In the early days of the New York Covid-19 outbreak, which ran from March to April, hematologist Jeffrey Laurence was called to consult on the case of a 32-year-old bodybuilder. Nurses had noticed a strange rash on his buttocks, “as if you were painting the skin layer kind of and saw what blood fats look like on his bottom,” recalls Laurence, who works at Weill Cornell Medicine in New York City. The vessels were so clearly sketched because the blood inside coagulated, almost jelly-like.
Within a few weeks, Laurence observed several similar, striking cases – made some of the first observations that the blood clotting process in Covid-19 severe cases could go horribly wrong. Researchers and clients are working to understand why, and are trying medications to suppress the clotting or the intense immune reactions it seems. Ongoing clinical trials may help to provide clearer guidelines in the future, but with so much about this virus still unknown, they now need to advise on best treatments and doses.
Coagulation is usually in good condition. When a blood vessel is damaged, cell fragments called platelets flow to stop the leak. Proteins in the blood called clotting factors range from dormant to active states in a chain reaction, building a fibrous mesh. “It’s a kind of domino effect,” says Hanny Al-Samkari, a hematologist at Massachusetts General Hospital in Boston.
Clotting in non-injured blood vessels is a common occurrence in hospital patients, especially those in the intensive care unit. Bed slides stimulate clotting, especially in the legs and pelvis, and the clots can migrate to the lungs where they hinder the organs’ ability to load blood with oxygen. Depending on their location, clumps can lead to problems such as breathing, heart attack, stroke and death.
Inflammation due to infection can also tip those clotting factor dominoes. However, when Covid-19 patients filled hospital wards, it was found that their clotting was more frequent, widespread, and more serious than in other infections. The clots filled with needles used to draw blood, like the snake that patients connected to medicine drips and machines. “Everything is fine,” Al-Samkari said.
This image shows a skin rash on the arm of a Covid-19 patient. Tissue biopsies showed the presence of lumps in small veins (b), as well as the presence of complement proteins in the skin and small blood vessels (c, d, e).
CREDIT: C. MAGRO ET AL / TRANSLATIONAL INVESTIGATION 2020
The consequences can be devastating. In a July report in the magazine Blood, Al-Samkari and colleagues found that nearly 10 percent of 400 people developed hospitalization for Covid-19 clots. In a February report by researchers in China, about 70 percent of the people who died from Covid-19 had widespread clotting, while a few survivors did so. And in a July article in the New England Journal of Medicine, autopsies revealed that the lungs of people who died of Covid-19 were nine times as likely to be speckled with small lumps as those of people who died of flu. Major risk factors for severe Covid-19 – such as diabetes, obesity and advanced age – are linked to worn-out blood vessels that make clotting more likely, says John Atkinson, an immunologist and rheumatologist at Washington University School of Medicine in St. Louis. ,
What Laurence rightly finds “spooky” is that all this clotting happens despite the common American practice of prescribing blood thinners, such as heparin, to hospital patients to prevent clotting.
Little blood
Why does clotting go overboard in some people with Covid-19? Theories abound. One possibility, Al-Samkari speculates, is that the virus activates one of the clotting factors and jumps the domino effect – but there is no specific evidence that this happens.
Another idea is that because SARS-CoV-2 infects and damages the cells that secrete blood fats, it can expose the tissue underneath. That tissue makes proteins that promote clotting and normally perform a vital function, says Al-Samkari: When blood fats become damaged, the egg proteins enter the bloodstream and stimulate clotting to stop any leakage.
A third possibility is that clotting results from inflammation. And here many experts see a set of egg whites called the complement system. These egg whites, collectively known as complement, attack invaders and invoke other parts of the immune system to help. They can also activate platelets and promote clotting.
Like the coagulation cascade, the complement proteins of the complement system are activated in sequence, and scientists now know that SARS-CoV-2 can activate one of them directly, Laurence says. This can damage damaged body tissues, which build up during the attack of the virus.
Clinicians have observed that the complement cascade seems to affect many people with severe Covid-19, says immunologist and complement expert Claudia Kemper of the National Heart, Lung, and Blood Institute, who co-authored an article on complement and immune cells in the Annual review of immunology. She and her colleagues found signs of complement activity in the lungs and livers of people who died of Covid-19, for example, and Laurence found several active complement proteins in the skin and blood vessels of his early Covid-19 coagulation cases. “There is currently no super-super-hard evidence, but many complementologists think this is a massive part of the disease,” says Kemper.
A series of proteins activate each other step by step to form a blood clot. External trauma to the blood vessel activates clotting through the faster extrinsic pathway, while the slower intrinsic pathway occurs when there are problems within the fascial system.
In another study of 11,000 people who had Covid-19, which was posted online prior to review by other scientists, a New York team found that patients were more likely to get very sick and die if they had a history of clotting or bleeding had, or if they had macular degeneration, may indicate some additional problems. The team also found that genes involved in supplementation and clotting reactions were active when the virus was present in patients’ nasal swabs.
Not only that, but the researchers also report that people with certain variants of genes involved in the complement and clotting systems were at higher risk for serious Covid-19 disease.
In addition to complement, another immune element can promote clotting in severe Covid-19 cases: an overreaction called a cytokine storm, in which the body releases an excess of inflammation-promoting cytokine molecules. “Your whole system is being redesigned,” Atkinson says. “If it is repaired, your clotting system will be adjusted because it feels dangerous.”
Triple threat
When treating their Covid-19 patients, physicians try to apply the inhibitor to this clotting, complement and cytokine effects. “What you’re trying to do is calm the trigger,” says Atkinson, who has an overview of abnormal complement control in macular degeneration and a childhood disorder for the Annual review of pathology: mechanisms of disease.
Early in the course of infection, it triggers the virus itself, so doctors are taking antiviral drugs such as inhibitor. But later, says Laurence, the body’s response is the biggest problem. “The virus, you might as well forget it,” he says. “You have to check the coagulation, you have to check the inflammation, you have to check the complement path – and that’s easier said than done.”
For clotting there are blood thinners like heparin. Hematologists are debating how much to use for Covid-19 patients, says Al-Samkari, because doctors need to balance the risk of clotting with the risk of bleeding. Al-Samkari has often observed bleeding in the digestive system for these patients, but they can also find bleeding in the lungs, brain or places where medical devices break through the skin.
Many hospitals are dismissing Covid-19 patients with a prescription for blood thinners in case the risk of clotting at home remains high, although there is currently no solid data to back up this practice, Al-Samkari says. More than a dozen clinical trials aim to identify the right course of action to manage clotting in addition to Covid-19.
Al-Samkari stresses that there is no evidence that people with less serious Covid-19, who do not need hospitalization, need to take blood thinners or aspirin to prevent clots.
For some patients, suffocating inflammation may help. Steroids such as dexamethasone calm the immune system, and other drugs specifically block cytokines as individual proteins in the clot and complement cascades. Argatroban, for example, is an anticoagulant approved by the Food and Drug Administration that interferes with thrombin, an element of the coagulation cascade. And eculizumab, which blocks one of the complement proteins, is approved for certain inflammatory conditions.
Once again, doctors are waiting for better supervision of trials. “Right now,” says Al-Samkari, “we use clinical judgment as best we can, and just do our best.”
