Proteins behaving badly. Substoichiometric molecular control and amplification of the initiation and nature of amyloid fibril formation, 2016, Kell+

Proteins behaving badly. Substoichiometric molecular control and amplification of the initiation and nature of amyloid fibril formation: lessons from and for blood clotting
Douglas Kell and Etheresia Pretorius

Abstract
The chief and largely terminal element of normal blood clotting is considered to involve the polymerisation of the mainly α-helical fibrinogen to fibrin, with a binding mechanism involving ‘knobs and holes’ but with otherwise little change in protein secondary structure.

We recognise, however, that extremely unusual mutations or mechanical stressing can cause fibrinogen to adopt a conformation containing extensive β-sheets. Similarly, prions can change morphology from a largely α-helical to largely β-sheet conformation, and the latter catalyses both the transition and the self-organising polymerisation of the β-sheet structures. Many other proteins can also do this, where it is known as amyloidogenesis.

When fibrin is formed in samples from patients harbouring different diseases it can have widely varying diameters and morphologies. We here develop the idea, and summarise the evidence, that in many cases the anomalous fibrin fibre formation seen in such diseases actually amounts to amyloidogenesis. In particular, fibrin can interact with the amyloid-β (Aβ) protein that is misfolded in Alzheimer's disease.

Seeing these unusual fibrin morphologies as true amyloids explains a great deal about fibrin(ogen) biology that was previously opaque, and provides novel strategies for treating such coagulopathies. The literature on blood clotting can usefully both inform and be informed by that on prions and on the many other widely recognised (β-)amyloid proteins.

PubMed
Full Text

 

The 2016 paper that describes in-depth the anomalous amyloid fibrin clots. This pre-dates their demonstration in long COVID.

 

A question that has also been asked on this forum:

"Dr Kell, Dr Pretorius— thank you for your interest and work on this. Seems like a potential breakthrough. But what do other hematologists say about your work? Why aren’t they shouting this from the tallest rooftop?"

Answer: "Well I think you’d have to ask them…(not invented here the usual reason..) - we discovered amyloid clotting in 2016 and it’s been very largely ignored, despite the simple assay. That may change now w the interest in its likely MAJOR tole in #LongCovid."

https://twitter.com/user/status/1477299695663910914