Are fibrinaloid microclots a cause of autoimmunity in Long Covid and other post-infection diseases?

Abstract

It is now well established that the blood-clotting protein fibrinogen can polymerise into an anomalous form of fibrin that is amyloid in character; the resultant clots and microclots entrap many other molecules, stain with fluorogenic amyloid stains, are rather resistant to fibrinolysis, can block up microcapillaries, are implicated in a variety of diseases including Long COVID, and have been referred to as fibrinaloids. A necessary corollary of this anomalous polymerisation is the generation of novel epitopes in proteins that would normally be seen as ‘self’, and otherwise immunologically silent. The precise conformation of the resulting fibrinaloid clots (that, as with prions and classical amyloid proteins, can adopt multiple, stable conformations) must depend on the existing small molecules and metal ions that the fibrinogen may (and is some cases is known to) have bound before polymerisation. Any such novel epitopes, however, are likely to lead to the generation of autoantibodies. A convergent phenomenology, including distinct conformations and seeding of the anomalous form for initiation and propagation, is emerging to link knowledge in prions, prionoids, amyloids and now fibrinaloids. We here summarise the evidence for the above reasoning, which has substantial implications for our understanding of the genesis of autoimmunity (and the possible prevention thereof) based on the primary process of fibrinaloid formation.

A Perspective on How Fibrinaloid Microclots and Platelet Pathology May be Applied in Clinical Investigations

“…Adapted in part from the CC-BY publications. 15 17 64 We also note that the spike protein is itself amyloidogenic. 172 Figure created by authors using Biorender.com.…”

“…This is true for amyloid proteins generally and is illustrated here for classical prion proteins. 17 64 …”

Automated microscopic measurement of fibrinaloid microclots and their degradation by nattokinase, the main natto protease

“…implying that these microclots are on the aetiological pathway of the disease, and they can explain many symptoms [183], including fatigue [184], post-exertional symptom exacerbation [185], autoantibody generation [107] and Postural Orthostatic Tachycardia Syndrome (POTS) [186]. Fibrin amyloid microclots also occur during sepsis [187], while amyloid deposits are also observed in the skeletal muscles of those with Long COVID [188].…”

“…[97-104]) that exactly reflected the clots seen in both the electron microscope [105] and in bright field optical microscopy [106]. As with prions and other amyloid forms of proteins [98,107], that are often highly resistant to proteolysis (e.g. [108,109]), the existence of these ‘fibrinaloid’ microclots implies their comparative resistance to normal fibrinolysis [110,111], with their precise structures [112] being affected by other small and macromolecules and ions that they may have bound [97,103,113-119].…”

“…More recently, we have established the prevalence of these fibrinaloid microclots in post-viral diseases such as Long COVID [106,175-178] (and see [179]) and ME/CFS (myalgic encephalopathy/chronic fatigue syndrome) [180,181]. The lower amyloidogenicity of omicron versus earlier variants of SARS-CoV-2 is also reflected in its lower virulence [182], implying that these microclots are on the aetiological pathway of the disease, and they can explain many symptoms [183], including fatigue [184], post-exertional symptom exacerbation [185], autoantibody generation [107] and Postural Orthostatic Tachycardia Syndrome (POTS) [186]. Fibrin amyloid microclots also occur during sepsis [187], while amyloid deposits are also observed in the skeletal muscles of those with Long COVID [188].…”