|Title:||An alpha II b beta 3 antagonist prevents thrombosis without causing Fc receptor γ-chain IIa-mediated thrombocytopenia||Authors:||Kuo Y.-J.
|Keywords:||binding sites; blood platelets; platelet glycoprotein GPIIb-IIIa complex; thrombocytopenia; thrombosis||Issue Date:||2017||Journal Volume:||15||Journal Issue:||11||Start page/Pages:||2230-2244||Source:||Journal of Thrombosis and Haemostasis||Abstract:||
Essentials FcγRIIa-mediated thrombocytopenia is associated with drug-dependent antibodies (DDAbs). We investigated the correlation between αIIbβ3 binding epitopes and induction of DDAbs. An FcγRIIa-transgenic mouse model was used to evaluate thrombocytopenia among anti-thrombotics. An antithrombotic with binding motif toward αIIbβ-propeller domain has less bleeding tendency. Summary: Background Thrombocytopenia, a common side effect of Arg-Gly-Asp-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 have different effects on induction of αIIbβ3 conformational change and platelet aggregation in the presence of AP2, an IgG1 inhibitory 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 Fc receptor γ-chain IIa (FcγRIIa) transgenic mice. Results TMV-7 has a binding motif that recognizes the αIIb β-propeller domain of αIIbβ3, unlike that of TMV-2. TMV-7 neither primed the platelets to bind ligand, nor caused a conformational change of αIIbβ3 as identified with the ligand-induced binding site mAb AP5. In contrast to eptifibatide and TMV-2, cotreatment of TMV-7 with AP2 did not induce FcγRIIa-mediated platelet aggregation and the 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 shows antiplatelet and antithrombotic activities resulting from a mechanism different from that of all other tested αIIbβ3 antagonists, and may offer advantages as a therapeutic agent with a better safety profile. ? 2017 International Society on Thrombosis and Haemostasis
|URI:||https://scholars.lib.ntu.edu.tw/handle/123456789/564103||ISSN:||15387933||DOI:||10.1111/jth.13803||SDG/Keyword:||alpha 2b beta 3 adrenergic receptor blocking agent; alpha 2b beta adrenergic receptor blocking agent; AP2 protein; beta 3 adrenergic receptor blocking agent; disintegrin; epitope; eptifibatide; Fc receptor IIa; immunoglobulin G1; monoclonal antibody; monoclonal antibody AP5; snake venom; TMV 2 snake venom; TMV 7 snake venom; unclassified drug; antibody; antithrombocytic agent; Fc receptor; FCGR2A protein, human; fibrinogen receptor; fibrinolytic agent; monoclonal antibody; peptide; phospholipase C gamma; protein kinase Syk; Syk protein, mouse; trimucrin; animal experiment; animal model; anticoagulation; antigen binding; antigen purification; antiplatelet activity; antithrombotic activity; Article; binding site; bleeding time; blood clotting time; controlled study; drug conformation; drug efficacy; drug half life; drug potency; hemostasis; human; idiopathic thrombocytopenic purpura; in vivo study; ligand binding; male; mouse; nonhuman; pathogenesis; priority journal; protein motif; signal transduction; snake; thrombocyte activation; thrombocyte aggregation; thrombocytopenia; thrombosis; transgenic mouse; Trimeresurus mucrosquamatus; animal; antagonists and inhibitors; blood; chemically induced; chemistry; comparative study; disease model; drug effect; genetic predisposition; genetics; immunology; immunoreceptor tyrosine based activation motif; Institute for Cancer Research mouse; metabolism; phenotype; protein conformation; structure activity relation; thrombocyte; thrombocytopenia; thrombosis; Animals; Antibodies; Antibodies, Monoclonal; Binding Sites; Blood Platelets; Disease Models, Animal; Fibrinolytic Agents; Genetic Predisposition to Disease; Humans; Immunoreceptor Tyrosine-Based Activation Motif; Male; Mice, Inbred ICR; Mice, Transgenic; Peptides; Phenotype; Phospholipase C gamma; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Protein Conformation; Receptors, IgG; Structure-Activity Relationship; Syk Kinase; Thrombocytopenia; Thrombosis
|Appears in Collections:||藥理學科所|
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