Preprint Increased fibrinaloid microclot counts in platelet-poor plasma are associated with Long COVID, 2024, Dalton et al.

Abstract

Outcomes following SARS-CoV-2 infection are variable; whilst the majority of patients recover without serious complications, a subset of patients develop prolonged illness termed Long COVID or post-acute sequelae of SARS-CoV-2 infection (PASC). The pathophysiology underlying Long COVID remains unclear but appears to involve multiple mechanisms including persistent inflammation, coagulopathy, autoimmunity, and organ damage. Studies suggest that microclots, also known as fibrinaloids, play a role in Long COVID. In this context, we developed a method to quantify microclots and investigated the relationship between microclot counts and Long COVID. We show that as a cohort, platelet-poor plasma from Long COVID samples had a higher microclot count compared to control groups but retained a wide distribution of counts. Recent COVID-19 infections were also seen to be associated with microclot counts higher than the control groups and equivalent to the Long COVID cohort, with a subsequent time-dependent reduction of counts. Our findings suggest that microclots could be a potential biomarker of disease and/or a treatment target in some Long COVID patients.

https://www.medrxiv.org/content/10.1101/2024.04.04.24305318v1

(This is an attempted replication of the microclots finding by a UK team)

 

The paper seems well written.

They note problems with artefacts with prior methodology and cleaned that up. They also not problems with leaving samples on the bench.

The structures they show are extremely sparse and don't look a lot like some previous reports.

The data on numbers of the fluorescent blobs for Long Covid and controls does look plausible. There is too much overlap for the origin of he blobs to be a major factor in whether you have LC or not, as they note, but it does suggest some sort of trend in plasma protein behaviour.

The thing I would be most worried about is that this could be due to use of anti-inflammatory pain killers, which have major effects on coagulation-related proteins and their activation.

The us of thioflavine T puts the emphasis on amyloid and I wonder if there is a shift in amyloid A or P levels. It may be mentioned. I have not read through everything in detail.

If this turns out to be just a very roundabout way to show that production or activation of certain acute phase proteins, or perhaps proteins that are not classic acute phase reactants but may go up with viral infection, is shifted in LC then it would be very interesting. The values only give statistical patterns, so this might not be that good for confirming anything in an individual but it would be objective evidence of a prolonged immune response.

As I say, my only concern is that this might be secondary to common drugs.

 

Methodology improvements they noted were —

Finding that —

 

RELEVANT?
I recall that Maureen Hanson highlighted that Andrew Grimson found platelets to be dysregulated** in ME/CFS potentially related to clotting?
So maybe there is something in micro clot findings.

**NIH Immunology webinar - https://www.ninds.nih.gov/news-events/events/mecfs-research-roadmap-webinar-series-immune-system

 

As far as I can tell they just look at the LC cohort without looking at how long their illness duration has been or when their last known infection was (for the Covid cohorts they look at microclots w.r.t. last known acute infection but they don't present this data for LC). As such I don't see how it's possible to differentiate anything, especially as they don't mention the mean illness duration of the LC group (only that the minimum illness duration is 12 weeks). Is the LC group possibly experiencing the same clearance of microclots as the other groups?

 

I am not sure what you mean by clearance of micro clots?

I think it swarth remembering that we have no evidence that these small structures exit in live people. They seem to occur in plasma incubated after centrifugation. The numbers of particles seem to be tiny. We see a few tiny dots. If you look at unseen blood it is more like looking at a brick wall. It is 50% solid particles roughly. I don't think these bits would do anything even if they were present in live people.

They still might be interesting.

 

The suggestion is that these microclots could be a marker of something happening during an acute Covid infection and that this process, whatever it may be, doesn't resolve after the acute phase in a subset of LC patients (the authors state "microclots are cleared over time"). However, as far as I can see the authors have failed to look at whether this process really resolved less in LC patients than in the general population as they didn't look at time since last known infection in this group. It might just be that nothing is happening apart from the fact that the LC group had more recent infections.

 

But marker of what?

Actual clots in circulation would be expected to clear within about 1 minute max I think.
If they are too small to embolise they would probably be cleared by spleen at least in half an hour.
So I am unclear what this is supposed to be about.