Fibrinaloid Microclots and Atrial Fibrillation

Abstract

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.

Keywords: Long COVID; arrhythmias; atrial fibrillation; fibrinaloid microclots; infection; inflammation; particulate matter; pollution.

Figure 1

A ‘mind map’ [49] setting out this review. This is a means of summarising the review in an easy-to-visualise format. It should be read clockwise from “twelve o’clock”. Created with Biorender.com.

Figure 2

Risk factors, observables, causes, and covariates. Created with BioRender.com. The coloured arrow indicates circumstances in which A can affect B and B can affect A.

Figure 3

A high-level illustration of fibrinogen polymerisation into fibrin as a part of blood clotting. Created with BioRender.com. Much of the first part is redrawn from a CC-BY article at [89].

Figure 4

Scanning electron microscopy figure of dense matted deposits entrapping a red blood cell. Healthy whole blood was exposed to ferric chloride (raw data from [103]).

Figure 5

Microclots and platelets in healthy individuals and in individuals with long COVID (raw data from the CC-BY-4 publication [118]). For microclots, Figure 5 shows, in the upper three panels, the microclots observable in healthy controls at the start of the SARS-CoV-2 pandemic, while the middle three panels show microclots from individuals suffering from COVID-19. The lowest panel shows pictures from the bright field (A), a thioflavin T-stained image of the same field (B), and the merged image (C). For platelets, after centrifuging freshly collected samples, the haematocrit fraction of each sample was retained and incubated for 30 min at room temperature with the two fluorescent markers, CD62P (PE-conjugated) (platelet surface P-selectin) and PAC-1 (FITC-conjugated) (340507, BD Biosciences, San Jose, CA, USA). Viewing used a 63× oil objective. (A) Healthy controls, with minimally activated platelets, seen as small round platelets with a few pseudopodia, seen as healthy/control platelets; (B) diseased with egg-shaped platelets, indicative of spreading and the beginning of clumping.

Figure 6

Cartoon illustrating the ability of fibrinogen to polymerise either to its α-helix-rich normal form or its crossed-β-sheet amyloid ‘fibrinaloid’ form, depending on the presence of various small-molecule triggers. Glyphs taken from the CC-BY Open Access publication [118]. Created with BioRender.com.

Figure 7

Some of the features on which we have focused in this review, indicating those (indicated by thick arrows) for which there is well-established evidence, plus others that we consider likely but for which further evidence needs to be sought. Created with BioRender.com.