Thrombosis with thrombocytopenia after vaccination with the ChAdOx1 nCoV-19 vaccine (Oxford–AstraZeneca): implications of gender-specific tissue-factor gene polymorphisms?

1. Introduction

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 SARS-CoV2 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 women than men [13]. It has been recognized that the TF 5466 A/G genotype relates to a high TF response and a poor outcome in acute coronary syndrome [12]. TF 5466A/G polymorphism has also been found to predict plasma TF levels in subjects with cryptogenic ischemic stroke [14]. Notably, the HIT has been suggested to be induced by large amounts of TF [15]. Animal testing has shown that estrogenic formulations may influence individual thrombotic risk by various mechanisms that control TF and TF pathway inhibitor in platelets and platelet–leukocyte interactions providing the rationale for assessment of interactions among platelets and TF and TFPI expression on thrombin generation during estrogen treatment in humans with a greater susceptibility to develop thrombosis in women than men [16]. Women on oral contraceptive pills appear to have a higher risk of venous as well as arterial thrombosis [17]. It has been recognized that the risk for venous thrombosis is increased in females affected by inherited thrombophilia, whereas those with some additional acquired risk factors such as smoking may be susceptibility to arterial thrombosis [16,17]. All these contentions led me to hypothesize that gender differences in frequencies of SNPs in the TF gene may be responsible for very rare cases of unusual embolic and thrombotic events in females following Oxford-AstraZeneca, Vaxzevria vaccine. That being so, females with certain TF gene polymorphisms may be at an even greater risk for thrombosis than males as a result of estrogenic regulation of TF and TF pathway inhibitors, notwithstanding that in women on oral contraceptive use and/or postmenopausal hormone therapy clotting can take place in the absence of vaccination. I assume that anamnesis remains an essential and preliminary step before vaccination for excluding a history of clotting disorders or thrombotic events in a family member, as well as additional risk factors such as any oral estrogen/contraceptive use and smoking in order to prevent possible thrombotic events in women at such high risk.

2. Expert opinion

Gender differences in the frequencies of SNPs in the TF gene may be responsible for very rare cases of unusual embolic and thrombotic events in females following Oxford-AstraZeneca, Vaxzevria vaccine. That being so, females with certain TF gene polymorphisms may be at an even greater susceptibility to thrombosis than males as a result of estrogenic regulation of TF and TF pathway inhibitors, notwithstanding that in women on oral contraceptive use and/or postmenopausal hormone therapy clotting can take place in the absence of vaccination.

Declaration of interest

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgments

In memory of my dad Sossio Mormile.

Additional information

Funding

This paper was not funded.