New Pitt, UPMC study examines how respiratory virus can trigger heart attack, stroke

For years, doctors have observed a troubling pattern: patients who seem to be recovering from a respiratory virus suddenly suffering a heart attack or stroke.

The phenomenon has often been attributed to inflammation or dismissed as bad luck.

But new research from the University of Pittsburgh School of Medicine and UPMC suggests there may be a clearer biological explanation - one that begins when a virus escapes the lungs and enters the bloodstream.

The study provides one answer to a question that has been interesting, which is: 'Why does a viral infection in your lung cause these horrible consequences'" outside the lung, said William Bain, a senior author on the study, a UPMC critical care pulmonologist and assistant professor of medicine in Pitt's School of Medicine's Department of Pulmonary, Allergy, Critical Care and Sleep Medicine.

Published Wednesday in the Journal of the American Heart Association, the study analyzed blood samples from hospitalized COVID-19 patients enrolled in the ACTIV-4a clinical trial, a large international study designed to determine the best way to prevent dangerous blood clots in those hospitalized with COVID.

Researchers found that patients with higher levels of viral RNA - essentially, genetic material from the virus - circulating in their blood were significantly more likely to develop blood clots and die within 90 days.

In the early days of the pandemic, this wasn't uncommon among the sickest patients.

Those being treated in intensive care units were found to have the most virus in their bloodstream, followed closely by patients who were in the hospital yet did not require ICU care. For those who had contracted COVID, but were not hospitalized, only about 5% were found to have the virus circulating in their blood, Bain estimated.

That suggested a clear pattern, he said: the more severe the illness, the more likely the virus is to spread beyond the lungs and potentially cause harm elsewhere.

Clues in damaged blood vessels

What makes this study different is not just the link between a virus in the blood and poor outcomes, a connection that was already known, but what might explain it.

Researchers zeroed in on a marker in the blood called soluble thrombomodulin, or sTM, which signals damage to the lining of blood vessels, Bain said.

In other words, the virus doesn't just circulate; it also may be injuring blood vessels, setting off a chain reaction that leads to dangerous clotting.

The study found that this blood vessel damage accounts for part of the increased risk of death in patients with viral RNA in their blood, offering one of the clearest explanations yet for COVID's cardiovascular complications.

Doctors have long known that respiratory infections like the flu can raise the risk of heart attacks and strokes, although such events are relatively rare, Bain said.

What hasn't been clear is why.

The new findings suggest that, once a virus enters the bloodstream, it may damage blood vessels and trigger clotting - the kind that can block arteries in the heart or brain.

Autopsy studies add to that picture, he said. Researchers have found viral material in arterial plaque in patients who died of COVID-19, raising the possibility that the virus may destabilize existing plaque and make it more likely to rupture.

"We haven't shown that," Bain cautioned, "but that is certainly one thing that we would hypothesize."

Why timing matters

One of the more puzzling aspects of virus-related heart complications is when they happen - often not at the peak of illness, but as patients seem to be stabilizing.

Bain said the risk may be particularly relevant for patients who are sick enough to be hospitalized, but not critically ill.

That pattern also mirrors findings from the ACTIV-4a trial itself, which tested blood-thinning treatments. Patients who were moderately ill benefited from anticoagulation treatment, while those in the ICU did not, he said, evidence suggesting that ICU patients may even have been harmed by that treatment.

The new study found a similar pattern, suggesting that timing and disease severity could be key to understanding who is most at risk.

While the study did not test any treatments for the condition, it did raise the possibility that simple blood tests could one day help doctors identify high-risk patients.

Bain said researchers are particularly interested in whether measuring viral RNA or markers like sTM could guide care, ultimately defining personalized treatments.

For example, patients with viruses in their bloodstream might benefit from blood thinners or other targeted therapies, although that remains to be proven, he said.

If more research is funded, Bain estimated that answering those questions could take another three to five years.

Looking beyond COVID-19

Although the study focuses only on COVID-19, its implications may extend to other respiratory viruses, including influenza and RSV.

Researchers already know that these viruses can sometimes enter the bloodstream. The next step is determining whether they trigger the same chain reaction as the COVID virus.

"The low-hanging fruit is determining if the virus in flu and RSV" show the same issues, Bain said. "I think that opens up a lot of opportunities. And then after that, it's trying to understand what is happening at the cell or the protein level that is causing it.

If researchers can also determine a link between the damage and the viruses that cause the flu and RSV, it could reshape how doctors think about and treat a wide range of viral illnesses, he said.

One possible explanation ties back to how the body protects itself in the lungs.

The lungs are naturally prone to clotting as a defense mechanism, helping to prevent bleeding when delicate tissue is damaged. But when a virus escapes into the bloodstream, that same clot-producing response may become harmful.

"What is good in the lung is now bad outside of the lung," Bain explained, describing a "pro-thrombotic response" that may help locally (in the lungs) but cause dangerous clots elsewhere (in blood vessels).

It's still a theory, but one that could unify years of observations across multiple diseases, he said.

Despite the risks, there is some reassurance: Blood vessel damage does not appear to be permanent, Bain said.

For now, the research offers something patients and doctors have long lacked: a clearer explanation of how a respiratory virus can lead to life-threatening complications far beyond the lungs. And with that understanding may come better ways to predict, prevent and treat them, Bain said.

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