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A man receives a dose of AstraZeneca’s COVID-19 vaccine at a conference center in Rome on 24 March. Italy halted use of the vaccine on 15 March but resumed immunizations four days later. ANTONIO MASIELLO\/GETTY IMAGES<\/p><\/div>\n
A rare clotting disorder may cloud the world’s hopes for AstraZeneca’s COVID-19 vaccine<\/h1>\n
By Kai Kupferschmidt, Gretchen Vogel
\nSciencemag<\/p>\n
In the tumultuous rollout of AstraZeneca’s COVID-19 vaccine, all eyes were on the United States this week, where the company had a\u00a0highly public communication breakdown<\/a>\u00a0over the vaccine’s efficacy with an expert panel overseeing a large study in the Americas. But on the other side of the Atlantic, 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.<\/p>\n Many European countries\u00a0suspended use of AstraZeneca\u2019s vaccine earlier this month<\/a>\u00a0following initial reports of the symptoms, which have led to at least 15 deaths. Most resumed vaccinations after the European Medicines Agency (EMA)\u00a0recommended doing so<\/a> on 18 March, saying the benefits of the vaccine outweigh any risks. EMA is continuing to investigate the matter and will convene a wideranging committee of experts on 29 March.<\/p>\n Now, a group of researchers led by German clotting specialist Andreas Greinacher of the University of Greifswald says the highly unusual combination of symptoms\u2014widespread blood clots and a low platelet count, sometimes with bleeding\u2014resembles a rare side effect of the blood thinner heparin, called heparin-induced thrombocytopenia (HIT).<\/p>\n 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. \u201cWe know what to do: how to diagnose it, and how to treat it,\u201d says Greinacher, who calls the syndrome vaccine-induced prothrombotic immune thrombocytopenia, or VIPIT. Greinacher says he has submitted a manuscript to the preprint server Research Square.<\/p>\n Even if Greinacher\u2019s mechanism isn\u2019t the whole story, multiple researchers told\u00a0Science<\/em>\u00a0they were convinced that 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\u2019s 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.<\/p>\n 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, but 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.<\/p>\n 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 5 cases\u2014despite administering 11 million doses of the AstraZeneca vaccine\u2014but the British Society of Haematology has\u00a0urged its members<\/a>\u00a0to be aware of \u201can important and emerging area of haemostasis and thrombosis practice\u201d 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.<\/p>\n It is not yet clear how the vaccine could trigger VIPIT, and not everyone thinks the case is closed. \u201cIt\u2019s intriguing, but I am not entirely convinced,\u201d 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\u2019s clinical trials.<\/p>\n \u201cPeople are absolutely working like crazy behind the scenes to provide more clarity,\u201d says Saskia Middeldorp, a vascular internist at Radboud University Medical Center in the Netherlands, who disagreed with the temporary halt of the vaccine because she says the benefits clearly outweigh the risks.<\/p>\n The VIPIT story began on 27 February, when Sabine Eichinger, a hematologist at Medical University 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\u2019s hospital. She had a low platelet count and computed tomography scans found thromboses\u2014blood clots\u2014in the veins in her abdomen and later in arteries as well. \u201cThere was little we could do at this stage,\u201d says Eichinger. The patient died the next day.<\/p>\n The combination of low platelet count, or thrombocytopenia, and clots kept Eichinger thinking, however. \u201cIt\u2019s very striking,\u201d she says. Platelets, also known as thrombocytes, help to form blood clots, so low levels usually lead to bleeding, not clotting. \u201cYou would think that low platelets and thromboses are opposites really.\u201d 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, \u201cbut she had none of these things,\u201d Eichinger says.<\/p>\n 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. \u201cI thought maybe this is some kind of immune reaction,” Eichinger says.<\/p>\n She reached out to Greinacher, who had studied HIT for decades. \u201cThen things started happening thick and fast,\u201d she says, as multiple countries responded to reports of clotting by suspending use of the AstraZeneca vaccine.<\/p>\n 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, if they had seen any cases. They had. PEI recommended that 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.<\/p>\n People are absolutely working like crazy behind the scenes to provide more clarity.<\/p>\nA ‘very striking’ disorder<\/h2>\n