BACKGROUND: Drugs that block platelet-platelet and platelet-fibrin interactions via the alpha(IIb)beta(3) (glycoprotein IIb/IIIa) receptor are used daily in patients undergoing percutaneous coronary interventions. Along with expected increases in spontaneous bleeding, clinical trials have revealed a surprising increase in thrombosis when these drugs are used without other anticoagulants. A better understanding of their mechanisms can minimize these risks. OBJECTIVES: This study tested the hypothesis that interventions designed to block fibrinogen binding inevitably leave the alpha(IIb)beta(3) receptor in an activated state. It compared the effects on platelet function and alpha(IIb)beta(3) conformation of the orally active compounds orbofiban and roxifiban, the i.v. agents eptifibatide and tirofiban, and echistatin, an arginine-glycine-aspartate (RGD) disintegrin. METHODS: The integrin antagonist concentrations required to saturate platelets and to block platelet-platelet and platelet-fibrin interactions were determined by flow cytometry, aggregometry, and clot-based adhesion assays, respectively. Analytical ultracentrifugation measured each antagonist's effects on the solution structure of alpha(IIb)beta(3). Fluorescence anisotropy provided equilibrium and kinetic data for integrin:antagonist interactions. RESULTS: Both orally active drugs bound more tightly and inhibited platelet aggregation and adhesion to fibrin more effectively than echistatin. Analytical ultracentrifugation yielded this order for perturbing alpha(IIb)beta(3) conformation (priming) and promoting oligomerization (clustering): echistatin > eptifibatide > orbofiban > tirofiban > roxifiban. Roxifiban was also most effective at disrupting the rapidly forming/slowly dissociating alpha(IIb)beta(3):echistatin complex. CONCLUSIONS: Our results suggest that the same molecular mechanisms that enable glycoprotein IIb/IIIa inhibitors to bind tightly to the alpha(IIb)beta(3) receptor and block fibrinogen binding contribute to their ability to perturb the resting integrin's conformation, thus limiting the safety and efficacy of both oral and i.v. integrin antagonists.
BACKGROUND: Drugs that block platelet-platelet and platelet-fibrin interactions via the alpha(IIb)beta(3) (glycoprotein IIb/IIIa) receptor are used daily in patients undergoing percutaneous coronary interventions. Along with expected increases in spontaneous bleeding, clinical trials have revealed a surprising increase in thrombosis when these drugs are used without other anticoagulants. A better understanding of their mechanisms can minimize these risks. OBJECTIVES: This study tested the hypothesis that interventions designed to block fibrinogen binding inevitably leave the alpha(IIb)beta(3) receptor in an activated state. It compared the effects on platelet function and alpha(IIb)beta(3) conformation of the orally active compounds orbofiban and roxifiban, the i.v. agents eptifibatide and tirofiban, and echistatin, an arginine-glycine-aspartate (RGD) disintegrin. METHODS: The integrin antagonist concentrations required to saturate platelets and to block platelet-platelet and platelet-fibrin interactions were determined by flow cytometry, aggregometry, and clot-based adhesion assays, respectively. Analytical ultracentrifugation measured each antagonist's effects on the solution structure of alpha(IIb)beta(3). Fluorescence anisotropy provided equilibrium and kinetic data for integrin:antagonist interactions. RESULTS: Both orally active drugs bound more tightly and inhibited platelet aggregation and adhesion to fibrin more effectively than echistatin. Analytical ultracentrifugation yielded this order for perturbing alpha(IIb)beta(3) conformation (priming) and promoting oligomerization (clustering): echistatin > eptifibatide > orbofiban > tirofiban > roxifiban. Roxifiban was also most effective at disrupting the rapidly forming/slowly dissociating alpha(IIb)beta(3):echistatin complex. CONCLUSIONS: Our results suggest that the same molecular mechanisms that enable glycoprotein IIb/IIIa inhibitors to bind tightly to the alpha(IIb)beta(3) receptor and block fibrinogen binding contribute to their ability to perturb the resting integrin's conformation, thus limiting the safety and efficacy of both oral and i.v. integrin antagonists.
Authors: Jieqing Zhu; Won-Seok Choi; Joshua G McCoy; Ana Negri; Jianghai Zhu; Sarasija Naini; Jihong Li; Min Shen; Wenwei Huang; Daniel Bougie; Mark Rasmussen; Richard Aster; Craig J Thomas; Marta Filizola; Timothy A Springer; Barry S Coller Journal: Sci Transl Med Date: 2012-03-14 Impact factor: 17.956
Authors: Jihong Li; Spandana Vootukuri; Yi Shang; Ana Negri; Jian-Kang Jiang; Mark Nedelman; Thomas G Diacovo; Marta Filizola; Craig J Thomas; Barry S Coller Journal: Arterioscler Thromb Vasc Biol Date: 2014-08-21 Impact factor: 8.311
Authors: Jihong Li; Yoshiyuki Fukase; Yi Shang; Wei Zou; José M Muñoz-Félix; Lorena Buitrago; Johannes van Agthoven; Yixiao Zhang; Ryoma Hara; Yuta Tanaka; Rei Okamoto; Takeshi Yasui; Takashi Nakahata; Toshihiro Imaeda; Kazuyoshi Aso; Yuchen Zhou; Charles Locuson; Dragana Nesic; Mark Duggan; Junichi Takagi; Roger D Vaughan; Thomas Walz; Kairbaan Hodivala-Dilke; Steven L Teitelbaum; M Amin Arnaout; Marta Filizola; Michael A Foley; Barry S Coller Journal: ACS Pharmacol Transl Sci Date: 2019-08-02
Authors: Cunji Gao; Brian Boylan; Dan Bougie; Joan C Gill; Jessica Birenbaum; Debra K Newman; Richard H Aster; Peter J Newman Journal: J Clin Invest Date: 2009-02-09 Impact factor: 14.808
Authors: Maddy Parsons; Anthea J Messent; Jonathan D Humphries; Nicholas O Deakin; Martin J Humphries Journal: J Cell Sci Date: 2008-02-01 Impact factor: 5.285