Integrin αiIbβ3: From discovery to efficacious therapeutic target

Circulation Research

Volumn 112, Issue 8, 2013, Pages 1189-1200

  Bledzka, Kamila ^a   Smyth, Susan S ^b   Plow, Edward F ^a  

^a LERNER RESEARCH INSTITUTE   (United States)

^b UNIVERSITY OF KENTUCKY   (United States)

Author keywords

IIb 3 antagonists; acute coronary syndromes; integrin; percutaneous coronary intervention

Indexed keywords

ABCIXIMAB; ALPHA2 INTEGRIN; ALPHA2BBETA3 INTEGRIN; ALPHA2BBETA3 INTEGRIN ANTAGONIST; ANTITHROMBOCYTIC AGENT; CLOPIDOGREL; EPTIFIBATIDE; THIENOPYRIDINE DERIVATIVE; TIROFIBAN; UNCLASSIFIED DRUG;

ACUTE CORONARY SYNDROME; BLEEDING; BRAIN HEMORRHAGE; DRUG DESIGN; DRUG EFFICACY; DRUG MARKETING; DRUG STRUCTURE; DRUG SYNTHESIS; DRUG TARGETING; GASTROINTESTINAL HEMORRHAGE; GLANZMANN DISEASE; GROIN HEMATOMA; HEART INFARCTION; HEART MUSCLE ISCHEMIA; HUMAN; INTRACORONARY INFUSION; NONHUMAN; PERCUTANEOUS CORONARY INTERVENTION; PRIORITY JOURNAL; PROTEIN FUNCTION; PROTEIN INDUCTION; RETROPERITONEAL HEMORRHAGE; REVIEW; THROMBOCYTE AGGREGATION; THROMBOCYTE AGGREGATION INHIBITION; THROMBOCYTOPENIA; THROMBOSIS;

ANIMALS; DRUG DISCOVERY; HUMANS; MOLECULAR TARGETED THERAPY; PLATELET AGGREGATION INHIBITORS; PLATELET GLYCOPROTEIN GPIIB-IIIA COMPLEX; THROMBOSIS; TREATMENT OUTCOME;

EID: 84876378206     PISSN: 00097330     EISSN: 15244571     Source Type: Journal    
DOI: 10.1161/CIRCRESAHA.112.300570     Document Type: Review

References (149)

1. Roger VL, Go AS, Lloyd-Jones DM, et al; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Executive summary: heart disease and stroke statistics-2012 update: a report from the American Heart Association. Circulation. 2012;125:188-197.
2. Coller BS. Translating from the rivers of Babylon to the coronary bloodstream. J Clin Invest. 2012;122:4293-4299.
3. Vanderslice P, Woodside DG. Integrin antagonists as therapeutics for in-fammatory diseases. Expert Opin Investig Drugs. 2006;15:1235-1255.
4. Cox D, Brennan M, Moran N. Integrins as therapeutic targets: lessons and opportunities. Nat Rev Drug Discov. 2010;9:804-820.
5. Millard M, Odde S, Neamati N. Integrin targeted therapeutics. Theranostics. 2011;1:154-188.
6. Goodman SL, Picard M. Integrins as therapeutic targets. Trends Pharmacol Sci. 2012;33:405-412.
7. Bizzozero G. Uber einen neuen formbestandteil des blutes und dessen rolle bei der thrombose und der blutgerinnung. Virchow Arch Path Anat Physiol 1882;90:267.
8. Glanzmann E. Hereditare haemorrhagische Thrombasthenie: ein beitrag zur patholigie der blutplattchen. Jahrb Kinderheilk 1918;88:113-141.
9. Nurden AT, Caen J P. Specifc roles for platelet surface glycoproteins in platelet function. Nature. 1975;255:720-722.
10. Phillips DR, Agin PP. Platelet plasma membrane glycoproteins. Evidence for the presence of nonequivalent disulfde bonds using non-reduced-reduced two-dimensional gel electrophoresis. J Biol Chem. 1977;252:2121-2126.
11. Phillips DR, Agin PP. Platelet membrane defects in Glanzmann's throm-basthenia. Evidence for decreased amounts of two major glycoproteins. J Clin Invest. 1977;60:535-545.
12. Kunicki TJ, Pidard D, Rosa JP, Nurden AT. The formation of Ca++-dependent complexes of platelet membrane glycoproteins IIb and IIIa in solution as determined by crossed immunoelectrophoresis. Blood. 1981;58:268-278.
13. Jennings LK, Phillips DR. Purifcation of glycoproteins IIb and III from human platelet plasma membranes and characterization of a calcium-dependent glycoprotein IIb-III complex. J Biol Chem. 1982;257:10458-10466.
14. Bennett JS. Structure and function of the platelet integrin alphaIIbbeta3. J Clin Invest. 2005;115:3363-3369.
15. Ma YQ, Qin J, Plow EF. Platelet integrin alpha(IIb)beta(3): activation mechanisms. J Thromb Haemost. 2007;5:1345-1352.
16. Marguerie GA, Plow EF, Edgington TS. Human platelets possess an inducible and saturable receptor specifc for fbrinogen. J Biol Chem. 1979;254:5357-5363.
17. Timmons S, Kloczewiak M, Hawiger J. ADP-dependent common receptor mechanism for binding of von Willebrand factor and fbrinogen to human platelets. Proc Natl Acad Sci USA. 1984;81:4935-4939.
18. Plow EF, McEver RP, Coller BS, Woods VL Jr, Marguerie GA, Ginsberg MH. Related binding mechanisms for fbrinogen, fbronectin, von Willebrand factor, and thrombospondin on thrombin-stimulated human platelets. Blood. 1985;66:724-727.
19. Reheman A, Gross P, Yang H, Chen P, Allen D, Leytin V, Freedman J, Ni H. Vitronectin stabilizes thrombi and vessel occlusion but plays a dual role in platelet aggregation. J Thromb Haemost. 2005;3:875-883.
20. André P, Prasad KS, Denis CV, He M, Papalia JM, Hynes RO, Phillips DR, Wagner DD. CD40L stabilizes arterial thrombi by a beta3 integrin-dependent mechanism. Nat Med. 2002;8:247-252.
21. Coller BS, Peerschke EI, Scudder LE, Sullivan CA. A murine monoclonal antibody that completely blocks the binding of fbrinogen to platelets produces a thrombasthenic-like state in normal platelets and binds to glycoproteins IIb and/or IIIa. J Clin Invest. 1983;72:325-338.
22. Plow EF, Pierschbacher MD, Ruoslahti E, Marguerie GA, Ginsberg MH. The effect of Arg-Gly-Asp-containing peptides on fbrinogen and von Willebrand factor binding to platelets. Proc Natl Acad Sci USA. 1985;82:8057-8061.
23. Kloczewiak M, Timmons S, Lukas TJ, Hawiger J. Platelet receptor recognition site on human fbrinogen. Synthesis and structure-function relationship of peptides corresponding to the carboxy-terminal segment of the gamma chain. Biochemistry. 1984;23:1767-1774.
24. Hynes RO. Integrins: a family of cell surface receptors. Cell. 1987;48:549-554.
25. Hynes RO. Integrins: versatility, modulation, and signaling in cell adhesion. Cell. 1992;69:11-25.
26. Springer TA, Wang JH. The three-dimensional structure of integrins and their ligands, and conformational regulation of cell adhesion. Adv Protein Chem. 2004;68:29-63.
27. Shattil SJ, Kim C, Ginsberg MH. The fnal steps of integrin activation: the end game. Nat Rev Mol Cell Biol. 2010;11:288-300.
28. Varner JA, Cheresh DA. Integrins and cancer. Curr Opin Cell Biol. 1996;8:724-730.
29. Byzova TV, Rabbani R, D'Souza S, Plow EF. Role of integrin aVb3 in vascular biology. Thromb Haemost 1998;80:726-734.
30. Bledzka K, Pesho MM, Ma YQ, Plow EF. Integrin alpha IIb beta 3. In: Michelson A, ed. Platelets. 3rd ed. Elsevier Science: San Diego, CA. 2012:233-248.
31. Felding-Habermann B, Cheresh DA. Vitronectin and its receptors. Curr Opin Cell Biol. 1993;5:864-868.
32. Brooks PC, Clark RA, Cheresh DA. Requirement of vascular integrin avb3 for angiogenesis. Science 1994;264:569-571.
33. Thiagarajan P, Kelly KL. Exposure of binding sites for vitronectin on platelets following stimulation. J Biol Chem. 1988;263:3035-3038.
34. Lawler J, Weinstein R, Hynes RO. Cell attachment to thrombospondin: the role of ARG-GLY-ASP, calcium, and integrin receptors. J Cell Biol. 1988;107:2351-2361.
35. Ruoslahti E. Integrins. J Clin Invest. 1991;87:1-5.
36. Ruoslahti E. Fibronectin and its receptors. Annu Rev Biochem. 1988;57: 375-413.
37. Egbertson MS, Chang CT, Duggan ME, Gould RJ, Halczenko W, Hartman GD, Laswell WL, Lynch JJ Jr, Lynch RJ, Manno PD. Non-peptide fbrinogen receptor antagonists. 2. Optimization of a tyrosine template as a mimic for Arg-Gly-Asp. J Med Chem. 1994;37:2537-2551.
38. Nurden AT, Pillois X, Nurden P. Understanding the genetic basis of Glanzmann thrombasthenia: implications for treatment. Expert Rev Hematol. 2012;5:487-503.
39. Nurden AT, Pillois X, Nurden P. Understanding the genetic basis of Glanzmann thrombasthenia: implications for treatment. Expert Rev Hematol. 2012;5:487-503.
40. Shpilberg O, Rabi I, Schiller K, Walden R, Harats D, Tyrrell KS, Coller B, Seligsohn U. Patients with Glanzmann thrombasthenia lacking platelet glycoprotein alpha(IIb)beta(3) (GPIIb/IIIa) and alpha(v) beta(3) receptors are not protected from atherosclerosis. Circulation. 2002;105:1044-1048.
41. Nurden AT, Fiore M, Nurden P, Pillois X. Glanzmann thrombasthenia: a review of ITGA2B and ITGB3 defects with emphasis on variants, phe-notypic variability, and mouse models. Blood. 2011;118:5996-6005.
42. Marguerie GA, Plow EF. The fbrinogen-dependent pathway of platelet aggregation. Ann N Y Acad Sci. 1983;408:556-566.
43. Takagi J, Petre BM, Walz T, Springer TA. Global conformational rearrangements in integrin extracellular domains in outside-in and inside-out signaling. Cell. 2002;110:599-511.
44. Qin J, Vinogradova O, Plow EF. Integrin bidirectional signaling: a molecular view. PLoS Biol. 2004;2:e169.
45. Luo BH, Carman CV, Springer TA. Structural basis of integrin regulation and signaling. Annu Rev Immunol. 2007;25:619-647.
46. Shattil SJ, Newman PJ. Integrins: dynamic scaffolds for adhesion and signaling in platelets. Blood. 2004;104:1606-1615.
47. Li Z, Delaney MK, O'Brien KA, Du X. Signaling during platelet adhesion and activation. Arterioscler Thromb Vasc Biol. 2010;30:2341-2349.
48. Quinn MJ, Plow EF, Topol EJ. Platelet glycoprotein IIb/IIIa inhibitors: recognition of a two-edged sword? Circulation. 2002;106:379-385.
49. Cox D, Smith R, Quinn M, Theroux P, Crean P, Fitzgerald DJ. Evidence of platelet activation during treatment with a GPIIb/IIIa antagonist in patients presenting with acute coronary syndromes. J Am Coll Cardiol. 2000;36:1514-1519.
50. Peter K, Schwarz M, Ylänne J, Kohler B, Moser M, Nordt T, Salbach P, Kübler W, Bode C. Induction of fbrinogen binding and platelet aggregation as a potential intrinsic property of various glycoprotein IIb/IIIa (alphaIIbbeta3) inhibitors. Blood. 1998;92:3240-3249.
51. Xiong JP, Stehle T, Diefenbach B, Zhang R, Dunker R, Scott DL, Joachimiak A, Goodman SL, Arnaout MA. Crystal structure of the extracellular segment of integrin alpha Vbeta3. Science. 2001;294:339-345.
52. Xiong JP, Stehle T, Zhang R, Joachimiak A, Frech M, Goodman SL, Arnaout MA. Crystal structure of the extracellular segment of inte-grin alpha Vbeta3 in complex with an Arg-Gly-Asp ligand. Science. 2002;296:151-155.
53. Xiao T, Takagi J, Coller BS, Wang JH, Springer TA. Structural basis for allostery in integrins and binding to fbrinogen-mimetic therapeutics. Nature. 2004;432:59-67.
54. Zhu J, Luo BH, Xiao T, Zhang C, Nishida N, Springer TA. Structure of a complete integrin ectodomain in a physiologic resting state and activation and deactivation by applied forces. Mol Cell. 2008;32:849-861.
55. Yang J, Ma YQ, Page RC, Misra S, Plow EF, Qin J. Structure of an integrin alphaIIb beta3 transmembrane-cytoplasmic heterocomplex provides insight into integrin activation. Proc Natl Acad Sci USA. 2009;106:17729-17734.
56. Lau TL, Kim C, Ginsberg MH, Ulmer TS. The structure of the integrin alphaIIbbeta3 transmembrane complex explains integrin transmembrane signalling. EMBO J. 2009;28:1351-1361.
57. Vinogradova O, Haas T, Plow EF, Qin J. A structural basis for integ-rin activation by the cytoplasmic tail of the alpha IIb-subunit. Proc Natl Acad Sci USA. 2000;97:1450-1455.
58. Vinogradova O, Velyvis A, Velyviene A, Hu B, Haas T, Plow E, Qin J. A structural mechanism of integrin alpha(IIb)beta(3) "inside-out" activation as regulated by its cytoplasmic face. Cell. 2002;110:587-597.
59. Ulmer TS, Yaspan B, Ginsberg MH, Campbell ID. NMR analysis of structure and dynamics of the cytosolic tails of integrin alpha IIb beta 3 in aqueous solution. Biochemistry. 2001;40:7498-7508.
60. Metcalf DG, Moore DT, Wu Y, Kielec JM, Molnar K, Valentine KG, Wand AJ, Bennett JS, DeGrado WF. NMR analysis of the alphaIIb beta3 cytoplasmic interaction suggests a mechanism for integrin regulation. Proc Natl Acad Sci USA. 2010;107:22481-22486.
61. Zhu J, Choi WS, McCoy JG, Negri A, Zhu J, Naini S, Li J, Shen M, Huang W, Bougie D, Rasmussen M, Aster R, Thomas CJ, Filizola M, Springer TA, Coller BS. Structure-guided design of a high-affnity platelet integrin alphaIIbbeta3 receptor antagonist that disrupts Mg(2)(+) binding to the MIDAS. Sci Transl Med 2012;4:125ra32.
62. Weiss EJ, Bray PF, Tayback M, Schulman SP, Kickler TS, Becker LC, Weiss JL, Gerstenblith G, Goldschmidt-Clermont PJ. A polymorphism of a platelet glycoprotein receptor as an inherited risk factor for coronary thrombosis. N Engl J Med. 1996;334:1090-1094.
63. Newman PJ, Derbes RS, Aster RH. The human platelet alloantigens, PlA1 and PlA2, are associated with a leucine33/proline33 amino acid polymorphism in membrane glycoprotein IIIa, and are distinguishable by DNA typing. J Clin Invest. 1989;83:1778-1781.
64. Vijayan KV, Goldschmidt-Clermont PJ, Roos C, Bray PF. The Pl(A2) polymorphism of integrin beta(3) enhances outside-in signaling and adhesive functions. J Clin Invest. 2000;105:793-802.
65. Bennett JS, Catella-Lawson F, Rut AR, Vilaire G, Qi W, Kapoor SC, Murphy S, FitzGerald GA. Effect of the Pl(A2) alloantigen on the function of beta(3)-integrins in platelets. Blood. 2001;97:3093-3099.
66. Zhu MM, Weedon J, Clark LT. Meta-analysis of the association of platelet glycoprotein IIIa PlA1/A2 polymorphism with myocardial infarction. Am J Cardiol. 2000;86:1000-5, A8.
67. Burr D, Doss H, Cooke GE, Goldschmidt-Clermont PJ. A meta-analysis of studies on the association of the platelet PlA polymorphism of glycopro-tein IIIa and risk of coronary heart disease. Stat Med. 2003;22:1741-1760.
68. Le Hello C, Morello R, Lequerrec A, Duarte C, Riddell J, Hamon M. Effect of PlA1/A2 glycoprotein IIIa gene polymorphism on the longterm outcome after successful coronary stenting. Thromb J. 2007;5:19.
69. Addad F, Elalamy I, Chakroun T, Abderrazek F, Dridi Z, Hamdi S, Hassine M, Ben-Farhat M, Gerotziafas G, Hatmi M, Gamra H. Platelet glycoprotein IIIa (platelet antigen 1/platelet antigen 2) polymorphism and 1-year outcome in patients with stable coronary artery disease. Blood Coagul Fibrinolysis. 2010;21:674-678.
70. Michelson AD, Furman MI, Goldschmidt-Clermont P, Mascelli MA, Hendrix C, Coleman L, Hamlington J, Barnard MR, Kickler T, Christie DJ, Kundu S, Bray PF. Platelet GP IIIa Pl(A) polymorphisms display different sensitivities to agonists. Circulation. 2000;101:1013-1018.
71. Wheeler GL, Braden GA, Bray PF, Marciniak SJ, Mascelli MA, Sane DC. Reduced inhibition by abciximab in platelets with the PlA2 polymorphism. Am Heart J. 2002;143:76-82.
72. Hanna EB, Rao SV, Manoukian SV, Saucedo JF. The evolving role of glycoprotein IIb/IIIa inhibitors in the setting of percutaneous coronary intervention strategies to minimize bleeding risk and optimize outcomes. JACC Cardiovasc Interv. 2010;3:1209-1219.
73. De Luca G, Navarese EP, Cassetti E, Verdoia M, Suryapranata H. Meta-analysis of randomized trials of glycoprotein IIb/IIIa inhibitors in high-risk acute coronary syndromes patients undergoing invasive strategy. Am J Cardiol. 2011;107:198-203.
74. Tricoci P, Newby LK, Hasselblad V, et al. Upstream use of small-molecule glycoprotein iib/iiia inhibitors in patients with non-ST-segment elevation acute coronary syndromes: a systematic overview of randomized clinical trials. Circ Cardiovasc Qual Outcomes. 2011;4:448-458.
75. Winchester DE, Wen X, Brearley WD, Park KE, Anderson RD, Bavry AA. Effcacy and safety of glycoprotein IIb/IIIa inhibitors during elective coronary revascularization: a meta-analysis of randomized trials performed in the era of stents and thienopyridines. J Am Coll Cardiol. 2011;57:1190-1199.
76. Kubica A, Kozinski M, Navarese EP, Grzesk G, Goch A, Kubica J. Intracoronary versus intravenous abciximab administration in STEMI patients: overview of current status and open questions. Curr Med Res Opin. 2011;27:2133-2144.
77. Bennett JS, Hoxie JA, Leitman SF, Vilaire G, Cines DB. Inhibition of fbrinogen binding to stimulated human platelets by a monoclonal antibody. Proc Natl Acad Sci USA. 1983;80:2417-2421.
78. Coller BS, Scudder LE. Inhibition of dog platelet function by in vivo infusion of F(ab')2 fragments of a monoclonal antibody to the platelet glycoprotein IIb/IIIa receptor. Blood. 1985;66:1456-1459.
79. Wagner CL, Mascelli MA, Neblock DS, Weisman HF, Coller BS, Jordan RE. Analysis of GPIIb/IIIa receptor number by quantifcation of 7E3 binding to human platelets. Blood. 1996;88:907-914.
80. Suzuki K, Sakai Y, Hisamichi N, Taniuchi Y, Sato K, Terazaki C, Kaku S, Kawasaki T, Yano S, Inagaki O, Masuho Y. Comparison of the antiplate-let effect of YM337 and abciximab in rhesus monkeys. Eur J Pharmacol. 1997;336:169-176.
81. Artoni A, Li J, Mitchell B, Ruan J, Takagi J, Springer TA, French DL, Coller BS. Integrin beta3 regions controlling binding of murine mAb 7E3: implications for the mechanism of integrin alphaIIbbeta3 activation. Proc Natl Acad Sci USA. 2004;101:13114-13120.
82. Gold HK, Coller BS, Yasuda T, Saito T, Fallon JT, Guerrero JL, Leinbach RC, Ziskind AA, Collen D. Rapid and sustained coronary artery recana-lization with combined bolus injection of recombinant tissue-type plas-minogen activator and monoclonal antiplatelet GPIIb/IIIa antibody in a canine preparation. Circulation. 1988;77:670-677.
83. Yasuda T, Gold HK, Fallon JT, Leinbach RC, Guerrero JL, Scudder LE, Kanke M, Shealy D, Ross MJ, Collen D. Monoclonal antibody against the platelet glycoprotein (GP) IIb/IIIa receptor prevents coronary artery reocclusion after reperfusion with recombinant tissue-type plasminogen activator in dogs. J Clin Invest. 1988;81:1284-1291.
84. The EPIC Investigators. Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angio-plasty. N Engl J Med 1994;330:956-961.
85. Simoons ML; GUSTO IV-ACS Investigators. Effect of glycoprotein IIb/IIIa receptor blocker abciximab on outcome in patients with acute coronary syndromes without early coronary revascularisation: the GUSTO IV-ACS randomised trial. Lancet. 2001;357:1915-1924.
86. Speich HE, Furman RR, Lands LT, Moodie GD, Jennings LK. Elevating local concentrations of GPIIb-IIIa antagonists counteracts platelet thrombus stability. J Thromb Thrombolysis. October 17, 2012. doi: 10.1007/s11239-012- 0814-7. http://link.springer.com/article/10.1007% 2Fs11239-012-0814-7. Accessed March 22, 2013.
87. Topol EJ, Lincoff AM, Kereiakes DJ, Kleiman NS, Cohen EA, Ferguson JJ, Tcheng JE, Sapp S, Califf RM. Multi-year follow-up of abciximab therapy in three randomized, placebo-controlled trials of percutaneous coronary revascularization. Am J Med. 2002;113:1-6.
88. Admiral Investigators. Three-year duration of beneft from abciximab in patients receiving stents for acute myocardial infarction in the randomized double-blind ADMIRAL study. Eur Heart J 2005;26:2520-2523.
89. Ndrepepa G, Kastrati A, Neumann FJ, Schmitt C, Mehilli J, Schömig A. Five-year outcome of patients with acute myocardial infarction enrolled in a randomised trial assessing the value of abciximab during coronary artery stenting. Eur Heart J. 2004;25:1635-1640.
90. Simon DI, Xu H, Ortlepp S, Rogers C, Rao NK. 7E3 monoclonal antibody directed against the platelet glycoprotein IIb/IIIa cross-reacts with the leukocyte integrin Mac-1 and blocks adhesion to fbrinogen and ICAM-1. Arterioscler Thromb Vasc Biol. 1997;17:528-535.
91. Coller BS. Binding of abciximab to alpha V beta 3 and activated alpha M beta 2 receptors: with a review of platelet-leukocyte interactions. Thromb Haemost. 1999;82:326-336.
92. Coller BS. Potential non-glycoprotein IIb/IIIa effects of abciximab. Am Heart J. 1999;138:S1-S5.
93. Hong YJ, Jeong MH, Lee SR, Hong SN, Kim KH, Park HW, Kim JH, Kim W, Ahn Y, Cho JG, Park JC, Kang JC. Anti-infammatory effect of abciximab-coated stent in a porcine coronary restenosis model. J Korean Med Sci. 2007;22:802-809.
94. Schühlen H, Kastrati A, Mehilli J, Hausleiter J, Dirschinger J, Dotzer F, Bollwein H, Schömig A. Abciximab and angiographic restenosis after coronary stent placement. Analysis of the angiographic substudy of ISAR-REACT-a double-blind, placebo-controlled, randomized trial evaluating abciximab in patients undergoing elective percutaneous coronary interventions after pretreatment with a high loading dose of clopi-dogrel. Am Heart J. 2006;151:1248-1254.
95. Kereiakes DJ, Runyon JP, Broderick TM, Shimshak TM. IIb's are not IIb's. Am J Cardiol 2000;85:23C-31C.
96. Phillips DR, Charo IF, Scarborough RM. GPIIb-IIIa: the responsive inte-grin. Cell. 1991;65:359-362.
97. Scarborough RM, Naughton MA, Teng W, Rose JW, Phillips DR, Nannizzi L, Arfsten A, Campbell AM, Charo IF. Design of potent and specifc integrin antagonists. Peptide antagonists with high specifcity for glycoprotein IIb-IIIa. J Biol Chem. 1993;268:1066-1073.
98. Lele M, Sajid M, Wajih N, Stouffer GA. Eptifbatide and 7E3, but not tirofban, inhibit alpha(v)beta(3) integrin-mediated binding of smooth muscle cells to thrombospondin and prothrombin. Circulation. 2001;104:582-587.
99. Phillips DR, Teng W, Arfsten A, Nannizzi-Alaimo L, White MM, Longhurst C, Shattil SJ, Randolph A, Jakubowski JA, Jennings LK, Scarborough RM. Effect of Ca2+ on GP IIb-IIIa interactions with integ-rilin: enhanced GP IIb-IIIa binding and inhibition of platelet aggregation by reductions in the concentration of ionized calcium in plasma antico-agulated with citrate. Circulation. 1997;96:1488-1494.
100. Ohman EM, Kleiman NS, Gacioch G, et al. Combined accelerated tissue-plasminogen activator and platelet glycoprotein IIb/IIIa integrin receptor blockade with Integrilin in acute myocardial infarction. Results of a randomized, placebo-controlled, dose-ranging trial. IMPACT-AMI Investigators. Circulation. 1997;95:846-854.
101. Harrington RA, Kleiman NS, Kottke-Marchant K, Lincoff AM, Tcheng JE, Sigmon KN, Joseph D, Rios G, Trainor K, Rose D. Immediate and reversible platelet inhibition after intravenous administration of a peptide glycoprotein IIb/IIIa inhibitor during percutaneous coronary intervention. Am J Cardiol. 1995;76:1222-1227.
102. Tcheng JE, Harrington RA, Kottke-Marchant K, Kleiman NS, Ellis SG, Kereiakes DJ, Mick MJ, Navetta FI, Smith JE, Worley SJ. Multicenter, randomized, double-blind, placebo-controlled trial of the platelet integ-rin glycoprotein IIb/IIIa blocker Integrelin in elective coronary intervention. IMPACT Investigators. Circulation. 1995;91:2151-2157.
103. Schulman SP, Goldschmidt-Clermont PJ, Topol EJ, et al. Effects of integrelin, a platelet glycoprotein IIb/IIIa receptor antagonist, in unstable angina. A randomized multicenter trial. Circulation. 1996;94:2083-2089.
104. The IMPACT II Investigators. Effects of competitive platelet glycopro-tein IIb/IIIa inhibition with integrilin in reducing complications of percutaneous coronary intervention. Lancet 1997;349:1422-1428.
105. Lincoff AM, Harrington RA, Califf RM, Hochman JS, Guerci AD, Ohman EM, Pepine CJ, Kopecky SL, Kleiman NS, Pacchiana CM, Berdan LG, Kitt MM, Simoons ML, Topol EJ. Management of patients with acute coronary syndromes in the United States by platelet glyco-protein IIb/IIIa inhibition. Insights from the platelet glycoprotein IIb/IIIa in unstable angina: receptor suppression using integrilin therapy (PURSUIT) trial. Circulation. 2000;102:1093-1100.
106. Harrington RA. Design and methodology of the PURSUIT trial: evaluating eptifbatide for acute ischemic coronary syndromes. Platelet glyco-protein IIb-IIIa in unstable angina: receptor suppression using integrilin therapy. Am J Cardiol. 1997;80:34B-38B.
107. The PURSUIT Investigators. Inhibition of the platelet glycoprotein IIb/IIIa with eptifbatide in patients with acute coronary syndromes. Platelet glycoprotein IIb/IIIa in unstable angina: receptor suppression using Integrilin therapy. N Engl J Med 1998;339:436-443.
108. The ESPRIT Investigators. Novel dosing regimen of eptifbatide in planned coronary stent implantation (ESPRIT): a randomised, placebo-controlled trial. Lancet 2000;356:2037-2044.
109. O'Shea JC, Hafey GE, Greenberg S, Hasselblad V, Lorenz TJ, Kitt MM, Strony J, Tcheng JE; ESPRIT Investigators (Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy trial). Platelet gly-coprotein IIb/IIIa integrin blockade with eptifbatide in coronary stent intervention: the ESPRIT trial: a randomized controlled trial. JAMA. 2001;285:2468-2473.
110. Tcheng JE, Talley JD, O'Shea JC, Gilchrist IC, Kleiman NS, Grines CL, Davidson CJ, Lincoff AM, Califf RM, Jennings LK, Kitt MM, Lorenz TJ. Clinical pharmacology of higher dose eptifbatide in percutaneous coronary intervention (the PRIDE study). Am J Cardiol. 2001;88:1097-1102.
111. Lynch JJ Jr, Cook JJ, Sitko GR, Holahan MA, Ramjit DR, Mellott MJ, Stranieri MT, Stabilito II, Zhang G, Lynch RJ. Nonpeptide glycoprotein IIb/IIIa inhibitors. 5. Antithrombotic effects of MK-0383. J Pharmacol Exp Ther. 1995;272:20-32.
112. Barrett JS, Murphy G, Peerlinck K, De Lepeleire I, Gould RJ, Panebianco D, Hand E, Deckmyn H, Vermylen J, Arnout J. Pharmacokinetics and pharmacodynamics of MK-383, a selective non-peptide platelet glyco-protein-IIb/IIIa receptor antagonist, in healthy men. Clin Pharmacol Ther. 1994;56:377-388.
113. Vickers S, Theoharides AD, Arison B, Balani SK, Cui D, Duncan CA, Ellis JD, Gorham LM, Polsky SL, Prueksaritanont T, Ramjit HG, Slaughter DE, Vyas KP. In vitro and in vivo studies on the metabolism of tirofban. Drug Metab Dispos. 1999;27:1360-1366.
114. Alexander JH, Harrington RA. Recent antiplatelet drug trials in the acute coronary syndromes. Clinical interpretation of PRISM, PRISM-PLUS, PARAGON A and PURSUIT. Drugs. 1998;56:965-976.
115. The RESTORE Investigators. Effects of platelet glycoprotein IIb/IIIa blockade with tirofban on adverse cardiac events in patients with unstable angina or acute myocardial infarction undergoing coronary angio-plasty. Circulation. 1997;96:1445-1453.
116. Herrmann HC, Swierkosz TA, Kapoor S, Tardiff DC, DiBattiste PM, Hirshfeld JW, Klugherz BD, Kolansky DM, Magness K, Valettas N, Wilensky RL. Comparison of degree of platelet inhibition by abciximab versus tirofban in patients with unstable angina pectoris and non-Q-wave myocardial infarction undergoing percutaneous coronary intervention. Am J Cardiol. 2002;89:1293-1297.
117. Topol EJ, Moliterno DJ, Herrmann HC, Powers ER, Grines CL, Cohen DJ, Cohen EA, Bertrand M, Neumann FJ, Stone GW, DiBattiste PM, Demopoulos L; TARGET Investigators. Do Tirofban and ReoPro Give Similar Effcacy Trial. Comparison of two platelet glycoprotein IIb/IIIa inhibitors, tirofban and abciximab, for the prevention of ischemic events with percutaneous coronary revascularization. N Engl J Med. 2001;344:1888-1894.
118. Schneider DJ, Herrmann HC, Lakkis N, Aguirre F, Lo MW, Yin KC, Aggarwal A, Kabbani SS, DiBattiste PM. Increased concentrations of tirofban in blood and their correlation with inhibition of platelet aggregation after greater bolus doses of tirofban. Am J Cardiol. 2003;91:334-336.
119. Valgimigli M, Campo G, Percoco G, et al; Multicentre Evaluation of Single High-Dose Bolus Tirofban vs Abciximab With Sirolimus-Eluting Stent or Bare Metal Stent in Acute Myocardial Infarction Study (MULTISTRATEGY) Investigators. Comparison of angioplasty with infusion of tirofban or abciximab and with implantation of siro-limus-eluting or uncoated stents for acute myocardial infarction: the MULTISTRATEGY randomized trial. JAMA. 2008;299:1788-1799.
120. Marzocchi A, Manari A, Piovaccari G, Marrozzini C, Marra S, Magnavacchi P, Sangiorgio P, Marinucci L, Taglieri N, Gordini G, Binetti N, Guiducci V, Franco N, Reggiani ML, Saia F; FATA Investigators. Randomized comparison between tirofban and abciximab to promote complete ST-resolution in primary angioplasty: results of the facilitated angioplasty with tirofban or abciximab (FATA) in ST-elevation myocar-dial infarction trial. Eur Heart J. 2008;29:2972-2980.
121. Jneid H, Anderson JL, Wright RS, Adams CD, Bridges CR, Casey DE Jr, Ettinger SM, Fesmire FM, Ganiats TG, Lincoff AM, Peterson ED, Philippides GJ, Theroux P, Wenger NK, Zidar JP. 2012 ACCF/AHA focused update of the guideline for the management of patients with unstable angina/non-ST-elevation myocardial infarction (updating the 2007 guideline and replacing the 2011 focused update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2012;60:645-681.
122. Pannu R, Andraws R. Effects of glycoprotein IIb/IIIa inhibitors in patients undergoing percutaneous coronary intervention after pretreat-ment with clopidogrel: a meta-analysis of randomized trials. Crit Pathw Cardiol. 2008;7:5-10.
123. Sabatine MS, Hamdalla HN, Mehta SR, Fox KA, Topol EJ, Steinhubl SR, Cannon CP. Effcacy and safety of clopidogrel pretreatment before percutaneous coronary intervention with and without glycoprotein IIb/IIIa inhibitor use. Am Heart J. 2008;155:910-917.
124. Michelson AD. Antiplatelet therapies for the treatment of cardiovascular disease. Nat Rev Drug Discov. 2010;9:154-169.
125. Singh IM, Holmes DR Jr. Myocardial revascularization by percutaneous coronary intervention: past, present, and the future. Curr Probl Cardiol. 2011;36:375-401.
126. Bosch X, Marrugat J, Sanchis J. Platelet glycoprotein IIb/IIIa blockers during percutaneous coronary intervention and as the initial medical treatment of non-ST segment elevation acute coronary syndromes. Cochrane Database Syst Rev 2010;9:CD002130.
127. Tcheng JE. Clinical challenges of platelet glycoprotein IIb/IIIa receptor inhibitor therapy: bleeding, reversal, thrombocytopenia, and retreatment. Am Heart J. 2000;139:S38-S45.
128. Tcheng JE, Kereiakes DJ, Lincoff AM, George BS, Kleiman NS, Sane DC, Cines DB, Jordan RE, Mascelli MA, Langrall MA, Damaraju L, Schantz A, Effron MB, Braden GA. Abciximab readministration: results of the ReoPro Readministration Registry. Circulation. 2001;104:870-875.
129. Curtis BR, Swyers J, Divgi A, McFarland JG, Aster RH. Thrombocytopenia after second exposure to abciximab is caused by antibodies that recognize abciximab-coated platelets. Blood. 2002;99:2054-2059.
130. Weitz JI, Bates SM. Beyond heparin and aspirin: new treatments for unstable angina and non-Q-wave myocardial infarction. Arch Intern Med. 2000;160:749-758.
131. Bougie DW, Wilker PR, Wuitschick ED, Curtis BR, Malik M, Levine S, Lind RN, Pereira J, Aster RH. Acute thrombocytopenia after treatment with tirofban or eptifbatide is associated with antibodies specifc for ligand-occupied GPIIb/IIIa. Blood. 2002;100:2071-2076.
132. Madan M, Berkowitz SD. Understanding thrombocytopenia and antigenic-ity with glycoprotein IIb-IIIa inhibitors. Am Heart J. 1999;138:317-326.
133. Bednar B, Cook JJ, Holahan MA, Cunningham ME, Jumes PA, Bednar RA, Hartman GD, Gould RJ. Fibrinogen receptor antagonist-induced thrombocytopenia in chimpanzee and rhesus monkey associated with preexisting drug-dependent antibodies to platelet glycoprotein IIb/IIIa. Blood. 1999;94:587-599.
134. Cox D. Oral GPIIb/IIIa antagonists: what went wrong? Curr Pharm Des. 2004;10:1587-1596.
135. Chew DP, Bhatt DL, Sapp S, Topol EJ. Increased mortality with oral platelet glycoprotein IIb/IIIa antagonists: a meta-analysis of phase III multicenter randomized trials. Circulation. 2001;103:201-206.
136. Du XP, Plow EF, Frelinger AL 3rd, O'Toole TE, Loftus JC, Ginsberg MH. Ligands "activate" integrin alpha IIb beta 3 (platelet GPIIb-IIIa). Cell. 1991;65:409-416.
137. Peter K, Schwarz M, Bode C. Activating effects of GPIIb/IIIa blockers: an intrinsic consequence of ligand-mimetic properties. Circulation. 2002;105:E180-E181.
138. Frelinger AL 3rd, Furman MI, Krueger LA, Barnard MR, Michelson AD. Dissociation of glycoprotein IIb/IIIa antagonists from platelets does not result in fbrinogen binding or platelet aggregation. Circulation. 2001;104:1374-1379.
139. Catella-Lawson F, Kapoor S, Moretti D, De Marco S, Vigilante GJ, Cucchiara AJ, Ramsey KE, Combe S, Rocca B, Theroux P, FitzGerald GA; AFIRME Investigators. Antagonism of the Fibrinogen Receptor after Myocardial Events. Oral glycoprotein IIb/IIIa antagonism in patients with coronary artery disease. Am J Cardiol. 2001;88:236-242.
140. Negri A, Li J, Naini S, Coller BS, Filizola M. Structure-based virtual screening of small-molecule antagonists of platelet integrin alphaIIb-beta3 that do not prime the receptor to bind ligand. J Comput Aided Mol Des 2012;26:1005-1015.
141. Koloka V, Christofdou ED, Vaxevanelis S, Dimitriou AA, Tsikaris V, Tselepis AD, Panou-Pomonis E, Sakarellos-Daitsiotis M, Tsoukatos DC. A palmitoylated peptide, derived from the acidic carboxyl-terminal segment of the integrin alphaIIb cytoplasmic domain, inhibits platelet activation. Platelets. 2008;19:502-511.
142. Blue R, Murcia M, Karan C, Jirousková M, Coller BS. Application of high-throughput screening to identify a novel alphaIIb-specifc small-molecule inhibitor of alphaIIbbeta3-mediated platelet interaction with fbrinogen. Blood. 2008;111:1248-1256.
143. Blue R, Kowalska MA, Hirsch J, Murcia M, Janczak CA, Harrington A, Jirouskova M, Li J, Fuentes R, Thornton MA, Filizola M, Poncz M, Coller BS. Structural and therapeutic insights from the species specifc-ity and in vivo antithrombotic activity of a novel alphaIIb-specifc al-phaIIbbeta3 antagonist. Blood. 2009;114:195-201.
144. Zhu J, Zhu J, Negri A, Provasi D, Filizola M, Coller BS, Springer TA. Closed headpiece of integrin αIIbβ3 and its complex with an αIIbβ3-specifc antagonist that does not induce opening. Blood. 2010;116:5050-5059.
145. Liu XY, Timmons S, Lin YZ, Hawiger J. Identifcation of a functionally important sequence in the cytoplasmic tail of integrin beta 3 by using cell-permeable peptide analogs. Proc Natl Acad Sci USA. 1996;93:11819-11824.
146. Petrich BG, Fogelstrand P, Partridge AW, Yousef N, Ablooglu AJ, Shattil SJ, Ginsberg MH. The antithrombotic potential of selective blockade of talin-dependent integrin alpha IIb beta 3 (platelet GPIIb-IIIa) activation. J Clin Invest. 2007;117:2250-2259.
147. Dehmer GJ, Weaver D, Roe MT, Milford-Beland S, Fitzgerald S, Hermann A, Messenger J, Moussa I, Garratt K, Rumsfeld J, Brindis RG. A contemporary view of diagnostic cardiac catheterization and percutaneous coronary intervention in the United States: a report from the CathPCI Registry of the National Cardiovascular Data Registry, 2010 through June 2011. J Am Coll Cardiol. 2012;60:2017-2031.
148. King A. Interventional cardiology: Radial access improves PCI outcomes. Nat Rev Cardiol. 2012;9:127.
149. De Luca G, Verdoia M, Suryapranata H. Benefts from intracoronary as compared to intravenous abciximab administration for STEMI patients undergoing primary angioplasty: a meta-analysis of 8 randomized trials. Atherosclerosis. 2012;222:426-433.