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Neutrophil activation and NETosis are the major drivers of thrombosis in heparin-induced thrombocytopenia

Author

Listed:
  • José Perdomo

    (Faculty of Medicine, University of New South Wales)

  • Halina H. L. Leung

    (Faculty of Medicine, University of New South Wales)

  • Zohra Ahmadi

    (Faculty of Medicine, University of New South Wales)

  • Feng Yan

    (Faculty of Medicine, University of New South Wales)

  • James J. H. Chong

    (The University of Sydney
    The University of Sydney
    Westmead Hospital
    Victor Chang Cardiac Research Institute)

  • Freda H. Passam

    (Faculty of Medicine, University of New South Wales)

  • Beng H. Chong

    (Faculty of Medicine, University of New South Wales
    New South Wales Health Pathology, St George and Sutherland Hospitals)

Abstract

Heparin-induced thrombocytopenia/thrombosis (HIT) is a serious immune reaction to heparins, characterized by thrombocytopenia and often severe thrombosis with high morbidity and mortality. HIT is mediated by IgG antibodies against heparin/platelet factor 4 antigenic complexes. These complexes are thought to activate platelets leading to thrombocytopenia and thrombosis. Here we show that HIT immune complexes induce NETosis via interaction with FcγRIIa on neutrophils and through neutrophil-platelet association. HIT immune complexes induce formation of thrombi containing neutrophils, extracellular DNA, citrullinated histone H3 and platelets in a microfluidics system and in vivo, while neutrophil depletion abolishes thrombus formation. Absence of PAD4 or PAD4 inhibition with GSK484 abrogates thrombus formation but not thrombocytopenia, suggesting they are induced by separate mechanisms. NETs markers and neutrophils undergoing NETosis are present in HIT patients. Our findings demonstrating the involvement of NETosis in thrombosis will modify the current concept of HIT pathogenesis and may lead to new therapeutic strategies.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-09160-7
    DOI: 10.1038/s41467-019-09160-7
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    Cited by:

    1. 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.

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