3 years ago

An αIIbβ3 antagonist prevents thrombosis without causing FcγRIIa-mediated thrombocytopenia

Ying-Ru Chen, Tur-Fu Huang, Chun-Chieh Hsu, Hui-Chin Peng, Yu-Ju Kuo
Background Thrombocytopenia, a common side effect of Arg-Gly-Asp (RGD)-mimetic antiplatelet drugs, is associated with drug-dependent antibodies (DDAbs) that recognize conformation-altered integrin αIIbβ3. Objective To explore the correlation between αIIbβ3 binding epitopes and induction of DDAb binding to conformation-altered αIIbβ3, we examined whether two purified disintegrins TMV-2 and TMV-7 with distinct binding motifs that have different effects on induction of αIIbβ3 conformational change and platelet aggregation in the presence of AP2, an IgG1 inhibitory monoclonal antibody (mAb) raised against αIIbβ3. Methods We investigated the possible mechanisms of intrinsic platelet activation of TMV-2 and TMV-7 in the presence of AP2 by examining the signal cascade, tail bleeding time and immune thrombocytopenia in FcγRIIa transgenic mice. Results TMV-7 has a binding motif that recognizes the αIIb β-propeller domain of αIIbβ3, different from that of TMV-2. TMV-7 neither primed the platelets to bind ligand, nor caused conformational change of αIIbβ3 identified by ligand-induced binding site (LIBS) mAb AP5. In contrast to eptifibatide and TMV-2, co-treatment of TMV-7 with AP2 did not induce FcγRIIa-mediated platelet aggregation and downstream activation cascade. Both TMV-2 and TMV-7 efficaciously prevented occlusive thrombosis in vivo. Notably, both eptifibatide and TMV-2 caused severe thrombocytopenia mediated by FcγRIIa, prolonged tail bleeding time in vivo, and repressed human whole blood coagulation-indexes, whereas TMV-7 did not impair hemostatic capacity. Conclusions TMV-7 displays antiplatelet and antithrombotic activities by a mechanism different from all other tested αIIbβ3 antagonists and may offer advantages as a therapeutic agent with a better safety profile. This article is protected by copyright. All rights reserved.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1111/jth.13803

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