‘Microclots’ could help solve the long COVID puzzle

For more than two years, scientists have been trying to understand why millions of people around the world experience persistent symptoms despite recovering from their COVID-19 infection. They proposed several hypotheses, including the presence of microclots, tiny blood clots that can block capillaries and potentially affect blood and oxygen flow.

In a 2021 study, physiologist Etheresia Pretorius at The University of Stellenbosch in South Africa and colleagues were the first to suggest that microclots could be linked to this debilitating condition called long COVID. In a follow-up study, she and her colleagues showed that the SARS-CoV-2 spike protein triggers the formation of such clots, which the body’s natural clot-clearing process doesn’t seem to break down easily.

This discovery led some scientists in the United States, with advice from Pretorius, to test people with long COVID for microclots. Lisa McCorkell, co-founder of the long-running COVID-focused patient-led research collaboration, was thrilled when she heard the news last year.

McCorkell had suffered from severe shortness of breath, extreme fatigue and brain fog for several months after his mild symptoms of COVID-19 in March 2020, when the pandemic began. In August of the same year, when she began to feel better, McCorkell took a workout course. But a day later, her heart rate increased, she struggled to breathe and she rushed to the emergency room. “It lowered my baseline significantly,” she says. «Before COVID, I was running half marathons, so that was a very dramatic change.»

In December 2020, the 28-year-old finally accepted how sick she was and that her illness was not temporary. In late 2021, her suspicions were confirmed when she was diagnosed with postural orthostatic tachycardia syndrome (POTS), a condition documented in several long-term COVID patients that can disrupt breathing and cause heart palpitations and dizziness in elevating. POTS has no cure, and some patients, including McCorkell, manage symptoms by increasing fluid and salt intake. But a year after her diagnosis, she still suffers from post-exercise malaise which aggravates these symptoms.

What’s frustrating for McCorkell and many other longtime COVID patients is that blood and other routine tests come back normal despite their debilitating condition. In November 2022, she flew from California to New York where David Putrino, a rehabilitation and long-time COVID scientist at Mount Sinai Health System, and his collaborators are taking blood samples to look for microclots. “We are very early,” says Putrino. «We’ve only tested a few dozen people so far.» But every sample of long COVID patients, including McCorkell’s, showed such clots.

When she first saw the microscope images of fluorescent green drops revealing the micro-clots, she cried with relief. For her, the confirmation that she has microclots felt like validation of her disease, «especially after not having had a PCR test at first and having been gaslit for the past few years».

Although some experts agree that the microclot hypothesis is plausible, they think it could be just one piece of the long COVID puzzle. But they want to see more research that demonstrates how these clots contribute to long-lasting COVID symptoms and whether removing them leads to better health outcomes.

How do microclots form?

Unlike blood clots that block arteries or veins, microclots occur in small blood vessels. They form when a soluble protein called fibrinogen is exposed to inflammation-causing molecules, which can bind to fibrinogen and aggregate into sticky blobs. “They are not capable of obstructing large ships; they are not capable of causing life-threatening symptoms,” Putrino says, but notes, “They can significantly affect organ function.

Pretorius and his colleagues have been studying these microclots for more than a decade and have observed them in patients with type 2 diabetes, chronic fatigue syndrome, Alzheimer’s disease and Parkinson’s disease. In a preliminary study from 2021, they found significant microclotting in the blood of patients with acute COVID-19, as well as people with long COVID who have persistent symptoms for six months or more. «The main difference between the microclots we find in diabetes and other conditions is that they break quite easily,» says Pretorius. COVID microclots are more difficult to disintegrate.

Trapped inside the lingering microclots, his team found high levels of inflammatory molecules and a protein called alpha 2-antiplasmin that prevents their breakdown. Such blockages in tiny blood vessels throughout the body could impede the delivery of oxygen and nutrients to organs and tissues, potentially leading to long-lasting COVID symptoms like fatigue, muscle aches and brain fog.

But what triggers the formation of micro-clots? Pretorius and his colleagues believe it is the SARS-CoV-2 spike protein, which can persist in the blood of long COVID patients for up to a year. In a 2021 study, the team added spike proteins to healthy blood and were able to trigger the development of microclots. They also found that in the presence of the spike, the microclots were more resistant to fibrinolysis, a natural process that allows clots to be removed. «Our belief is that the spike protein binds to healthy fibrinogen,» says Pretorius. “We believe that the interaction perhaps makes closer [microclot] structure and a larger structure.

If these micro-clots persist for prolonged periods, the body could produce autoantibodies, proteins that inadvertently attack the body’s own healthy tissues and cause debilitating disorders. «These are the people we are particularly concerned about,» she said.

How scientists detect microclots

Detecting microclots requires a specialized laboratory technique called fluorescence microscopy. «You can’t just go to the doctor and get tested for microclots,» says microbiologist Amy Proal, of the nonprofit PolyBio Research Foundation and co-founder of the long-running COVID Research Initiative.

The process involves drawing blood, swirling it around, and adding a fluorescent agent to view the clots under a fluorescent microscope. It is not a widely available tool in general pathology laboratories.

But what is unknown is the sensitivity and specificity of this method. “If you have 500 long-time COVID patients, is this test positive 100% of the times or 20%,” asks hematologist Jeffery Laurence of Weill Cornell Medical College in New York, who is not involved in the research. of Putrino or Pretorius. “Given that a similar phenomenon occurs in other diseases, how specific is this for COVID.”

He also points out that published microclot studies have been done on a small number of COVID patients for a long time, but future work should involve testing blood samples from many more people and replicating the research in multiple labs. . Putrino, in collaboration with immunologist Akiko Iwasaki, of Yale University, plans to test hundreds of long COVID patients «because a few dozen is by no means valid to tell everyone [with long COVID] has microclots,” he says.

So far, Putrino and his team are seeing a correlation between the number of microclots on a microscope slide and the severity of a patient’s cognitive impairment. These include their ability to regulate emotions, plan and implement long-term solutions to problems, or find ways to deal with real-time situations as they evolve. The research team is also developing an objective measurement of microclots. «We’re still at a very rudimentary stage,» Putrino says.

University of Utah hematologist Yazan Abou-Ismail, who is not associated with microclot research but finds the theory plausible in the context of long COVID, also hopes to see studies that document what is happening. passes inside the capillaries and organs of long COVID patients with microclots. «One can hypothesize that the microclots end up blocking small blood vessels,» he says, «but we don’t really know if there’s a real blockage.»

Treat micro-clots

As researchers try to determine the prevalence of microclots in people with long COVID and why they form, patients are suffering and desperate for treatment.

In a preprint study from December 2021, which has yet to be peer-reviewed, Pretorius and his team showed decreased microclotting and reduced platelet activation – a condition that accompanies the presence of microclotting – in 24 COVID patients. patients who received a combination of anticoagulant Apixiban and dual antiplatelet therapy for one month. However, they are revising the study to include more patients and measures of their health outcomes after treatment. «But we need clinical trials to show that anticoagulation approaches and antiplatelet approaches are effective,» Putrino says. He also wonders if clots in small blood vessels may require different blood thinners than those used for large clots.

McCorkell, on the other hand, is taking his treatment into his own hands and experimenting with over-the-counter enzyme supplements like serrapeptas and nattokinase which appear to break down blood clots but are not approved by the US Food and Drug Administration.

Like many other people with long-term COVID, McCorkell is disappointed and angry that there are no clinical trials to test the use of these supplements and other off-label therapies some patients are using. to relieve himself. Many health care providers are also often unable to help. Although she hasn’t experienced any side effects so far, McCorkell knows of some people who have had bouts of nausea and vomiting while taking the same supplements. Pretorius and his team plan to conduct a study to test whether these supplements are effective, but until then many patients are on their own.

«Given the scale of the problem and its impact on people’s lives, we need an Operation Warp Speed ​​situation,» McCorkell said. «It’s frustrating that we’re not more advanced.»

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