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Adenovirus vaccines and thrombosis
(https://www.who.int/emergencies/diseases/novel-coronavirus- 2019/covid-19-vaccines; https://ourworldindata.org/covid-vacci- nations).
Although careful scrutiny of vaccine safety in con- trolled randomized phase III clinical trials did not high- light significant thrombotic risks, exceedingly rare events may have been missed and indeed during the vaccination campaign several cases of thrombosis, in particular thrombotic events at unusual sites associated with thrombocytopenia, were reported. Most events occurred in subjects who had received the ChAdOx1 (Vaxzevria) vaccine in the preceding weeks, but more recently several cases have also been reported following the Ad26-CoV2S Johnson&Johnson (Janssen) vaccine.1-9 Not only was the observed/expected ratio of these thromboses abnormally high in subjects receiving the Vaxzevria vaccine, but the clinical characteristics of the events were unique, associ- ating unusual site venous thromboses, mainly cerebral vein sinus thrombosis (CVST), with thrombocytopenia and sometimes disseminated intravascular coagulation (DIC). In contrast, no thromboses were reported in about 90 million subjects who had received the messenger RNA (mRNA)-based Pfizer BioNTech and only very few in those who had received the Moderna vaccine (Spikevax), although the latter had characteristics apparently dissim- ilar from those observed in Vaxzevria recipients, with one exception.10
These findings suggest that the reported thrombotic complications, which have variously been called vaccine- induced prothrombotic immune thrombocytopenia (VIPIT), vaccine-induced immune thrombotic thrombo- cytopenia (VITT), thrombotic thrombocytopenia syn- drome (TTS) and vaccine-associated thrombotic throm- bocytopenia syndrome (VATTS),2,11-13 are peculiar to aden- oviral (Ad) vector-based vaccines and have led to limita- tions and/or temporary suspensions of the use of such vaccines in several countries.
From the most recently available UK pharmacovigilance data (July 7, 2021), CVST and other major thromboembol- ic events with concurrent thrombocytopenia had been reported in 147 (average age, 54 years) and 258 subjects (average age, 54 years), respectively, among an estimated 24.6 million recipients of a first dose and an estimated 22.3 million recipients of a second dose of the Vaxzevria vac- cine. Thus, the overall incidence after first or unknown doses was 14.8 cases per million doses in the UK (https://www.gov.uk/government/publications/coronavirus- covid-19-vaccine-adverse-reactions/coronavirus-vaccine-summa- ry-of-yellow-card-reporting). Concerning Europe, as of June 27, 2021, there were spontaneous reports to EudraVigilance of 479 suspected cases, 100 of which had had a fatal outcome, among recipients of about 51.4 mil- lion doses of Vaxzevria, i.e. 19.3 cases per million doses (https://www.ema.europa.eu/en/documents/covid-19-vaccine- safety-update/covid-19-vaccine-safety-update-vaxzevria-previ- ously-covid-19-vaccine-astrazeneca-14-july-2021_en.pdf), and 21 cases of suspected TTS associated with the Janssen COVID-19 vaccine, four of which were fatal, among recipients of about 7 million doses of this vaccine, i.e. 3 cases per million doses (https://www.ema.europa.eu/en/docu- ments/covid-19-vaccine-safety-update/covid-19-vaccine-safety- update-covid-19-vaccine-janssen-14-july-2021_en.pdf).
This review aims to discuss the interactions between Ad vectors and Ad-based vaccines and the hemostatic system and the hypotheses on the mechanisms triggering VITT.
Adenoviruses, platelets and the blood coagulation system
Based on available data and given that VITT has been associated with Ad-vector-based vaccines, hypotheses on a direct role of the interaction between Ad and blood components can be made.
Ad are non-enveloped DNA viruses with a nucleopro-
tein core encapsulated by an icosahedral protein capsid
from which proteinaceous fibers protrude. The C-termi-
nal knob domain at the distal end of these fibers is
responsible for virus binding to its primary cellular recep-
tor, a 46-kDa transmembrane protein14-16 which also func-
tions as a receptor for Coxsackie B virus and is, therefore,
called coxsackie and Ad receptor (CAR).15-17 The high
affinity binding of Ad to CAR starts receptor-mediated
endocytosis.18 Moreover, Ad have evolved other mecha-
nisms to facilitate cell entry via recognition of the argi-
nine-glycine-aspartate (RGD) sequence on cell surface
integrins. Molecules expressed on host cell surfaces
involved in cell infection include the vitronectin-binding
integrins αvb3 and αvb5,19 the fibronectin-binding integrin
α5b 20 and others, such as α b ,21 all characterized by a com- 1V1
mon RGD peptide sequence which is recognized by the
RGD ligand in the HI fiber knob loop of the Ad penton
base protein. Although the CAR is expressed in almost all
tissues, including the adult nervous system and cerebral
vasculature,22,23 muscle,24 heart25 and the hematopoietic
system,26 its presence in platelets is debated. Othman et al.
identified CAR (by flow cytometry) and its mRNA (by
reverse transcriptase polymerase chain reaction) in
human platelets27 while Shimony et al. did not confirm
the presence of the receptor and proposed that binding of
Ad to platelets is mediated by an interaction between
RGD-binding motifs of Ad and platelet αVb28 (Figure 1). 3
Indeed, human megakaryocytes either do not express mRNA for CAR or express it at extremely low levels (J. Rowley and A.S. Weyrich, University of Utah, personal communication). After intravenous inoculation in mice, Ad rapidly bind circulating platelets causing their activation and subsequent entrapment in liver sinusoids where virus-platelet aggregates are taken up by Küpffer cells and degraded. Platelet activation is followed by activation of blood coagulation, leading to DIC.29 Activated platelets also release cytokines promoting endothelial cell activa- tion with secretion of von Willebrand factor, binding of platelets to endothelial cells and the formation of platelet/leukocyte aggregates, eventually triggering the development of microthrombi in liver sinusoids.21,29 There is also a complex interplay between Ad and the coagula- tion system. In fact, the distribution and activity of Ad in blood is affected by interactions with plasma proteins, including complement and vitamin K-dependent coagula- tion factors, which act as opsonizing agents. Our knowl- edge of these interactions derives mainly from in vitro observations and it is unknown whether the interplay of Ad with coagulation proteins affects the activity of the latter. Vitamin K-dependent coagulation factors, including the anticoagulant protein C, interact with Ad-5, the most widely used Ad vector. Activated protein C is generated on endothelial cells via the interaction of protein C with the thrombin-thrombomodulin complex and the endothelial protein C receptor (EPCR). Activated protein C requires protein S to express anticoagulant activity.30 Protein S circulates either free or associated with C4BP, a
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