Looking at the long covid “micro-clot” hypothesis.

Nature investigates the idea that the various symptoms of long covid – which can include cardiac trouble, neurological problems, muscle pain, and general fatigue – might possibly be due to tiny blood clots lodging into different tissues throughout the body:

Now some scientists, and an increasing number of people with the condition, have been lining up behind the as-yet-unproven hypothesis that tiny, persistent clots might be constricting blood flow to vital organs, resulting in the bizarre constellation of symptoms that people experience.

Proponents of the idea (#teamclots, as they sometimes refer to themselves on Twitter) include Etheresia Pretorius, a physiologist at Stellenbosch University in South Africa, and Douglas Kell, a systems biologist at the University of Liverpool, UK, who led the first team to visualize micro-clots in the blood of people with long COVID. They say that the evidence implicating micro-clots is undeniable, and they want trials of … anticoagulant treatment.

When it comes to long COVID, “we’ve now got little scattered of bits of evidence”, says Danny Altmann, an immunologist at Imperial College London. “We’re all scuttling to try and put it together in some kind of consensus. We’re so far away from that. It’s very unsatisfying.”

Blood clotting is a complex process, but one of the key players is a cigar-shaped, soluble protein called fibrinogen, which flows freely in the bloodstream. When an injury occurs, cells release the enzyme thrombin, which cuts fibrinogen into an insoluble protein called fibrin. Strands of fibrin loop and criss-cross, creating a web that helps to form a clot and stop the bleeding.

Under a microscope, this web typically resembles “a nice plate of spaghetti”, Kell says. But the clots that the team has identified in many inflammatory conditions look different. They’re “horrible, gunky, dark”, Kell says, “such as you might get if you half-boiled the spaghetti and let it all stick together.” Research by Kell, Pretorius and their colleagues suggests that the fibrin has misfolded1, creating a gluey, ‘amyloid’ version of itself. It doesn’t take much misfolding to seed disaster, says Kell. “If the first one changes its conformation, all the others have to follow suit”, much like prions, the infectious misfolded proteins that cause conditions such as Creutzfeldt–Jakob disease.

Pretorius first saw these strange, densely matted clots in the blood of people with a clotting disorder2, but she and Kell have since observed the phenomenon in a range of conditions1 — diabetes, Alzheimer’s disease and Parkinson’s disease, to name a few. But the idea never gained much traction, until now.

When the pandemic hit in 2020, Kell and Pretorius applied their methods almost immediately to people who had been infected with SARS-CoV-2. “We thought to look at clotting in COVID, because that is what we do,” Pretorius says. Their assay uses a special dye that fluoresces when it binds to amyloid proteins, including misfolded fibrin. Researchers can then visualize the glow under a microscope. The team compared plasma samples from 13 healthy volunteers, 15 people with COVID-19, 10 people with diabetes and 11 people with long COVID3. For both long COVID and acute COVID-19, Pretorius says, the clotting “was much more than we have previously found in diabetes or any other inflammatory disease”. In another study4, they looked at the blood of 80 people with long COVID and found micro-clots in all of the samples.

So far, Pretorius, Kell and their colleagues are the only group that has published results on micro-clots in people with long COVID.

But in unpublished work, Caroline Dalton, a neuroscientist at Sheffield Hallam University’s Biomolecular Sciences Research Centre, UK, has replicated the results. She and her colleagues used a slightly different method, involving an automated microscopy imaging scanner, to count the number of clots in blood. The team compared 3 groups of about 25 individuals: people who had never knowingly had COVID-19, those who had had COVID-19 and recovered, and people with long COVID. All three groups had micro-clots, but those who had never had COVID-19 tended to have fewer, smaller clots, and people with long COVID had a greater number of larger clots. The previously infected group fell in the middle. The team’s hypothesis is that SARS-CoV-2 infection creates a burst of micro-clots that go away over time. In individuals with long COVID, however, they seem to persist.

Dalton has also found that fatigue scores seem to correlate with micro-clot counts, at least in a few people.

You can read more of Pretorius and Kell’s research here, in Biochemical Journal, and here, in Pharmaceuticals, and here, in a Research Square pre-print.