One of the major mysteries in treating patients with COVID-19 is the frequent development of blood clots that can subsequently damage their organs and sometimes be fatal. New findings led by Yale Cancer Center (YCC) researchers and experts across several medical specialties at Yale identify a leading mechanism behind the pathophysiology of COVID-19 and pinpoint a biological marker for the mechanism that may aid in treating these patients. The study was published today in The Lancet Haematology.

“While many forms of illness can generate blood clots, the endothelial cells that line the inside of blood vessels play a surprisingly large role in COVID-19 clotting,” said Alfred Lee, M.D., Ph.D., Associate Professor of Medicine (Hematology) at YCC and co-senior author on the paper. “Endothelial damage is a central component in the entire spectrum of Covid-19 disease. Our study is the first to demonstrate that this process of endothelial damage is present in a wide range of COVID-19 patients, particularly as people become critically ill.”

The clinical study examined the blood of 68 patients with COVID-19, 48 of them critically ill in an intensive care unit (ICU) and 20 receiving care on a non-ICU hospital unit, along with 13 disease-free volunteers who acted as a control arm. Several markers of endothelial cell and blood platelet activation were about twice as high in the ICU group than in the non-ICU group, and also higher in the non-ICU group than in the control group.

One of the biomarkers, a soluble form of a protein on the surface of endothelial cells called thrombomodulin, was highly correlated with survival among all COVID-19 patients. This finding suggests that measuring thrombomodulin levels might aid in managing patients. “If we have a marker to identify which patients are most likely to progress towards critical illness and possibly death, that would be hugely helpful, as these patients might benefit from closer monitoring and possibly earlier intervention,” said Lee.

Hyung Chun, M.D., FAHA, Associate Professor of Medicine (Cardiology) and Pathology at Yale School of Medicine, Director of Translational Research in the Yale Pulmonary Vascular Disease Program and co-senior author on the paper, is now exploring opportunities to develop a diagnostic test based on thrombomodulin, which is also elevated in other life-threatening diseases.

“The other goal we’re pursuing in parallel is to find therapeutic strategies that could safeguard the endothelial layer and may prevent the blood clots from forming,” said Chun, whose lab studies endothelial cells. “Are there approved drugs we could potentially repurpose for this context, or could we think about other mechanisms to come up with novel therapies to ultimately protect endothelial cells?”

One early candidate among approved therapies is an oral drug called dipyridamole, long used to prevent stroke and for other conditions. The research began with a Yale COVID-19 initiative that brought together medical experts charged with making recommendations on standard treatments for the Yale New Haven Health System.

Clinical fellows George Goshua, M.D., and Alexander Pine, M.D., Ph.D., both in the hematology/oncology fellowship training program at Yale Cancer Center, and M.D./Ph.D. student Matthew Meizlish are co-first authors on the paper. Altogether, 23 Yale physicians and researchers contributed to the work. “As terrible as it is, COVID-19 brought people together who almost never would have the chance to intersect, so that we could all exchange amazing ideas and learn from each other and accomplish great science,” Lee added.

The study was supported by a gift from Jack Levin to Yale’s Benign Hematology program and by the National Institutes of Health.