To clot or not to clot? Ad is the question—Insights on mechanisms related to vaccine‐induced thrombotic thrombocytopenia

Abstract

Vaccine‐induced immune thrombotic thrombocytopenia (VITT) has caused global concern. VITT is characterized by thrombosis and thrombocytopenia following COVID‐19 vaccinations with the AstraZeneca ChAdOx1 nCov‐19 and the Janssen Ad26.COV2.S vaccines. Patients present with thrombosis, severe thrombocytopenia developing 5–24 days following first dose of vaccine, with elevated D‐dimer, and PF4 antibodies, signifying platelet activation. As of June 1, 2021, more than 1.93 billion COVID‐19 vaccine doses had been administered worldwide. Currently, 467 VITT cases (0.000024%) have been reported across the UK, Europe, Canada, and Australia. Guidance on diagnosis and management of VITT has been reported but the pathogenic mechanism is yet to be fully elucidated. Here, we propose and discuss potential mechanisms in relation to adenovirus induction of VITT. We provide insights and clues into areas warranting investigation into the mechanistic basis of VITT, highlighting the unanswered questions. Further research is required to help solidify a pathogenic model for this condition.

ChAdOx1 interacts with CAR and PF4 with implications for thrombosis with thrombocytopenia syndrome

“…If large immune complexes formed directly with components of the vaccine formulation, then it seems more likely that they would lead to platelet activation and clot formation immediately following vaccination, rather than >5 days later. The discussion surrounding potential mechanisms for TTS has recently been reviewed (9). Fig.…”

“…Similar observations have been made in recipients of the Janssen HAdV-D26.COV2.S vaccine, derived from the species D human adenovirus type 26 (HAdV-D26) ( 5 , 7 ). The pathological mechanism underpinning TTS is unknown, although recent reports highlight a probable role for platelet factor 4 (PF4) ( 8 , 9 ).…”

Process- and product-related impurities in the ChAdOx1 nCov-19 vaccine

“…Shortly after receiving conditional marketing authorization in Europe, cases of thrombotic thrombocytopenia were observed, an unusual and, if untreated, often fatal syndrome of thrombosis of the cerebral venous sinuses and other large vessels together with low platelet counts. Occurring between 5 and 28 days after vaccination ( Othman et al, 2021 ), this syndrome, now coined vaccine-induced immune thrombotic thrombocytopenia (VITT) or thrombosis with thrombocytopenia syndrome, and related to autoimmune heparin-induced thrombocytopenia ( Greinacher et al, 2017 ), was found to be linked to vaccination with ChAdOx1 ( Paul-Ehrlich-Institut, 2021 ), and has been described to be mediated by platelet-activating antibodies against platelet factor 4 (PF4) ( Greinacher et al, 2021a ; Greinacher et al, 2021b ; Pavord et al, 2021 ; Schultz et al, 2021 ; Scully et al, 2021 ; Tiede et al, 2021 ; Wolf et al, 2021 ). Also Ad26.COV2.S has been linked to VITT ( Muir et al, 2021 ; Paul-Ehrlich-Institut, 2021 ), however at a lower frequency ( Paul-Ehrlich-Institut, 2022 ).…”

The aetiopathogenesis of vaccine-induced immune thrombotic thrombocytopenia

“…It has been shown that the electrostatic nature of the adenovirus capsid coupled with shape complementarity provides an opportunity for the adenovirus to cluster PF4, potentially creating neoantigens, which trigger the production of anti-PF4 from memory B-cells. 24,25 This 'clustering' of PF4 on the adenovirus capsid appears to occur primarily at the interface between the major capsid protein (hexon), and appears to be a relatively low affinity (∼300 -600 nM) and largely electrostatic interaction.…”