Possible Role of Fibrinaloid Microclots in Postural Orthostatic Tachycardia Syndrome (POTS): Focus on Long COVID

Abstract

Postural orthostatic tachycardia syndrome (POTS) is a common accompaniment of a variety of chronic, inflammatory diseases, including long COVID, as are small, insoluble, 'fibrinaloid' microclots. We here develop the argument, with accompanying evidence, that fibrinaloid microclots, through their ability to block the flow of blood through microcapillaries and thus cause tissue hypoxia, are not simply correlated with but in fact, by preceding it, may be a chief intermediary cause of POTS, in which tachycardia is simply the body's exaggerated 'physiological' response to hypoxia. Similar reasoning accounts for the symptoms bundled under the term 'fatigue'. Amyloids are known to be membrane disruptors, and when their targets are nerve membranes, this can explain neurotoxicity and hence the autonomic nervous system dysfunction that contributes to POTS. Taken together as a system view, we indicate that fibrinaloid microclots can serve to link POTS and fatigue in long COVID in a manner that is at once both mechanistic and explanatory. This has clear implications for the treatment of such diseases.

Keywords: Long COVID; TeamClots; fibrinaloid microclots; postural orthostatic tachycardia syndrome (POTS).

Figure 1

Autonomic nervous system regulation of heart function (after [92]). Created with BioRender.com. Access date: 26 November 2023.

Figure 2

Microclot size distribution as seen with imaging flow cytometry (taken from [166]). Representative micrographs of microclots in (A) controls and (B) long COVID patients using an imaging flow cytometer. The brightfield images are displayed in Channel 1 (Ch01) and fluorescence intensity due to ThT binding in Channel 7 (Ch07). All images were captured using a 20x objective. The event number is displayed in the top-left corner of each image. NB: In these pictures, the POTS status of the individuals was not assessed.

Figure 3

(A) Representation of healthy blood flow in microcapillaries (B) versus in an individual where damaged microcapillaries are (temporarily) blocked by microclots. Created with BioRender.com (accessed on 26 November 2023).

Figure 4

Membrane disruption models (redrawn from [201]). (A) The barrel-stave model suggests that proteins perpen-dicularly insert into the phospholipid bilayer plane, with the hydrophobic regions of protein oligomers contacting the hydrophobic interior of the membrane. (B) The toroidal pore model suggests that proteins insert perpendicular to the phospholipid bilayer, with the protein hydrophilic ends remaining in contact with the lipid head layer. (C) The deter-gent-like model, suggests that positively charged residues in the amyloidogenic protein bind to the membrane. (D) The membrane remodeling model suggests that membrane-bound peptides self-assemble into β-sheets that subsequently either form pores on the membrane surface (Pore formation model) or drag lipids out of the bilayer core (Detergent-like model). Created with BioRender.com (accessed on 26 November 2023).

Figure 5

A system approach to defining dysautonomia. (A) Various causes of disease and symptoms resulting in vascular damage, microclots, and platelet hyperactivation (B) known to be involved in a variety of diseases (C) and in POTS (D). Similarly, vascular damage pathologies cause POTS (E) and other diseases (F), while POTS is found in various diseases (G). Created with BioRender.com (accessed on 26 November 2023).