How Long COVID Research Could Change the Way We Think About Blood Microclots
Knowledge of the condition’s microclots could make a macro difference.
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Back in March 2020, Resia Pretorius was virtually alone in her lab at Stellenbosch University, South Africa.
“We were in a hard lockdown. I was the only one in the lab, basically,” she recounts.
A distinguished research professor specializing in blood coagulation, Pretorius was using her expertise to help understand how SARS-CoV-2 – the newly named virus that had just shut down the world – was affecting patients' blood. She began her research by adding amyloid clotting biomarkers to blood samples collected from acute COVID patients and inspected the results under a microscope.
“I said, ‘OK, let’s see where I get.’ And I was knocked out of the room,” she tells Technology Networks. “I couldn't believe what I saw; these amyloid signals were everywhere. And I got back to the control sample and did the same, and I saw little bits, but not much.”
Pretorius had become one of the first in the world to discover that COVID-19 could induce widespread clotting in the blood of patients. At the time, however, the finding was contrary to the growing assumption among clinicians that the viral disease thinned the blood of patients and that anticoagulants could pose additional risk to life.
“Everyone was thinking, ‘Oh dear, it’s a bleeding disease,’” Pretorius recollects. “People were terrified that if you treat acute COVID with anticoagulants you will have everyone going into bleeding and dying. At that stage, nobody understood the disease – that it was an endothelial vascular disease. Everyone was saying it’s a lung disease, and they were all wrong.”
Fortunately, for a few acute COVID patients in Stellenbosch, one doctor, a colleague of Pretorius’s, was convinced enough by her findings to administer blood thinners.
“He lost six or seven very ill patients; the rest all recovered,” she says. “Now, you must remember at that stage, he was in a very, very precarious position. He knew he was helping his patients, but everyone around him said you are going to kill them. But his patients recovered really well.”
Not only did most of the patients go on to recover from SARS-CoV-2, but they were also seemingly spared from any lingering or new symptoms post-infection – a phenomenon that would come to be dubbed “long COVID”.
This particular fortune began to intrigue Pretorius as anecdotes and research papers detailing a global long COVID crisis mounted. Were anticoagulants the answer to this new chronic malady? To find out, she would first have to sample blood from long COVID patients.
Clotted team
“I then got hold of some patients who had been in hospital on Respiratory,” says Pretorius. “They had recovered, but they weren't the same. So, I got the first South African long COVID patients by searching around for people and saying, ‘Are you okay? Are you recovered?’ And they said they're not; they’ve got this brain fog; they suddenly can’t count – typically what you find in long COVID. So I got the first few patients’ blood samples.”
And what did she find? The exact same clotting pattern observed in the blood of acute COVID patients.
“We did our first trypsin digestion step, which is a bog-standard method for mass spectrometry, and we looked at the sample and it was like a ray of light coming through the lab,” she says. “We looked at the controls, the diabetes [blood taken from diabetes patients], the acute, the long COVID. I could see nothing in controls, in the diabetes, because all of the plasma was perfectly digested, as you would expect, but I could see all the clots still in the acute COVID and long COVID.”
This observation seemingly confirmed a biomolecular link between the immediate symptoms experienced by acute COVID patients and the lingering symptoms of those with long COVID. But a key question remained: what had prevented the trypsin from performing its usual thinning effect?
“We went back to the drawing board,” she recounts, “and we said, ‘OK, so, trypsin, which is an enzyme that digests protein, that doesn't seemingly work for acute COVID or long COVID.’ So we developed a second trypsin digestive process. And when we ran proteomics [experiments], we found all the proteins that you would expect – the fibrinogens, the alpha and the beta, all of those – and we found another molecule: alpha 2-antiplasmin, and that molecule prevents clot breakdown.”
“So now we had an answer as to why trypsin doesn’t break down the clots,” she says.
Armed with this new understanding, Pretorius and her team at Stellenbosch felt ready to share their discovery to the global research community. They soon filed a patent for their clot test and drafted a paper on their work. Just before sending the manuscript off for publication, however, a colleague of Pretorius’ made one small suggestion.
“She said, ‘This is really nice. However, dense amyloid deposits is too difficult on the ear; change it.’ And I was sitting there thinking, ‘What else can I call it?’ And ‘microclots’ just came to me,” says Pretorius. “And 10 minutes before I submitted the paper, I changed the words to microclots, and that’s where microclots started.”
It proved to be a canny move in medical marketing. Soon the word “microclots” began clogging up long COVID online support groups. Pleas and questions swirled across social media. Did every long-hauler have clots thickening their blood? Could the clots explain every symptom or just the crushing fatigue that characterized most long COVID cases? And, crucially, could blood thinners help rid sufferers of the minuscule globs?
As a blood coagulation researcher rather than a clinician, Pretorius wasn’t able to fully answer the last question, which has been posed to her many, many times since her microclot paper was first published. She could not conduct any clinical trials that may prove the benefits of anticoagulants – although she does believe the drugs, in some quantity, could help some patients.
“The issue is, what are the dosages?” she asks. “Can triple anticoagulation work for 5% of the people? 10%? 50%? 80%? We don’t know that until we do a proper clinical trial.”
In lieu of such trials, though, some desperate long COVID patients have sought to thin their blood by other means.
Inflamed in the deep vein
Nattokinase is an enzyme isolated from natto, a traditional Japanese dish made from fermented soybeans. It exhibits strong fibrinolytic activity when in contact with human blood clots.
Since Pretorius first published her findings, many sufferers have trialed the supplement in the hopes of bursting their microclots and reducing their debilitating symptoms.
Some researchers and clinicians have cast doubt, however, on whether the protein, when taken as an oral supplement, still exhibits any clot-busting effects once digested in the gut. Other researchers, though – including Pretorius – have upheld its medical potential.
“Nattokinase, instead of blocking the clots, breaks down the clots,” says Pretorious. “So it’s a safer option than triple anticoagulation therapy, because triple anticoagulation therapy blocks the platelets to hyper-activate and it prevents new clots to form. But there’s a risk; you could bleed. Nattokinase breaks the clot down and you don’t have the worry that you’re going to bleed. It acts on the clot that’s already there.”
Given the relative safety of nattokinase when compared to blood thinners like warfarin or clopidogrel, Pretorius doesn’t see the harm in long COVID sufferers trying out a course of the health supplement. If taken in safe but high enough doses, it may just help give the body’s damaged endothelial layer time to heal itself, if only slightly.
“The clotting issues started in a perfectly healthy individual with acute COVID,” Pretorius explains. “Something triggered then a continuation of clotting pathology that never was taken care of. The bottom line is, if the clotting pathology was taken care of in the acute phase, nobody [would have] went into long COVID. But the clotting pathology just continued and made massive damage to the endothelial layers.”
Endothelial cells form a single cell layer that lines all blood vessels and regulates exchanges between the bloodstream and the surrounding tissues.
“If all of your endothelial layers are damaged, oxygen transport can’t go to your muscle,” Pretorius explains. “Your body will have this persistent post-exertional malaise. [As for] brain fog, your blood‒brain barrier is vasculature.”
“We think long COVID symptoms [are due to] a damaged endothelial layer,” she continues. “Do we say microclots cause it? No. We say the spike protein [of the SARS-CoV-2 virus] and inflammatory molecules, antibodies, auto-antibodies – all those things cause it, but [microclots] are central in the disease pathway.”
“Now, what do you do?” she asks. “There’s no real treatment for endothelial damage. So we thought if we could get rid of the clots and you get rid of the platelet hyperactivation, then you get to give your endothelial layers a chance to heal. If that happens, you’ve got a fighting chance that the person with long COVID might be better.”
More testing, more blood clotting conditions
While countless long COVID sufferers put Pretorius’s theory to the test, her new focus is raising its awareness. Not only could wider recognition benefit long COVID patients across the globe, but also thousands of patients with other inflammatory illnesses.
“Rheumatoid arthritis, psoriasis, Parkinson’s, Alzheimer’s – in all of those diseases, you will have inflammatory molecules in circulation,” says Pretorius. “They [the inflammatory molecules] will bind to the endothelial layers via receptors, then we’ll have a protein‒protein interaction to change the intimate amyloid shape.”
“Microclots are not only found in acute COVID and long COVID, they’re also found in all of the others,” she says.
Sepsis, in particular, has already been shown to have the exact kind of microclots that can be detected by the test, as evidenced by the recent research of Cheng-Hock Toh, a professor of clinical infection at the University of Liverpool.
“Professor Toh’s group did our method,” says Pretorius. “And they found that by detecting microclots in the sepsis patients, they could predict who [would have] died and who would not. The microclot load during the sepsis event, if that was high, then it predicted whether you recover or not. And they suggested that this is a first for an ICU condition to use as a possible predictor of how sick the individual is.”
“Hopefully, research like that will point to uses of looking at it as a diagnostic tool to prevent disease progression – in the case of sepsis, perhaps even suggest how sick the patient is. I hope this could be a diagnostic that they could just add on – an add-on biomarker as part of a broad spectrum that you are looking at. Look at the D-dimer, look at platelet markers, look at antibodies, auto-antibodies, but just have this as an add-on to further direct clinician approaches to treatment.”
“Fifteen years from now, I hope that this method will be in every single pathology lab,” Pretorius enthuses, “that anyone with long COVID or any inflammatory disease that might think that have gotten a clotted pathology, can go to a laboratory and ask for the test and get results from it.”
