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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23:945.)
© 2003 American Heart Association, Inc.

ATVB In Focus

Integrin _IIbß₃ and Its Antagonism

Martin J. Quinn; Tatiana V. Byzova; Jun Qin; Eric J. Topol; Edward F. Plow

From the Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Departments of Cardiovascular Medicine (M.J.Q., E.J.T.) and Molecular Cardiology (T.V.B., J.Q., E.F.P.), Cleveland Clinic Foundation, Cleveland, Ohio.

Correspondence to Edward F. Plow, Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Department of Molecular Cardiology/NB50, Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195. E-mail plowe{at}ccf.org

Series Editor: Lawrence Brass
ATVB In Focus Platelet Activation and the Formation of the Platelet Plug

Previous Brief Reviews in this Series:

•Tsai H-M. Deficiency of ADAMTS13 causes thrombotic thrombocytopenic purpura. 2003;23:388–396.

	Abstract

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_IIbß₃, the major membrane protein on the surface of platelets, is a member of the integrin family of heterodimeric adhesion receptors. The _IIb and ß₃ subunits are each composed of a short cytoplasmic tail, a single transmembrane domain, and a large, extracellular region that consists of a series of linked domains. Recent structural analyses have provided insights into the organization of this and other integrins and how a signal is initiated at its cytoplasmic tail to transform the extracellular domain of _IIbß₃ into a functional receptor for fibrinogen or von Willebrand factor to support platelet aggregation and thrombus formation. These functions of _IIbß₃ have been targeted for antithrombotic therapy, and intravenous _IIbß₃ antagonists have been remarkably effective in the setting of percutaneous coronary interventions, showing both short-term and long-term mortality benefits. However, the development of oral antagonists has been abandoned on the basis of excess of mortality in clinical trials, and the extension of therapy with existing _IIbß₃ antagonists to broadly treat acute coronary syndromes has not fully met expectations. An in-depth understanding of how antagonists engage and influence the function of _IIbß₃ and platelets in the context of the new structural insights may explain its salutary and potential deleterious effects.

Key Words: platelets • acute coronary syndromes • aggregation • platelet function inhibitors

	Introduction

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In what is considered to be the first description of platelets, the Italian physician Bizzozero noted that these tiny elements of the blood could aggregate and that this propensity might contribute to thrombosis.¹ By the early 1900s, the Swiss physician Glanzmann had identified a group of patients in whom abnormal platelet aggregation was associated with a bleeding tendency.² Thus, the pathological importance of platelet aggregation has long served as a driving force to understand the molecular and cellular basis of this response. In the 1960s to 1970s, platelet aggregation was shown to be agonist induced, and fibrinogen and divalent cations were identified as cofactors.^3–5 As investigators began to characterize the membrane proteins of platelets by gel electrophoresis, they observed that the patterns of Glanzmann’s platelets were abnormal,⁶ and 2 glycoproteins, GPIIb (_IIb) and IIIa (ß₃), were missing from the surface of these platelets.⁷ Fibrinogen was found to bind to platelets with the characteristics of a receptor-mediated interaction, platelet aggregation was a consequence of this interaction, and this binding function was markedly diminished with Glanzmann’s platelets.^8–11 Within the first 5 years of the 1980s, ligands other than fibrinogen were shown to bind to _IIbß₃,^12,13 and peptides and antibodies that inhibited binding of these ligands and platelet aggregation were identified.^14–18 These latter observations established the principle that blockade of _IIbß₃ could be an antithrombotic target.

During the past 20 years, research on _IIbß₃ branched into 3 broad directions. First, fundamental analyses of the structure and function of the receptor have gained momentum. About 1 year ago, a breakthrough in these structure-function relations was provided with the report of the crystal structure of the extracellular domain of _IIbß₃,¹⁹ an integrin that shares the same ß-subunit with _IIbß₃. Second, the entire concept of bidirectional signaling across integrins in general and across _IIbß₃ in particular has emerged as a dominant theme. Activation of _IIbß₃ to become a competent receptor to bind ligand depends on transmission of a signal from within the cell to the extracellular domain, and occupancy of integrins generates signals that initiate numerous cellular responses.^20–24. Third, _IIbß₃ has been explored intensively and extensively as a target for antithrombotic therapy. These efforts led to US Food and Drug Administration (FDA) approval of 3 _IIbß₃ antagonists by 1999 and the expectation that additional antagonists and indications would soon follow.²⁵ To comprehensively address all aspects of _IIbß₃ in a brief review, we shall focus on recent advances relating to _IIbß₃ structure, ligand recognition, activation, and antagonism.

	Structure of IIbß3

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_IIbß₃ is restricted primarily to platelets and megakaryocytes, although it is found occasionally on tumor cells as well.²⁶ On platelets, _IIbß₃ is present at the highest density of all of the membrane proteins, 80 000 copies per resting platelet.²⁷ The membranes of platelet -granules also contain _IIbß₃²⁸ that becomes externalized on platelet secretion to increase the surface expression of _IIbß₃ by 25% to 50%.^29,30 As a typical integrin, _IIbß₃ is a noncovalent complex of an - and a ß-subunit (see Figure 1). Each subunit spans the platelet membrane once in a type I orientation. Both _IIb and ß₃ are glycosylated, and each is the product of a single gene located on chromosome 17.³¹ _IIb consists of 1008 amino acids. It is proteolytically processed into a heavy and a light chain (Figure 1). The light chain contains a 20–amino acid cytoplasmic tail, a transmembrane helix, and an extracellular segment that is disulfide linked to the heavy chain, which is entirely extracellular. The ß₃ subunit, 762 amino acids long, has a cytoplasmic tail of 48 amino acids.

View larger version (28K): [in this window] [in a new window]   Figure 1. Schematic representation of the structure of IIbß3 based on structural analyses. See Xiong et al19 and Beglova et al39 for details.

The model in Figure 1 and the following commentary rely heavily on the crystal structure of _vß_3.¹⁹ Each subunit consists of a series of linked domains. At the N-terminal aspects of the -subunits, a "ß-propeller," a large domain composed of a series of 60 amino acid repeats, which are arranged to form 7 "blades" that extend outward from a central core. This structure, first observed in G proteins, was predicted to be present in integrin -subunits by Springer.³² Within the blades at the base of the ß-propeller in the _IIb subunit are 4 divalent binding motifs, in which oxygenated amino acids within short hairpin loops coordinate cations. The remainder of the -subunit consists of 1 "thigh" and 2 "calf" domains. Between the thigh and the first calf module is a "genu," a bend that allows the molecule to compact. Not present in the crystallized molecule were the transmembrane and cytoplasmic tail regions. The structure of the cytoplasmic tail peptide of _IIb was solved by nuclear magnetic resonance (NMR)³³ and was found to be composed of a membrane-proximal helix that terminates in a bend. Six of the last 8 residues of _IIb are acidic and form a divalent cation–binding site.^34,35

The N-terminal aspect of ß₃ was not present in the crystal structure. Notable features of this region are Cys5, which forms a long disulfide loop to Cys435,^36,37 and position 33, the site of the PL^A1/2 polymorphism, which has been linked to an increased risk of coronary artery disease in some studies.³⁸ The first identifiable domain in the ß₃ subunit, the A domain, homologous to I domains within several integrin -subunits, contains 2 or 3 divalent cations sites, including a MIDAS motif that is prominently involved in ligand binding. A hybrid and a PSI domain, implicated in integrin activation, follow and connect to a protease-resistant region, in which a series of disulfide repeats are arranged into 4 endothelial growth factor (EGF)–like domains that were resolved by NMR.³⁹ The final structural motif discerned in the crystal structure was the ßTD. Molecular modeling suggested that a transmembrane helix might extend into the cytoplasmic tail.⁴⁰ Circular dichroism^34,40 and NMR⁴¹ support the propensity of the ß₃ tail to form an extended helix and a turn motif.

Rotary shadow images developed a number of years ago visualized _IIbß₃ as 2 "stalks" extending from a globular head,⁴² whereas the crystal structures of the extracellular domain of _vß₃ are compact structures.^19,43 This disparity led to considerable discussion in the literature (eg, Liddington⁴⁴). Most recently, it has been suggested that these conformational differences might be biologically relevant (see following section); they might represent the extremes in a series of conformational states between resting and activated forms of the ß₃ integrins.⁴⁵

	Ligand Recognition by IIbß3

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A defining characteristic of integrins is the capacity of each family member to bind multiple ligands. The ligand repertoire of _IIbß₃ includes fibrinogen, fibronectin, von Willebrand factor (vWF) vitronectin, CD40L, a number of the snake venom disintegrins, and a number of pathogens (reviewed in Plow et al⁴⁶). Fibrinogen and vWF support platelet aggregation. Although fibrinogen is present at substantially higher concentrations than vWF in plasma, initial platelet adhesion to the injured vessel wall is often mediated by vWF’s engaging GPIb on the platelet surface, which may lead to _IIbß₃:vWF interactions.⁴⁷ Moreover, in mice rendered deficient in both vWF and fibrinogen, _IIbß₃-dependent thrombus formation still occurs,⁴⁸ suggesting that still other ligands can support platelet aggregation. A recent study that also included deficient mice demonstrated that CD40L engagement of _IIbß₃ influences the growth and stability but not the initial formation of thrombi.⁴⁹

Two peptides, frequently referred to as the -chain and the RGD peptides, define the recognition specificity of _IIbß₃ (reviewed in Plow et al⁵⁰); these peptides inhibit the binding of most ligands to _IIbß₃ and inhibit platelet aggregation. The dimeric fibrinogen molecule contains 1 set of -chain and 2 sets of RGD sequences; mutation of the -chain but not the RGD sequences blocks fibrinogen binding to _IIbß₃.⁵¹ In contrast, mutation of the RGD sequence in vWF blocks its recognition by _IIbß₃.⁵² Recent data suggest that the RGD and -chain peptides interact with different but allosterically linked sites in _IIbß₃.⁵³ Accordingly, the _IIbß₃ antagonists can bind to different sites in the receptor, which has been demonstrated,^54,55 and which implies that their interaction with platelets can have different functional consequences.

In electron photomicrographs, fibrinogen contacted the globular head of _IIbß₃.⁴² On the basis of the first crystal structure of _vß₃, Xiaong et al¹⁹ suggested that the ß-propeller from _IIb and the A domain from ß₃ would form the ligand-binding site and hence, the globular head of the receptor (see Figure 1). In the crystal structure showing an RGD peptide bound to _vß₃, the Asp in RGD coordinated to the MIDAS-bound metal in the ß₃A domain, and the Arg coordinated with residues in the ß-propeller of _V.⁴³ The direct involvement of a ß₃A divalent cation and the _IIb ß-propeller domain establishes a molecular explanation for numerous studies implicating these regions in ligand binding.^56–63 Differences in the structure of the liganded and unliganded forms of _vß₃ were relatively subtle.

Although the crystal structure allows us to visualize how a peptide ligand binds to the receptor, protein ligand binding to _IIbß₃ is more complex. Fibrinogen binding to _IIbß₃ is a multistep process; initial reversible contact is followed by irreversible binding, such that the bound ligand no longer readily dissociates.^64–66 Internalization of bound fibrinogen might contribute to this transition in intact platelets⁶⁷ but might also involve formation of additional ligand-receptor contacts. As these contacts form, the conformations of the bound ligand and the occupied receptor change, which lead to the generation of neoepitopes that can be detected by antibodies to ligand-induced binding sites, in the receptor and receptor-induced binding sites, in the ligands.^68,69 Whereas _IIbß₃ is required for platelets to retract clots, fibrinogen with mutated -chain and RGD sites still retracts clots,^70,71 a likely reflection of additional _IIbß₃ contact sites.

	Activation of IIbß3

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_IIbß₃ was the first and remains the most prominent example of an integrin in which activation is pivotal for function.⁷² It is now clear that multiple integrins, including _vß₃, undergo activation.^73,74 Integrin activation can involve a change in affinity for ligand, a consequence of a conformational change in the receptor, or, in avidity for ligand, a consequence of receptor clustering.⁷⁵ Both mechanisms can lead to activation of _IIbß₃ (Figure 2), but affinity modulation appears to be dominant.⁷⁶ Activation of _IIbß₃ can be induced by a wide variety of physiologic agonists, which interact with 1 or more receptors on the platelet surface. The complex network of intracellular signaling events that lead from the agonist receptors to activation of _IIbß₃ have been considered in other reviews.^23,77 From studies of other receptor systems, it was anticipated that tyrosine phosphorylation of the cytoplasmic tails of integrins might play a key role in activation of _IIbß₃. With stringent efforts to inactivate phosphatases, Law et al⁷⁸ showed that 2 tyrosines in the cytoplasmic tail of ß₃ do undergo phosphorylation, but as a postreceptor occupancy event. Serine/threonine phosphorylation in the ß₃cytoplasmic tail does occur, although the stoichiometry may be low.^79,80

View larger version (51K): [in this window] [in a new window]   Figure 2. Mechanisms of integrin activation. In platelets, a variety of agonists, acting through specific receptors, can trigger intracellular signaling pathways that induce activation of the receptor. The inside-outside signal associates the complex of the IIb and ß3 cytoplasmic tails to induce affinity modulation or avidity modulation. Conformational change in the receptor underlies affinity modulation, whereas clustering of the receptors is the basis for avidity modulation.

Studies with peptides and molecular biology approaches suggested that the cytoplasmic tails of _IIbß₃ interact with each other,^{34,35,81–83} and mutational analyses suggested that this complex might regulate activation.^82,83 Earlier attempts by NMR to detect the complex between the cytoplasmic tails had been unsuccessful,^41,84 but 2 recent studies did detect such a complex.^85,86 In the most recent study, interaction was shown to occur between the membrane-proximal helical regions of the _IIb and ß₃ cytoplasmic tails (Figure 2). Mutations of residues in the interface that were previously shown to constitutively activate _IIbß₃, disrupted the tail complex, supporting the hypothesis that the complex maintains _IIbß₃ in a resting state and that its dissociation activated _IIbß₃. Therefore, molecules that dissociate the tail complex are predicted to activate _IIbß₃. Consistent with this prediction, incorporation of peptides that duplicated certain portions of the cytoplasmic tail of _IIb into platelets can influence activation of _IIbß₃^33,87,88 and might do so by dissociating the complex or by competing with molecules that bind to the cytoplasmic tails. Recent attention on such binding molecules with _IIbß₃-activating activity has focused on talin. This cytoskeletal protein binds directly to _IIbß₃,⁸⁹ and overexpression of talin domains in heterologous cells expressing _IIbß₃ induces activation.^90,91 Modifications of talin, such as its cleavage by calpain, may generate fragments that bind to the ß₃ tail with high affinity.⁹² Consistent with the postulated role of talin, NMR shows that the talin head domain generated by calpain dissociates the complex of _IIb and ß₃ cytoplasmic tails by displacing the _IIb from the ß₃ cytoplasmic tail.⁸⁶ Talin also binds to a second site on the ß₃ cytoplasmic tail.⁹¹ Several molecules that interact with the tails of _IIb and/or ß₃/ß₁ have been identified, and the physiologic role of these interactions in integrin activation remains to be established.

Several events, none of which are mutually exclusive, might occur subsequent to dissociation of the cytoplasmic tail complex and lead to ligand binding to _IIbß₃. One possibility raised by Li et al⁸⁴ is that the _IIb and ß₃ subunits self-associate through their transmembrane segments (Figure 2). These investigators observed homoaggregates of transmembrane plus cytoplasmic tail constructs. Formation of such complexes could represent a physiologic mechanism for integrin clustering. Takagi et al⁴⁵ suggested that the ß₃ integrins might activate by transitioning from the compact state observed in the crystal structure through a series of more open formats and ultimately could assume a form with extended stalks as observed in the early photomicrographs. This "switchblade" mechanism was proposed on the basis of microscopic, mutational, and biophysical measurements. Consistent with this model, it has long been known that _IIbß₃ can exist in multiple conformational states on the platelet surface: several different activated and occupied conformers of the receptor, as well as a resting state of _IIbß₃, can be distinguished with specific ligands and antibodies.⁹³

In the extracellular domain of _IIbß₃, it has been suggested that disulfide exchange might be involved in receptor activation.^94–96 Reducing agents can induce platelet aggregation⁹⁷ and activate _IIbß₃, Yan and Smith⁹⁶ noted that additional sulfhydryls in the ß₃ subunit can be labeled in activated compared with resting _IIbß₃. Previously, Essex and Li⁹⁸ had show that an antibody to protein disulfide isomerase could induce platelet aggregation, whereas O’Neill et al⁹⁴ suggested that _IIbß₃ might have intrinsic thiol isomerase activity. The possibility that disulfide rearrangement might trigger activation within the ligand-binding domain is intriguing but must be reconciled with crystallography data.

	Antagonism of IIbß3

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When we reviewed the status of _IIbß₃ antagonists about 3 years ago, their future appeared to be bright.²⁵ The benefit of _IIbß₃ antagonism with intravenous agents in the setting of percutaneous coronary interventions (PCIs) had been truly impressive, and their efficacy in other clinical settings appeared promising. Orally active agents were in the midst of development and provided the potential to extend the benefit of short-term therapy to the long-term secondary prevention of cardiovascular disease. In addition, the use of _IIbß₃ antagonists in conjunction with other antithrombotic or thrombolytic agents was under active consideration. This promising future, which raised the possibility that virtually all patients with ischemic heart disease might receive an _IIbß₃ antagonist, has now been replaced by the realization that the therapeutic niche of _IIbß₃ antagonists may be narrower than anticipated.⁹⁹

The 3 intravenous _IIbß₃ antagonists that were approved by the FDA were abciximab, a chimeric monoclonal antibody fragment; eptifibitide, a cyclic peptide based on a snake venom disintegrin; and tirofiban, a nonpeptide analogue of an RGD peptide. These agents, together with lamifiban, another nonpeptide antagonist, provide marked protection from ischemic events in patients undergoing PCI, leading to a relative risk reduction of 16% to 56% in 30-day ischemic end points in 6 clinical trials involving >12 000 patients (see Topol et al²⁵ and Figure 4 therein). With abciximab, the agent that has been most extensively studied in this setting, this early protection has translated into a long-term protection from death: in a combined analysis of the 3 major abciximab trials, EPIC, EPILOG, and EPISTENT, involving a total of 5799 patients, there was a 22% reduction in mortality (P=0.03) up to the 3-year follow-up.¹⁰⁰

It was hoped that the impressive benefits seen in the PCI setting would extend to the larger population of patients with the acute coronary syndromes of unstable angina or non–ST-segment elevation myocardial infarction. Six large trials of _IIbß₃ antagonism in acute coronary syndromes have been conducted (see Table). Overall, the outcomes in these trials indicated a benefit of _IIbß₃ antagonism, but they did not match that observed in a strict PCI setting. A combined analysis of the 6 trials (N=31 402) revealed a 9% reduction in 30-day ischemic events, from 11.8% to 10.8% (P=0.015).¹⁰¹ The benefit of _IIbß₃ antagonists was most pronounced in patients undergoing PCIs, particularly those with diabetes¹⁰² or with elevation of the cardiac marker troponin, suggesting that blockade of _IIbß₃ would be of benefit only in the high-risk acute coronary syndrome patients, a much more restrictive population. In fact, it was the high-risk acute coronary syndrome patient who was the target of therapy in the GUSTO IV trial; 59% of the enrolled patients were troponin-positive.¹⁰³ Patients were randomized to placebo or a bolus and a 24- or 48-hour infusion of abciximab. However, the drug did not show a benefit in the primary end point of 30-day death or myocardial infarction (8.0% for the placebo vs 8.2% for the 24-hour– and 9.1% for the 48-hour–treated groups; P=0.19). Unexpectedly, mortality increased significantly during the first 48 hours of drug infusion (from 0.3% in the placebo to 0.9% in the 48-hour abciximab infusion groups; P=0.008). The lack of treatment effect was consistent in all subgroups examined, including the high-risk, troponin-positive population. On the basis of these findings, the updated American Heart Association/American College of Cardiology guidelines for the management of patients with non–ST-segment elevation acute coronary syndromes now recommend the use of GPIIb/IIIa antagonists only in patients at high risk or in those in whom PCI is planned, a considerably restricted population than initially anticipated.

View this table: [in this window] [in a new window]   Summary of ACS Trials (30 Day Death/MI) Using IIbß3Antagonists

The development of orally active _IIbß₃ antagonists provided the potential for long-term therapy in the secondary prevention of cardiovascular disease. However, to the surprise of many, none of the 5 large trials of oral _IIbß₃ antagonism was successful; rather, a consistent increase in adverse events was demonstrated. A combined analysis confirmed this lack of efficacy and revealed a highly significant (35% relative, or 0.7% absolute) increase in the risk of death in the 45 523 patients studied.¹⁰⁴ These disappointing results halted further investigations into the use of these oral agents, and it now seems unlikely that oral _IIbß₃ inhibition will play a role in the secondary prevention of cardiovascular disease.

The combination of _IIbß₃ antagonists and thrombolytic agents showed the potential for faster, more durable, and more complete reperfusion in patients in phase II trials and pilot studies. These observations led to 2 larger phase III trials, GUSTO V and ASSENT III. In GUSTO V (N=16 588), patients were randomized within 6 hours of an evolving ST-segment elevation myocardial infarction to a standard dose of the intravenous thrombolytic agent reteplase or the combination of abciximab and half-dose reteplase.¹⁰⁵ Combination therapy failed to influence the primary end point of 30-day mortality, 5.9% in patients receiving standard therapy and 5.6% in the combination arm (P=0.43). The combination of reteplase and abciximab reduced the incidence of ischemic complications of myocardial infarction but was associated with increased bleeding, particularly in patients >75 years of age.¹⁰⁶ ASSENT-III compared the efficacy of the thrombolytic agent tenecteplase in combination with various heparins and abciximab in patients within 6 hours of the onset of acute ST-segment elevation myocardial infarction (N=6095).¹⁰⁷ The primary end point of 30-day death/myocardial infarction or refractory ischemia was reduced in the abciximab and low-molecular-weight heparin arms: abciximab 11.4%, P=0.0002; low-molecular-weight heparin 15.4%; and unfractionated heparin 11.1%, P<0.0001, but major bleeding, particularly in diabetics and older patients, increased. Whether the benefits of combination therapy will outweigh the risks and/or costs and compare favorably to catheter-based reperfusion therapy remains uncertain.

The reason why the _IIbß₃ antagonists have not lived up to expectations outside the setting of PCIs and might have induced deleterious effects has been the subject of considerable speculation. Potential mechanisms receiving particular attention have been (1) paradoxical _IIbß₃ antagonist–induced platelet and inflammatory cell activation and (2) the level of platelet inhibition targeted or achieved in the trials. _IIbß₃ antagonist–induced platelet and inflammatory cell activation has been demonstrated both ex vivo, as an increase in expression of markers of platelet activation,^108,109 and in vitro, as the induction of fibrinogen binding,¹¹⁰ calcium transients,¹¹¹ thromboxane A₂ production,¹⁰⁸ platelet-leukocyte aggregates,¹¹² and release of the inflammatory mediator CD40L.¹¹³ However, the reports of in vitro _IIbß₃ antagonist–induced activation have been conflicting and in some cases might have been attributed to prothrombin activation within the plasma.¹¹⁴ Furthermore, it is unclear whether all _IIbß₃ antagonists possess partial agonist effects. There is growing evidence that antagonists interact with a number of sites on _IIbß₃, resulting in distinct functional consequences. Thus, paradoxical platelet activation may only be a problem with certain _IIbß₃ antagonists.

Low levels of platelet inhibition have been associated with adverse outcomes. This factor undoubtedly played an important role in the failures of long-term oral therapy, as lower levels of platelet inhibition were targeted in these trials to limit bleeding side effects. In these trials, moderately fluctuating levels of platelet inhibition were seen owing to short half-lives and variable bioavailabilities of the oral compounds.¹¹⁵ Loss of platelet inhibition might also have been important in the apparent early untoward effect of abciximab in the GUSTO IV trial. Here, the usual abciximab bolus and 12-hour infusion were extended to 24 and 48 hours in the hope of prolonging platelet inhibition. However, this might not have been the case, as a loss of platelet inhibition demonstrated between 12 and 24 hours was observed with a 36-hour abciximab infusion.^116,117 Partial agonist effects of _IIbß₃ antagonists discussed in the preceding paragraph also must depend on the level of platelet inhibition. Hence, the 2 explanations for the undesirable outcomes obtained with _IIbß₃ antagonists are clearly interrelated.

In summary, the clinical development of antagonists of _IIbß₃ has been far from straightforward. The initial promise has been replaced by the realization that potent platelet inhibition with _IIbß₃ blockade does not necessarily translate into a dramatic improvement in clinical outcomes. At present, the indication of _IIbß₃ antagonists appears limited to short-term therapy at high levels of platelet inhibition in patients undergoing PCIs or initial medical therapy in high-risk patients with acute coronary syndromes. Patients receiving these agents with PCIs derived a pronounced benefit of mortality reduction and protection from myocardial infarction. With >1.5 million procedures per year worldwide, this is a substantial clinical benefit in the field of ischemic heart disease. In the future, further refinements in therapy might be possible. Needed is the ability to integrate recent structural information developed on the integrins and their activation into a clearer understanding of how _IIbß₃ antagonists affect the receptor and to determine whether still better and safer ways to antagonize the receptor can be achieved.

Received January 16, 2003; accepted February 24, 2003.

	References

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