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The federal COVID-19 public health emergency ended last week, but millions in the U.S. — and across the globe — are still dealing with the repercussions of the COVID-19 pandemic in the form of Long COVID.

Estimates show that more than 65 million worldwide have the condition, which encompasses a wide range of symptoms that are worsened or appear after initial SARS-CoV-2 infection. But three years after the first people with persistent symptoms were documented, there is no biomarker for the disease — no test or swab that can diagnose someone with Long COVID.

A group of researchers is looking to change that.

From lungs to blood

Early in the pandemic, most thought of COVID-19 as a respiratory disease. Resia Pretorius, a professor of physiological sciences at Stellenbosch University in South Africa was seeing something else. After spending years studying blood clotting patterns in other diseases, like diabetes, lupus and arthritis, she was seeing hints of similar, blood-related symptoms in COVID patients.

"It was quite clear from sample one that we are looking at severe clotting pathology," she says.

Currently, Pretorius and her collaborators are seeing what the blood of Long COVID patients can tell them about the disease but it started as they tried to understand what COVID was doing to the blood during an acute infection.

"The spike protein has the capability to change your soluble clotting protein to insoluble little microclots and that's where everything starts," Pretorius says. "So when you have acute COVID you will have activated platelets, you will have vascular damage in endothelial damage and you will have a micro cloud presence in some individuals."

In some people, after around two weeks, the body will begin to break down those insoluble microclots and they will return to normal. But for others, those microclots hang around and they can damage blood vessels as well as block blood flow to many organs — which could help explain Long COVID's wide-ranging symptoms.

"You get widespread and systemic-induced ... inflammation of your blood vessels—the inside of your blood vessels. If it's systemic, it means it's in every organ. It's in every part of your body," Pretorius says. "It means that oxygen transfer cannot happen as it should, between your blood and your organ systems because the vehicle, the blood, is damaged these clots [are] in there. But more importantly, your vasculature is compromised."

A possible biomarker

Without a consistent way to test for and identify people with Long COVID, it's more difficult for researchers to study the disease and often harder for patients to get the care they need.

Pretorius says that many Long COVID patients see doctors who don't believe the full extent of their symptoms, even if they test patients' blood. Which means that when patients "go to clinicians, they do the standard pathology workup, blood workup and they say 'Sorry, you don't have anything, there's nothing wrong with you because all your blood tests are normal,'" she says. "The reason for that is they're not looking at the right place."

The goal of Pretorius and her collaborators is to help design a better test that physicians can use to identify those with high levels of microclots. One of those collaborators is David Putrino, the director of rehabilitation innovation for Mount Sinai Health System. He hopes that the test they are developing can go further for patients with other post viral illnesses too.

"Often we are told, well, 'Everything's testing normal. We tested all the standard panels, everything's come back normal.' I think one of the things that we need to say over and over again is that, you know, the blood panels, the standard blood panels that we test for, they really only capture a very narrow scope of our physiology," he says. The work he and Pretorius are doing shows that the microclots they are seeing, in addition to hyperactivated platelets, "can really mess with your body's ability to function." The next step is to find a way to make a mainstream test for it.

All of the Long COVID patients Putrino has tested have had microclots and hyperactivated platelets, which is something he doesn't commonly see in people who have never had COVID or who have fully recovered. It's this high level of microclots in Long COVID patients that Putrino thinks might be the biomarker. One of the questions that remains is, if they continue to see this pattern on a bigger scale, is targeting and getting rid of these microclots an effective treatment?

Roy Silverstein, a hematologist at the Medical College of Wisconsin who isn't involved with this work, says he has two main questions going forward. "If [microclots] present in the blood in patients with Long COVID and not in the blood of patients without Long COVID, could they therefore be used as a marker for various treatments to see if, first of all, to define the level of plausibility that the patient has one COVID? And then to use as a marker in treatment studies?"

There are other diseases that are marked by changes to the blood's clotting patterns in the capillaries, namely Thrombotic Thrombocytopenic Purpura (TTP) and Hemolytic Uremic Syndrome (HUS). The clots caused by Long COVID are made of unique proteins. "They're not the typical micro clots that we see with those other disease ... they're made up almost fully of abnormal type of fibrin, which is the protein and blood that forms the blood clot and creates these unusual structures that are called amyloid," he says.

A unique source of funding

Pretorius and her lab have been working around the clock with the hope of helping Long COVID patients sooner rather than later. The first group of people who have Long COVID are now reaching the three year mark with the disease.

"That's a really, really long time to be suffering with this illness, which, in many cases has a quality of life that is just so, so low, like unfathomably low to most people — definitely unfathomably low to me, you know, not having known about Post-Viral illness beforehand," says Hannah Davis, a co-founder and lead researcher of the Patient Led Research Collaborative, who has had Long COVID since March 2020.

Because of that urgency, Pretorius took an unusual step — crowdfunding donations to buy a flow cytometer, which uses lasers to analyze individual cells. Initially, she was using standard fluorescent microscopes, which are common in research labs but not hospitals. In order to iron out a methodology that could work for clinical settings, she started using the much more common flow cytometer.

She says the speed with which she got sufficient money points to the need for this research in a moment where traditional grants may be too slow. "If it wasn't for the desperate nature of the disease, I think we would not have been able to crowdfund in such a short time."

While Pretorius and her colleagues are making progress, Davis says that it shouldn't have come to this.

"I get to be part of this, this test development process that all of our patient advocacy and patient relationships and things like that have led to — this moment and ... kind of a very concrete impact on our life," she says. "It shouldn't have to be like this, right? Like, it should be the case that millions of dollars are designated for finding a biomarker or identifying and creating a test or both."

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This episode was produced by Margaret Cirino and Berly McCoy, edited by Gabriel Spitzer and managing producer Rebecca Ramirez. It was fact-checked by Emily Kwong, Rebecca and Berly. The audio engineer was Robert Rodriguez.