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Blood clots continue to wreak havoc on patients with severe COVID-19 infection, and a new study explains what can cause them in about half of patients.
The culprit: An autoimmune antibody that circulates in the blood, attacks cells and causes blood clots to form in microscopic arteries, veins and vessels. Blood clots can cause life-threatening events such as stroke. In COVID-19, microscopic clots can restrict blood flow in the lungs and impair oxygen exchange.
Outside of a new coronavirus infection, these clot-causing antibodies typically appear in patients with antiphospholipid syndrome, the autoimmune disease. The link between autoantibodies and COVID-19 was unexpected, says co-author Yogen Kanthi, MD, assistant professor at the Frankel Cardiovascular Center of Michigan Medicine and Lasker Investigator at the National Heart, Lung, and Blood Institute of the National Institutes of Health.
“In patients with COVID-19, we continue to see a relentless, self-reinforcing cycle of inflammation and clots in the body,” says Kanthi. “We are now learning that autoantibodies can be a culprit in this cycle and inflammatory cycle that makes people who have already had problems even sicker.”
“Some of the worst clots we’ve ever seen”
Corresponding author Jason Knight, MD, Ph.D., a rheumatologist with Michigan Medicine, has been studying antibodies to antiphospholipid syndrome in the general population for years.
“Half of the hospitalized patients with COVID-19 were positive for at least one of the autoantibodies, which was a real surprise,” said Knight, also associate professor of internal medicine and the leading expert on autoantibody-induced diseases.
In the new publication Science Translational Medicine, they found that about half of the very sick COVID-19 patients had a combination of high concentrations of both the dangerous antibodies and super-activated neutrophils, which are destructive and explosive white blood cells. In April, the team first reported that patients hospitalized for severe COVID-19 had higher levels of extracellular neutrophil traps in their blood.
To learn more, they worked together to study explosive neutrophils and COVID-19 antibodies in mouse models to see if this could be the dangerous combination behind the clots.
“Antibodies from patients with active COVID-19 infection caused a significant amount of clotting in animals, some of the worst clots we’ve ever seen,” says Kanthi. “We have discovered a new mechanism by which patients with COVID-19 can develop blood clots.”
Attacking COVID-19 blood clots from all angles
The researchers say these findings are not yet ready for clinical practice, but they offer a new perspective for robust research on thrombosis and inflammation in COVID-19 patients.
Kanthi, Knight, first author Yu (Ray) Zuo, MD, and colleagues would like to know whether critically ill patients with high levels of these antibodies would perform better if the antibodies were blocked or removed.
If so, it could justify aggressive treatment like plasmapheresis, which is commonly used for severe autoimmune diseases, explains Zuo. The blood is drained through an infusion, filtered and replaced with fresh plasma that does not contain the antibodies associated with blood clots.
“We know that people with the highest levels of autoantibodies had poorer respiratory function and that the antibodies also caused inflammation in healthy cells,” says Zuo, assistant professor of internal medicine and rheumatologist at Michigan Medicine.
“We still don’t know what causes the body to make these antibodies. So the next step would be to do more research to identify antibody triggers and targets, ”Knight added.
Furthermore, these findings raise new questions related to the use of convalescent plasma as a potential COVID-19 treatment. However, the team believes more research is needed to investigate this issue.
“We are now studying how long these antibodies remain in circulation after recovery from the novel coronavirus,” says Knight.
The researchers are also conducting a randomized clinical trial called DICER that is testing a well-known anticoagulant, dipyridamole, in patients with COVID-19 to see if it is more effective than a placebo at reducing excessive blood clots.
“Dipyridamole is a safe, inexpensive, and scalable old drug,” says Kanthi. “The FDA approved it 20 years ago to prevent clotting. However, we have only recently discovered that it can block this specific type of inflammation that occurs with COVID. “
Reference: “Prothrombotic autoantibodies in serum of hospitalized patients with COVID-19” by Yu Zuo, Shanea K. Estes, Ramadan A. Ali, Alex A. Gandhi, Srilakshmi Yalavarthi, Hui Shi, Gautam Sule, Kelsey Gockman, Jacqueline A Madison Melanie Zuo, Vinita Yadav, Jintao Wang, Wrenn Woodard, Sean P. Lezak, Njira L. Lugogo, Stephanie A. Smith,
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