What’s the link between the AstraZeneca/Oxford vaccine and the few cases of blood clot development?
Since the enrollment of the vaccination campaign, over 617 million vaccine doses (Pfizer/ BioNTech, Moderna or AstraZeneca/ Oxford) have been administered. This equals to an average of 8 doses per 100 people. From this, over 20 million (ongoing) people in the UK and European Union have been vaccinated with the AstraZeneca vaccine. However, recently there have been around 258 serious and 45 fatal cases of thrombosis, thrombocytopenia and/-or bleeding observed in people vaccinated with the AstraZeneca vaccine, and these cases have been reported to the European Medicines Agency (EMA). In response to this, many countries e.g., Germany, Italy, France, Spain, Denmark, Netherlands, and Sweden stopped the use of certain batches or all of the AstraZeneca vaccinations and started an intensive investigation performed by the Pharmacovigilance Risk Assessment Committee (PRAC). The review committee includes experts in blood disorders from Europe and the rest of the world.
Different types of blood clotting disorders that have been observed
According to EMA and PRAC, few cases of two different types of blood clots have been observed in these patients:
blood clots in multiple vessels, also known as disseminated intravascular coagulation (DIC), and
blood clots in vessels draining from the brain, also known as cerebral venous sinus thrombosis (CVST), in combination with a low platelet number (thrombocytopenia).
The CVSTs occurred predominantly in women of younger age (under 60 years), but this might reflect the vaccination of healthcare professionals that are mostly women in the specific EU member states. To this date, EMA/ PRAC has requested further studies in order to identify or rule out that the AstraZeneca vaccine causes these types of blood clots. However, EMA/ PRAC listed the observed blood clots with low platelets as very rare side effects. In response to this, many European countries e.g. Germany, France and the UK re-started the use of the AstraZeneca vaccine, whereas Denmark recently banned the AstraZeneca vaccine completely.
Blood clotting disorders occur in the “background” without vaccination
The experts in blood disorders of the PRAC review committee made it very clear that we will always observe related and non-related side effects of a vaccine when we vaccinate a large population in the range of several millions and more. Some of the side effects might be directly caused by the effects the vaccine has, while other side effects occur for other reasons and aren’t caused by the vaccine itself. Moreover, more than 100 new cases of thrombotic/ thromboembolic events per 100,000 people occur each year in the Western world and about half a million people die each year from these events in the European Union (EU). When looking specifically at CVSTs, there are around 13.2 and 15.7 cases per million people every year and these are more than twice as common in women of reproductive age than in men.
Conclusively, a certain level of thromboembolic events and specifically CVSTs occur in the “background”.
SARS-CoV-2 infection itself can cause blood clotting
Now, what is the link between the AstraZeneca vaccine and the development of blood clots? Although EMA/ PRAC has listed these blood clots with low platelet count to the list of very rare side effects of the vaccine, no specific risk factor has been confirmed yet and they are still investigating the potential causes. So far, we can only discuss the most likely hypotheses.
First of all, it is worthy to mention that an infection with the SARS-CoV-2 virus (causing COVID-19) itself can lead to blood issues such as hypercoagulability, microangiopathy, and venous or arterial thromboembolic events, that can lead to inflammation and to the development of blood clots as a post-COVID19 effect. A recent study showed that it took an average of 7 days from the onset of COVID19 symptoms to the diagnosis of CVST in COVID-19 patients.
From the observed blood clot events linked to the vaccine, there is either no information or people have been tested negative for SARS-CoV-2 (by PCR), but this doesn’t exclude that they might have been infected at an earlier time point with SARS-CoV-2 (without experiencing COVID-19 symptoms). The body takes up to 3 weeks to build up a full protection to fight SARS-CoV-2 when vaccinated with the AstraZeneca vaccine. Therefore, you can still get infected with the virus within this time frame and technically develop symptoms or very mild to no symptoms at all.
Other possible causes
Now, what else could have caused the development of these blood clots? Well, women who are in the reproductive age and use hormonal contraceptives have a 6-fold higher chance of experiencing CVSTs than women not using these. However, no link has been found between the use of contraceptive pills and the reported thromboembolic events linked to the vaccine.
According to the PRAC, many people experiencing this clinical condition had underlying pre-existing conditions such as autoimmunity, allergy, or chronic hepatitis B. These factors might have contributed to the effects, as chronic immune stimulation. Also, based on people's genes, some people might be more susceptible, or more likely, to develop these blood clots with or without taking the AstraZeneca vaccine. Apropos, people's different gene makeup is a risk factor of experiencing side effects for all medicines.
A recent study looked at 9 patients (mainly women), having thromboembolic clinical conditions in combination with thrombocytopenia followed by the AstraZeneca vaccination. The researchers showed that 4 out of 9 patient blood samples contained platelet-activating antibodies directed against platelet factor 4 (PF4)/ heparin. According to these experts, this disorder clinically resembles heparin-induced thrombocytopenia (HIT) and is typically triggered by heparin and sometimes other environmental factors.
However, none of these patients received heparin prior to the development of these clinical conditions. Moreover, EMA/ PRAC ruled out a batch or quality issue of the vaccine, therefore no contaminating agents such as heparin were in the vaccine that might have caused these blood clot events. Till now, they haven’t been able to identify whether these patients developed the antibodies against PF4 due to an autoimmune reaction of the body or if it was triggered by the AstraZeneca vaccine itself.
Correlation isn’t causation
EMA/ PRAC are proceeding with the investigations using laboratory tests to find a potential causal link between the blood clot events and the AstraZeneca vaccine. Keep in mind that correlation is not the same as causation, but it’s rather a hint to dive deeper into investigations and find if there is causation.
An example of this might be that you observe that many fast cars drive past a red light and thereby you conclude that fast drivers don’t respect any rules. But how can you prove there is a causal relationship ? You would need to observe and get to know each fast driver to draw a conclusion, don’t you? This investigation takes time, just like the investigation of the potential link between the blood clot events and the AstraZeneca vaccine. It’s like looking for the needle in a haystack, but EMA/ PRAC is currently going to the haystack and follows all the traces to reach the needle.
Finally, it is very important to realize that the risk of getting COVID19 is still much higher than the risk of developing blood clots subsequent to the vaccination, and remember that patients with COVID-19 are at a high risk of developing blood clots.
Conclusively, taking all data together, if you have had one of the vaccines, the chance of having these thrombolytic events occur is very low. However, the EMA and other regulatory agencies advise that you should still be aware of the symptoms of this condition so you can seek medical care to avoid it getting serious if it happens to you.
The symptoms to look out for are:
Shortness of breath
Chest pain
Swelling in the leg
Persistent abdominal (belly) pain
Neurological symptoms such as severe and persistent headaches or blurred vision
Tiny red blood spots under the skin, or new or easy bruising, away from the site of injection
Symptoms may occur within 3 weeks of vaccination. Contact your health care provider or seek medical care and let them know when you got vaccinated with which vaccine.
Contributed by: Text: Julia Brinkmeier, Images: Tania Castillo
References
AstraZeneca’s COVID-19 vaccine: EMA finds possible link to very rare cases of unusual blood clots with low blood platelets
Tracking Coronavirus Vaccinations Around the World by Josh Holder Updated April 2, 2021
Press briefing on the conclusion of the investigation of COVID-19 Vaccine AstraZeneca and thromboembolic events by the Pharmacovigilance Risk Assessment Committee (PRAC)
Signal assessment report on embolic and thrombotic events (SMQ)with COVID-19 Vaccine (ChAdOx1-S [recombinant])–COVID-19 Vaccine AstraZeneca (Other viral vaccines)
AstraZeneca COVID-19 vaccine: review of very rare cases of unusual blood clots continues
Contraception and Thrombophilia –A statement from the German Society for Gynecological Endo-crinology and Reproductive Medicine (DGGEF e.V.) and theProfessional Association of German Gynaecologists (BVF e.V.)T. Rabe1,B. Luxembourg2, M. Ludwig3, J. Dinger4, R. Bauersachs5, H. Rott6,A. O.Mueck7, C. Albrin (2011)
Epidemiology and pathophysiology of venous thromboembolism: similarities with atherothrombosis and the role of inflammation. Nicoletta Riva, Marco P. Donadini, Walter Ageno (2015)
Epidemiology of venous thromboembolism. John A. Heit (2015)
A Prothrombotic Thrombocytopenic Disorder Resembling Heparin-Induced Thrombocytopenia Following Coronavirus-19 Vaccination by Andreas Greinacher et al. (in press)