Review of the Global Vaccine Safety Advisory Board (GACVS) of the latest evidence on rare adverse events of blood coagulation with AstraZeneca COVID-19 (Vaxzevria and Covishield)

Following vaccination with COVID-19 by Vaxzevria and Covishield, a very rare new type of adverse event called thrombosis with thrombocytopenia syndrome (TTS) has been reported, which includes unusual and severe platelet-related blood clotting events. The Brighton Collaboration is developing a specific case definition for TTS¹. This will help identify and assess reported TTS events and help support causality assessments.

The biological mechanism of this TTS syndrome is still being investigated. At this stage, a “platform-specific” mechanism associated with adenoviral vector vaccines is uncertain, but cannot be ruled out. Ongoing review of TTS cases and related research should include all vaccines using adenoviral vector platforms. The GACVS noted that an investigation had been launched into the occurrence of TTS following the Johnson & Johnson vaccine administered in the United States. TTS syndrome is not associated with mRNA-based vaccines (such as Comirnaty or Modern mRNA-1273 vaccines).

Based on the latest available data, the risk of TTS with Vaxzevria and Covishield vaccines appears to be very low. Data from the UK suggest that the risk is approximately four cases per million adults (1 case per 250,000) who receive the vaccine, while the rate is estimated at approximately 1 per 100,000 in the European Union (EU). Countries assessing the risk of TTS after vaccination against COVID-19 should conduct a benefit-risk analysis that takes into account local epidemiology (including incidence and mortality from COVID-19 disease), the age group targeted for vaccination, and the availability of alternative vaccines.

Work is underway to understand the risk factors for TTS. Some researchers have studied TTS rates by age². GACVS supports further research to understand age risk, because although the available data suggest an increased risk in younger adults, it requires further analysis. Regarding gender risk, although more cases have been reported in women, it is important to note that more women have been vaccinated and that some cases of TTS have also been reported in men. Therefore, further analyzes are needed to determine gender-related risk. GACVS recommends further epidemiological, clinical, and mechanistic studies to fully understand TTS.

Thrombosis in certain places (such as the brain and abdomen) appears to be a key feature of TTS. Clinicians should be alert to any new, severe, persistent headache or other significant symptoms, such as severe abdominal pain and shortness of breath, beginning between 4 to 20 days after vaccination against COVID-19 adenovirus.

States should at least encourage clinicians to measure platelet levels and conduct appropriate radiological imaging studies as part of a thrombosis investigation. Clinicians should also be aware that, although heparin is generally used to treat blood clots, the use of heparin in TTS can be dangerous and alternative treatments such as immunoglobulins and non-heparin anticoagulants should be considered.

There may be geographical differences in the risk of these rare adverse events. It is therefore important to assess potential cases of TTS in all countries. Countries are encouraged to review, report and investigate all cases of TTS after vaccination against COVID-19. Countries should assess cases according to the presence of thrombosis with thrombocytopenia and the time to vaccination, using Brighton’s definition of the TTS case.

Although we have some information on Comirnaty, Moderna (mRNA-1273), Vaxzevria, and Covishield vaccines, there is limited post-market surveillance data on other COVID-19 vaccines and from low- and middle-income countries. GACVS strongly recommends that all countries conduct security surveillance all COVID-19 vaccines and provide data to their local authorities and the WHO global database on case safety reports. This is urgently needed to support evidence-based recommendations on these life-saving vaccines.

Open, transparent and evidence-based communication about the potential benefits and risks for recipients and the community is key to maintaining trust. The WHO is closely monitoring the introduction of all vaccines against COVID-19 and will continue to work closely with countries in managing potential risks and using science and data to trigger responses and recommendations.