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Complement Activation in Heparin Induced Thrombocytopenia

Program: Special Scientific Symposia
Session: Special Symposium on the Basic Science of Hemostasis and Thrombosis
Hematology Disease Topics & Pathways:
Biological, antibodies, Diseases, Bleeding and Clotting, HIT, Therapies, Thrombosis, Biological Processes, Immune Disorders, Clinically relevant, immune mechanism
Monday, December 7, 2020, 1:25 PM-1:30 PM

Gowthami M. Arepally, MD

Division of Hematology, Duke University Medical Center, Durham, NC

Heparin induced thrombocytopenia (HIT) is an aggressive thrombotic disorder initiated by ultralarge immune complexes (ULICs) containing IgG antibodies to a multivalent antigen composed of platelet factor 4 (PF4) and heparin (H). Despite significant advances in understanding HIT pathogenesis, patients with HIT remain at risk for death, amputation, recurrent thromboembolism and bleeding while receiving maximally tolerated doses of factor Xa or direct thrombin inhibitors (DTIs). The mechanisms underlying thrombosis in HIT are only partially understood. It is recognized that HIT ULICs activate cellular FcgRIIA to initiate a diverse array of cellular effector functions that engender a prothrombotic environment. However, ULICs also exert biologic effects apart from cellular FcgR. Studies performed over 40 years ago show that HIT serum and IgG robustly activate complement leading to complement deposition on endothelial cells and circulating platelets from HIT patients. To what extent these disparate activities of HIT ULICs are linked or contribute to the hypercoagulable state in HIT is not known. In this session, we will review recent data showing the complement activating effects of HIT antibodies essentially mediate FcgR-dependent cellular activation. Using in vitro and in vivo models, we demonstrate that HIT ULICs activate complement via the classical pathway, mediate cellular activation via FcgRIIA and essentially support the procoagulant effects of HIT antibodies. These studies provide a rationale for developing non-anticoagulant interventions in HIT and provide additional insights into the contribution of complement to other immune-complex mediated thrombotic disorders.

Disclosures: Arepally: Novartis: Consultancy; Annexon Biosciences: Consultancy, Other; Veralox Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biokit: Consultancy, Patents & Royalties; Apotex: Consultancy, Research Funding; Alexion: Other.

OffLabel Disclosure: discussion of complement therapeutics as potential therapies for HIT.

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