Blood clots linked to AZ vaccine stem from rare antibody reaction

New research has identified unusual antibodies that appear to have caused, in rare cases, serious and sometimes fatal blood clots in people who received the Covid vaccine made by AstraZeneca.

The vaccine has been a mainstay of inoculation programs in more than 100 countries. Exactly why the rare reactions to the vaccine occurred is still a mystery.

Scientific teams from Germany and Norway found that people who developed the clots after vaccination had produced antibodies that activated their platelets, a blood component involved in clotting. The new reports add extensive details to what the researchers have already stated publicly about the blood disorder.

Younger people appear more susceptible than older ones, but researchers say no pre-existing health conditions are known to predispose people to the rare reaction. That is worrisome, they say, because there is no way to tell if an individual is at high risk.

Reports of the clots have already led a number of countries to limit AstraZeneca’s vaccine to older people, or to stop using it entirely. These cases have dealt a crushing blow to global efforts to halt the pandemic, because the AstraZeneca shot — easy to store and relatively cheap — has been a mainstay of vaccination programs in more than 100 countries.

The European Medicines Agency, the regulator for the European Union, has emphasized repeatedly that the clotting disorder is rare, and that the vaccine’s benefits far outweigh its risks. But when a side effect has the potential to be devastating or fatal — like the blood clots in the brain linked to this vaccine — some regulators and segments of the public are finding that the risk is unacceptable, even if it is extremely rare.

As of Sunday, European regulators had received reports of 222 cases of the rare blood-clotting problem in Britain and the 30-nation European Economic Area (the European Union plus Iceland, Norway and Liechtenstein).

They said that about 34 million people had received the AstraZeneca vaccine in those countries, and that the clotting problems were appearing at a rate of about one in 100,000 recipients.

European regulators said that as of March 22, they had carried out detailed reviews of 86 cases, 18 of which had been fatal.

The safety bar for vaccines is set high because they are given to healthy people. The seemingly greater vulnerability of younger people to the clotting disorder is of particular concern, because their risk of severe illness from Covid itself is lower than that in older people.

Those differences suggest that overall, compared to older people, younger people may have less to gain and more to lose from the AstraZeneca vaccine.

Germany, the Netherlands, the Philippines, Portugal, and Spain have recommended that the AstraZeneca vaccine be given only to people over 60.

Canada and France have limited it to those over 55; Australia, over 50; Belgium, over 56. Britain, where the vaccine was developed, has been its staunchest defender, but announced on Wednesday that it would begin offering alternative shots to people under 30.

The University of Oxford, which developed the vaccine with AstraZeneca, said on Tuesday that it had suspended a two-month-old trial of the vaccine in children and teenagers in Britain while it waits for regulatory guidance.

Cameroon, the Democratic Republic of Congo, Denmark, and Norway have stopped using the vaccine.

Full vaccination with the AstraZeneca vaccine requires two doses, but regulators in France and Germany have recommended that people under 55 who have had one dose get a different vaccine for their second shot.

The AstraZeneca vaccine is not authorized for use in the United States, but the company has said it plans to apply to the Food and Drug Administration for permission for emergency use. The agency declined on Friday to comment on the rare clotting disorder.

On Wednesday, the European Medicines Agency said that the vaccine’s labelling should be revised to include listing the clotting disorder as a “very rare” side effect of the vaccine.

In a statement on its website, AstraZeneca said it was “actively collaborating with the regulators to implement these changes to the product information and is already working to understand the individual cases, epidemiology and possible mechanisms that could explain these extremely rare events.”

The two new studies were published by The New England Journal of Medicine. One from Germany described 11 patients, including nine women ages 22 to 49. From five to 16 days after vaccination, they were found to have one or more clots. Nine had cerebral venous thrombosis, a clot blocking a vein that drains blood from the brain. Some had clots in their lungs, abdomen, or other areas. Six of the 11 died, one from a brain haemorrhage.

Although most of the patients were female, it is not known whether women are more vulnerable than men. Many health care workers in Germany are women, and they were among the first to be vaccinated.

One patient had pre-existing conditions that affected clotting. During a news briefing on Friday, Dr. Andreas Greinacher, an author of the report, said those conditions most likely played only a minor role in the reaction that occurred after vaccination.

He also said it was a “likely possibility” that the people who developed the clotting disorder had some rare, unknown biological traits — what he called “individual co-factors” — that predisposed their immune systems to make powerful, misdirected antibodies in response to the vaccine. He called that “good news” for the general population, who do not have the co-factors.

There is “clear evidence” that the AstraZeneca vaccine in rare cases leads the body to make antibodies that activate platelets, and that those antibodies are causing blood clots, Dr. Greinacher said.

But, he added: “We have no way to predict who will develop these antibodies.”

So far, his laboratory has identified only about 40 cases of 1.4 million people in Germany who have received the vaccine. If the vaccine alone were causing the problem, without individual co-factors, there would be many, many more cases, Dr. Greinacher said.

He called the deaths in young people “tragic,” but noted that the numbers were small. “Not vaccinating will bring many, many more people with severe complications than vaccination,” Dr. Greinacher warned.

All of the first 11 patients in his study, as well as 17 others with clots after vaccination whose blood was tested, had the antibodies known to activate platelets.

The antibodies led to a condition called thrombotic thrombocytopenia, which caused both clotting and abnormal bleeding. The researchers suggested naming the newly identified version in these patients “vaccine-induced immune thrombotic thrombocytopenia,” or VITT.

Various theories have been offered by scientists as to what touches off the immune reaction. The AstraZeneca vaccine employs a chimpanzee adenovirus to carry DNA into recipients to spark an immune response against the coronavirus.

Laboratory studies have suggested that the chimp virus or the DNA might cause the problem. Some researchers have suggested that bleeding from the injection, mixed with the vaccine, might put platelets in the crosshairs of the immune system.

Dr. Greinacher called the theories plausible but unproven.

The article described specialized blood tests that can be used to diagnose the disorder, and distinguish it from other, more common clotting problems not related to the vaccine. The research team suggested treatment with a blood product called intravenous immune globulin, which is used to treat various immune disorders. Dr. Greinacher likened the treatment to putting out a fire.

Drugs called anti-coagulants, or blood thinners, can also be administered. But the researchers recommended against prescribing a commonly used one, heparin — because the vaccine-related condition is very similar to a severe reaction that occurs, rarely, in people given heparin.

The second report, from Norway, described five patients, one male and four female health care workers ages 32 to 54, who had clots and bleeding from seven to 10 days after receiving the AstraZeneca vaccine. Four had severe clots in the brain, and three died. Severe headaches were among their early symptoms. Like the German patients, all had high levels of antibodies that could activate platelets.

The team from Norway also recommended treatment with intravenous immune globulin. The researchers said the disorder was rare, but “a new phenomenon with devastating effects for otherwise healthy young adults,” and they suggested that it may be more common than previous studies of the AstraZeneca vaccine had indicated.

On Friday, European regulators also said they were reviewing reports of a few blood clot cases that occurred in people who had received the Johnson and Johnson vaccine.

In the United States, federal agencies are investigating reports of a different type of unusual blood disorder involving a precipitous drop in platelets that emerged in a few dozen people who had received either the Pfizer-BioNTech or Moderna vaccines.

The New York Times