The death toll from COVID-19 continues to rise daily. But how SARS-CoV-2, the new coronavirus that causes the disease, actually causes death remains poorly understood.
Clinical reports show that people with severe COVID-19 develop pneumonia, acute respiratory distress syndrome, and multiple organ failure.
Age and underlying medical conditions are factors that increase a person’s risk of severe disease.
In a collection of articles published in the journal Radiology, experts now highlight that a significant proportion of those with severe COVID-19 show signs of blood clots, which can lead to life-threatening complications.
Blood clotting is a natural mechanism in response to an injury. However, when a blot clot forms within a blood vessel, it can restrict blood flow. Known as a thrombus, it can lead to severe medical emergencies.
If a thrombus breaks free and travels to another part of the body, doctors call it an embolus. If an embolus reaches the lungs, brain, or heart, the ensuing embolism can become life-threatening.
But why would thrombi and emboli be an issue in COVID-19? The SARS-CoV-2 virus can infect cells in the lung. In severe cases, this leads to inflammation in the lungs and shortness of breath.
Yet, how breathlessness or impaired pulmonary ventilation progresses to death is not entirely clear.
“Worldwide, COVID-19 is being treated as a primary pulmonary disease,” explains Professor Edwin van Beek from Queens Medical Research Institute at the University of Edinburgh in the United Kingdom. “From the analysis of all available current medical, laboratory, and imaging data on COVID-19, it became clear that symptoms and diagnostic tests could not be explained by impaired pulmonary ventilation alone.”
Prof van Beek is the senior author of one of the papers in Radiology. Along with a team of experts, he reviewed whether blood clots might play a role in COVID-19.
Viral infections can activate the blood clotting pathway. Experts believe that this process evolved as a mechanism to limit the spread of a viral infection.
To assess blood clotting in a person, healthcare professionals often measure the amount of a protein complex called D-dimer they have in their blood. D-dimer remains in the blood after an enzyme called plasmin degrades the blood clot in a process called fibrinolysis.
High D-dimer levels in the blood are an indication of thrombosis and embolism.
Reviewing the evidence to date, Prof. van Beek and his colleagues write: “There is a strong association between D-dimer levels, disease progression, and chest CT features suggesting venous thrombosis.”
Radiology has also published a research letter written by a team from Centre Hospitalier Universitaire de Besancon in France. The group reports that 23 out of 100 patients in the hospital with severe COVID-19 had signs of pulmonary embolism, which is a blood clot that has traveled to the lung.
These patients were more likely to be in the critical care unit and require mechanical ventilation than those without pulmonary embolism.
Another research team from Hôpitaux Universitaires de Strasbourg in France echoed the findings. In their research letter, also published in Radiology, the team reports that 30% of 106 patients in the hospital with severe COVID-19 showed signs of blood clots in their lungs.
According to the authors, “This rate of [pulmonary embolus] is higher than usually encountered in critically ill patients without COVID-19 infection (1.3%) or in emergency department patients (3–10%).”
The Strasbourg team also found that these people also had higher levels of D-dimer in their blood than those without pulmonary embolus.
In his paper, Prof. van Beek explains that there is already evidence of a link between high levels of D-dimers and poor outcomes for patients with COVID-19.
As researchers begin to understand more about how and why COVID-19 is deadly for some people, this knowledge will help identify the best treatment options.
In light of their analysis, Prof. van Beek and his colleagues recommend measuring D-dimer levels, monitoring for signs of embolism or thrombosis, and early initiation of anticoagulation therapies to avoid blood clots.
One of the team’s recommendations is to give a low dose of heparin, which prevents clot formation, to all patients admitted to the hospital with suspected or confirmed COVID-19.
Other scientists have recently suggested using tissue plasminogen activator (tPA), which helps to dissolve blood clots, to treat people with severe COVID-19.
Purple rashes, swollen legs, clogged catheters and sudden death — blood clots, large and small, are a frequent complication of COVID-19, and researchers are just beginning to untangle why. For weeks, reports have poured in of the disease’s effects throughout the body, many of which are caused by clots. “This is like a storm of blood clots,” says Behnood Bikdeli, a fourth-year cardiology fellow at Columbia University in New York City. Anyone with a severe illness is at risk of developing clots, but hospitalized patients with COVID-19 seem to be more susceptible.
Studies from the Netherlands and France suggest that clots arise in 20–30% of critically ill COVID-19 patients. Scientists have a few plausible hypotheses to explain the phenomenon, and they are just beginning to launch studies aimed at gaining mechanistic insights. But with the death toll rising, they are also scrambling to test clot-curbing medications.
Blood clots, jelly-like clumps of cells and proteins, are the body’s mechanism to stop bleeding. Some researchers view clotting as a key feature of COVID-19. But it’s not just their presence that has scientists puzzled: it’s how they show up. “There are so many things about the presentations that are a little bit unusual,” says James O’Donnell, director of the Irish Centre for Vascular Biology at the Royal College of Surgeons in Dublin.
Blood thinners don’t reliably prevent clotting in people with COVID-19, and young people are dying of strokes caused by the blockages in the brain. And many people in hospital have drastically elevated levels of a protein fragment called D-dimer, which is generated when a clot dissolves. High levels of D-dimer seem to be a powerful predictor of mortality in hospitalized patients infected with coronavirus.
Researchers have also observed miniature clots in the body’s smallest vessels. Jeffrey Laurence, a haematologist at Weill Cornell Medicine in New York City, and his colleagues examined lung and skin samples from three people infected with COVID-19 and found that the capillaries were clogged with clots. Other groups, including a team led by O’Donnell, have reported similar findings.
“This is not what you’d expect to see in someone who just has a severe infection,” he says. “This is really very new.” This might help to explain why some people have critically low blood-oxygen readings, and why mechanical ventilation often doesn’t help. It’s a “double hit”, says O’Donnell. Pneumonia clogs the tiny sacs in the lungs with fluid or pus, and microclots restrict oxygenated blood from moving through them.
Why this clotting occurs is still a mystery. One possibility is that SARS-CoV-2 is directly attacking the endothelial cells that line the blood vessels. Endothelial cells harbour the same ACE2 receptor that the virus uses to enter lung cells. And there is evidence that endothelial cells can become infected: researchers from the University Hospital Zurich in Switzerland and Brigham and Women’s Hospital in Boston, Massachusetts, observed SARS-CoV-2 in endothelial cells inside kidney tissue6. In healthy individuals, the blood vessel is “a very smoothly lined pipe”, says Peter Liu, chief scientific officer at the University of Ottawa Heart Institute in Canada. The lining actively stops clots from forming. But viral infection can damage these cells, prompting them to churn out proteins that trigger the process.
The virus’s effects on the immune system could also affect clotting. In some people, COVID-19 prompts immune cells to release a torrent of chemical signals that ramps up inflammation, which is linked to coagulation and clotting through a variety of pathways. And the virus seems to activate the complement system, a defence mechanism that sparks clotting. Laurence’s group found that small, clogged vessels in lung and skin tissue from people with COVID-19 were studded with complement proteins. All these systems — complement, inflammation, coagulation — are interrelated, says Agnes Lee, director of the Hematology Research Program at the University of British Columbia in Vancouver, Canada. “In some patients with COVID, all of those systems are kind of in hyperdrive.”
Even as researchers begin to unravel how clotting occurs in people with COVID-19, they’re sprinting to test new therapies aimed at preventing and busting clots. Blood-thinning medications are standard of care for patients in the intensive-care unit, and those with COVID-19 are no exception. But dosing is a matter of hot debate. “The question is now, how aggressive should you be?” ,says Robert Flaumenhaft, chief of the division of haemostasis and thrombosis at Beth Israel Deaconess Medical Center in Boston. Researchers from Mount Sinai School of Medicine in New York City reported that hospitalized people with COVID-19 on mechanical ventilation who received blood thinners had a lower mortality than those who weren’t treated with them. But the team couldn’t rule out other explanations for the observation, and high doses of these drugs carry risks.