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A man receives a dose of AstraZenecas COVID-19 vaccine at a conference center in Rome on 24 March. Italy halted use of the vaccine on 15 March, but resumed immunizations 4 days later.

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A rare clotting disorder may cloud the world’s hopes for AstraZeneca’s COVID-19 vaccine

Science’s COVID-19 reporting is supported by the Heising-Simons Foundation.

In the tumultuous rollout of AstraZeneca’s COVID-19 vaccine, all eyes this week were on the United States, where the company had a highly public communication breakdown over the vaccine’s efficacy with an expert panel overseeing a large study in the Americas. But on the other side of the Atlantic Ocean, the vaccine faces new concerns about safety as an explanation gains ground for the unusual strokes and clotting disorders recorded in at least 30 recipients.

Many European countries suspended use of AstraZeneca’s vaccine earlier this month following initial reports of the symptoms, which have led to at least 15 deaths. Most resumed vaccinations after the European Medicines Agency (EMA) recommended doing so on 18 March, saying the benefits of the vaccine outweigh any risks. EMA is continuing to investigate the matter and will convene a wide-ranging committee of experts on 29 March.

Now, a group of researchers led by German clotting specialist Andreas Greinacher of the University of Greifswald says the highly unusual combination of symptoms—widespread blood clots and a low platelet count, sometimes with bleeding—resembles a rare side effect of the blood thinner heparin called heparin-induced thrombocytopenia (HIT).

The scientists, who first described their findings during a 19 March press conference, recommend a way to test for and treat the disorder and say this can help ease worries about the vaccine. “We know what to do: how to diagnose it, and how to treat it,” says Greinacher, who calls the syndrome vaccine-induced prothrombotic immune thrombocytopenia (VIPIT). Greinacher has posted a manuscript on the preprint server Research Square.

Even if Greinacher’s mechanism isn’t the whole story, multiple researchers told Science they were convinced the vaccine was causing the rare set of symptoms. If that turns out to be true, it could have major consequences for the vaccine, which is one of the cornerstones of the World Health Organization’s push to immunize the world. AstraZeneca is working with partners around the globe to make and distribute billions of doses in low- and middle-income countries, which might have a harder time identifying and treating rare side effects.

Europe is relying heavily on the vaccine as well; the European Union bought 400 million doses. The company’s failure to deliver on time has delayed vaccine rollouts on the continent, and now dented confidence is exacerbating the delays. And even if the risk is very low, it may make sense to use the vaccine only in those who also stand to gain the most from it: elderly people at high risk of dying from COVID-19. Several European countries have started to do this. The situation has scientists walking a tightrope: They want to make the medical profession aware of their concerns without sowing panic.

But Greinacher’s hypothesis is being taken seriously. Two German medical societies put out press releases lauding him for solving the issue. In the Netherlands, the Dutch Internal Medicine Society urged internists to be aware of the symptoms and the recommended course of action. The United Kingdom has officially reported only five cases—despite administering 11 million doses of the AstraZeneca vaccine—but the British Society for Haematology has urged its members to be aware of “an important and emerging area of haemostasis and thrombosis practice” and to report any possible cases. The Australian Technical Advisory Group on Immunisation has recommended against giving any COVID-19 vaccine to people with a history of HIT.

It is not yet clear how the vaccine could trigger VIPIT, and not everyone thinks the case is closed. “It’s intriguing, but I am not entirely convinced,” says Robert Brodsky, a hematologist at Johns Hopkins University. AstraZeneca, meanwhile, has not directly responded to the reports of the rare constellation of symptoms except to say that they did not appear in any of the company’s clinical trials.

“People are absolutely working like crazy behind the scenes to provide more clarity,” says Saskia Middeldorp, a vascular internist at Radboud University Medical Center, who disagreed with the temporary halt of the vaccine because she says the benefits clearly outweigh the risks.

A “very striking” disorder

The VIPIT story began on 27 February, when Sabine Eichinger, a hematologist at the Medical University of Vienna, was confronted with an unusual patient. A 49-year-old nurse had sought help at a local hospital the day before, suffering from nausea and stomach discomfort, and was transferred to Eichinger’s hospital. She had a low platelet count and computed tomography scans found thromboses—blood clots—in the veins in her abdomen and later in arteries as well. “There was little we could do at this stage,” Eichinger says. The patient died the next day.

The combination of low platelet count, or thrombocytopenia, and clots kept Eichinger thinking, however. “It’s very striking,” she says. Platelets, also known as thrombocytes, help form blood clots, so low levels usually lead to bleeding, not clotting. “You would think that low platelets and thromboses are opposites really.” One condition where they occur together is called disseminated intravascular coagulation, when severe infection, injury, or cancer trigger clotting so widespread it uses up all the platelets, “but she had none of these things,” Eichinger says.

The unusual combination also appears in HIT, which can occur in patients given heparin as a drug. Heparin binds to a protein called platelet factor 4 (PF4), forming a complex. For reasons that aren’t understood, some people produce antibodies against the complex, setting off an out-of-control clotting reaction. Eichinger’s patient had not received heparin, but she had gotten a shot of the AstraZeneca vaccine 5 days before her symptoms began. “I thought maybe this is some kind of immune reaction,” Eichinger says.

She reached out to Greinacher, who had studied HIT for decades. “Then things started happening thick and fast,” she says, as multiple countries responded to reports of clotting by suspending use of the AstraZeneca vaccine.

Greinacher says he contacted other colleagues who had studied HIT in Canada and Germany and asked the Paul Ehrlich Institute (PEI), which oversees vaccine safety in Germany, whether they had seen any cases. They had. PEI recommended Germany pause use of the vaccine as well and asked Greinacher to help investigate. He soon received blood samples from eight additional patients. All had both low platelets and unusual clotting, he says. In four samples, the researchers also found evidence for antibodies against PF4, a hallmark of HIT. He and his colleagues are now checking whether other vaccine recipients and former COVID-19 patients have similar antibodies.

People are absolutely working like crazy behind the scenes to provide more clarity.

Saskia Middeldorp, Radboud University Medical Center

Brodsky says it isn’t clear whether VIPIT explains all of the cases. He agrees that the PF4 antibodies and the clotting seen in patients resemble HIT, but the link has not been proved, he says: “I’m convinced that these patients have platelet factor 4 antibodies, at least four of them. But I’m not convinced that those … antibodies are explaining the thrombocytopenia or the clotting.”

Treatable condition

Greinacher agrees on the need for more data. But he says it’s crucial to alert doctors to the potential complication. When recognized in time, HIT can be treated with immunoglobulins—nonspecific antibodies from blood donors—that help put the brakes on platelet activation. Nonheparin blood thinners can help dissolve the clots. VIPIT should be treated in a similar way, he says. In at least one case, Greinacher says, a doctor sought the group’s advice and the patient recovered. The German Society for the Study of Thrombosis and Hemostasis, of which Greinacher is a member, has issued a set of recommendations for diagnosing and treating VIPIT. Greinacher says he has also been in touch with safety representatives at AstraZeneca.

Nigel Key, a hematologist at the University of North Carolina, Chapel Hill, agrees on the need to alert doctors. “Maybe it is too much to expect at this point that there would be a very detailed molecular mechanism,” he says, but the advice to physicians who may encounter patients is crucial.

Brodsky and Key say the cases are striking enough that they probably represent a real side effect. “I think the vaccine is mostly safe. I think the benefits probably outweigh the risk for a general population,” Brodsky says. “But these cases raise concern that this vaccine is potentially life-threatening in a small subset of patients.”

Scientists are now scrambling to understand how big that subset is and who’s in it. So far, most cases have been observed in women under age 65. But that could be because of the vaccinated population: Many countries initially used AstraZeneca only in people younger than 65 because early clinical trials included few older recipients. That meant the vaccine was used in priority groups such as health care workers and teachers, a majority of whom are women. In Norway, for example, 78% of the AstraZeneca doses went to women, says Sara Viksmoen Watle, chief physician at the Norway Institute of Public Health. The United Kingdom, however, used the vaccine first in older people, which may explain why fewer unusual clotting events have been spotted there.

Data from Norway—whose extensive health registries make this type of research easier—suggest previous COVID-19 infection does not predispose vaccinees to a severe reaction, Watle says. Alerting clinicians will help ensure that fewer cases are missed for analysis, Key says. A global database of cases may be helpful, too.

Many countries are, for now, accepting the risk that the AstraZeneca vaccine may carry, but several have restricted its use to people who are at the highest risk of dying from COVID-19: those ages 55 or older in France, 65 or older in Sweden and Finland, and 70 or older in Iceland. That approach makes sense, says Sandra Ciesek, a virologist at Goethe University, Frankfurt. “The argument I keep hearing is that the risk-benefit ratio is still positive. But we do not have just one vaccine, we have several. So, restricting the AstraZeneca vaccine to older people makes sense to me, and it does not waste any doses.”

Denmark and Norway are waiting for more data. Norway, which has administered the AstraZeneca vaccine to 130,000 people under age 65, has reported five patients who had low platelets, hemorrhage, and widespread thromboses, three of whom died. That’s about one case in 25,000 vaccinees, “a high number with a very critical outcome in previously healthy, young individuals,” Watle says. The country hopes to make a decision on the vaccine within 3 weeks. It can afford to hold off: COVID-19 cases are relatively low and AstraZeneca is delivering so few doses that the extended pause won’t make a big difference in the short term.

Middeldorp says she expects more clarity after Monday’s meeting of EMA’s expert group, which includes clotting experts, neurologists, virologists, immunologists, and epidemiologists. The agency says it will issue an update on the vaccine during the next meeting of its safety committee, being held from 6 to 9 April. Ideally, that meeting will help clarify how frequently the condition occurs and whether the risk varies by age or sex, Middeldorp says. The world needs AstraZeneca’s vaccine, she says—but that means it is crucial to fully understand its benefits and its risks.

*Update, 29 March, 4:45 a.m.: A link to Greinacher’s preprint was added to this story after Research Square had posted the preprint.