PRT-060318, a novel Syk inhibitor, prevents heparin-induced thrombocytopenia and thrombosis in a transgenic mouse model

• Published in: Blood 2011-02, Vol.117 (7), p.2241-2246
• Main Authors: Reilly, Michael P., Sinha, Uma, André, Pierrette, Taylor, Scott M., Pak, Yvonne, DeGuzman, Francis R., Nanda, Nisha, Pandey, Anjali, Stolla, Moritz, Bergmeier, Wolfgang, McKenzie, Steven E.
• Format: Article
• Language: English
• Subjects: Animals; Antigen-Antibody Complex - blood; Antigen-Antibody Complex - drug effects; Biological and medical sciences; Blood Platelets - drug effects; Blood Platelets - enzymology; Blood Platelets - immunology; Hematologic and hematopoietic diseases; Heparin - adverse effects; Humans; In Vitro Techniques; Intracellular Signaling Peptides and Proteins - antagonists & inhibitors; Intracellular Signaling Peptides and Proteins - blood; Medical sciences; Mice; Mice, Transgenic; Platelet Activation - drug effects; Platelet Activation - immunology; Platelet diseases and coagulopathies; Platelets and Thrombopoiesis; Protein Kinase Inhibitors - pharmacology; Protein-Tyrosine Kinases - antagonists & inhibitors; Protein-Tyrosine Kinases - blood; Receptors, IgG - antagonists & inhibitors; Syk Kinase; Thrombocytopenia - chemically induced; Thrombocytopenia - immunology; Thrombocytopenia - prevention & control; Thrombosis - chemically induced; Thrombosis - immunology; Thrombosis - prevention & control; Thrombosis and Hemostasis
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2010-03-274969

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.