Embolic and thrombotic events after COVID-19 vaccination

Post-vaccination embolic and thrombotic events (also termed vaccine-induced prothrombotic immune thrombocytopenia/VIPIT or vaccine-induced thrombocytopenia and thrombosis/VITT) are rare types of blood clotting events that have been observed in a very small number of people who had previously received the Oxford–AstraZeneca COVID-19 vaccine during the 2020 COVID-19 pandemic. Both the European Medicines Agency (EMA) on 28 March 2021 and UK's Medicines and Healthcare Products Regulatory Agency (MHRA) on 1 April 2021 have emphasized the benefits vaccination of using the AstraZeneca vaccine continue to far outweigh any potential risks, noting that there is currently no evidence that the vaccine caused them but that it could not be ruled out completely. At a briefing on 7 April 2021 the EMA reconfirmed the benefits of AZD1222 but were choosing to publish rare blood clots scenarios as a possible very rare side effect.

Background

A number of COVID‑19 vaccines began to become approved and available at scale in late 2020 with vaccinations beginning to ramp up at scale from the beginning of 2021, among them the Oxford–AstraZeneca COVID-19 vaccine, based on an adenovirus vector and internally termed AZD1222. The World Health Organization (WHO) Global Advisory Commiittee on Vaccine Safety thought necessary on 19 March 2021 to issue a statement relating to safety signals related to AZD1222 relating to thromboembolic events and thrombocytopenia following review of available data and conclusions included that AZD1222 "a positive benefit-risk profile, with tremendous potential to prevent infections and reduce deaths across the world".

In its safety update of 29 March 2021 the EMA indicated it had initiated investigations into the very rare cases of specific embolic and thrombotic events in combination with thrombocytopenia (low levels of blood platelets) and related bleeding including disseminated intravascular coagulation and cerebral venous sinus thrombosis (CVST), noting any link with AZD1222 was not proven but could not be excluded. The EMA also initiated an assessment for all COVID-19 vaccines used in the EU for immune thrombocytopenia (ITP), described as low blood platelet levels that could lead to bruising and bleeding, as a possible side effect, whilst also stating that up to this point no link with any COVID-19 had been established.

Observations

The Paul Ehrlich Institute of has recorded 31 cerebral venous sinus thromboses (CVST) and nine deaths out of 2.7 million vaccinated with in Germany with the AZD1222. On 2 April 2021 the UK's Medicines and Healthcare Products Regulatory Agency reported 22 cases of CVST and a further eight cases of clotting problems both associated with a low level of blood platelets following a "rigorous review" of its "Yellow card" reporting. The institute also reported finding no events of this type which occurred after vaccination with the Pfizer–BioNTech COVID-19 vaccine. The EMA had earlier said that a linkage between certain very rare blood clots and the AstraZeneca vaccine is "not proven, but is possible".

Observations in Germany of these rare events seemed to relate mostly women aged under 55. However, because Germany had previously restricted AZD1222 to under 65s, the population vaccinated there with AZD1222 was comparatively younger, and consequently contained a higher proportion of women taking the contraceptive pill. As CVSTs are more likely in women using hormonal contraceptives, this inherent risk factor may be an influence on the reported preponderance of women experiencing these events. The UK, in contrast, has applied its Pfizer and AZD1222 vaccines generally to older groups first, then by decreasing age.

Regulatory response

According to the European Medicines Agency (EMA), as of 28 March 2021, the reported rate of such events was lower than in the general population overall, but higher than in the population prior to the pandemic. The EMA also said that there is no proof that these events are caused by the vaccines, but that the possibility could not yet be ruled out completely. Accordingly, the EMA advised that people who received the vaccine and experienced symptoms suggestive of thrombosis, including shortness of breath, blurred vision and severe or persistent headache, should seek medical attention.

As of 7 April 2021 the EMA and UK MHRA (both stringent regulatory authorities) are undertaking assessments of the occurrences of the rare blood clotting events with WHO endorsing the EMA's investigations.

In a press briefing in the Afternoon of 7 April 2021 by Emer Cooke executive director of the EMA began by stating "Our safety committee, the Pharmacovigilance and Risk Assessment Committee (PRAC) of the European Medicines Agency, has confirmed that the benefits of the AstraZeneca vaccine in preventing COVID-19 overall outweigh the risks of side effects. COVID-19 is a very serious disease with high hospitalization and death rates and every day COVID is still causing thousands of deaths across the EU. This vaccine has proven to be highly effective, it prevents severe disease and hospitalization, and it is saving lives. Vaccination is extremely important in helping us in the fight against covet 19 and we need to use the vaccines we have to protect us from the devastating effects". She went on to say "The PRAC after a very in-depth analysis has concluded that the reported cases of unusual blood clotting following vaccination with the astrazeneca vaccine should be listed as possible side effects of the vaccine". At the same briefing Dr. Samina Strauss of PRAC confirmed "our conclusion is that these clotting disorders are very rare side effects of the vaccine".

The UK MHRA also held a new conference on 7 April 2021 and while there was no proof the AZD1222 vaccination caused the rare blood clots but indicated the possibility of a link was getting stronger. The UK was to offer under 30s alternative vaccines. The reasoning was because in the 20-29 age range the benefits to individual of vaccination were less as their likelihood of harm from COVID-19 was less and closer to the potential risk of harm from the vaccine (at a medium exposure risk with Covid-19 infection cases running at a rate of 60 per 100,000). For higher age groups the benefit to risk ratio increased.

Vaccination campaign responses

The advisory panel for the government of Ontario, Canada has recommended against the use of heparin for management of thrombosis after vaccination until more is known.

In response to the concerns over the adverse effects relating to rare blood clotting types Germany has suspended use of the AZD1222 to those under 60 years of age; in contrast to a period previously having suspended use of AZD1222 to over–65s due to limited data of the efficacy of the vaccine to this age group at that time.

Following a few days of suspended use of AZD1222, the Ministry of Health, Welfare and Sport of the Netherlands decided to continue administering the vaccine only to persons above the age of 60.

On 8 April 2021, the Australian Technical Advisory Group on Immunisation (ATAGI) advised the federal government that the Pfizer COVID-19 vaccine is recommended over the AstraZeneca for adults aged under 50 years. The advice is "based on the increasing risk of severe outcomes from COVID-19 in older adults (and hence a higher benefit from vaccination) and a potentially increased risk of thrombosis with thrombocytopenia following AstraZeneca vaccine in those under 50 years." The AstraZeneca vaccine is still recommended for people over 50, and those under 50 who have already had their first dose with no ill effects. In the state of Victoria, there were reports of some, aged under 50, being turned away from vaccination centres, despite having confirmed appointments. It is understood a special consent process will be developed by the Australian Government for people under 50 who choose to receive the AstraZeneca vaccine.

See also

• Oxford–AstraZeneca COVID-19 vaccine

References

Sources

• EMA (7 April 2021). EMA press conference 7th April — Conclusion of the assessment of the Pharmacovigilance Risk Assessment Committee (PRAC) of COVID-19 Vaccine AstraZeneca and thromboembolic events. European Medicines Agency (EMA). Retrieved 7 April 2021 – via Youtube.