LAUSR

A number of cases of unusual thrombotic events connected with thrombocytopenia and particularly severe clinical courses have been reported after vaccination with the recombinant adenoviral vector encoding the spike protein antigen of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (ChAdOx1 nCov-19, Oxford-AstraZeneca, Vaxzevria) [1–6]. In general, venous thromboembolic events occurring in individuals who had received the Oxford-AstraZeneca vaccine were no higher than those expected in the unvaccinated people [2]. However, rare cases of cerebral venous sinus thrombosis and/or splanchnic vein thrombosis, frequently associated with thrombi in many sites and thrombocytopenia, with serious bleeding and occasionally disseminated intravascular coagulation (DIC) have been described [2]. Moreover, it has been observed that the occurrence of potential thrombotic events in females is approximately double than males [1– 6]. The EMA’s Pharmacovigilance Risk Assessment Committee have concluded that rare thromboses with low blood platelets should be scheduled as very rare side effect of Oxford–AstraZeneca vaccine suggesting a possible link [6]. The EMA’s Pharmacovigilance Risk Assessment Committee have expressed the same concern about the COVID-19 Jansen (ad.26.COV2.S Johnson & Johnson) based on the recombinant adenovirus type 26 vector encrypting the viral spike protein [6]. Yet, it remains debated to support a causal effect of the Oxford – Astra Zeneca vaccine on the number of thromboembolic events testified, particularly in women [1,3]. Various mechanisms linking the cases of uncommon blood clots and low platelets to Oxford-Astra Zeneca vaccine have been proposed including the development of platelet-activating antibodies against platelet factor 4 (PF4), which clinically mimics autoimmune heparin-induced thrombocytopenia (HIT), therefore called vaccine-induced immune thrombotic thrombocytopenia (VITT) and, the amount of adenoviral vector leakage into the circulation with presence of specific and/or cross-reactive antibodies and high enough titer of aberrantly glycosylated antibodies [1–6]. It is still unclear whether the other COVID-19 vaccines approved in Europe, the Pfizer/Moderna mRNA COVID-19 vaccines, are related to clot formation [7]. However, severe thrombocytopenia has been documented to be significantly more recurrent among women vaccinated with Oxford-Astra Zeneca COVID-19 vaccine in comparison with counterparts vaccinated with Pfizer/Moderna vaccines [5]. The mechanism of coagulopathy induced by Janssen/Johnson & Johnson vaccine has been supposed to be associated with the use of a recombinant vector DNA adenovirus as experimentally proven in animal models [7]. SARS-CoV2 infection has been demonstrated to trigger the release of tissue factor (TF)-positive extracellular vesicles (EVs) into the circulation [8]. TF has been advised to be involved in the pathogenesis of hypercoagulability related to COVID-19 infection [9]. TF represents a major activator of the coagulation cascade [8]. TF-positive EVs have been suggested to be likely to drive thrombosis in patients with COVID-19 [8]. An increase in the activity of circulating TF-positive EVs has been connected with higher severity and mortality in COVID-19 patients [8]. SARS-CoV2 has been shown to promote overexpression of TF in platelets and macrophages through downregulation of angiotensin converting enzyme 2 (ACE-2) leading to an increase in angiotensin II levels [9]. Interestingly, it has previously been detected in the murine model that expression of ACE-2 on the cell surface is down-regulated in response to both the infection of SARSCoV2 and recombinant spike protein alone implying that exposure to recombinant spike protein alone may trigger TF overexpression [9]. ChadOx1 nCOV-19 vaccine Oxford– AstraZeneca is an Adenovector vaccine [1]. Intriguingly, adenovirus has also been proven to cause a shift from anticoagulant to pro-coagulant activity in endothelial cells via induction of TF expression [10]. It has been written that there are gender differences in the frequencies of TF gene polymorphisms with additional changes in plasma levels corresponding to the different TF single nucleotide polymorphisms (SNPs) [11]. For instance, it has been observed that the TF 5466 A/G SNP is significantly more frequent in women when compared to men [12]. It has been demonstrated that in the coronary heart disease (CHD) population, the TF 5466 A/G SNP is significantly more common in