Millions of people in dozens of countries have received the AstraZeneca Covid-19 vaccine with few reports of ill effects, and its prior testing in tens of thousands of people found it to be safe.

But recently, blood clots and abnormal bleeding in a small number of vaccine recipients in European countries have cast doubt on its safety, although no causative link has been found between the patients’ conditions and the vaccine.

The reports have prompted more than a dozen countries to either partly or fully suspend the vaccine’s use while the cases are investigated. Most of the nations said they were doing so as a precaution until leading health agencies could review the cases.

What types of problems caused the countries to take precautionary steps?

The cascade of decisions to pause the use of AstraZeneca’s vaccine, mainly by European countries, followed reports of four serious cases in Norway, which were described among health workers under age 50 who received the vaccine.

Most developed clots or bleeding abnormalities and had low platelet counts, health authorities there said. Two of them have died from brain haemorrhages, and the other two are hospitalised.

The death of a 60-year-old woman in Denmark and of a 57-year-old man in Italy also fuelled quick decisions, although none of the deaths have been fully investigated.

What is a blood clot and what causes them?

A blood clot is a thickened, gelatinous blob of blood that can block circulation. Clots form in response to injuries and can also be caused by many illnesses, including cancer and genetic disorders, certain drugs and prolonged sitting or bed rest. Clots that form in the legs sometimes break off and travel to the lungs or brain, where they can be deadly.

Can the vaccine cause blood clots?

Vaccines have not been shown to cause blood clots, said Daniel Salmon, director of the Institute for Vaccine Safety at Johns Hopkins University.

Blood clots are common in the general population, and health authorities suspect that the cases reported in vaccine recipients are most likely coincidental and not related to the vaccination.

“There are a lot of causes of blood clotting, a lot of predisposing factors, and a lot of people who are at increased risk — and these are often also the people who are being vaccinated right now,” said Mark Slifka, a vaccine researcher at Oregon Health and Science University.

From 300,000 to 600,000 people a year in the US develop blood clots in their lungs or in veins in the legs or other parts of the body, according to the Centers for Disease Control and Prevention.

Based on that data, about 1,000 to 2,000 blood clots occur in the US population every day, according to Dr Stephan Moll, a hematologist and professor of medicine at the University of North Carolina.

“The United States has 253 million adults,” Dr Moll said. “So, if every day 2.3 million people in the United States get Covid-vaccinated, that means about 1 per cent of the adult population gets vaccinated every day.”

Calculating further, he said, roughly 1 per cent of the 1,000 to 2,000 daily blood clots — 10 to 20 a day — would occur in the vaccinated patients just as part of the normal background rates, not related to the vaccine. “Only if epidemiological data show that that rate is higher, would one start to wonder about a causative relationship,” Dr Moll said.

What can existing data on AstraZeneca’s vaccine tell us?

Dr David Wohl, director of the vaccine clinic at the University of North Carolina, said he had seen no evidence that any of the Covid vaccines had caused blood clots, also called thrombosis, in the large clinical trials that led to their authorisation.

But Dr Wohl also noted, “There are differences between trials and real life.”

The most extensive safety results from the real-world rollout of AstraZeneca’s vaccine come from Britain, where 9.7 million doses of the vaccine had been given out through last month. Britain’s data found that at least some clotting conditions, while extremely rare, were equally prevalent for people vaccinated with AstraZeneca’s vaccine compared to those who got Pfizer’s product. But abnormally low platelet levels were more common among people who got AstraZeneca’s vaccine.

Outside trials, the vaccines are given to a broader array of people. So if safety questions arise once a vaccine comes into more general use, the questions should be investigated, Dr Wohl said.

“We don’t want to ignore a signal that could indicate a larger problem,” he said. “But at this point it’s premature to think AstraZeneca causes thrombosis.”

Do vaccines cause other bleeding disorders?

Other vaccines, particularly the one given to children for measles, mumps and rubella, have been linked to temporarily lowered levels of platelets, a blood component essential for clotting.

Lowered platelet levels have been reported in small numbers of patients receiving the Moderna, Pfizer-BioNTech and AstraZeneca vaccines. One recipient, a physician in Florida, died from a brain haemorrhage when his platelet levels could not be restored.

US officials have said that the cases are being investigated, but they have not reported the findings of those reviews and have yet to indicate that there is any link to the vaccines.

How will investigators determine whether there is a link?

The European Medicines Agency said on Monday that it was working with AstraZeneca and health authorities to scrutinise “all the available data and clinical circumstances surrounding specific cases”.

The authorities have not detailed what that assessment will look like. But when assessing a possible connection between a vaccine and a serious side effect, investigators generally focus on estimating how often such medical problems would be expected to turn up by chance in the group of people in question.

That might mean looking at people in the same group from before they got vaccinated. It could also mean looking at a similar group of people. If the rate of these problems is higher in the vaccinated group than would be expected in a comparable population, that’s a sign that the safety issue may be real, or at least worth more scrutiny.

Such investigations typically do not hinge on figuring out whether the vaccine was the cause of a death or a serious medical problem, because in most cases that cannot be conclusively determined. But investigators do take clinical history into account, such as whether a person had been treated for similar problems before being vaccinated.

Investigators also keep in mind factors that might make a group of people more likely to fall ill. Older people, who have been prioritised in vaccination campaigns around the world, are at higher risk of developing blood clots than younger people.

What has the company said about the safety scare?

AstraZeneca first publicly addressed the safety concerns a week ago, after Austria halted vaccinations from one batch of vaccine. A spokesman said no serious vaccine side effects had been confirmed.

New York Times News Service