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

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL110860-02
Application #
8574173
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
2
Fiscal Year
2013
Total Cost
$230,164
Indirect Cost
$50,287
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Yeung, Jennifer; Tourdot, Benjamin E; Fernandez-Perez, Pilar et al. (2014) Platelet 12-LOX is essential for Fc?RIIa-mediated platelet activation. Blood 124:2271-9
Cines, Douglas B; Cuker, Adam; Semple, John W (2014) Pathogenesis of immune thrombocytopenia. Presse Med 43:e49-59
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Zhi, Huiying; Rauova, Lubica; Hayes, Vincent et al. (2013) Cooperative integrin/ITAM signaling in platelets enhances thrombus formation in vitro and in vivo. Blood 121:1858-67
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Cuker, Adam; Rux, Ann H; Hinds, Jillian L et al. (2013) Novel diagnostic assays for heparin-induced thrombocytopenia. Blood 121:3727-32

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