Hypothesis Fibrinaloid Microclots and Atrial Fibrillation, 2024, Kell, Lip, Pretorius

[SNT Gatchaman]

Fibrinaloid Microclots and Atrial Fibrillation
Kell, Douglas B.; Lip, Gregory Y. H.; Pretorius, Etheresia

Atrial fibrillation (AF) is a comorbidity of a variety of other chronic, inflammatory diseases for which fibrinaloid microclots are a known accompaniment (and in some cases, a cause, with a mechanistic basis). Clots are, of course, a well-known consequence of atrial fibrillation.

We here ask the question whether the fibrinaloid microclots seen in plasma or serum may in fact also be a cause of (or contributor to) the development of AF. We consider known ‘risk factors’ for AF, and in particular, exogenous stimuli such as infection and air pollution by particulates, both of which are known to cause AF. The external accompaniments of both bacterial (lipopolysaccharide and lipoteichoic acids) and viral (SARS-CoV-2 spike protein) infections are known to stimulate fibrinaloid microclots when added in vitro, and fibrinaloid microclots, as with other amyloid proteins, can be cytotoxic, both by inducing hypoxia/reperfusion and by other means. Strokes and thromboembolisms are also common consequences of AF.

Consequently, taking a systems approach, we review the considerable evidence in detail, which leads us to suggest that it is likely that microclots may well have an aetiological role in the development of AF. This has significant mechanistic and therapeutic implications.

Link | PDF (Biomedicines) [Open Access]

 

[SNT Gatchaman]

A couple of cheeky comments* — "It's turtles microclots all the way down"; alternatively "Everything's coming up Milhouse microclots."

I also chuckled at the mind-map, which I think could otherwise have been called a "circular table of contents"



* Of course, if the theory's correct, this will all be a medical game-changer.

 

[SNT Gatchaman]

Some abbreviated passages —

Much of modern analytics in medicine is concerned with identifying ‘risk factors’, most of which are really in fact covariates. To illustrate this point, we take a different cardiovascular disease (pre-eclampsia), where, because this is a disorder of pregnancy, we do at least know the time and nature of the origin (of the pregnancy). Thus, we know that the likelihood of developing pre-eclampsia increases with certain pre-conditions (first pregnancy with the father, existing diabetes, maternal age, BMI, blood pressure at first visit, infection, etc.), but a priori, there is no way of knowing whether any of the above conditions are truly on a causal pathway or simply covariates. The infeasibility of establishing causality solely from measurements of variables is widely encapsulated in the mantra ‘correlation does not equal causation’, although any co-variation has the potential to contain useful information. Unravelling such relationships by causal inferencing either requires good longitudinal data and/or (better) affects them as independent variables.

Thus, the fact that the long-term use of antibiotics following a toxoplasma infection lowers the risk of pre-eclampsia by a massive 11-fold, along with a mass of other evidence, strongly implies an infectious origin for pre-eclampsia, but because these are not always even recognised, they do not appear in most lists of risk factors.

Clotting and clot removal happen all the time, so that the body is ‘primed’ for any desirable clotting to be initiated rapidly in response, say, to a wound. At a high level, soluble fibrinogen, typically as a 5 × 45 nm complex of three different polypeptides (α2β2γ2) (MW ~ 340 kDa) plus internal fibrinopeptides A and B, and one of the most abundant proteins in plasma (present at typically 2–4 g·L−1), is acted upon by the serine protease thrombin. This action removes two fibrinopeptides, exposing ‘knobs’ and ‘holes’, and leading to a remarkable self-assembly in which fibrin monomers polymerise to make staggered oligomers, which themselves lengthen into protofibrils that aggregate laterally to make fibres, finally branching to create a three-dimensional network which represents the clots. Typical fibre diameters are a few hundred nm (say, 100–400 nm), with a fractal morphology, meaning that a ‘unit’ of fibrin fibre contains many hundreds of fibrinogen monomers contributing to its diameter at any point. Clots are then degraded by plasmin, which itself has a variety of activators and inhibitors. For our purposes, we note that the clots may not be fully formed, that they form anomalous conformations, and that their rate of degradation is, in many cases, unusually low. This means that there may be, in certain diseases, a standing crop of fibrinaloid microclots.

Highlighting here that amyloid and the amyloid stains were a later finding, initially microclots were seen under the electron microscope as "dense matted deposits".

Early studies in the electron microscope by one of us (EP) showed that while images of the fibrin fibres of 'normal' clots looked much like nicely cooked spaghetti, those in a variety of chronic, inflammatory and other conditions looked much as if such spaghetti had been parboiled and stuck together in an unholy mess, a finding referred to at the time as 'dense matted deposits'. These anomalous fibres could be induced by the presence of free iron.

Many proteins can fold into a stabler, beta-sheet-rich 'amyloid' form, with no change in sequence. Some of these are related to a variety of more-or-less well known diseases ('classical amyloidoses') [...]. The apotheosis of this kind of behaviour is represented by prion proteins, that can adopt a variety of stable, amyloid-type states (without changes in primary sequence) that can even catalyse their own (con)formation. We later showed that the 'dense matted deposits' were in fact amyloid in character, as they could be stained with the well-established amyloid stain thioflavin T, as well as the commercial 'Amytracker' stains. This was confirmed by correlating images from the electron and fluorescence microscopes.

we see this causal chain as consistent with the known ability of infections and particulate matter to lead to AF by means of what was previously an unknown mechanism.

AF is widely recognised as predictive of thrombus formation, our proposal is that the converse is also true (if not even more so). Is there further evidence for this?

“Virchow’s triad” reflects or consists of ’abnormal blood constituents’, ’vessel wall abnormalities’ (endothelialitis), and ’abnormal blood flow’, a set of coagulopathies leading to venous thrombosis, that also occur in AF, and indeed are common in both acute and long COVID (which, of course, are also characterised by fibrinaloid microclots). It should again be noted that the special feature of these fibrinaloid microclots not only makes them easy to see but makes them significantly more resistant to the normal means of fibrinolysis. This again points strongly to the potential for microclots as being causative in AF and not merely a consequence. Similarly, it is easy to suppose that microclots are potentially able to aggregate into the better known macroclots; it seems highly desirable to test these as to whether or not they are amyloid in character.

Specifically, if microclots themselves lead to AF [...] one mechanism is their known membrane activities that would more or less directly cause channelopathies, which are themselves known to be causative in AF, especially when inherited.

 

[Jonathan Edwards]

I am trying very hard to take the micro clot story seriously and the work from Caroline Dalton makes it look as if there may actually be some underlying shift in plasma protein basis to these findings, even if not actually micro clots in vivo. But this reads like someone who has lost the plot entirely. It is sort of 'maybe there are aliens on Mars, so maybe there are aliens in your fridge too'.
A bit like Linus Pauling deciding that germs come from space.

 

[Jonathan Edwards]

And what exactly are, or is, 'Biomedicines' - the name of the journal?
I think I understand what biomedicine means as a wide area of study that includes biology relevant to medicine, but what does the plural 'biomedicines' mean?

Are there treatments called 'biomedicines' like antibiotics perhaps?
But this paper has nothing to do with them if there are it seems.

Is the word simply as meaningless as possible to make it clear that it is a journal that will happily accept, for a fee, papers that are as meaningless as possible?

 

[SNT Gatchaman]

Yes I had the same response when looking at previous articles from this journal - it's an odd name. FWIW Impact factor is 4.7, so reasonable. None of the papers I've downloaded have earned 4 or 5 stars from me and there are a few 1 and 2 star papers, so a mixed bag in my view. Anyway from the journal's about page —

an open access journal devoted to all aspects of research on human health and disease, the discovery and characterization of new therapeutic targets, therapeutic strategies, and research of naturally driven biomedicines, pharmaceuticals, and biopharmaceutical products. Topics include pathogenesis mechanisms of diseases, translational medical research, clinical studies and applications, biomaterial in biomedical research, natural bioactive molecules, biologics, biosimilar, vaccines, gene therapies, cell-based therapies, targeted specific antibodies, recombinant therapeutic proteins, nanobiotechnology-driven products, targeted therapy, bioimaging, biosensors, biomarkers, biosimilars, and nano-biosimilars.

This paper does reference their other recent preprint looking at nattokinase which might fit the journal's interest: Automated microscopic measurement of fibrinaloid microclots and their degradation by nattokinase, the main natto protease (2024, Preprint: BioRxiv) - currently an initial post only thread.

We encourage authors to publish their experimental, theoretical, and computational results in as much detail as possible. There is no restriction on the maximum length of papers or the number of electronic multimedia and supplementary files. For all articles, the full experimental details must be provided so that the results can be reproduced. Electronic files regarding the full details of the experimental procedure, if unable to be published in a normal way, can be deposited as Supplementary Materials (including animated pictures, videos, interactive Excel sheets, software executables and others).

Off-topic for this thread, but just to note —

According to the editors page, the current editor-in-chief has interests in neuromodulation; pain perception modulation; neurophysiology; neuroplasticity and was senior author of an editorial on fibromyalgia (in another journal of which he's editor in chief and founder) Physical Conditioning, Obesity and Fibromyalgia:Causal Relationship or Confounding? (2024, Principles and Practice of Clinical Research). It concludes —

The cumulative evidence does not allow us to draw strict conclusions regarding the relationship between physical conditioning, obesity, and FMS. Most studies have a cross-sectional and retrospective design, introducing some important limitations. However, some longitudinal investigations have been conducted, providing relevant preliminary findings.Therefore, there are at least some possibilities to explore these variables and the potential causal relationship with the development and pathophysiology of FMS. Understanding the causal relationship and the possible contribution of confounding factors will be crucial for designing and interpreting clinical research, which is paramount for advancing the field. Regardless of the mechanisms and causal relationships, controlling body weight and exercising are positive and efficacious strategies to be included in the management of this condition. Further research is warranted to clarify the association with the patho-physiology of FMS

 

[Jonathan Edwards]

FWIW Impact factor is 4.7,

Which is worth absolutely nothing, please note!

 

[Jonathan Edwards]

an open access journal devoted to all aspects of research on human health and disease, the discovery and characterization of new therapeutic targets, therapeutic strategies, and research of naturally driven biomedicines, pharmaceuticals, and biopharmaceutical products. Topics include pathogenesis mechanisms of diseases, translational medical research, clinical studies and applications, biomaterial in biomedical research, natural bioactive molecules, biologics, biosimilar, vaccines, gene therapies, cell-based therapies, targeted specific antibodies, recombinant therapeutic proteins, nanobiotechnology-driven products, targeted therapy, bioimaging, biosensors, biomarkers, biosimilars, and nano-biosimilars.

In other words whoever thought up the name hasn't a clue what it is supposed to mean and is just touting for as much income as possible. It bears about as much relation to what journals used to be a bout as a 'Rolex' from a Chinese online source.

 

[Jonathan Edwards]

According to the editors page, the current editor-in-chief

Hasn't a clue, as I said.

 

[Jonathan Edwards]

I just cannot see any motivation for a serious scientists to write an article like this in a journal like this - or anywhere. At least not an academic motivation.

 

[shak8]

...

According to the editors page, the current editor-in-chief has interests in neuromodulation; pain perception modulation; neurophysiology; neuroplasticity and was senior author of an editorial on fibromyalgia (in another journal of which he's editor in chief and founder) Physical Conditioning, Obesity and Fibromyalgia:Causal Relationship or Confounding? (2024, Principles and Practice of Clinical Research). It concludes —

This focus on obesity as "causal or confounding" for FM is a bit disingenuous.

References listed in the paper about FM and obesity are many and include one that states (International Rheumatology) that 40% of FM patients are obese (and 30% are overweight). Not sure which country or countries this refers to. And a recent WHO report (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9107388/) stated that 59% of adults in Europe were either obese or overweight.

According to the CDC office of health statistics, 41.9% of US adults (2017-2020) were obese.