NETosis and thrombosis in vaccine-induced immune thrombotic thrombocytopenia

Halina H. L. Leung, Jose Perdomo, Zohra Ahmadi, Shiying S. Zheng, Fairooj N. Rashid, Anoop Enjeti, Stephen B. Ting, James J. H. Chong and Beng H. Chong ()
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Halina H. L. Leung: University of New South Wales
Jose Perdomo: University of New South Wales
Zohra Ahmadi: University of New South Wales
Shiying S. Zheng: University of New South Wales
Fairooj N. Rashid: University of Sydney
Anoop Enjeti: Calvary Mater Hospital
Stephen B. Ting: Eastern Health and Monash University
James J. H. Chong: University of Sydney
Beng H. Chong: University of New South Wales

Nature Communications, 2022, vol. 13, issue 1, 1-11

Abstract: Abstract Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare yet serious adverse effect of the adenoviral vector vaccines ChAdOx1 nCoV-19 (AstraZeneca) and Ad26.COV2.S (Janssen) against COVID-19. The mechanisms involved in clot formation and thrombocytopenia in VITT are yet to be fully determined. Here we show neutrophils undergoing NETosis and confirm expression markers of NETs in VITT patients. VITT antibodies directly stimulate neutrophils to release NETs and induce thrombus formation containing abundant platelets, neutrophils, fibrin, extracellular DNA and citrullinated histone H3 in a flow microfluidics system and in vivo. Inhibition of NETosis prevents VITT-induced thrombosis in mice but not thrombocytopenia. In contrast, in vivo blockage of FcγRIIa abrogates both thrombosis and thrombocytopenia suggesting these are distinct processes. Our findings indicate that anti-PF4 antibodies activate blood cells via FcγRIIa and are responsible for thrombosis and thrombocytopenia in VITT. Future development of NETosis and FcγRIIa inhibitors are needed to treat VITT and similar immune thrombotic thrombocytopenia conditions more effectively, leading to better patient outcomes.

Date: 2022
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DOI: 10.1038/s41467-022-32946-1

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