Whether it’s strange rashes on the toes or blood clots in the brain, the widespread ravages of COVID-19 have increasingly led researchers to focus on how the novel coronavirus sabotages blood vessels.
As scientists have come to know the disease better, they have homed in on the vascular system — the body’s network of arteries, veins and capillaries, stretching more than 60,000 miles — to understand this wide-ranging disease and to find treatments that can stymie its most pernicious effects.
Some of the earliest insights into how COVID-19 can act like a vascular disease came from studying the aftermath of the most serious infections. Those reveal that the virus warps a critical piece of our vascular infrastructure: the single layer of cells lining the inside of every blood vessel, known as the endothelial cells or simply the endothelium.
Dr. William Li, a vascular biologist, compares this lining to a freshly resurfaced ice rink before a hockey game on which the players and pucks glide smoothly along.
“When the virus damages the inside of the blood vessel and shreds the lining, that’s like the ice after a hockey game,” said Li, a researcher and founder of the Angiogenesis Foundation. “You wind up with a situation that is really untenable for blood flow.”
In a study published this summer, Li and an international team of researchers compared the lung tissues of people who died of COVID-19 with those of people who died of influenza. They found stark differences: The lung tissues of the COVID victims had nine times as many tiny blood clots (“microthrombi”) as those of the influenza victims, and the coronavirus-infected lungs also exhibited “severe endothelial injury.”
“The surprise was that this respiratory virus makes a beeline for the cells lining blood vessels, filling them up like a gumball machine and shredding the cell from the inside out,” Li said. “We found blood vessels are blocked and blood clots are forming because of that lining damage.”
It’s already known that the coronavirus breaks into cells by way of a specific receptor, called ACE2, which is found all over the body. But scientists are still trying to understand how the virus sets off a cascade of events that cause so much destruction to blood vessels. Li said one theory is that the virus directly attacks endothelial cells. Lab experiments have shown that the coronavirus can infect engineered human endothelial cells.
It’s also possible the problems begin elsewhere, and the endothelial cells sustain collateral damage along the way as the immune system reacts — and sometimes overreacts — to the invading virus.
Endothelial cells have a slew of important jobs; these include preventing clotting, controlling blood pressure, regulating oxidative stress and fending off pathogens. And Li said uncovering how the virus jeopardizes the endothelium may link many of COVID-19’s complications: “the effects in the brain, the blood clots in the lung and elsewhere in the legs, the COVID toe, the problem with the kidneys and even the heart.”
In Spain, skin biopsies of distinctive red lesions on toes, known as chilblains, found viral particles in the endothelial cells, leading the authors to conclude that “endothelial damage induced by the virus could be the key mechanism.”
Is Blood Vessel Damage Behind COVID Complications?
“The endothelium has developed a distant early warning system to alert the body to get ready for an invasion if there’s trouble brewing,” said Dr. Peter Libby, a cardiologist and research scientist at Harvard Medical School. When that happens, endothelial cells change the way they function, he said. But that process can go too far.
“The very functions that help us maintain health and fight off invaders, when they run out of control, then it can actually make the disease worse,” Libby said.
In that case, the endothelial cells turn against their host and start to promote clotting and high blood pressure.
“In COVID-19 patients, we have both of these markers of dysfunction,” said Dr. Gaetano Santulli, a cardiologist and researcher at the Albert Einstein College of Medicine in New York City.
The novel coronavirus triggers a condition seen in other cardiovascular diseases called endothelial dysfunction. Santulli, who wrote about this idea in the spring, said that may be the “cornerstone” of organ dysfunction in COVID patients.
“The common denominator in all of these COVID-19 patients is endothelial dysfunction,” he said. “It’s like the virus knows where to go and knows how to attack these cells.”
Runaway Immune Response Adds a Plot Twist
A major source of damage to the vascular system likely also comes from the body’s own runaway immune response to the coronavirus.
“What we see with the SARS-CoV-2 is really an unprecedented level of inflammation in the bloodstream,” said Dr. Yogen Kanthi, a cardiologist and vascular medicine specialist at the National Institutes of Health who’s researching this phase of the illness. “This virus is leveraging its ability to create inflammation, and that has these deleterious, nefarious effects downstream.”
When inflammation spreads through the inner lining of the blood vessels — a condition called endothelialitis — blood clots can form throughout the body, starving tissues of oxygen and promoting even more inflammation.
“We start to get this relentless, self-amplifying cycle of inflammation in the body, which can then lead to more clotting and more inflammation,” Kanthi said.
Another sign of endothelial damage comes from analyzing the blood of COVID patients. A recent study found elevated levels of a protein produced by endothelial cells, called von Willebrand factor, that is involved in clotting.
“They are through the roof in those who are critically ill,” said Dr. Alfred Lee, a hematologist at the Yale Cancer Center who coauthored the study with Hyung Chun, a cardiologist and vascular biologist at Yale.
Lee pointed out that some autoimmune diseases can lead to a similar interplay of clotting and inflammation called immunothrombosis.
Chun said the elevated levels of von Willebrand factor show that vascular injury can be detected in patients while in the hospital — and perhaps even before, which could help predict their likelihood of developing more serious complications.
But he said it’s not yet clear what is the driving force behind the blood vessel damage: “It does seem to be a progression of disease that really brings out this endothelial injury. The key question is, what’s the root cause of this?”
After they presented their data, Lee said, Yale’s hospital system started putting patients who were critically ill with COVID-19 on aspirin, which can prevent clotting. While the best combinations and dosages are still being studied, research indicates blood thinners may improve outcomes in COVID patients.
Chun said treatments are also being studied that may more directly protect endothelial cells from the coronavirus.
“Is that the end-all-be-all to treating COVID-19? I absolutely don’t think so. There’s so many aspects of the disease that we still don’t understand,” he said.
COVID Is Often a Vascular ‘Stress Test’
Early in the pandemic, Dr. Roger Seheult, a critical care and pulmonary physician in Southern California, realized the patients he expected to be most vulnerable to a respiratory virus, those with underlying lung conditions such as chronic obstructive pulmonary disease and asthma, were not the ones ending up disproportionately in his intensive care unit. Seheult, who runs the popular medical education website MedCram, said, “Instead, what we are seeing are patients who are obese, people who have large BMIs, people who have Type 2 diabetes and with high blood pressure.”
Over time, all those conditions can cause inflammation and damage to the lining of blood vessels, he said, including a harmful chemical imbalance known as oxidative stress. Seheult said infection with the coronavirus becomes an added stress for people with those conditions that already tax the blood vessels: “If you’re right on the edge and you get the wind blown from this coronavirus, now you’ve gone over the edge.”
He said the extensive damage to blood vessels could explain why COVID patients with severe respiratory problems don’t necessarily resemble patients who get sick from the flu.
“They are having shortness of breath, but we have to realize the lungs are more than just the airways,” he said. “It’s an issue with the blood vessels themselves.”
This is why COVID patients struggle to fill their blood supply with oxygen, even when air is being pumped into their lungs.
“The endothelial cells get leaky, so instead of being like saran wrap, it turns into a sieve and then it allows fluid from the bloodstream to accumulate in the air spaces,” Harvard’s Libby said.
Doctors who treat COVID-19 are now keenly aware that complications such as strokes and heart problems can appear even after a patient gets better and their breathing improves.
“They are off oxygen, they can be discharged home, but their vasculature is not completely resolved. They still have inflammation,” he said. “What can happen is they develop a blood clot, and they have a massive pulmonary embolism.”
Patients can be closely monitored for these problems, but one of the big unknowns for doctors and patients is the long-term effects of COVID-19 on the circulatory system. The Angiogenesis Foundation’s Li puts it this way: “The virus enters your body and it leaves your body. You might or might not have gotten sick. But is that leaving behind a trashed vascular system?”