagenic. And we decided that this must be involved in this anomalous clotting. So we tested it, just by adding small amounts. And it really was small amounts, one molecule of LPS per 100 million fibrinogen molecules. And we found indeed, it would form anomalous clots. And by some means that I don't recollect as through our discussions who actually came up with it, we just wondered whether it might be to an amyloid form. And there's a very well known stain for that called Fire flaming T. And lo and behold, the things lit up like Roman candles, when you tested this ability to clot in vitro in these conditions, and adding LPS. And indeed, subsequently, we fou nd like protacoic acid, which was a gram positive bacterial equivalent, would do this. 

So as the famous saying goes, Chance favors the prepared mind. But our minds were fully prepared for seeing amyloid clots because we had seen them in all these other diseases. And we could stain them with other statins as a set of stains also called ami tracker that also stain them very well. 

And in the case of the COVID, when, like many other scientists, we said, well, can we help with the COVID problems, although we obviously we're not virologists? First of all, we looked at the literature because there was this oddity that acute people were hypercoagulable and indeed, dripping with clots, the so called ground glass phenomenon in their lungs. And yet some of them later were dying because of bleeding. And so it wasn't immediately obvious how you reconcile these apparently paradoxical observations until we worked out that they were separated in time. And what was going on was that the extensive hyper coagulation at the beginning and caused all of the von Willebrand factor and some other factors to be used up so you couldn't then clot, so that explained that. 

And then we realized that we could see these clots even without adding any thrombin in vitro because they were just so prevalent. And then as Resia says, we moved from acute to long COVID when we started seeing people who weren't treated in the first place, so none of whom - not just a small fraction of whom didn't - none of whom had gone on to get long COVID. So Jaco Laubscher recognized this, and there's a video on the web page, I put up linked to that, in already June 2020, saying this is a vascular disease, not a respiratory disease, then the activated platelets came up, that's really Resia's territory.

Resia Pretorius  10:37  
Yes, absolutely. So the hyper activated platelets and the micro clots go hand in hand, where both is usually seen together in patients with both acute COVID and long COVID. And they drive or are driven by - so it's a circular process - by endothelial inflammation widespread endothelial inflammation, or a significant inflammatory, inflamed inside layers of your blood vessels. So we think that is the reason for the development of the persistent symptoms in long COVID. Both the micro clots and the platelets and the endothelial damage, or endothelitis, they also call it, where the whole blood vasculature is inflamed. 

So if one takes that into consideration, and you note that the vasculature is also inside the brain and the blood brain barrier, and goes right into the muscles, one can imagine that if all of these inflammatory layers of your vasculature are present, and you can then have these micro clots in circulation together with a hyper activated platelets, that it can drive a cellular widespread systemic hypoxia, where the muscles, the brain, the tissue, simply do not get enough oxygen to them, due to this inflamed vasculature and the presence of the micro clots and the platelets that might be entrapped in the small fibers of the muscle and inside the small vasculature. 

And if you take into account that the finest smallest little blood vessels, the capillaries, the smallest diameter is around about 24 micrometers in diameter, it's very small. And some of these micro clots are significantly larger, although they are porous, and like a little sponge, and they can also squeeze through the vasculature we believe, then it makes sense that they might be entrapped inside the small capillaries, and they might lead to oxygen deprivation or widespread hypoxia.

Jackie Baxter  13:03  
Yeah, so they're basically in very layman's terms, kind of clogging up the system.

Doug Kell  13:09  
So that's the thinking - that they're essentially they go and block up the capillaries, which normally would be the source of blood cells and oxygen to whichever tissues they're close by to. And that therefore essentially causes anoxia or ischemia.

Jackie Baxter  13:24  
Yeah, and of course, because they travel around the entire body, like you just said, that can explain the massive variation of symptoms in different people. So you've tested lots of blood, I think, haven't you for the clots? And I think you said that there are no clots present in people without long COVID - But are the clots present in every body that does have long COVID?

Resia Pretorius  13:52  
So perhaps I could just qualify that. If you look at a healthy individual, whether you are very young or you are healthy, and an 80 year old individual, if you have low levels of inflammation, you will be relatively micro clot free, but you will always have some areas in your blood plasma that might be misfolded. So you will have a little bit of signal, whether you are 24 year old that's healthy or or a 90 year old that is a healthy individual, you would not be able to distinguish between a healthy young and a healthy old person if the person is relatively inflammation free. 

So if you now look at someone with diabetes, or any of the other inflammatory conditions - rheumatoid arthritis, psoriasis, those cardiovascular type diseases as well, you will see a increase in the clotability of the blood, so you will have more clots, in those individuals and you will have a significant difference when you compare the clots in these individuals. However, in acute COVID, in long COVID, the amount and the size of the clots are just significantly more increased than I have ever seen previously. So if you have a blood sample of a person with inflammatory disease, diabetes or cardiovascular disease, next to someone with long COVID, or acute COVID, there's a visual difference in the size and the sheer number of clots that you will see. So definitely inflammation causes clotting, but non COVID and COVID in those individuals - that's in overdrive.

Doug Kell  15:43  
And the other thing that can cause clotting in normal plasma is adding the spike protein recombinant from a bottle to the normal plasma. What we've also found, as yet anecdotally, is that if you buy commercial plasma now, it's got more micro clots in it than the old stuff used to, from quote normal people, because of course, lots of people have had COVID, and been vaccinated with Spike protein. So the background is not quite as pristine as it used to be when we first started publishing in this space. 

But certainly, we've no doubt at all that like adding small amounts of live polysaccharide from the bacteria, small amounts of Spike protein from long COVID, at least the earlier variants, are highly able to induce this amyloid form of fibrin that is known to be resistant to proteolysis, and indeed, is resistant to proteolysis, much as prions actually, in a similar way.

Resia Pretorius  16:45  
And just to add to that, what we then believe is happening is that there are Protein -Protein interactions, so the spike protein interacting with a plasma protein. So typically, if you have cells involved, the spike protein will enter the cell via a receptor. But obviously on fibrinogen, or a protein - the plasma proteins - there are no receptors as on a cell membrane. So instead of entering the cell via a receptor, and that typical pathway, the ACE receptor, as we now all know about that already from various publications, that is not the case, it is a direct Protein Protein interaction, which makes it more difficult also to resolve, because it's just you know, there's no receptor to block

Jackie Baxter  17:43  
Right. So it's the fact that they're interacting without the receptor that's making the difference.

Doug Kell  17:48  
So so how fibrinogen polymerizes - so if you imagine that something like my index finger, the fibrinogen molecule is about five nanometers by 45. So it's the sort of shape of my index finger. And what happens is that thrombin nips out two little bits of those proteins - two peptides called fibrinopeptides - and that causes them to self assemble into these much more massive fibers, which are typically about 280 per unit length, the diameter, as you go along. So that the diameter of the fibrinogen fiber is something of the order of 50 to 100 microns, depending upon where you are - nanometers, excuse me - whereas the individual molecule is five nanometers. So there's no thermodynamic problem, the clotting is going to happen anyway, the free energy has been given to you by the thrombin doing its reaction and the fibrinopeptides coming out. 

The only question is, do you turn left or right? Do you make the amyloid form or the normal form? And what determines that is what is bound to you. If LPS or spike protein is bound to you, then you're going to be able to turn right and if you start going amyloid, then your next door neighbour's got to as well, in order to pack into the fiber in the appropriate way. So you only need a tiny fraction of the fibrinogen molecules to have something that will cause this to happen to be bound, for it to happen. So that gives a good explanation of what seems to be a massive amplification of a relatively small amount of virus or virus protein that may be lurking, and we believe probably is persisting in long haulers.

Jackie Baxter  19:41  
Sure. So it's causing a sort of snowball effect, basically. 

Doug Kell  19:44  
Yeah. 

Jackie Baxter  19:44  
Wow.

Doug Kell  19:45  
But the good news is although the micro clots are resistant, they're not infinitely resistant, they still are degraded just at a lower rate, and that's why you see them, but the triple treatment which we may or may not get onto in the podcast, doesn't remove existing ones, the body naturally removes them. It just stops new ones from forming.

Jackie Baxter  20:07  
Sure. So we were talking about earlier the inflammation. And am I right in thinking that that is kind of what's causing the micro clots? Is that correct?

Doug Kell  20:18  
Both directions. Whenever you get a big effect in biology, it's due to something called positive feedback, which sounds positive, but it's not positive - it's a negative thing. So if A causes B and B causes A, you can therefore get this strong amplification. And if A is inflammation, and B is micro clots, or A is inflammation, and B is endothelial damage, they feed back upon each other actually, all in that triangle feeds upon itself. And so we're pretty sure - although that's a qualitative statement - that that's the sort of thing that's going on. Again, the good news is if you can manage to break any part of that cycle, you will help.

Jackie Baxter  20:58  
Sure. Why did clots seem to affect some people more than others?

Doug Kell  21:03  
Well, we don't know why some people are more resistant to clots - have them but don't have the symptoms of long COVID, whereas others are extremely sensitive. We believe in general terms, you may say this is slightly hand waving, that when you have potentially 200 different symptoms of long COVID, and individuals have a subset of them, which is not random, it's deterministic, but not predictable - in general terms, and micro clots can explain it because you just say well, that's where they've gone and blocked up the capillaries and caused the inflammation. But any level of detail, these sorts of measurements have not been done at all.

Resia Pretorius  21:44  
Yeah, and one must remember that there are theories of genetic predisposition, environmental predisposition, your weight, your previous disease state, how inflammatory you have been before you developed acute COVID. So all of those information that one can gather about a patient is obviously of importance. Whether you had high blood pressure, whether you've had various cholesterol issues, or too much sugar in your diet, all of that can play into how inflammatory you have been. 

And it's just like the in the acute COVID, with all of these additional inflammagens, like Doug said, the spike protein, perhaps other molecules in circulating - just pushes the person into a time, or a situation where that whole body just cannot cope anymore. And these persistent clots and endothelial inflammation, just then, is then perpetuated. 

And one must also remember any cardiovascular disease - if you look at diabetes, high blood pressure, people with too much cholesterol, they anyway have low grade endothelial inflammation in any case. So their endothelial layers are not healthy to start off with. So if you have this additional load of a new onslaught of molecules coming from the virus, it just triggers this positive feedback loop that Doug just explained,

Jackie Baxter  23:32  
Of course, and then once you get into that loop, that sort of self perpetuating?

Resia Pretorius  23:37  
Exactly. 

Doug Kell  23:39  
And there's a general rule, or I would say increasing recognition, that to a significant degree people with MECFS are broadly suffering the same kinds of things as long haulers are - not exactly the same, but many, many overlaps. In almost all cases, MECFS is a postviral disease as well

Jackie Baxter  24:02  
yeah, that actually brings me very neatly on to my next question, because am I right in thinking you have been looking at the blood of people with ME?

Resia Pretorius  24:10  
Yes, we are currently busy with the study. So we're not going to say too much because we still analyzing the samples. But we have looked at 25 patients already. That is obviously not a huge number of patients, but it is a start. So we have been looking at the clotting and the platelets, and also using techniques that we discussed previously, fluorescence microscope, as well as the clotting profiles point of care, the thrombo Lester graph, and we've been studying the blood samples before and after addition of thrombin that Doug also mentioned, and we hope to have some results available within the next few weeks. 

But as always with these things, we do the analysis and then we say to each other, let's do one more experiment. So instead of saying that we will have data available in X number of weeks, we just rather not say anything. And when we are ready, we will be able to share with everyone and I do understand that the ME CFS community are sitting on on the edge of their chairs, because they want information, and we would want to share it with them. However, we'd rather make sure that we've got enough data and not just, you know, say something and later it's disapproved.

Jackie Baxter  25:37  
Of course, no I totally understand, maybe you can come back and talk to me when you have your results for that? 

Resia Pretorius  25:42  
Absolutely. 

Jackie Baxter  25:43  
So we've talked quite a lot about the clots themselves, and what's causing them and around that, but what possible treatments might there be? I think you've touched on it earlier, Doug. But what options might there be to resolve it?

Resia Pretorius  26:00  
So I think before we talk about the types of interventions that one can do, one must be very careful to say that these interventions should be based on an informed process where you looked at what the origins of the disease is. So you need to determine whether platelets are hyper activated, you need to determine the presence of microclots. So diagnostics will be the key for treatment, because you cannot go along and just start treating individuals without the informed decision on what is happening with these individuals. Neither myself or Doug, we're not clinicians. So we are working with clinicians that do treat individuals. But just to keep in mind that we cannot say much about the treatment regimes except what our clinical collaborators have been doing. 

So on that note, our clinical collaborator, Dr. Jaco Laubscher and other clinicians that we work with, have been identifying the long COVID patients based on the best clinical practice and identify the patients as having COVID and then long COVID. And then we have had the opportunity to look at some of these individuals blood samples before and after their treatment. And it seems that patients are getting better after a triple therapy treatment where their patients are treated with something to calm down the platelets and to prevent the micro clots from forming. 

However, this is not an accepted treatment regime in any country, because currently they are none. So we have been very carefully writing about this, myself and Doug and our clinical collaborators. But we must say that the most important next thing to happen is that we desperately need clinical trials to both use a diagnostic method, but also to sort out treatment because obviously they are many thoughts in the medical fraternity and amongst clinicians on what you should and should not treat people with. And the issue with anticoagulation is they are always the chance of bleeding if you do not identify the patients that need the actual treatment due to the presence of micro clots and platelet hyper-activation, 

Jackie Baxter  28:35  
of course,

Doug Kell  28:36  
So I'd add that when Resia says this isn't an accepted treatment - that means this isn't an accepted treatment in long COVID. But then nothing else is either - it's a perfectly well accepted treatment in various kinds of cardiovascular problems and people with atrial fibrillation and stroke and so forth. So it's not like it's totally unknown out of the blue treatment - it's a perfectly well established thing, but it does have well established issues connected with ensuring that the patient doesn't go into bleeding. Hypocoagulation. But this is doable. 

The interesting thing is it seems to be that because the medical profession is so siloed - who do you go to for your long COVID? Do you go to a respiratory physiologist, a hematologist, a cardiovascular person? Your GP of course, isn't any of those things. They're a GP. By and large, most people don't know of the existence of this kind of strategy, then leave alone that accepting that the micro clots are a thing. So if you follow, as many people who listen to this probably do, #teamclots on Twitter, you will see much discussion of people telling us about how they went to their GP and the GP said Never heard of it. I'm not doing anything like that. 

So some things need to change because the biggest problem is in part and then again, this is discussed in the Twitter. The longer you wait the harder it is to reverse some of these things. And so we don't want to have people waiting on and on and on for a clinical trial if it's then going to make it much harder to reverse these things. But equally, we're perfectly well aware that you can't just have people going around selling snake oil without a randomized controlled trial. Although, in this case, we think the basis is well established. But unfortunately, it's like driving tests, the fact that it was shown in South African doesn't mean that anyone in the UK pays any attention to it. So we have to repeat all of this stuff in the UK, which we are currently trying to do.

Jackie Baxter  30:34  
Oh, that's so frustrating, isn't it? 

Doug Kell  30:38  
Yes.

Resia Pretorius  30:41  
Obviously, other treatments as well. So there are a whole group of researchers and clinicians using Help Apheresis, not only in Europe, in Mullheim, and in Germany, Dr. Beate Jaeger is doing that, but also in various hospital settings in America. And the idea of that is then to remove the clot load via a process that is Help Apheresis that filters out the clots. 

But then obviously, that also needs to be looked at, and also studied further. And perhaps the good idea would be to have a joint protocol where you filter out the clots and then follow up with some sort of treatment. We do know that some clinicians also suggest a treatment of a set of molecules that they give patients, or pills that they give patients, there is statins that treat cholesterol. And that has also been noted to actually calm down the endothelial layers, the inflammatory nature of the endothelial layer

Doug Kell  31:49  
Statins work because they're anti inflammatory, it's a myth that they work to have anything to do with cholesterol, which is not a risk factor in the normal range. But they are good for you. But the reason is because they're anti inflammatory.

Resia Pretorius  32:00  
So many people have some good results with that. And also, sometimes other medications are used. So there's a real need to put all of these bits and pieces together of the various researchers and to see which are the correct dosage, which worked together, which should not be used together. Antihistamines, for example, have been one of the molecules or pill medications that some people use, and I think Professor Danny Altmann  from the UK have been looking into that. So they are, they are lots of various pockets of information. And obviously, we need to be in a hurry. But unfortunately, science do not work that way. And it takes a very long time to filter down from a basic science perspective - as what we are working in - into an actual treatment regime that is well accepted and widely available,

Jackie Baxter  33:01  
Of course. And you're still going to need both the diagnostics and the treatment to kind of work in parallel, aren't you? Because like you say, you can't just start treating everybody with something without knowing that they have the clots. 

Resia Pretorius  33:13  
Precisely

Jackie Baxter  33:14  
But nobody's - Well, I don't know about nobody. But there doesn't seem to be a lot of willingness to test for the microclots. In anywhere that I've seen anyway,

Resia Pretorius  33:24  
yeah, I think there is a willingness; the equipment is the problem. So they are, and Doug can talk about the the UK individuals and researchers we have been working with - there is a group in Sheffield, that has actually repeated our results in their microscopy laboratory. But the issue is not every pathology lab has got a microscope. So that is the problem rather than the not being willing to test for it.

Doug Kell  33:54  
So the need is - and we are doing it - is to build an instrument that will essentially validate the laboratory style fancy microscope things and make it into a form in which you can literally shove your sample in and press the button and it'll tell you what's going on. So we're doing that. But as Resia says, it does take a little bit of time.

Jackie Baxter  33:55  
Yes, well, understandably, it's all quite complex. So it must it must be must be a challenge for sure. I guess the other part of my question was when my treatments become available, and I guess the answer to that is that we don't really know?

Resia Pretorius  34:34  
I think widely available - the answer to that is after clinical trial results come out. And then after that, it must be widely distributed methods in the various healthcare fraternities. And obviously, if you look at the UK, it must be accepted within that healthcare system as one of the treatment options. So obviously, it's not going to be a fast process. Unfortunately,

Doug Kell  35:06  
we also think that once the micro clot results have been reproduced in the UK and published properly in the rest of it, that will push a lot more doctors over into the recognition that they can start doing these treatments, especially if patients are happy to sign a disclaimer saying, Look, I really need this, and I recognize the issues. And so I will sign to that effect.

Jackie Baxter  35:33  
Is there anything that us as patients can do to help speed along the process at all?

Resia Pretorius  35:38  
Well, I think you have been doing quite a lot on the Twittersphere, I think, sharing just how the patient feels and what the symptoms are. Because I think both myself and Doug have just been overwhelmed by patients that are really very sick. We get emails daily from patients that are desperate to find clinicians that might want to look into clotting in their blood. But what is more extraordinary, I think, for me, was how many of these patients actually have anecdotal complaints where they say now with long COVID, suddenly, blood doesn't, you know, you can't draw blood, it just clots in the needle. Or some say they they've got all of these deep vein thrombosis that's happening, clotting issues that they are now recognizing themselves. So I think that would be an important thing to look how you are feeling and telling that and sharing it with your clinician, so that somehow the clinicians are made aware that there are clotting issues in the patients that they know of themselves. So I think that is important. 

And I think, to just keep the faith because there's also a lot of clinicians that do not - still do not believe that long COVID is a real disease with real biomarkers, because all of the tests that are done are just basically showing that they are healthy. Now perhaps I could just end off with the reason for that, again, to reiterate why all the tests are coming back within the normal ranges. And I think we were the first to show that all of the molecules that the clinicians or pathology labs are testing are not soluble in the soluble part of the plasma that they run the tests on. It's actually trapped inside the clots and our proteomics analysis showed that. 

So I think the other issue is that because all the patient's blood sample and analysis come back within the healthy ranges, there are a group of clinicians that do believe it's all psychological. And that is not the case. Obviously, if you struggle for a few months to some of these individuals, more than 24 months, going into six months or longer, you will be you know, struggling with keeping your head together, you will have psychological issues simply because nobody believes you actually. So obviously, that is a major issue. So we're not downplaying the psychological part of long COVID. Because it is there. But it's not because of a psychological issue that the patients are suffering from Long Covid. 

Doug Kell  38:40  
It's an effect, not a cause. 

Resia Pretorius  38:42  
Exactly.

Jackie Baxter  38:44  
Yes. Yeah. That's so true. The mental health aspect of it is caused by the symptoms, not the other way around. Yeah, there was something - I think it might have been in an article that you wrote Resia. And it was the reason that the tests are coming back clear is because we're not testing for the right things. I probably paraphrased that but...

Doug Kell  39:05  
No, you said it exactly right. And we're trying to point people at the right things such as low venous oxygen saturation, and these are not easy tests. But if you want to know what's going on, then you do have to do the right tests. That's a statement of the obvious. Obviously, we think that the micro clots and platelets are two of the right tests. And there's a lot of mythology out there, people measure ferritin and think it's got something to do with iron. It's got nothing to do with iron - ferritin is an intracellular molecule. It shouldn't even be in plasma. It's a cell death marker, actually. And we wrote a review on that in 2014.

Jackie Baxter  39:39  
So I guess, my I think final question is probably a little bit cheeky and maybe not one that you can answer. But you know, we've acknowledged that treatments are going to take a bit of time - we need trials and you know that the whole thing is going to take time. And given you know, the sheer number of people with long COVID, even if once treatments do become available, it's going to take a bit of time to help everybody. So, you know, is there anything that people can do, reasonably safely themselves, to try to help in the meantime?

Resia Pretorius  40:13  
I think for us, it's very difficult to answer because not myself or Doug are conditions. So to try to hypothesize or suggest anything would be not ethical for us to do. However, there are wide reports of various nutraceuticals that might be helpful to support the endothelial function. So I think that is possibly a route to go. 

And also just to simply try to get as healthy as possible, with the restrictions of long COVID. So if you are overweight, look at that. If you do not have a healthy diet, look at that. That's not to say that if you do do the changes, you will lose weight, you eat healthy, that your long COVID will now miraculously disappear. That's not what's going to happen. But try to keep yourself or get yourself as healthy as possible. Look at your cholesterol, look at your heart rate, look at your blood pressure - at least those are treatable and acceptable treatments. And look at that, and ask for your clincian to check that out. At least if you try to cover that part of your treatment regime, then perhaps it might have an effect on the endothelial dysfunction that we have noted.

Doug Kell  41:41  
I certainly agree about the nutraceuticals. I think there's a lot of stuff out there, from reducing agents and polyphenols, and the sorts of things you've seen in fruit and veg, but you can buy them as more concentrated things. Ionculators, which are in green tea, clotbusters - safe ones, such as Nattokinase, lumbrokinase, and serrapeptase, which at least the first of those is available from online purchasing places. None of them is likely to do anyone any harm. And there are some good reasons why they could help quite a bit. Because they're not pharmaceuticals they are not regulated as such,

Resia Pretorius  42:21  
Both of myself and Doug, both of us - we are overwhelmed by the sheer extent of this disease. And we have never seen anything like that, or at least I have never never seen anything like that. And I think the message that I would want to leave your listeners is - please don't give up. We have heard numerous reports of people that do give up, and we cannot lose people while we are waiting for a treatment. So so just hang in there - we are really working day and night to try to find solutions. We have to work with lots of constraints, lots of clinicians not believing what we are saying - we have that on one side. And on the other side, we've got desperate patients, so please don't give up.

Doug Kell  43:16  
So the analogy I often consider is Barry Marshall and Robin Warren and the helicabacta  pylori and ulcers, where they were told it was a load of rubbish and the bacterial infections had nothing to do with ulcers and so forth. And it was all just stress and acid and so forth. And anyway, in the event they were proved right, but it did take quite unconscionable amounts of time. And if you look at the history of science, there are many things that where the true version, of course, was controversial when it came out, but eventually triumphed.

Jackie Baxter  43:51  
So yeah, but hang on in there. Well thank you both so much for your time today. It's been an absolute pleasure to hear what you're up to. And I think I speak for the entire long COVID community in wishing you all the best with continuing your research and thanking you for all that you're doing. So thank you so much.

Doug Kell  44:13  
Oh, it's been a great pleasure and we really hope that we can make a difference.

Resia Pretorius  44:17  
Thank you so much for having us.

Thank you so much to all of my guests, and to you for listening. I hope you've enjoyed it, or at least found it useful. The long COVID podcast is entirely self produced and self funded. I'm doing all of this myself. If you're able to please go to buymeacoffee.com/longCOVIDpod to help me cover the costs of hosting the podcast. Please look out for the next episode of the long COVID podcast - it's available on all the usual podcast hosting things and do get in touch - I'd love to hear from you.

Transcribed by https://otter.ai