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AstraZeneca vaccine: Blood clots are “extremely rare” and benefits outweigh risks, regulators conclude

BMJ 2021; 373 doi: (Published 08 April 2021) Cite this as: BMJ 2021;373:n931

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Vaccine-induced, thrombotic, immune-mediated thrombocytopenia: Pathogenetic issues

Dear Editor,

The European Medicines Agency (EMA) has officially recognized, a few days ago, the existence of a likely cause-effect relationship between administration of the AstraZeneca anti-CoViD-19 vaccine, on one side, and occurrence of an extremely rare blood clotting disorder, named "thrombotic, immune-mediated thrombocytopenia" (TIMTC), on the other.

The aforementioned pathologic condition, most commonly affecting a brain venous sinus termed "cavernous sinus" , has been reported in approximately 1 out of 150,000 vaccinated individuals, mostly females less than 50 years-old, with a fatal outcome involving 1 out of 1,500,000 immunized people.

From a pathogenetic standpoint, vaccine-induced TIMTC has been linked to an autoimmune disorder, with affected patients developing autoantibodies against their thrombocytes (otherwise called "platelets"). According to an interesting article just published in the "New England Journal of Medicine" (1), these antibodies appear to selectively target an autoantigen (or "self-antigen") expressed on their platelet cell surface and termed "platelet factor 4 (PF4)-heparin", with the resulting affection (platelet activation followed by thrombocytopenia) resembling a similar autoimmune disease condition rarely seen in people administered heparin.

Based upon the above, there are some crucial pathogenetic (and epidemiological) issues, related to vaccine-induced TIMTC, which would deserve special attention, namely:

1) Why is vaccine-induced TIMTC (far) more common in females than in males? And, what about the role, if any, of female sex hormones (oestrogens)? This would be of additional interest in the light of the documented role played by male sex hormones (androgens) in modulating SARS-CoV-2 infection's susceptibility, with male patients being much more prone than females to develop particularly severe CoViD-19 disease forms (2).

2) Why is this vaccine-induced, autoimmune disorder reported much more frequently in subjects (especially females) younger than 50 years? Under natural disease conditions, in fact, the most consistent rates of CoViD-19-related/associated intensive care unit hospitalization and mortality are notoriously found in elderly people, with special emphasis on those affected by preexisting comorbidities (2).

3) Being the anti-CoViD-19 AstraZeneca, an adenoviral vector-based vaccine utilizing an identical simian adenovirus on both injections received by each treated individual, it would be interesting to compare the frequency rate (albeit very low, as previously mentioned) of vaccine-induced TIMTC with that, if any, following large-scale administration of "Sputnik V", a similarly conceived anti-CoViD-19 Russian vaccine employing, however, two different adenoviruses upon first and second dose injection.

This could help decipher, in fact, if a role may be played, within such context, by the adenoviral vector used for vaccine production and subsequent large-scale administration.

4) All the anti-CoViD-19 vaccines currently available on the market are aimed at providing - either through the "mRNA-based technology", as in the case of the Pfizer-BioNTech and Moderna vaccines, or through the aforementioned adenoviral vector-based strategy, which is also a peculiar feature of the Johnson & Johnson vaccine, for which just a single injection is needed - a safe and effective host's immune response against SARS-CoV-2 spike (S) protein, the major surface antigen allowing viral entry into susceptible (ACE-2 receptor-expressing) host cells and also eliciting, at the same time, a protective antiviral immune response.

Noteworthy, the most severe cases of CoViD-19, leading to a fatal outcome in approximately 2% of SARS-CoV-2-infected patients, are pathogenetically linked to an autoimmune reaction targeting platelets among others, with "multiorgan inflammation" and "cytokine storm", coupled with "disseminated intravascular coagulation", being sides of the same coin (2). Within such context, clotting disorders similar to those characterizing vaccine-induced TIMTC are observed, with their occurrence justifying the question, alternative if not even complementary to that raised at "point 3", of a common pathogenetic role exerted by the host's immune response to SARS-CoV-2 S antigen, which is shared under natural disease (CoViD-19) conditions as well as under the luckily very uncommon TIMTC reported after AstraZeneca vaccine administration.

To this aim, it would be of additional interest to investigate whether these autoimmune reactions, both in natural disease and in vaccinated subjects, tend to preferentially occur in Th1-dominant versus Th2-dominant individuals.

A lot of food for thought, undoubtedly, but also an absolutely firm and objective conclusion: whatever vaccine you take, the benefits of getting vaccinated against CoViD-19 are enormously greater than the (statistically negligible) risks deriving from vaccination, given that SARS-CoV-2 has already caused over 130 million cases of infection, with a dramatic death toll of 3 million people globally.

1) Greinacher A., et al. (2021) - New England Journal of Medicine, April 09, 2021; DOI: 10.1056/NEJMoa2104840.
2) Albini A., et al. (2020) - Internal and Emergency Medicine 15:759-766.

Competing interests: No competing interests

10 April 2021
Giovanni Di Guardo
Past Professor of General Pathology and Veterinary Pathophysiology
University of Teramo, Faculty of Veterinary Medicine, Località Piano d'Accio, 64100 - Teramo, Italy
Viale Pasteur, 77 - 00144 - EUR - Rome, Italy