What causes the rare blood clots linked with some covid-19 vaccines?

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A pharmacist administering the covid-19 vaccine in Pennsylvania

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Use of the Johnson & Johnson covid-19 vaccine has been suspended in the US after six people experienced blood clots, out of 6.8 million who received the vaccine in the country. The cases seem to be similar to the rare blood clots seen in recipients of the Oxford/AstraZeneca vaccine, which has caused some countries to restrict use of the AstraZeneca vaccine.

The blood clot syndrome involves people having an unusual type of clot, often one that forms in the brain – called cerebral venous sinus thrombosis or CVST – coupled with low levels of platelets, small particles in the blood that stick together to make clots.

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It has been seen mainly in people under about 60, and more often in women than men. But the sex difference may be because more women have been vaccinated, as they comprise more healthcare workers and care home staff. In an analysis of 79 UK cases seen after the Oxford/AstraZeneca jab, they occurred at the same rate in men and women, says Munir Pirmohamed, chair of the UK’s Commission on Human Medicines. The overall rate was 4 cases per million people who have received the vaccine in the UK.

It is unknown why younger people seem more at risk, but the age distribution is partly why some countries have said this vaccine should only be given to those above a certain age. The other reason is that older people are more at risk from covid-19 itself, so the benefit of the vaccine may outweigh the risk.

The six cases of CVST newly reported in recipients of the Johnson & Johnson vaccine, one of which has been fatal, were all in women aged between 18 and 48.

Johnson & Johnson announced today they would delay European rollout of their product. “We have been working closely with medical experts and health authorities, and we strongly support the open communication of this information to healthcare professionals and the public,” the firm said in a statement.

What could be causing the clots? In the Oxford/AstraZeneca cases, many of those affected have tested positive for antibodies that bind to a molecule released by platelets, called platelet factor 4 or PF4. The vaccine may somehow trigger production of these antibodies, which cause multiple small clots to form in the blood and that can use up platelets, says Andreas Greinacher at the University of Greifswald in Germany. It resembles a syndrome in which similar antibodies can be triggered by the blood-thinning treatment heparin, says Greinacher, who is an expert on the heparin side-effect.

Recently issued guidelines in some countries advise that a test for the platelet antibodies should be given if someone has symptoms suggestive of the clotting syndrome within two weeks of getting a covid-19 vaccine. If positive, they should receive the same treatments normally given to people who get the rare heparin side-effect, which are different to those given for ordinary blood clots.

Greinacher says a previous study in mice suggests that DNA can bind to PF4, triggering antibodies to form and promoting blood clots. He speculates that this could be why the effect has only been seen with the DNA-containing adenovirus-based vaccines.

The Oxford/AstraZeneca vaccine consists of a gene for the coronavirus spike protein carried within the DNA of a chimpanzee adenovirus, a harmless cold virus. The Johnson & Johnson vaccine works in a similar way but uses DNA from a human adenovirus.

The Pfizer/BioNTech vaccine and the Moderna vaccines, on the other hand, are based on mRNA, a strand of genetic material encoding the spike protein, that gives the body’s cells instructions to make the spike protein. There have been no cases of CVST with low platelets reported after either of these vaccines, said Peter Marks at the US Food and Drug Administration in a press conference.

“What we are seeing with the Johnson & Johnson vaccine looks very similar to the AstraZeneca vaccine,” says Marks. “The probable cause, we can speculate, is a similar mechanism that may be going on with the other adenoviral vector vaccine.”

However, the clot syndrome is seen so rarely, it suggests those who experience it have some other factor that makes them susceptible to it, says Greinacher. “There must be individual co-factors to trigger this. Otherwise we would see this problem in many more individuals, which is luckily not the case.”

Marks did not say if the six cases seen after the Johnson & Johnson vaccine had the hallmark antibodies against platelets. But the FDA did say one reason for pausing use of the vaccine was to give time for doctors to learn how to diagnose and correctly treat the unusual blood clot syndrome. The agency also needs to fully investigate the six cases, says Anne Schuchat of the US Centers for Disease Control and Prevention.

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