Immune complexes, innate immunity, and NETosis in ChAdOx1 vaccine-induced thrombocytopenia

Abstract

Aims We recently reported five cases of vaccine-induced immune thrombotic thrombocytopenia (VITT) 7–10 days after receiving the first dose of the ChAdOx1 nCoV-19 adenoviral vector vaccine against corona virus disease 2019 (COVID-19). We aimed to investigate the pathogenic immunological responses operating in these patients. Methods and results We assessed circulating inflammatory markers by immune assays and immune cell phenotyping by flow cytometry analyses and performed immunoprecipitation with anti-platelet factor (PF)4 antibody in plasma samples followed by mass spectrometry from all five patients. A thrombus was retrieved from the sinus sagittal superior of one patient and analysed by immunohistochemistry and flow cytometry. Precipitated immune complexes revealed multiple innate immune pathway triggers for platelet and leucocyte activation. Plasma contained increased levels of innate immune response cytokines and markers of systemic inflammation, extensive degranulation of neutrophils, and tissue and endothelial damage. Blood analyses showed activation of neutrophils and increased levels of circulating H3Cit, dsDNA, and myeloperoxidase–DNA complex. The thrombus had extensive infiltration of neutrophils, formation of neutrophil extracellular traps (NETs), and IgG deposits. Conclusions The results show that anti-PF4/polyanion IgG-mediated thrombus formation in VITT patients is accompanied by a massive innate immune activation and particularly the fulminant activation of neutrophils including NETosis. These results provide novel data on the immune response in this rare adenoviral vector-induced VITT.

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“…These NETs are cytotoxic to pulmonary endothelial cells, and Zuo et al discovered that anti-NET antibodies contribute to NET stabilization, which may impair their clearance and exacerbate thromboinflammation. Very recently, NETs were also implicated in VIPIT following the Oxford/AstraZeneca vaccine [100], but the potential involvement of anti-NET antibodies remains to be determined.…”

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“…Procoagulant NETs biomarkers were elevated in serum of VITT patients, and abundant NETs were seen in cerebral venous thrombi from VITT patients by immunohistochemistry. Study by Holm et al [20] also found formation of immune complexes resulted in the release of an enormous amount of innate immune response cytokines and markers of systemic inflammatory into blood, extensive degranulation of neutrophils. Activated inflammatory response can lead to tissue and endothelial damage and promote thrombosis.…”

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“…Additionally, CD62P is a key ligand for platelet binding to neutrophils and monocytes ( 39 ), which can enhance platelet-neutrophil interactions during ALI, leading to the production of neutrophil extracellular traps (NETs) ( 64 ). NETs are associated with a type of cell death distinct from apoptosis and necrosis, a process known as NETosis ( 65 ), and the mechanism of their formation is not fully understood. They may provide the conditions for platelet capture and thrombosis in the pulmonary microcirculation through exposure to their extracellular histones, neutrophil granule proteins and extracellular DNA networks, ultimately leading to pulmonary endothelial injury and participating in the progression of ALI ( 66 , 67 ).…”