This evidence synthesis has been compiled by members of the CITF Secretariat and does not necessarily represent the views of all CITF members.

By Mariana Bego

Vaccination is the main means to control the COVID-19 pandemic worldwide. With such a massive vaccine rollout underway, monitoring the safety of these vaccines is critical and includes the routine reporting and study of rare adverse events. We have compiled and summarized reports about the rare abnormal clotting events linked to two COVID-19 vaccines.

The vectors and spike protein inserts used in the three adenovirus-based vaccines deployed to date (AstraZeneca, Johnson & Johnson/Janssen and Sputnik V) are substantially different and may have quite different biological effects on people. Several sources raised alarm regarding rare clotting events linked to AstraZeneca and Johnson & Johnson vaccines. No side effects related to clotting have been reported by the manufacturers to date for the Sputnik V vaccine.

Benefits outweigh the risks

That said, regulators continue to recommend these vaccines, since the risk of blood clots is extremely low (1:250,000) and clotting complications from SARS-CoV-2 infection is as high as 1:5. Indeed, in a recent meta-analysis of 42 studies involving more than 8000 patients, researchers found clotting disorders in as many as 1 in 5 SARS-CoV-2 infected individuals, giving them poor prognoses and higher risks of death.

Understanding the abnormal clotting events linked to these vaccines

The New England Journal of Medicine recently published a series of articles with a detailed analysis of many of the abnormal thrombotic/thromboembolic events (abnormal clotting) and thrombocytopenia (abnormally low levels of platelets: the blood components required for clot formation and bleeding prevention). The clots that have been tentatively linked to the AstraZeneca and Johnson & Johnson vaccines occur in unusual parts of the body, such as the brain or abdomen. The patients present the hallmarks of a condition known as heparin-induced thrombocytopaenia (HIT): a rare side effect sometimes seen in people who have taken the anti-coagulant heparin. HIT develops when heparin binds to a protein called platelet factor 4 (PF4), which triggers the immune system to make antibodies against PF4, ultimately leading to the destruction of the platelets and the release of their clot-promoting factors. But vaccine recipients have not been in contact with heparin and the vaccine components responsible for the unwanted immune response against PF4 have not been identified. A recent pre-print, which has not been peer-reviewed yet, hints that some of the side effects observed could be the direct result of certain components in the vaccine formulation.

In the reports listed below, the authors describe the presence of anti-PF4 antibodies in patients after receiving AstraZeneca (studies 1-3) or Johnson & Johnson (study 4) vaccines.

  1. Greinacher and colleagues studied 11 patients in Germany and Austria (nine were women, aged 22 to 49).
  2. Schultz and colleagues described outcomes for five health care workers from Norway (four were women, aged 32 to 54).
  3. Scully and colleagues reported findings in 23 patients from the United Kingdom. The patients in this study had a median age of 46 years (ranging from 21 to 77 but with 70% younger than 50 years) and 61% were female (14/23).
  4. Muir and colleagues from the United States, reported a case study of a female patient under 50.

There seems to be an early – but not confirmed – link between these events and young, otherwise healthy females, but sex and age connections could be highly biased. For instance, many countries prioritized vaccination for health-care workers, who are predominantly female. In addition, blood clots and strokes may be investigated more in-depth in younger vaccine recipients as they are generally more common in older people. Nevertheless, rapid identification of this rare pathogenic PF4-dependent syndrome is important as treatment options are available.

 

For more information, refer to the cited studies:

  1. Greinacher A, Thiele T, Warkentin TE, Weisser K, Kyrle PA, Eichinger S. (2021) Thrombotic thrombocytopenia after ChAdOx1 nCov-19 vaccination. N Engl J Med. doi: 10.1056/NEJMoa2104840.
  2. Schultz NH, Sørvoll IH, Michelsen AE, et al. (2021) Thrombosis and thrombocytopenia after ChAdOx1 nCoV-19 vaccination. N Engl J Med. doi: 10.1056/NEJMoa2104882.
  3. Scully Marie, Singh Deepak, Lown Robert, Poles Anthony, Solomon Thomas, Levi Marcel, Goldblatt David, Kotoucek Pavel, Thomas William, Lester William. (2021) Pathologic Antibodies to Platelet Factor 4 after ChAdOx1 nCoV-19 Vaccination. N Engl J Med doi: 10.1056/NEJMoa2105385.
  4. Muir Kate-Lynn, Kallam Avyakta, Koepsell Scott A., Gundabolu Krishna. (2021) Thrombotic Thrombocytopenia after Ad26.COV2.S Vaccination. N Engl J Med doi: 10.1056/NEJMc2105869.