Thrombotic Thrombocytopenia after COVID-19 Vaccination: In Search of the Underlying Mechanism

The rollout of COVID-19 vaccines brings hope for successful pandemic mitigation and getting the transmission of SARS-CoV-2 under control. The vaccines authorized in Europe displayed a good safety profile in the clinical trials. However, during their post-authorization use, unusual thrombotic events associated with thrombocytopenia have rarely been reported for vector vaccines. This led to the temporary suspension of the AZD1222 vaccine (Oxford/AstraZeneca) in various European countries and the Ad26.COV2 vaccine (Janssen/Johnson&Johnson) in the United States, with regulatory bodies launching investigations into potential causal associations. The thromboembolic reactions were also rarely reported after mRNA vaccines. The exact cause of these adverse effects remains to be elucidated. The present paper outlines the hypotheses on the mechanisms behind the very rare thrombotic thrombocytopenia reported after the COVID-19 vaccination, along with currently existing evidence and future research prospects. The following are discussed: (i) the role of antibodies against platelet factor 4 (PF4), (ii) the direct interaction between adenoviral vector and platelets, (iii) the cross-reactivity of antibodies against SARS-CoV-2 spike protein with PF4, (iv) cross-reactivity of anti-adenovirus antibodies and PF4, (v) interaction between spike protein and platelets, (vi) the platelet expression of spike protein and subsequent immune response, and (vii) the platelet expression of other adenoviral proteins and subsequent reactions. It is also plausible that thrombotic thrombocytopenia after the COVID-19 vaccine is multifactorial. The elucidation of the causes of these adverse events is pivotal in taking precautionary measures and managing vaccine hesitancy. It needs to be stressed, however, that the reported cases are currently sporadic and that the benefits of COVID-19 vaccines vastly outweigh their potential risks.