title: PRT-060318, a novel Syk inhibitor, prevents heparin-induced thrombocytopenia and thrombosis in a transgenic mouse model.
abstract: Heparin-induced thrombocytopenia (HIT) is a major cause of morbidity and mortality resulting from the associated thrombosis. Extensive studies using our transgenic mouse model of HIT have shown that antibodies reactive with heparin-platelet factor 4 complexes lead to FcγRIIA-mediated platelet activation in vitro as well as thrombocytopenia and thrombosis in vivo. We tested PRT-060318 (PRT318), a novel selective inhibitor of the tyrosine kinase Syk, as an approach to HIT treatment. PRT318 completely inhibited HIT immune complex-induced aggregation of both human and transgenic HIT mouse platelets. Transgenic HIT model mice were treated with KKO, a mouse monoclonal HIT-like antibody, and heparin. The experimental group received orally dosed PRT318, whereas the control group received vehicle. Nadir platelet counts of PRT318-treated mice were significantly higher than those of control mice. When examined with a novel thrombosis visualization technique, mice treated with PRT318 had significantly reduced thrombosis. The Syk inhibitor PRT318 thus prevented both HIT immune complex-induced thrombocytopenia and thrombosis in vivo, demonstrating its activity in HIT.
authors.affiliation: Cardeza Foundation for Hematological Research, Department of Medicine, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Reilly
authors.forename: Uma
authors.initials: U
authors.lastname: Sinha
authors.forename: Pierrette
authors.initials: P
authors.lastname: André
authors.forename: Scott M
authors.initials: SM
authors.lastname: Taylor
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Pak
authors.forename: Francis R
authors.initials: FR
authors.lastname: Deguzman
authors.forename: Nisha
authors.initials: N
authors.lastname: Nanda
authors.forename: Anjali
authors.initials: A
authors.lastname: Pandey
authors.forename: Moritz
authors.initials: M
authors.lastname: Stolla
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Bergmeier
authors.forename: Steven E
authors.initials: SE
authors.lastname: McKenzie
mesh_terms: D000818:Animals; D000936:Antigen-Antibody Complex / Q000097:blood / Q000187:drug effects; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D006493:Heparin / Q000009:adverse effects*; D006801:Humans; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000097:blood; D051379:Mice; D008822:Mice, Transgenic; D015539:Platelet Activation / Q000187:drug effects / Q000276:immunology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000097:blood; D017452:Receptors, IgG / Q000037:antagonists & inhibitors; D000072377:Syk Kinase; D013921:Thrombocytopenia / Q000139:chemically induced / Q000276:immunology / Q000517:prevention & control*; D013927:Thrombosis / Q000139:chemically induced / Q000276:immunology / Q000517:prevention & control*
chemical_list: D000936:Antigen-Antibody Complex; D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D017452:Receptors, IgG; D006493:Heparin; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse