A team of 32 Emory University researchers and two Harvard Medical School (Mass.) scientists discovered a key pathway involved in acute COVID-19 multi-organ dysfunction.
The study, which was published on April 4, began at the height of the COVID-19 pandemic, according to one of the article’s authors, Professor of Pediatrics and Biomedical Engineering Wilbur Lam. Lam noted that at this time many patients dying from the virus were experiencing small blood clots throughout their body, particularly in their lungs.
This interaction of COVID-19 with human blood became the focus of their study. Their research found that, in acute cases, the COVID-19 virus led to blood vessel damage, hindering blood flow and causing organ damage.
“It was very obvious to everybody from the get-go that there was something different about how this virus was behaving, particularly when it came to what was going on in the blood vessels and the smallest blood vessels,” Pulmonary and Critical Care Medicine Fellow and co-first author Elizabeth Iffrig (16G, 18M, 21MR) said.
Iffrig, who acts as a fellow in Lam’s lab, said that the study examined the blood of patients at Grady Memorial Hospital’s intensive care unit (ICU) who were diagnosed with sepsis — an extreme inflammatory response triggered by infection that causes organ damage and often death — either due to a severe case of COVID-19 or a non-COVID-19 related infection.
Assistant Professor of Pathology Cheryl Maier (15MR, 17FM), who is the medical director of Emory's special coagulation laboratory and a transfusion medicine specialist, was the senior author of the paper. Maier was a part of a large multidisciplinary consult service that helped care for patients in critical care and the ICU, which allowed her to obtain adult and pediatric blood samples for the study.
“It was only because of my direct experience with patients that I started thinking about the mechanisms driving severe disease and how COVID was unique compared to other illnesses,” Maier wrote in an email to the Wheel. “This study is a beautiful example demonstrating the importance of physician scientists in making connections between what we observe clinically from patients and what is happening at the molecular level.”
Blood clotting
To effectively identify how COVID-19 influenced blood, Lam said that researchers took autopsies and examined the pathologies of patients who died from the virus.
Samuel Druzak (13Ox, 15C, 22G), who is a postdoctoral fellow and the co-first author of the study, looked at the “omics” processes which involved analyzing multiple datasets at once, to identify how different genes and proteins interacted with the virus. Iffrig said that her and Druzak’s “polar opposite” skillsets benefitted the research.
“It was very informative to go back and forth between someone for whom what I was doing was very out of his wheelhouse and for what he was doing was something I had never done before,” Iffrig said. “It allowed for a different take on the data that I think really helped us bring together a cohesive narrative to kind of describe the phenomenon that we did.”
According to Druzak, researchers aimed to identify the processes of the different “omics” — the sum of constituents within a cell, such as genomics, epigenomics and proteomics — and investigate if there were any altered lipids, metabolites or proteins that could explain the blood clotting. Specifically, Druzak said that he helped discover that fluid shear stress, a pathway that involves the frictional force from blood flow on vascular cells, was related to the interaction of the virus and blood.
Additionally, Lam’s lab created microfluidic devices that can manipulate small amounts of fluids to visualize the biophysical effects of the virus on blood. Lam said the technology used to create the microfluidic devices was similar to that which produces computer chips.
“But instead of making computer chips, we actually make really, really small pipes — pipes that are the size of really small blood vessels,” Lam said. “Since these are transparent and we look at them under a microscope, we now have a way to see how cells behave at that scale.”
Lam added that the “omics” approach identified biological processes, while the microfluidic technique proved how the cells moved and interacted in an environment that mimicked human blood vessels.
“Really the only way to make major scientific discoveries these days is to take this multidimensional, multidisciplinary approach because every approach has its pros and cons,” Lam said. “If you play your cards right, you can therefore have each approach balance the pros and cons of all the other approaches.”
Their study ultimately found that the interaction between COVID-19 and the human host led to an upregulation of the fibrinogen protein, which is involved in the formation of blood clots, Druzak said.
According to Lam, the blood of patients with COVID-19 was very “sticky,” causing individual red blood cells to stick together and form a “giant mass” that damaged the lining of blood vessels, leading to the formation of clots.
Iffrig stated that she was not surprised by the change in biophysics of the red blood cells, since aggregation of cells is a typical byproduct of sepsis.
“What we were able to show in COVID is that these changes were wildly exaggerated,” Iffrig said. “On top of that, they had a direct impact on the pathophysiology. They weren't just a bystander, they were an active player in contributing to how this particular disease is affected by it.”
Age-dependent effects
Though access to pediatric blood samples was somewhat limited, Druzak stated that their fibrinogen-based inflammatory study showed an age-dependent phenomenon.
“The older you are, the higher your basal levels of fibrinogen are,” Druzak said. “So if I have this inflammatory response that acts almost like a second thing to further increase these circulating levels, it can get to a critical range where you start seeing red blood cell aggregates for patients.”
Interim School of Medicine Dean Carlos Del Rio (86MR, 88FM) emphasized that the study importantly distinguished between the severity of COVID-19 effects in children versus adults, since fibrinogen levels were not found to be responsible for inflammation responses in children.
“What the studies show very nicely is that while severe COVID is a problem with children and adults, the pathogenesis and mechanisms of COVID disease are very different between one and the other,” Del Rio said.
In terms of future research and technological developments, Iffrig emphasized that she hopes to see biotechnology quantify the red blood cells’ response to disease, especially in the ICU, which currently lacks a method to identify those measurements. Iffrig noted that her future research will evaluate how to develop a point-of-care tool to measure the changes in red blood cells of sepsis patients and related therapies.
Lam also said that measuring blood response to disease could help physicians intervene before the clotting irreversibly damages blood vessels. Large aggregates of red blood cells, Druzak said, can lead to organ failure, especially renal failure, and potentially death.
“In the near future, now, we can start to measure how sticky patients’ red blood cells are, and as they get more sticky, we can kind of say, ‘Well, this is a warning sign that things might end up bad, like this severe COVID-19 patients,’ and then, could we get more proactive about it?” Lam said. “Could we dilute their blood? Could we take out some of their proteins, these inflammatory proteins that make the red blood cells sticky?”
Del Rio emphasized that their research has implications beyond understanding acute manifestations of COVID-19 as a singular disease. Druzak agreed, saying that their work could open up doors to understanding the interactions between many host path disorders and how an inflammatory state could affect cardiometabolic health.
“This has become the bedrock of what I anticipate my career to look like for the next at least probably decade,” Iffrig added. “There's a lot of room for biotechnology development at the bedside in the ICU to quantify how the red blood cell is changing in response to disease and how we think we can interfere with that process to improve outcomes.”
