Caption: Study coauthors Jana Jacobs and William Bain
By An-Li Herring
Early in the COVID-19 pandemic, physicians were puzzled that the virus produced dramatically different outcomes from one patient to another. While many patients recovered with mild symptoms, others developed dangerous complications outside the lungs—blood clots, strokes, heart attacks and inflammation that spread throughout the body.
Researchers have long observed this pattern in other viral respiratory infections, including influenza and respiratory syncytial virus. Scientists at the University of Pittsburgh School of Medicine and collaborating institutions now believe damage that occurs to the lining of blood vessels after the virus enters the bloodstream might help to explain why.
In a study published May 6 in the Journal of the American Heart Association, investigators identified a blood marker associated with severe illness and death in hospitalized COVID-19 patients. The marker, called soluble thrombomodulin, is released into the bloodstream when the endothelium, the thin layer of cells lining blood vessels, becomes injured. Notably, researchers found that patients with detectable viral material in their blood were more likely to have elevated levels of soluble thrombomodulin and faced a higher risk of death, suggesting that severe viral respiratory infections are not solely diseases of the lungs, but can also lead to serious vascular injury in some patients.
To examine this relationship, researchers analyzed blood samples from patients enrolled in ACTIV-4a, a large international clinical trial studying complications of COVID-19. The team compared soluble thrombomodulin levels with patient outcomes and with the presence of viral RNA in the bloodstream, sometimes referred to as RNAemia or viremia.
“What most interested us about this is that there’s sort of a middle group of patients that may be sick enough to end up in the hospital but not so sick that they’re in the intensive care unit (ICU), and that group can be more at risk for cardiovascular complications like heart attacks and strokes,” said senior author William Bain, assistant professor of medicine (Division of Pulmonary, Allergy, Critical Care and Sleep Medicine) at Pitt.
Bain noted that these patients appeared to benefit from taking anticoagulants, unlike patients in the ICU who required the support of a ventilator. “A lot of people were scratching their heads at that,” he said. “And so, one of our ideas is that it could be that the virus is getting outside the lungs and causing these heart attacks and strokes.”
Under normal conditions, thrombomodulin remains attached to the surface of endothelial cells, where it helps to regulate blood clotting and inflammation. But when blood vessels are damaged, the protein breaks away and enters the bloodstream.
Researchers believe the clotting seen in severe viral infections may begin as a protective response in the lungs. Because the lungs’ air-blood barrier is extremely thin, clotting may help to reinforce that barrier and prevent fluid from leaking into surrounding tissue. But if viral material enters the bloodstream, researchers think the same clotting response may occur in blood vessels elsewhere in the body—including in the heart or brain—where it can become dangerous.
The findings suggest that endothelial injury may play a central role in determining which patients develop the most dangerous complications of viral respiratory infections. They could eventually help physicians to identify hospitalized patients at greatest risk and guide decisions about monitoring and treatment.
“This brings us a little bit closer to understanding how viral RNA or viral particles in the blood are leading to a higher degree of poor outcomes like mortality and thrombosis,” said study coauthor Jana Jacobs, research assistant professor of medicine (Division of Infectious Diseases) at Pitt. “The logical next step for us is to look at it through a more mechanistic lens to try to figure out exactly what’s happening.”
Media contact: HSNews@pitt.edu