Interactions of adenoviruses with platelets and coagulation and the vaccine-induced immune thrombotic thrombocytopenia syndrome

Abstract

The Covid-19 pandemic has heavily impacted global health and economy and vaccination remains the primary way of controlling the infection. During the ongoing vaccination campaign some unexpected thrombotic events have emerged in subjects who recently received the AstraZeneca Vaxzevria vaccine or the Johnson&Johnson (Janssen) vaccine, two adenovirus vector-based vaccines. Epidemiological studies confirm that the observed/expected rate of these unusual thromboses is abnormally increased, especially in women in the fertile age. The characteristics of this complication, with venous thromboses at unusual sites, most frequently cerebral vein sinus but also splanchnic, often multiple associated thromboses, thrombocytopenia, and sometimes disseminated intravascular coagulation, are unique and the time course and tumultuous evolution are suggestive of an acute immunological reaction, and indeed platelet-activating anti-PF4 antibodies have been detected in a large fraction of the affected patients.
 Several data suggest that adenoviruses may interact with platelets, the endothelium and the blood coagulation system. Here we review the interactions between adenoviral vectors and the haemostatic system of possible relevance for the vaccine associated thrombotic thrombocytopenia syndrome, we analyse systematically the clinical data on the reported thrombotic complications of adenovirus-based therapeutics and discuss all the current hypotheses on the mechanisms triggering this novel syndrome.
 Although considering current evidence the benefit of vaccination clearly outweighs the potential risks, it is of paramount importance to fully unravel the mechanisms leading to the vaccine associated thrombotic thrombocytopenia syndrome and to identify prognostic factors through further research.

Safety of COVID-19 vaccination in patients with previous cerebral venous sinus thrombosis

“…In rare cases, CVST has been associated with adenovirus-vectored vaccines in the context of vaccine-induced immune thrombocytopenia (VITT) [1] , [2] . Adenoviruses may interact with platelets, the endothelium and the blood coagulation system causing its activation and, in rare cases, triggering an immunological reaction leading to the development of microthrombi in unusual sites [9] . However, experts conclude that benefits of vaccination outweigh the low risk of postvaccination thrombotic events.…”

Vaccine-induced massive pulmonary embolism and thrombocytopenia following a single dose of Janssen Ad26.COV2.S vaccination

“…To the best of our knowledge, this is the first case of VITT associated to the Ad26.COV2.S vaccine described in Italy. VITT has been mainly reported among females aged <55 years old and between 4 and 16 days after receiving adenoviral vector-based vaccines, although exceptions exist, such as 6 cases observed in males, in subjects up to 77 years old, and occurring as early as 2 to late 28 days after vaccination [Gresele, 2021a]. Its pathogenesis is still unclear and under investigation, but many reports highlight similarities with autoimmune heparin-induced thrombocytopenia (HIT), tracking a continuum between different platelet-activating anti-PF4/heparin disorders.…”

“…Autoimmune HIT is a form of HIT without any previous exposure to heparin. A possible role of the adenoviral vector platform and/or of free nucleic acids in the development of the autoimmune response have been suggested [Gresele, 2021a] Venous thrombosis in VITT typically occurs in unusual sites, including cerebral, splanchnic (splenic, portal, mesenteric, adrenal), and ophthalmic veins. Anticoagulation is a cornerstone of HIT-related thrombosis but is prevented by severe thrombocytopenia and DIC.…”

Potential Anionic Substances Binding to Platelet Factor 4 in Vaccine-Induced Thrombotic Thrombocytopenia of ChAdOx1-S Vaccine for SARS-CoV-2

“…As for substance 1 and substance 2, Gresele et al ( 16 ) pointed out that VITT develops usually at least 1 week after vaccination, it is very unlikely that circulating Ad-vector or vaccine excipients would still be present in the blood, rendering more likely alternative explanations, and in particular an immunological reaction.…”