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NETosis and thrombosis in vaccine-induced immune thrombotic thrombocytopenia

Author

Listed:
  • 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
    New South Wales Health Pathology)

  • Fairooj N. Rashid

    (University of Sydney
    University of Sydney)

  • Anoop Enjeti

    (Calvary Mater Hospital
    University of Newcastle)

  • Stephen B. Ting

    (Eastern Health and Monash University)

  • James J. H. Chong

    (University of Sydney
    University of Sydney
    Westmead Hospital)

  • Beng H. Chong

    (University of New South Wales
    New South Wales Health Pathology)

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.

Suggested Citation

  • Halina H. L. Leung & Jose Perdomo & Zohra Ahmadi & Shiying S. Zheng & Fairooj N. Rashid & Anoop Enjeti & Stephen B. Ting & James J. H. Chong & Beng H. Chong, 2022. "NETosis and thrombosis in vaccine-induced immune thrombotic thrombocytopenia," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32946-1
    DOI: 10.1038/s41467-022-32946-1
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    References listed on IDEAS

    as
    1. José Perdomo & Halina H. L. Leung & Zohra Ahmadi & Feng Yan & James J. H. Chong & Freda H. Passam & Beng H. Chong, 2019. "Neutrophil activation and NETosis are the major drivers of thrombosis in heparin-induced thrombocytopenia," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    2. Thi-Huong Nguyen & Nikolay Medvedev & Mihaela Delcea & Andreas Greinacher, 2017. "Anti-platelet factor 4/polyanion antibodies mediate a new mechanism of autoimmunity," Nature Communications, Nature, vol. 8(1), pages 1-12, August.
    3. Angela Huynh & John G. Kelton & Donald M. Arnold & Mercy Daka & Ishac Nazy, 2021. "Antibody epitopes in vaccine-induced immune thrombotic thrombocytopaenia," Nature, Nature, vol. 596(7873), pages 565-569, August.
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