In puzzle of rare blood clots and Covid vaccines, researchers see clues

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A week after receiving the AstraZeneca Covid-19 vaccine, a 37-year-old woman in Norway went to the emergency department with fever and persistent headaches. A CAT scan of her head showed a blood clot in blood vessels involved in draining the brain, but her levels of platelets, involved in clotting, were low. She was treated with platelet infusions and a blood thinner, but had a bleed in her brain the next day. She underwent surgery to relieve the pressure on her brain but died two days later.

This is the side effect, known as cerebral venous sinus thrombosis, that has caused a week of worries around the Covid-19 vaccine developed by AstraZeneca. On Tuesday, the U.S. government said that it had seen the same effect six times among the 6.8 million people given a dose of a similar vaccine, from Johnson & Johnson, and that it recommended a pause on use of that vaccine “out of an abundance of caution,” while researchers investigated.

The news puts a spotlight on the question of whether and how these vaccines are causing this side effect.

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The woman in Norway was one of 16 patients described in two different papers in the New England Journal of Medicine that not only described cerebral venous sinus thrombosis, but also offered a partial explanation for why it might be seen in rare cases tied to the AstraZeneca vaccine. The papers likened the condition to the one doctors sometimes see in patients treated with heparin, one of the most common and potent blood thinners. There, too, patients have low platelets and blood clots.

“It’s extremely convincing,” said David Juurlink, the head of the division of Clinical Pharmacology and Toxicology at Sunnybrook Health Sciences Centre in Toronto. He was not involved with the research and, like others interviewed for this story, spoke before the U.S. recommended a pause on the J&J vaccine.

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Most tellingly, both the paper from Norway and the second paper, which looked at patients from Austria and Germany, found that blood clots were seen in people who had high levels of antibodies to platelet factor 4, the same types of antibodies reported, infrequently, after treatment with heparin. That doesn’t explain why a vaccine is causing the immune system to produce those antibodies, or whether other vaccines might do the same. But it provides a first step toward explaining the side effect, which experts say is extremely rare, and to looking into whether the same types of rare clots could occur with other shots.

“It’s now a recognized syndrome, a recognized disorder, and most importantly there is a combination of tests that can establish if a patient has this or not,” said Theodore Warkentin, a professor at McMaster University, a co-author of one of the papers and an expert on the rare clots that can be caused by heparin.

The new discovery still raises questions about what, exactly, is going on.

The challenge for public health officials is that these deadly clots occur without vaccines. It’s possible that some people who developed clots after being vaccinated would have developed them even without being vaccinated. So officials have to compare the vaccines against each other, and to try and model the normal rate of clots with low levels of platelets.

On Tuesday, Peter Marks, head of the FDA center that regulates vaccines, said on a call with reporters that there have been no cases of CVST with thrombocytopenia with the Pfizer/BioNTech and Moderna vaccines, indicating that the side effect is not occurring with those vaccines.

Earlier, the European regulators had said it was not clear that the effect existed for any vaccine other than AstraZeneca’s.

“If you look at those reports of blood clots with thrombocytopenia for those other vaccines and then compare them to the background rate we would expect to see, they are not raised,” Peter Arlett, the European Medicines Agency’s head of pharmacovigilance, said at an April 7 press conference.

He gave somewhat mismatched figures — cases of clots worldwide, along with the number of people who received vaccine only in Europe. Still, he said there were 35 cases of serious blood clots with the vaccine made by Pfizer/BioNTech among 54 million doses given; five cases with the Moderna vaccine among 4 million Europeans dosed; and three cases, later updated to four, of blood clots with low platelet counts among 4.5 million people doses — apparently worldwide — with the vaccine developed by Johnson & Johnson. That is the number the U.S. appears to have updated to six cases out of 6.8 million doses.

By contrast, he said, there were 169 cases of cerebral venous sinus thrombosis, and another 53 similar clots in a blood vessel draining the abdomen, among 34 million people.

Arlett did say that, in clinical trials of the Johnson & Johnson vaccine, there had been “an early sign” of an increase in venous thromboembolism. Two days later, the EMA said that it was investigating the clots. J&J said its investigations had found “no clear causal relationship” but that it is working closely with experts and regulators to assess the data. That early, but inconclusive, sign had also been noted by the Food and Drug Administration in its earlier review of the J&J vaccine as something to monitor.

Whatever the precise numbers, there is no question the cases of blood clotting after vaccination are extremely rare.

Speaking of the AstraZeneca vaccine, Juurlink said that for some patients the risk is outweighed by the benefits.

“‘Any port in a storm’ is a little bit trite to say, but if the only vaccine a 52-year-old who’s carrying a few extra pounds and maybe has diabetes can get is the AstraZeneca vaccine, I still think that that is the right call,” he said.

All the currently authorized vaccines in the U.S. and Europe teach the body to make antibodies to a key protein in the SARS-CoV-2 virus, which causes Covid-19. This is known as the spike protein. The AstraZeneca vaccine uses a modified version of what’s known as an adenovirus to sneak genetic material coding for the spike protein into the recipient’s cells. The cells make the spike protein, which the recipient’s immune system recognizes as foreign and learns to attack. This blocks the real SARS-CoV-2 virus.

The J&J vaccine, like the Sputnik V vaccine developed in Russia, also uses a form of adenovirus — in J&J’s case, a less common strain, Ad26, that is found in humans. (The Pfizer/BioNTech and Moderna vaccines use a different technology, known as mRNA.)

Dan Barouch, a researcher at Beth Israel Deaconess Medical Center who played a key role in the development of the J&J vaccine, said Friday that the Ad26 adenovirus used in the J&J vaccine is evolutionarily distant from the adenovirus used by AstraZeneca, even using a different cellular receptor to enter cells. Barouch described the process of looking at side effects tied to the vaccine as normal.

“We’re delighted that it’s being deployed and saving lives and it’s natural to have a lot of scrutiny for something of such relevance to the population,” Barouch said.

Still, Paul Offit, the director of the Vaccine Education Center at Children’s Hospital of Philadelphia and a veteran of discussions about vaccine safety, rattled off a list of questions even before the news about the J&J vaccine broke. Why, he asked, would a vaccine lead to the production of antibodies against platelet factor 4? He emphasized that even when the FDA authorized the vaccine, the plan had been to carefully monitor for cases of thromboses. Offit sits on a key FDA committee involved in reviewing vaccine data.

“What you really would love to know,” Offit said, “is what is causing the immune response to platelet factor 4?”

Is some part of the adenovirus mimicking platelet factor 4? If so, would that same mimicry occur with other adenoviruses? There’s no clear answer. But Offit suspects it’s a class-wide problem, meaning the same phenomenon associated with AstraZeneca’s vaccine is associated with Johnson & Johnson’s.

“There is going to be something about the adenovirus — whether it’s adenoviral DNA or an adenovirus protein — that complexes with platelet factor 4. So that will be determined, I suspect soon.”

Warkentin, the expert on heparin-induced thrombocytopenia, said that free DNA — that is, DNA not contained in the virus — could, if it were to be exposed to platelet factor 4, itself trigger the immune system to create antibodies against platelet factor 4. It’s not clear how that risk would differ between vaccines.

While researchers try to figure out the biology behind the blood clots, doctors and people who need vaccines are left to balance the risks and benefits of the AstraZeneca and Johnson & Johnson vaccines with incomplete information.

While that might seem troubling, it’s also common, and, perhaps, the central quandary in medicine.

Juurlink, the drug safety researcher, points out that people commonly take sleeping pills without much thought to whether they would develop dependence, be sleepy the next day, or sleepwalk. Nor do they think about the risks, he said, when taking a common painkiller such as ibuprofen or naproxen. But he says he occasionally sees people with drug-induced meningitis or the skin disorder Stevens-Johnson syndrome.

“No one even thinks about this,” Juurlink said. “They want their pain gone, they take something they can get without having to interact with a doctor or let alone a health professional. And people sometimes die over this.”

Those drugs may also increase the risk of heart attack and stroke somewhat. Juurlink says his mother takes one of these drugs, known as an NSAID, for rheumatoid arthritis. He said if she were to have a heart attack, he will “always wonder” if the drug played a role. “But she accepts that risk and so do I.”

Offit points out that this calculus has always played a role in the use of vaccines. The oral polio vaccine, which has helped eliminate the virus in the U.S., in rare cases causes polio. For decades, that was considered acceptable, even when the only cases of polio in the U.S. were from the vaccine, because there were cases elsewhere in the world. Now, a different vaccine, an injection that can’t ever cause the virus, is used.

In the 1998, the drugmaker Wyeth introduced a vaccine against rotavirus, a disease that causes childhood diarrhea. But the vaccine caused an unacceptable side effect: a condition called intussusception, in which the intestine telescopes in on itself and becomes blocked. Even in the U.S., where rotavirus killed only about 60 children a year, the vaccine would have saved lives overall. But the risk was unacceptable and the vaccine was withdrawn. Offit helped develop one of two newer vaccines that increased the risk of intussusception less — and are still in use today. The vaccines save tens of thousands of lives globally every year.

When it comes to the Covid vaccines, regulators in the U.K and some other countries have made this calculus in public, saying that people under 30, who are at lower risk from Covid-19 complications, should receive the Pfizer/BioNTech or Moderna vaccines, but that the AstraZeneca vaccine is a good choice for older people, who are at much higher risk from the virus.

The AstraZeneca vaccine has been a key part of the U.K.’s apparently successful vaccine campaign. Still, many experts in the U.S., where the AstraZeneca vaccine has yet to be authorized, express a sense of regret about the vaccine, which also showed disappointing results in a clinical trial testing it against the tougher-to-prevent variant in South Africa.

“We’ve always hoped it was going to be the AZ vaccine that was going to vaccinate the world,” said Ashish Jha, the dean at the Brown School of Public Health. “It’s just feeling like it’s going to be hard.” He says he worries the vaccine may be “not as great as many of the others.” Still, he has family in India, where the vaccine is offered, and he has in the past told them to get it if they can.

“This virus is everywhere and we’re only going to be as safe as the weakest country out there,” said Offit. “So we need a worldwide vaccine. AstraZeneca committed to that. So you hate to see them stumble.”

Helen Branswell contributed reporting.





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