LONDON – The EMA has concluded that the rare cases of serious blood clots with low platelet counts seen after administration of Astrazeneca plc’s COVID-19 vaccine are caused by the vaccine, but said the benefits of its use continue to outweigh the risks.

The possibility of cerebral venous sinus thrombosis (CVST) and splanchnic vein thrombosis (SVT) in the abdomen will now be listed as rare side effects and the EMA’s guidance to health care professionals will be updated.

Up to March 22, most of the 62 cases of CVST and 24 cases of SVT reviewed by the EMA’s safety committee have occurred in women under the age of 60. Across all cases, there were 18 deaths.

However, Emer Cooke, executive director of the EMA, said there is still not enough evidence to show age- or gender-specific factors are in play, or to make specific recommendations on risk reduction. “Based on currently available evidence, specific risk factors are not confirmed. [Thromboses] have been seen in all ages, and in men and women,” Cooke said.

There are more data to chew on, with 169 cases of CVST and 53 cases of SVT now reported up to April 4, in 34 million people who have had the Astrazeneca vaccine. These await detailed analysis, but Sabine Straus, head of the EMA’s safety committee said the initial review did not change the committee’s view that there should be no move to limit use in women, or in any age group.

Simultaneously, in the U.K., the Medicines and Healthcare products Agency (MHRA) announced its review had concluded evidence of a link is stronger than seen previously, but not proven. More research is needed, the MHRA said.

As with the EMA, the MHRA is to update its guidance to health care professionals to make them aware of the rare adverse events, but maintained the benefits are greater than the risks.

However, the Joint Committee on Vaccination and Immunization (JVCI), which designed the COVID-19 vaccines rollout program in the U.K., said healthy people ages 18 to 29 should be offered an alternative to the Astrazeneca product.

To date, there have been no reports of CVST or SVT following the second dose of the Astrazeneca vaccine. JVCI said unless they have suffered a serious clot after the first dose, people should get their second dose.

There has been much searching for the mechanism behind the serious thromboses, and Cooke said a “plausible mechanism” is that the Astrazeneca vaccine is triggering an immune response similar to that seen in heparin-induced thrombocytopenia (HIT).

Antibodies to platelet factor 4 (PF4) have been found in people who suffered serious thromboses, leading to the comparison with HIT. Blood tests are showing low fibrinogen and very raised levels of the fibrin degradation product D-Dimer, also features of HIT.

The EMA has commissioned new research and made amendments to existing studies, to investigate this and other possible mechanisms.

The incidence of rare blood clots and pinpointing their cause “clearly demonstrates the challenges posed by large-scale vaccination campaigns,” but also illustrates the pharmacovigilance system is working, said Cooke. “These very rare events have been picked up and [we] have come to a science-based assessment to allow continued use,” she said.

“The messages from both MHRA and EMA are in close agreement, which is reassuring,” said Ian Douglas, professor of pharmacoepidemiology at the London School of Hygiene & Tropical Medicine. “The evidence from the case reports seems to be compelling enough to conclude at least a possible causal link between the AZ vaccine and rare clots accompanied by low platelet counts,” he said.

While there is still some doubt about causal connections, two other things are beyond doubt, Douglas said. “First, the well-quantified and large benefits provided by all the currently available vaccines, and second, that any risk from clotting appears to be very rare.”

While the EMA is altering the label, it is not making any changes to the approved use in adults ages 18 and older.

It will be up to national regulators to decide if there should be any restrictions, bearing in mind such factors as the state of the epidemic and the availability of other COVID-19 vaccines, said Cooke.

Denmark, the Netherlands, Latvia and Norway have stopped using the Astrazeneca vaccine, while other European countries, including Germany, France and Spain, have restricted use to older age groups.

The U.K. review is based on 79 cases of rare blood clots that have caused 19 deaths. Of those, 51 were in women and 28 in men, but it should be noted that more women have received the Astrazeneca vaccine than men.

Eleven of the 19 people who died were under the age of 50, and of those, three were under 30.

The MHRA said the cases reported up to and including March 31 mean the risk is now slightly higher than its previous analysis based on cases to March 24.

June Raine, chief executive of the MHRA, said the balance of risks and benefits is still very favorable “for the majority of people,” but for healthy, younger people the position is “more finely balanced.”

Jonathan Van-Tam, deputy chief medical officer for England, described the move to offer an alternative to the Astrazeneca vaccine for 18- to 29-year-olds as a “course correction,” saying such changes are a regular feature of vaccines programs, as for example, recommending different flu vaccines for different age groups. The situation will be kept under review. “We don’t want it to result in a loss of vaccine confidence,” Van-Tam said.

The U.K. program started with the over 80s and moved down the age groups in five-year chunks. Currently 45- to 49-year-olds are being contacted to make vaccine appointments. All over 18s are due to be vaccinated by the end of July, and Van-Tam said the effect of restricting use of Astrazeneca’s vaccine will be “zero or negligible.”

Search for the cause

There have been just two cases of CVST in the U.K. in people who received the Pfizer Inc./Biontech SE vaccine. With a similar number of Astrazeneca and Pfizer/Biontech doses administered, the disparity in cases gives more reason to believe the rare thromboses are caused by the Astrazeneca product, said Anthony Harnden, deputy chair of JVCI.

Among the possible mechanisms to have been floated is that there is a rare immune reaction to the adenoviral vector used in Astrazeneca’s vaccine. That suggestion has sparked concerns that the same problem could occur with other adenoviral vector-based vaccines, including Johnson & Johnson Inc.’s single-dose product.

A further possibility is that the antibodies generated against the virus spike protein mimic antibodies to platelet factor-4. That would activate platelets, consuming them all in forming clots, so there are none in circulation, suggested Beverley Hunt, professor of thrombosis and hemostasis at King’s College London.

Hunt has been part of the expert group reviewing U.K. cases of serious thromboses. In addition to thrombocytopenia, high D-dimer levels and low fibrinogen levels, there also is a temporal association, with cases occurring four to 14 days post vaccination.

“We now feel we can say ‘this is a case’ before we look at the anti-platelet antibodies,” Hunt said, adding, “We have a treatment for it.” As with HIT, that involves intravenous gamma globulin to mop up anti-platelet antibodies, followed by a direct thrombin inhibitor drug, she said.