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 #
1P01HL110860-01A1
Application #
8534258
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2012-09-01
Budget End
2013-06-30
Support Year
1
Fiscal Year
2012
Total Cost
$339,810
Indirect Cost
$126,000
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Reppschl├Ąger, Kevin; Gosselin, Jeanne; Dangelmaier, Carol A et al. (2016) TULA-2 Protein Phosphatase Suppresses Activation of Syk through the GPVI Platelet Receptor for Collagen by Dephosphorylating Tyr(P)346, a Regulatory Site of Syk. J Biol Chem 291:22427-22441
McKenzie, Steven E (2016) Syk Inhibition in Ischemic Stroke. Arterioscler Thromb Vasc Biol 36:1054-5

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