Researchers in Germany, Norway and Austria have put forward a hypothesis for why in some very rare cases the coronavirus vaccine developed by AstraZeneca and the University of Oxford seems to trigger an abnormal and potentially life-threatening combination of blood clotting and low platelet counts.
The apparent side effect has been documented in a little more than 220 people among the more than 34 million vaccinated with the shot in Europe and the U.K. through April 4. On Wednesday, the European Medicines Agency confirmed a possible link to the vaccine and asked AstraZeneca to conduct more tests. The regulator reiterated the benefits of immunization outweigh the risks, noting the side effect's extreme rarity as well as the risks of COVID-19 from which the vaccine protects.
But the safety concerns have already imperiled rollout of the vaccine in Europe, where many countries temporarily halted use as reports began to emerge last month. Several have kept vaccinations on pause. Government health advisers in the U.K. have recommended other vaccines be used in healthy adults under 30, for whom the benefit-risk balance to AstraZeneca's shot is less favorable. And in France and Germany, regulators have taken the unusual step of instructing younger people who previously received the first dose to follow up with a second dose of another vaccine.
With COVID-19 cases rising and vaccinations in Europe behind schedule, scientists have raced to understand the side effect and its cause. Two studies published Friday in The New England Journal of Medicine give a better sense of both.
The two research teams, each studying separate groups of patients, zeroed on a similar answer: They both suggest the development of serious blood clots alongside falling levels of platelets — the sticky cells that promote clotting — resembles a well-known autoimmune condition that's sometimes triggered in people taking the blood thinner heparin.
The EMA, in its Wednesday statement, called this hypothesis "plausible," although it did not detail the evidence that's been gathered in support.
One group, led by Andreas Greinacher and Thomas Thiele of the University of Griefswald in Germany, studied 11 patients in Germany and Austria who had clotting and low platelets between five to 16 days after vaccination. In nine, the clotting occurred in the veins that drain blood from the brain, and five had evidence of "disseminated" clotting throughout their body's veins. Six later died.
All 11, as well as another 17 other patients for whom the researchers had blood samples, tested positive for antibodies against a type of protein cluster that contains what's known as platelet factor 4, or PF4. These antibodies are also observed in people who develop heparin-induced thrombocytopenia following treatment with the anticoagulant.
But none of the patients had received heparin as a medication before vaccination, raising the question of whether AstraZeneca's vaccine triggered the reaction somehow.
"Whether these antibodies are autoantibodies against PF4 induced by the strong inflammatory stimulus of vaccination or antibodies induced by the vaccine that cross-react with PF4 and platelets requires further study," Greinacher and colleagues wrote. Their research was previously available as a preprint.
Meanwhile, researchers in Norway, studying five healthcare workers between 32 and 54 years old, observed a similar pattern.
All workers had high levels of antibodies against PF4 protein complexes, but none had previously received heparin. Three died, including one 42 year old woman, who checked into the emergency room after having headaches post-vaccination. Physicians found clots and a brain hemorrhage, and she ultimately died after two weeks in intensive care.
Noting the "shared pathophysiological basis" of the five patients' conditions, the group wrote that their findings "strengthen the view that vaccination may have triggered the syndrome."
In both reports, researchers suggest possible responses, including treatment with intravenous immune globulin and non-heparin blood thinners as well as testing for PF4 antibodies.
So far, a majority of the cases reported in Europe and the U.K. have occurred in women under 60 years old. But an EMA investigation couldn't identify any specific risk factors. EMA director Emer Cooke noted the skewed finding could simply be a result of how the vaccine has been used in Europe — where immunizations in the elderly had been limited — versus the U.K.
The findings could also have implications for Johnson & Johnson's vaccine, which is cleared in the U.S. and Europe. J&J's shot is different than AstraZeneca's but both use a similar delivery technology. Clinical testing of J&J's vaccine was temporarily halted in the U.S. last year after one vaccinated trial participant developed a similar type of abnormal clot, though investigators didn't link the case to immunization.
Earlier this week, EMA official Peter Arlett said the regulator has identified three cases among the roughly 4.5 million people who had received the shot in the U.S. as of then. On Friday, the EMA said it has started to investigate and "will decide whether regulatory action may be necessary," such as updating the labeling information for the shot.
AstraZeneca's vaccine is cleared for use in more than 50 countries and should soon be under review in the U.S., where the shot was shown to be strongly protective against COVID-19 in a study of about 32,000 volunteers.
AstraZeneca didn't see an increased risk of clots among vaccinated trial participants. But the safety concerns overseas may limit the shot's use in the U.S., which has enough supply from Pfizer, Moderna and J&J to vaccinate its entire adult population.