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αIIbβ3 Priming And Clustering By Orally Active And Intravenous Integrin Antagonists

R. Hantgan, M. C. Stahle, J. Connor, R. Connor, S. Mousa
Published 2007 · Chemistry

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Background: Drugs that block platelet–platelet and platelet–fibrin interactions via the αIIbβ3 (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 αIIbβ3 receptor in an activated state. It compared the effects on platelet function and αIIbβ3 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 cytometery, aggregometry, and clot‐based adhesion assays, respectively. Analytical ultracentrifugation measured each antagonist's effects on the solution structure of αIIbβ3. 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 αIIbβ3 conformation (priming) and promoting oligomerization (clustering): echistatin > eptifibatide > orbofiban > tirofiban > roxifiban. Roxifiban was also most effective at disrupting the rapidly forming/slowly dissociating αIIbβ3:echistatin complex. Conclusions: Our results suggest that the same molecular mechanisms that enable glycoprotein IIb/IIIa inhibitors to bind tightly to the αIIbβ3 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.
This paper references
10.1182/BLOOD.V76.2.345.BLOODJOURNAL762345
Glycoprotein Ib, von Willebrand factor, and glycoprotein IIb:IIIa are all involved in platelet adhesion to fibrin in flowing whole blood.
R. Hantgan (1990)
10.1161/01.CIR.0000157138.02645.11
Clopidogrel Loading With Eptifibatide to Arrest the Reactivity of Platelets: Results of the Clopidogrel Loading With Eptifibatide to Arrest the Reactivity of Platelets (CLEAR PLATELETS) Study
P. Gurbel (2005)
10.1016/S0735-1097(02)02666-9
Intravenous glycoprotein IIb/IIIa receptor antagonists reduce mortality after percutaneous coronary interventions.
E. Karvouni (2003)
10.1111/j.1423-0410.1974.tb02396.x
International Society on Thrombosis and Haemostasis
I. Peake (1974)
10.1016/J.AHJ.2005.02.024
A contemporary assessment of low-molecular-weight heparin for the treatment of acute coronary syndromes: factoring in new trials and meta-analysis data.
E. Topol (2005)
10.1016/J.JMB.2004.08.009
The Disintegrin Echistatin Stabilizes Integrin αIIbβ3's Open Conformation and Promotes Its Oligomerization
R. Hantgan (2004)
10.1182/blood.v64.4.896.896
A study of the kinetics of ADP-triggered platelet shape change.
R. Hantgan (1984)
10.1055/S-2003-40670
GPIIb/IIIa antagonists and other anti-integrins.
A. Nurden (2003)
Effects of ligand - mimetic peptides Arg - Gly - Asp - X ( X 1⁄4 Phe , Trp , Ser ) on a IIb b 3 integrin conformation and oligomerization
RR Hantgan (1999)
The PyMOL Molecular Graphics System
W. Delano (2002)
10.1055/S-0037-1613104
Tirofiban blocks platelet adhesion to fibrin with minimal perturbation of GpIIb/IIIa structure.
R. Hantgan (2002)
10.1056/nejm199805213382102
Inhibition of the platelet glycoprotein IIb/IIIa receptor with tirofiban in unstable angina and non-Q-wave myocardial infarction.
(1998)
a IIb b 3 priming and clustering by integrin antagonists 549
10.1161/01.CIR.103.2.201
Increased Mortality With Oral Platelet Glycoprotein IIb/IIIa Antagonists: A Meta-Analysis of Phase III Multicenter Randomized Trials
D. Chew (2001)
10.1016/J.AMJCARD.2005.04.009
Impact of platelet glycoprotein IIb/IIIa Inhibition on the paclitaxel-eluting stent in patients with stable or unstable angina pectoris or provocable myocardial ischemia (a TAXUS IV substudy).
P. Teirstein (2005)
10.1110/ps.3001
Binding of a fibrinogen mimetic stabilizes integrin αIIbβ3's open conformation
R. Hantgan (2001)
10.1161/01.CIR.0000137912.11655.F6
Association Between Platelet Receptor Occupancy After Eptifibatide (Integrilin) Therapy and Patency, Myocardial Perfusion, and ST-Segment Resolution Among Patients With ST-Segment–Elevation Myocardial Infarction: An INTEGRITI (Integrilin and Tenecteplase in Acute Myocardial Infarction) Substudy
C. Gibson (2004)
10.1074/jbc.274.53.37809
Structural Requirements of Echistatin for the Recognition of αvβ3 and α5β1Integrins*
I. Wierzbicka-Patynowski (1999)
10.1136/hrt.2003.017749
Distinct yet complementary mechanisms of heparin and glycoprotein IIb/IIIa inhibitors on platelet activation and aggregation: implications for restenosis during percutaneous coronary intervention
J. R. Day (2004)
Intravenous glycoprotein IIb/IIIa inhibitors in acute coronary syndromes: lessons from recently conducted randomized clinical trials.
E. Boersma (2004)
10.1021/BI9907680
Effects of ligand-mimetic peptides Arg-Gly-Asp-X (X = Phe, Trp, Ser) on alphaIIbbeta3 integrin conformation and oligomerization.
R. Hantgan (1999)
10.1016/S0002-9149(97)00572-9
Clinical pharmacology of eptifibatide.
D. R. Phillips (1997)
10.1097/01.mbc.0000164423.90545.a0
Using thrombelastography to determine the efficacy of the platelet glycoprotein IIb/IIIa antagonist, roxifiban, on platelet/fibrin-mediated clot dynamics in humans
S. Mousa (2005)
10.1016/S0731-7085(02)00481-8
A double antibody radioimmunoassay for the determination of XV459, the active hydrolysis metabolite of roxifiban, in human plasma.
H. Pieniaszek (2003)
10.1016/J.AHJ.2006.02.017
Lack of effect of enteric coating on aspirin-induced inhibition of platelet aggregation in healthy volunteers.
J. Karha (2006)
10.1016/s0021-9258(18)54042-4
Design of potent and specific integrin antagonists. Peptide antagonists with high specificity for glycoprotein IIb-IIIa.
R. Scarborough (1993)
10.1110/ps.052049506
Integrin αIIbβ3:ligand interactions are linked to binding‐site remodeling
R. Hantgan (2006)
Platelet glycoprotein IIb/IIIa inhibitors: recognition of a two-edged sword? Circulation
MJ Quinn (2003)
10.1016/S0735-1097(00)00919-0
Evidence of platelet activation during treatment with a GPIIb/IIIa antagonist in patients presenting with acute coronary syndromes.
D. Cox (2000)
Tirofiban ( Aggrastat )
JJ Cook (1999)
10.1124/mol.106.023986
Prevention of Platelet Glycoprotein IIb/IIIa Activation by 3,4-Methylenedioxy-β-Nitrostyrene, A Novel Tyrosine Kinase Inhibitor
Wei-Ya Wang (2006)
10.1111/j.1538-7836.2006.01829.x
Thrombocytopenia associated with the use of GPIIb/IIIa inhibitors: position paper of the ISTH working group on thrombocytopenia and GPIIb/IIIa inhibitors
R. Aster (2006)
10.1056/nejm199805213382103
A comparison of aspirin plus tirofiban with aspirin plus heparin for unstable angina.
(1998)
10.1016/S0002-9149(03)00816-6
Meta-analysis of survival with platelet glycoprotein IIb/IIIa antagonists for percutaneous coronary interventions.
D. Kong (2003)
10.1124/JPET.103.058883
Reversibility versus Persistence of GPIIb/IIIa Blocker-Induced Conformational Change of GPIIb/IIIa (αIIbβ3, CD41/CD61)
M. Schwarz (2004)
dence of platelet activation during treatment with a GPIIb / IIIa antagonist in patients presenting with acute coronary syndromes
D Cox (2000)
10.1016/S0002-8703(03)00186-8
Effects of roxifiban on platelet aggregation and major receptor expression in patients with coronary artery disease for the Roxifiban Oral Compound Kinetics Evaluation Trial-I (ROCKET-I Platelet Substudy).
V. Serebruany (2003)
10.1038/nature02976
Structural basis for allostery in integrins and binding to fibrinogen-mimetic therapeutics
T. Xiao (2004)
10.1016/J.AHJ.2005.09.004
Provisional glycoprotein IIb/IIIa blockade in a randomized investigation of bivalirudin versus heparin plus planned glycoprotein IIb/IIIa inhibition during percutaneous coronary intervention: predictors and outcome in the Randomized Evaluation in Percutaneous coronary intervention Linking Angiomax t
J. Exaire (2006)
10.1016/S0731-7085(02)00675-1
Simultaneous quantification of seven active metabolites of roxifiban in human plasma by LC/MS/MS in the presence of an interfering displacer at millimolar concentrations.
G. Shi (2003)
10.1016/J.AHJ.2006.02.013
Statins are associated with lower risk of gastrointestinal bleeding in patients with unstable coronary syndromes: analysis of the Orbofiban in Patients with Unstable coronary Syndromes-Thrombolysis In Myocardial Infarction 16 (OPUS-TIMI 16) trial.
S. Atar (2006)
10.1001/JAMA.284.12.1549
Current role of platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes.
Deepak L. Bhatt (2000)
10.1016/S0002-9343(02)01106-3
The failure of orally administered glycoprotein IIb/IIIa inhibitors to prevent recurrent cardiac events.
L. Newby (2002)
10.2165/00003495-200565140-00007
Eptifibatide: a review of its use in patients with acute coronary syndromes and/or undergoing percutaneous coronary intervention.
M. Curran (2005)
10.1016/0140-6736(90)90615-C
Audit of transfer of unconscious head-injured patients to a neurosurgical unit
D. Gentleman (1990)
Schematic diagram of priming and clustering effects linked to integrin antagonist binding to a IIb b 3 . The a IIb (blue) and b 3 (red) polypeptide
10.1016/J.AMJMED.2003.09.028
Integrating antithrombin and antiplatelet therapies with early invasive management for non-ST-segment elevation acute coronary syndromes.
A. Rebeiz (2004)
10.1074/jbc.M208869200
Ligand Binding Promotes the Entropy-driven Oligomerization of Integrin αIIbβ3 *
R. Hantgan (2003)
10.1016/J.TOXICON.2005.02.024
Snake venom disintegrins: evolution of structure and function.
J. Calvete (2005)
10.1097/00003246-200205001-00025
Platelet glycoprotein IIb/IIIa antagonists: lessons learned from clinical trials and future directions.
J. Leclerc (2002)
10.1161/01.RES.0000232317.84122.0c
Conformation-Specific Blockade of the Integrin GPIIb/IIIa: A Novel Antiplatelet Strategy That Selectively Targets Activated Platelets
M. Schwarz (2006)
Echistatin. A potent platelet aggregation inhibitor from the venom of the viper, Echis carinatus.
Z. Gan (1988)
10.1016/S0140-6736(99)00464-X
Difficulties with oral platelet glycoprotein IIb/IIIa receptor antagonists
C. Heeschen (2000)
10.1016/S0049-3848(99)00175-9
Antiplatelet and antithrombotic effects of orbofiban, a new orally active GPIIb/IIIa antagonist, in guinea pigs.
T. Ogawa (2000)
10.1016/S0002-9149(99)00778-X
Increased platelet reactivity in patients given orbofiban after an acute coronary syndrome: an OPUS-TIMI 16 substudy. Orbofiban in Patients with Unstable coronary syndromes. Thrombolysis In Myocardial Infarction.
M. B. Holmes (2000)
10.1016/J.PEP.2004.11.005
Functional expression of bitistatin, a disintegrin with potential use in molecular imaging of thromboembolic disease.
L. Knight (2005)
10.1161/01.CIR.0000019581.22812.B2
Platelet Glycoprotein IIb/IIIa Inhibitors: Recognition of a Two-Edged Sword?
M. Quinn (2002)
10.1016/J.AHJ.2005.02.022
Enoxaparin and glycoprotein IIb/IIIa inhibition in non-ST-elevation acute coronary syndrome: insights from the INTERACT trial.
S. Goodman (2005)
10.1016/J.AMJCARD.2005.08.066
Frequency and management of thrombocytopenia with the glycoprotein IIb/IIIa receptor antagonists.
Lindsay M Huxtable (2006)



This paper is referenced by
10.1126/scitranslmed.3003576
Structure-Guided Design of a High-Affinity Platelet Integrin αIIbβ3 Receptor Antagonist That Disrupts Mg2+ Binding to the MIDAS
J. Zhu (2012)
10.1021/bi1009858
Dynamic regulation of fibrinogen: integrin αIIbβ3 binding.
R. Hantgan (2010)
10.1111/j.1365-2125.2010.03879.x
Anti-platelet therapy: glycoprotein IIb-IIIa antagonists.
David J Schneider (2011)
10.1172/JCI36745
Eptifibatide-induced thrombocytopenia and thrombosis in humans require FcgammaRIIa and the integrin beta3 cytoplasmic domain.
C. Gao (2009)
10.1021/bi900475k
Integrin priming dynamics: mechanisms of integrin antagonist-promoted alphaIIbbeta3:PAC-1 molecular recognition.
R. Hantgan (2009)
10.1021/bc5000737
RGD labeled Ru(II) polypyridyl conjugates for platelet integrin αIIbβ3 recognition and as reporters of integrin conformation.
K. Adamson (2014)
10.1242/jcs.018440
Quantification of integrin receptor agonism by fluorescence lifetime imaging
M. Parsons (2008)
10.1101/264804
Morphometric analysis of spread platelets identifies integrin αIIbβ3-specific contractile phenotype
Sebastian Lickert (2018)
10.1101/620765
Novel Pure αVβ3 Integrin Antagonists That Do Not Induce Receptor Extension, Prime the Receptor, or Enhance Angiogenesis at Low Concentrations
J. Li (2019)
10.1161/ATVBAHA.114.303724
RUC-4: A Novel &agr;IIb&bgr;3 Antagonist for Prehospital Therapy of Myocardial Infarction
Jihong Li (2014)
10.1160/TH11-10-0727
GPIIb/IIIa inhibitors: from bench to bedside and back to bench again.
P. Armstrong (2012)
10.1021/bi701877a
Entropy drives integrin alphaIIbbeta3:echistatin binding--evidence from surface plasmon resonance spectroscopy.
R. Hantgan (2008)
10.1016/j.bmcl.2015.01.053
Discovery of novel antagonists of glycoprotein IIb/IIIa-mediated platelet aggregation through virtual screening.
Y. Wang (2015)
10.5005/JP/BOOKS/12415_19
Triple Antiplatelet Therapy in Acute Coronary Syndrome in 2014
R. Lochan (2014)
10.2741/3177
Disintegrins in health and disease.
M. A. McLane (2008)
10.1016/j.thromres.2011.11.054
Heparin modulates the conformation and signaling of platelet integrin αIIbβ3.
M. Yagi (2012)
10.1172/JCI66867
Translating from the rivers of Babylon to the coronary bloodstream.
B. Coller (2012)
10.1021/jm8003448
3,4-Dihydro-2H-1,4-benzoxazine derivatives combining thrombin inhibitory and glycoprotein IIb/IIIa receptor antagonistic activity as a novel class of antithrombotic compounds with dual function.
J. Ilaš (2008)
10.1097/EJA.0b013e32832eb521
Premature preoperative discontinuation of antiplatelet drug therapy in cardiovascular risk patients: a preliminary study on the role of P2Y12 receptor monitoring
H. Metzler (2010)
10.1038/s41598-018-23684-w
Morphometric analysis of spread platelets identifies integrin αIIbβ3-specific contractile phenotype
Sebastian Lickert (2018)
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