Yale News

Scientists at Yale have synthesized research from around the world to suggest new treatment methods for COVID-19.

A multidisciplinary team of Yale physician scientists, researchers, nursing staff and others have collaborated since early on in the pandemic to figure out why COVID-19 patients are so prone to blood-clotting. Their recent review, published on Nov. 19 in Nature Reviews Cardiology, details how COVID-19 causes blood clots in sick patients and why the disease has been so difficult to treat.

“Blood clotting is a complex process that involves many types of cells in the body including platelets and endothelial cells,” John Hwa, professor of medicine at the Yale Cardiovascular Research Center and one of the review’s senior authors, wrote in an email to the News. “It isn’t often that all components involved are in serious disarray and thus synergizing to promote massive blood clotting. In some ways it’s like ‘a perfect storm’ where all the components are perturbed and are tipped over the edge by COVID-19.”

Hwa said his colleague Hyung Chun, co-author of the review and director of Translational Research at the Yale Pulmonary Vascular Disease Program, contacted him in March when he suspected that endothelial cells, which line the interior surface of blood vessels, might be involved in the pathogenesis of COVID-19. 

Alfred Lee, associate professor of Medicine and another author of the review, also reached out to Hwa in March and informed him of potential abnormalities in platelets — cells responsible for blood clotting — that he was observing in COVID-19 patients. The team, which included Lee, Hwa and Chun, expanded those observations into a massive collaborative effort that included many frontline healthcare workers helping with patient treatment.

Platelets and endothelial cells are not usually considered important in the development of a disease from viral infection, according to Hwa. But COVID-19 and the body’s resulting immune response can lead to damage in many different cells and cause a wide range of complications — including those related to platelets and endothelial cells.

“A major adverse outcome of those critically ill with Covid19 is formation of blood clots, many of which are likely undiagnosed,” Chun wrote in an email to the News. “This is likely occurring due to a combination of endothelial injury/activation and platelet activation.”

To make matters worse, the functions of these cells can already be compromised in elderly people and in people with diabetes or other cardiovascular risk factors. Then, when the cells are introduced to COVID-19, the “perfect storm” that Hwa described forms. 

Another complication can come in the form of elevated cytokine levels, according to Jennifer Kwan, co-author of the review and clinical fellow at the Yale School of Medicine.

“The cytokines are essentially our messaging system released by immune cells to ramp up the immune defense or offense against a microbial threat,” Kwan said. “But when the cytokine levels get too high, the cytokines themselves can cause damage to other organs. There is a correlation between higher cytokine levels and worse outcomes, particularly mortality, so increased risk of death, associated with high cytokine levels.”

Kwan emphasized that these high levels of cytokines are one way that younger people who are infected with COVID-19 can be severely affected. Their immune systems can go into “overdrive” and form a “cytokine storm” in a way that would not happen in a less functional immune system, such as among the elderly, according to Kwan.

Due to the vast array of complications that can be caused by COVID-19, the researchers’ review acknowledges that combination therapies, which utilize multiple drugs and target individual components of the disease, will likely be more effective than any single drug.

“Given the severe clotting, [the most comprehensive treatment] has included strategies to target the coagulation defect with anticoagulants, as well as the platelet defect with antiplatelet agents,” Hwa wrote. “There are many experimental strategies that are also being explored.”

All of the team members interviewed by the News emphasized their confidence in and appreciation for their colleagues in the medical community. Hwa is sure that the progress in treatment from reviews like theirs has saved many lives and hopes that the team’s findings will provide insights that are beneficial for dealing with future pandemics.

“Scientists can develop effective vaccines,” Kwan said. “We have the technology, we have the knowledge, we have the expertise … The importance of supporting science and making sure that we do not lose sight of the importance of science is going to be important. Thanks to science, there is some hope. And that is coming in the form of the vaccine.”

As of Thursday, over 270,000 Americans have died from COVID-19, according to the Centers for Disease Control and Prevention.

Jonathan Jalbert | jonathan.jalbert@yale.edu