AstraZeneca and Johnson & Johnson are two amongst many vaccines which have been accepted for immunisation against SARS-CoV-2 (coronavirus) – the virus causing the COVID-19 pandemic. Despite passing all clinical trials and being approved for emergency use to halt the spread of coronavirus, these vaccines have recently made headlines due to their possible link to rare cases of blood clots, some of which were fatal. When the correlation was first suspected for the AstraZeneca vaccine, many European countries decided to suspend its use and wait for more information regarding its safety . Similarly, in recent weeks, the rollout of the Johnson & Johnson vaccine was also suspended under the same suspicion. After careful consideration, the European Medicines Association (EMA) have now concluded that blood clots should be listed as a very rare side effect of both the AstraZeneca and Johnson & Johnson vaccines . As a result, many countries have now resumed vaccinations with AstraZeneca  and the same is expected for the Johnson & Johnson vaccine.
What does ‘very rare’ really mean?
As of the 7th of April, over 25 million doses of AstraZeneca vaccines were administered and 86 people who received it developed blood clots (<0.0005%), 19 of which died . Considering Johnson & Johnson, out of over 7 million people who received it, 8 developed blood clots (~0.0001%) and 1 died (data from 21st of April). These numbers, although very small, are slightly higher than seen in the non-vaccinated population, therefore, raising concerns. However, it is important to remember that the risk of developing blood clots after receiving the vaccine is significantly lower than when infected with coronavirus .
What are these aforementioned ‘blood clots’?
The blood clots that can be caused by one of the mentioned vaccines are formally called cerebral venous sinus thrombosis (CVST) which means that they form in large veins in the brain. They can block blood flow to the brain and hence reduce oxygen supply which can lead to damage of the brain tissue. When this damage is severe it can affect the function of the central nervous system and can potentially lead to death. Fortunately, when identified early, many blood clots can be treated preventing brain damage and death. To learn more about blood clots and their symptoms, visit the BBC news article all about it .
Although the biological mechanism linking vaccines to blood clots is currently unknown, scientists came up with several possible theories. It is important to note that these are not mutually exclusive and can overlap or reinforce one another.
1. Antibodies Against Platelet Factor 4
The focus on platelets was triggered by the findings that many patients developing CVSTs had low platelet blood count. This might seem unintuitive since platelets are the building blocks of blood clots. However, this phenomenon has previously been seen in some patients receiving a blood-thinning drug called heparin. In those patients, heparin forms a complex with a molecule called platelet factor 4, which is released by damaged platelets and this complex can be mistaken by the immune system for a pathogen. The immune system will then react by attacking this complex and can proceed onto attacking platelets themselves which sometimes can lead to the formation of clots. This theory is supported by studies finding antibodies against platelet factor 4 in 100% and 80% of patients who developed blood clots after receiving the AstraZeneca or Johnson & Johnson vaccine respectively. A lot remains to be confirmed and further research should be done to determine whether these vaccines are the only ones causing this immune reaction .
2. The Spike Protein
The spike protein is a protein present on the surface of the virus and is used to infect cells. It is also involved in every currently available vaccine, highlighting it as a possible culprit in blood clot formation. Some scientists suggested that due to the structural similarity to the mentioned platelet factor 4, the spike protein can trigger the immune system to produce antibodies which might attack platelet factor 4 and consequently platelets. However, a study by Greinacher et al.  found that antibodies against the platelet factor 4 do not bind to the spike protein and hence contradict this theory. Other explanations include the spike protein directly interacting with platelets stimulating them to produce platelet factor 4; or damaging blood vessels and releasing molecules that can bind to platelet factor 4 turning it into a target for the immune system. Although plausible, these theories require a lot of further research in order to be confirmed .
3. A problem with delivery
Both the AstraZeneca and Johnson & Johnson vaccines contain genetic material for the spike protein delivered by an adenovirus vector. While adenoviruses are harmless to humans, some studies suggest that they can stimulate platelets to secret clotting molecules which increase the risk of clot formation. Additionally, there were some suspicions around the ‘promoter’ region used in the genetic material of the AstraZeneca vaccine as it is derived from a gene coding for a tissue Plasminogen Activator (tPA) which is involved in blood clotting. However, this theory was largely disregarded as the genetic fragment used does not produce tPA and should not have any effect on blood clotting. Nonetheless, these theories remain an important note in future further research .
4. Other factors
Finally, some scientists urge not to put all the blood clotting cases in one bag as there is no guarantee there is a single common biological mechanism behind them. There are multiple proteins and molecules involved in blood clotting, such as annexin A2 or fibrinogen, which can be detected at altered levels in COVID-19 patients or people who received the vaccine. This is supported by a study involving a patient diagnosed with blood clots after receiving the AstraZeneca vaccine, who did not have antibodies against the platelet factor 4 or its complexes .
While it is important to understand the biological mechanism causing these rare blood clots, we should remember that the risk of developing them is significantly lower in vaccinated people than in COVID-19 patients. The key message remains that vaccines are safe and efficacious, and they continue to save thousands of lives every day.
- ‘The blood clot problem is multiplying: so are theories to explain it’ – Roxanne Khamsi, The Atlantic: SCIENCE
- ‘Covid vaccines and rare clots – what you need to know’ – Smitha Mundasad, BBC News
- Oliver Holmes, (2021) ‘Which European states have paused AstraZeneca jabs due to clotting concerns?’ Available online: https://www.theguardian.com/society/2021/mar/15/which-european-states-have-paused-astrazeneca-jabs-due-to-clotting-concerns
- European Medicines Agency, (2021) ‘AstraZeneca’s COVID-19 vaccine: EMA finds possible link to very rare cases of unusual blood clots with low blood platelets’ Available at:https://www.ema.europa.eu/en/news/astrazenecas-covid-19-vaccine-ema-finds-possible-link-very-rare-cases-unusual-blood-clots-low-blood#:~:text=EMA’s%20safety%20committee%20(PRAC)%20has,COVID%2D19%20Vaccine%20AstraZeneca
BBC News, (2021) ‘Johnson & Johnson vaccine: EU regulator says blood clot very rare side effect.’ Available at: https://www.bbc.co.uk/news/world-europe-56820970
Kai Kupferschmidt, (2021) ‘European countries resume use of AstraZeneca’s COVID-19 vaccine, hoping pause has not dented confidence’ Available at: https://www.sciencemag.org/news/2021/03/european-countries-resume-use-astrazenecas-covid-19-vaccine-hoping-pause-has-not-dentedSmitha Mundasad, (2021) ‘Covid vaccines and rare clots – what you need to know’. Available at: https://www.bbc.co.uk/news/health-56674796
- BBC News, (2021) ‘Brain clots ‘more likely’ with Covid Infection rather than vaccine’ https://www.bbc.co.uk/news/health-56760163
- Roxanne Khamsi , (2021) ‘The blood clot problem is multiplying: so are theories to explain it’ Available at: https://www.theatlantic.com/science/archive/2021/04/vaccine-related-blood-clot-mystery-must-be-solved/618623/?utm_source=Nature+Briefing&utm_campaign=81889634d4-briefing-dy-20210420&utm_medium=email&utm_term=0_c9dfd39373-81889634d4-46155150
- Andreas Greinacher, Kathleen Selleng, Julia Mayerle et al. (2021) ‘Anti-SARS-CoV-2 Spike Protein and Anti-Platelet Factor 4 Antibody Responses Induced by COVID-19 Disease and ChAdOx1 nCov-19 vaccination’. Research square, PREPRINT (Version 1). Available at: [https://doi.org/10.21203/rs.3.rs-404769/v1]https://www.researchsquare.com/article/rs-404769/v1