Tiny, Menacing Microclots May Explain Long COVID’s Symptoms

Dec. 7, 2022 – When Hannah Davis saw the first visual confirmation of long COVID in her blood – a firework-like display of fluorescent green dots against a black background – she was overwhelmed with an odd sense of relief. In early November, she became one of the first U.S. long COVID patients to be tested for microscopic blood clots, catching up to South Africa, Germany, the U.K., and other countries that are already experimenting with related treatments.

“It was validating,” says Davis, who excitedly shared the images of her clots on Twitter. “It's basically the first test specific to long COVID that is promising and scientifically sound and incorporates research from other post-viral illnesses.”

Big news: I was lucky to get tested for micro blood clots, & I have a lot of them! #LongCovid Healthy control blood on the left. Mine on the right. The green is all microclots! These clots are likely blocking oxygen from getting around my body & could explain many symptoms. 1/ pic.twitter.com/5rtuzN8D8f

Davis donated her blood at Mount Sinai Hospital in New York City, with a few other founding members of the Patient-Led Research Collaborative, all of whom had been infected in the first wave of the pandemic and are still sick nearly 3 years later. Seeing the pictures of their blood clots, Davis and her fellow patients cried what she called happy tears. Then the reality of having those notorious blood clots sank in.

Early in the COVID-19 pandemic, emergency room doctors and others treating patients noticed the sickest produced excessive blood clots. The clots clogged kidney dialysis machines, caused strokes, and killed patients long after they left the hospital. Some long COVID researchers have suspected smaller, less obvious blood clots may be causing many of the puzzling symptoms reported by patients who have lasting effects of the virus.

The theory is that these weird and persistent clots, called microclots, might be blocking delicate blood vessels throughout the body, and stopping oxygen from getting to where it needs to go, causing everything from shortness of breath and organ damage to brain fog and debilitating fatigue. But if all the havoc is being done inside these minuscule clots, regular pathology tests won’t pick it up. A network of specialists is now setting out to see if specialized tests can be accessible and if the clots can be treated.

Clots Are Complicated

Blood clotting is an important and elaborate process that prevents excessive bleeding. Normally, the body will dissolve blood clots on its own, but in certain conditions, such as chronic fatigue syndrome (also known as myalgic encephalomyelitis or ME/CFS), diabetes, Alzheimer’s, Parkinson’s, and acute and long COVID, researchers have noticed that damage to the blood vessel walls caused by inflammation can lead to abnormal proteins and platelet activity. This leads to small, strange clots that can block capillaries – the smallest blood vessels – from taking enough oxygen to tissues throughout the body.

Net-like protein strands called fibrin are a critical part of clots. Viewed on an electron microscope, "they look like a bowl of spaghetti that you’ve just drained in a colander,” says Douglas Kell, PhD, a systems biologist at the University of Liverpool in the United Kingdom. The unusual “amyloid”-like version of the proteins seen in microclots, on the other hand, resemble “a disgusting mess that you sort of parboiled. It's all stuck together,” Kell says.

Fluorescence microscopy of sample micrographs showing microclots (green) in the circulation of controls (A) and in patients with Long COVID (B–D).

These misfolded clots stain strongly with a special dye that glows bright green so they can be seen under a microscope, and they take longer to break down than normal clots through a natural process called fibrinolysis.

This problematic clotting may persist in blood for months or years after infection, according to research by Kell and physiologist Etheresia Pretorius, PhD, of Stellenbosch University in South Africa. Kell and Pretorius had studied unusual clotting for years before the pandemic. They also led the first team to discover these microclots in the blood of people with both acute and long COVID and have since authored a series of papers on the subject.

There are a number of theories as to what causes long COVID – from viral reservoirs and debris to overactive immune and antibody responses – but approaching the disease with a “systems biology mindset,” they actually feed into each other, says Pretorius.

Microclots in long COVID are being studied around the world by researchers and clinicians who refer to themselves as #TeamClots on Twitter, and who are hopeful that this theory represents a new and vital target in understanding and treating long COVID and related disorders. And they’re working to put this research into clinical practice.

In November, Pretorius traveled to the United States to train research teams on her identification techniques and help set up the equipment.

Still, why microclots happen after COVID-19 in the first place isn’t entirely understood. Pretorius and Kell believe that the spike protein in the virus might be the trigger in people with long COVID. That potential cause has been supported by a recent Harvard Medical School study that detected the SARS-CoV-2 spike antigen in most long COVID patients up to 12 months after diagnosis, suggesting the presence of an active and persistent viral reservoir in the body after infection.

“One core question is: Do these microclots actually represent a root cause, or are they in response to something else that's ongoing?” says Michael VanElzakker, PhD, a neuroscientist and long COVID researcher at Massachusetts General Hospital and Harvard Medical School and co-founder of the PolyBio Research Foundation, which is focused on studying the viral reservoir. “If the clots are leftover residual from acute COVID, that would be one story. But if they’re forming in response to spike protein that's leaking out from a reservoir … then that would be another story because you could clear the clots all day, but then they'll just re-form.”

Treatment for Microclots

There are a number of early experimental treatments for these COVID-related microclots that still need to be tested in clinical trials.

Among them, a small but promising preprint study from Pretorius and Kell shows that a combination of antiplatelet and anticoagulant drugs for those with microclots improved long COVID symptoms and reduced microclots.

Meanwhile, researchers in Germany are reporting some success after an expensive and controversial dialysis-like treatment called heparin-induced extracorporeal LDL precipitation, or HELP apheresis, which has been performed on thousands of patients.

There is also considerable interest in far more accessible over-the-counter enzyme supplements that Pretorius and Kell will be studying in a lab environment next year. These include serrapeptase, lumbrokinase, and nattokinase (made from bacteria in silkworm gut, from earthworms, and from a bacterial fermentation of soybeans, respectively) that work as natural clot busters.

These supplements have long been available at health food stores, and long COVID patients are self-reporting their effects.

Most long COVID experts and hematologists advise against taking unproven supplements, anticoagulants, or blood-thinning treatments because of the obvious risks of excessive and even fatal bleeding. But they certainly understand why patients would feel the desperate need for them.

“I can't imagine being in a situation where you're just supposed to sit around and wait for genius researchers to solve it,” says VanElzakker. “The way that it played out with AIDS, is that a lot of the information about the things tested came from the patients.”

Davis is also worried about patients recommending unproven treatments to each other, as individuals could react poorly.

In the meantime, Davis, Pretorius, and other long COVID advocates and researchers who believe that microclots are the best explanation for the condition say the next steps should be made urgently: Make the tests accessible, fund more studies, and start clinical trials.

Relying on routine lab tests that show long COVID patients are perfectly healthy when they obviously are not is no longer acceptable, not just for the patients, but for researchers seeking solutions. “These individuals are really, really sick,” says Pretorius. “So just because Western medicine hasn't found the biomarker that the regular pathology laboratory can easily test doesn’t mean it doesn't exist.”