Thrombocytopenia and splenic platelet directed immune responses after intravenous ChAdOx1 nCov-19 administration

Vaccines against SARS-CoV-2 are based on a range of novel platforms, with adenovirus-based approaches (like ChAdOx1 nCov-19) being one of them. Recently a novel complication of SARS-CoV-2 targeted adenovirus vaccines has emerged: immune thrombocytopenia (ITP), either isolated, or accompanied by thrombosis (then termed VITT). This complication is characterized by low platelet counts, and in the case of VITT also by platelet-activating platelet factor 4 (PF4) antibodies reminiscent of heparin-induced thrombocytopenia leading to a prothrombotic state with clot formation at unusual anatomic sites. Here, we detected anti-platelet antibodies targeting platelet glycoprotein receptors in 30% of patients with proven VITT (n=27), as well as 42% of patients with isolated thrombocytopenia after ChAdOx1 nCov-19 vaccination (n=26), indicating broad antiplatelet autoimmunity in these clinical entities. We employ in vitro and in vivo models to characterize possible mechanisms of these platelet-targeted autoimmune responses leading to thrombocytopenia. We show that intravenous but not intramuscular injection of ChAdOx1 nCov-19 triggers platelet-adenovirus aggregate formation and platelet activation. After intravenous injection, these aggregates are phagocytosed by macrophages in the spleen and platelet remnants are found in the marginal zone and follicles. This is followed by a pronounced B-cell response with the emergence of circulating antibodies binding to platelets. Our work contributes to the understanding of platelet associated complications after ChAdOx1 nCov-19 administration and highlights accidental intravenous injection as a potential mechanism of platelet targeted autoimmunity. Hence, preventing intravenous injection when administering adenovirus-based vaccines could be a potential measure against platelet associated pathologies following the vaccination.