Program Director/Principal Investigator (Last, First, Middle): Poncz. Mortimer ABSTRiAtef Heparin-induced thrombocytopenia (HIT) is a serious complication of heparin therapy. Despite standard of care, withdrawal of heparin and use of a direct thrombin inhibitor (DTI), patients remain at significant risk for thrombosis. The pathogenesis of HIT has two major components: 1) formation of ultralarge complexes (ULC) of platelet factor 4 (PF4)/heparin (H)-containing immune complexes (IC) that activate platelets and other blood and vascular cells, and 2) events downstream of cellular activation by HIT IC, notably thrombin generation and action. DTIs do not prevent IC formation nor do they inhibit activation of platelets by HIT ICs. We hypothesize that combination therapy that targets critical effector molecules specific to HIT will be more effective than existing approaches to treatment. We recently reported that a specific inhibitor of Syk kinase, which mediates platelet activation via FcyRlla, prevents HIT-related thrombocytopenia and thrombosis in vivo in the HIT mouse model. We have observed that the Syk inhibitor is effective in reversing established HIT in vivo. In other preliminary studies, we identified novel small molecule PF4 antagonists (PAs) that prevent formation of PF4/H ULC immune complexes. We will pursue our studies in the following
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| Rauova, Lubica; Arepally, Gowthami; Poncz, Mortimer et al. (2018) Molecular and cellular pathogenesis of heparin-induced thrombocytopenia (HIT). Autoimmun Rev 17:1046-1052 |
| Khandelwal, Sanjay; Ravi, Joann; Rauova, Lubica et al. (2018) Polyreactive IgM initiates complement activation by PF4/heparin complexes through the classical pathway. Blood 132:2431-2440 |
| Gollomp, Kandace; Kim, Minna; Johnston, Ian et al. (2018) Neutrophil accumulation and NET release contribute to thrombosis in HIT. JCI Insight 3: |
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| Hayes, Vincent; Johnston, Ian; Arepally, Gowthami M et al. (2017) Endothelial antigen assembly leads to thrombotic complications in heparin-induced thrombocytopenia. J Clin Invest 127:1090-1098 |
| Arepally, Gowthami M (2017) Heparin-induced thrombocytopenia. Blood 129:2864-2872 |
| Nevzorova, Tatiana A; Zhao, Qingze; Lomakin, Yakov A et al. (2017) Single-Molecule Interactions of a Monoclonal Anti-DNA Antibody with DNA. Bionanoscience 7:132-147 |
| Lee, Grace M; Joglekar, Manali; Kuchibhatla, Maragatha et al. (2017) Serologic characterization of anti-protamine/heparin and anti-PF4/heparin antibodies. Blood Adv 1:644-651 |
| Zhou, Junsong; Wu, Yi; Chen, Fengwu et al. (2017) The disulfide isomerase ERp72 supports arterial thrombosis in mice. Blood 130:817-828 |
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