Platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes

Boersma, Eric; Harrington, Robert A.; Moliterno, David J.; White, Harold J.; Simoons, Maarten L.

doi:10.1016/s0140-6736(02)09532-6

Cited by 58 publications

(34 citation statements)

References 5 publications

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“…Several GPIIb/IIIa antagonists have been developed based on the fact that the binding of fibrinogen to GPIIb/IIIa is the final common pathway for platelet aggregation. Although intravenous GPIIb/IIIa antagonists have had a significant impact on outcomes of percutaneous coronary intervention by reducing the rate of postprocedure ischemic complications, their efficacy in the treatment of acute coronary syndromes is restricted to high-risk patients (Boersma et al, 2002). Moreover, the oral GPIIb/IIIa antagonists have been discontinued because of a lack of efficacy and increased mortality (Leclerc, 2002;Quinn et al, 2003).…”

mentioning

confidence: 99%

Prevention of Platelet Glycoprotein IIb/IIIa Activation by 3,4-Methylenedioxy-β-Nitrostyrene, A Novel Tyrosine Kinase Inhibitor

Wang

Wu²,

2006

Mol Pharmacol

112

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Binding fibrinogen to activated glycoprotein (GP)IIb/IIIa is the final common pathway of platelet aggregation and has become a successful target for antiplatelet therapy. In the present study, we found that a small chemical compound, 3,4-methylenedioxy-␤-nitrostyrene (MNS), exhibited potent and broadspectrum inhibitory effects on human platelet aggregation caused by various stimulators. Moreover, addition of MNS to human platelets that had been aggregated by ADP caused a rapid disaggregation. We demonstrated that the antiaggregatory activity of MNS is due to inhibition of GPIIb/IIIa activation by measuring the binding amount of PAC-1 in platelets. In contrast, MNS is not a direct antagonist of GPIIb/IIIa, because MNS did not affect fibrinogen binding to fixed ADP-stimulated platelets. By investigating how MNS inhibits GPIIb/IIIa activation, we found that MNS potently inhibited the activity of tyrosine kinases (Src and Syk) and prevented protein tyrosine phosphorylation and cytoskeletal association of GPIIb/IIIa and talin, but it had no direct effects on protein kinase C, Ca 2ϩ mobilization, Ca 2ϩ -dependent enzymes (myosin light chain kinase and calpain), and arachidonic acid metabolism, and it did not affect the cellular levels of cyclic nucleotides. Therefore, MNS represents a new class of tyrosine kinase inhibitor that potently prevents GPIIb/IIIa activation and platelet aggregation without directly affecting other signaling pathways required for platelet activation. Because MNS inhibits GPIIb/IIIa functions in a manner different from GPIIb/IIIa antagonists, this feature may provide a new strategy for treatment of platelet-dependent thrombosis.

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mentioning

confidence: 99%

Prevention of Platelet Glycoprotein IIb/IIIa Activation by 3,4-Methylenedioxy-β-Nitrostyrene, A Novel Tyrosine Kinase Inhibitor

Wang

Wu²,

2006

Mol Pharmacol

112

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“…9,18 The rate of use in the positive group was higher than in a previous study showing patients treated with GP IIb/IIIa inhibitors had lower unadjusted in-hospital mortality. 19 Because having any POC test performed was associated with more rapid treatment with GP IIb/IIIa inhibitors, it is possible that the POC test may have prompted that action, particularly when the test was positive.…”

Section: Discussionmentioning

confidence: 62%

The Usage Patterns of Cardiac Bedside Markers Employing Point‐of‐Care Testing for Troponin in Non‐ST‐Segment Elevation Acute Coronary Syndrome: Results from CRUSADE

Takakuwa

Peterson

et al. 2009

Clinical Cardiology

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Background: Point-of-care (POC) testing may expedite the care of emergency department (ED) patients suspected of having acute coronary syndromes (ACS). We evaluated the use patterns of cardiac bedside markers or POC testing for troponin in patients with non-ST-segment elevation (NSTE) ACS. Methods: NSTE ACS data were collected from the Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the American College of Cardiology/American Heart Association (ACC/AHA) Guidelines (CRUSADE) registry. We compared hospital and patient characteristics, in-hospital events, and process-of-care variables between hospitals to those that did not use POC testing in ≥ 50% of enrolled patients. We examined characteristics, in-hospital events, and process-of-care differences between patients with negative vs positive troponin POC testing results. Results: Of 568 hospitals, 74 (16,276 patients) had high POC usage compared with 197 hospitals (50 782 patients) with no troponin POC usage. From the high POC usage hospitals, 12 604 patients had recorded troponin POC test results. Hospitals with high POC usage had a shorter ED length of stay and were less likely to administer aspirin, β-blockers, and heparin during the first 24 hours of care. Patients with positive troponin POC results were more often older, minority, female, Medicare-insured, diabetic, and renally impaired. They had fewer electrocardiograms within 10 minutes but were more likely to get aspirin, β-blockers, glycoprotein IIb/IIIa inhibitors, and heparin within 24 hours of arrival. They also had longer ED lengths of stay, received fewer in-hospital and interventional procedures, and had more adverse clinical events. Conclusion: Differences existed in how hospitals used POC testing and the care given based on those results. Positive POC results are associated with expedited and higher use of anti-ischemic therapies. IntroductionEmergency department (ED) care of patients with possible acute coronary syndrome (ACS) is complex. With issues such as ED crowding, cost containment, and capitated reimbursement, evaluating patients for ACS and rapidly admitting, observing, or discharging them without error

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“…A combined analysis of the 6 trials (Nϭ31 402) revealed a 9% reduction in 30-day ischemic events, from 11.8% to 10.8% (Pϭ0.015). 101 The benefit of ␣ IIb ␤ 3 antagonists was most pronounced in patients undergoing PCIs, particularly those with diabetes 102 or with elevation of the cardiac marker troponin, suggesting that blockade of ␣ IIb ␤ 3 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.…”

Section: Antagonism Of ␣ Iib ␤mentioning

confidence: 99%

Integrin α _IIb β ₃ and Its Antagonism

Quinn

Byzova

Qin

et al. 2003

ATVB

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Abstract-␣ IIb ␤ 3 , the major membrane protein on the surface of platelets, is a member of the integrin family of heterodimeric adhesion receptors. The ␣ IIb and ␤ 3 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 ␣ IIb ␤ 3 into a functional receptor for fibrinogen or von Willebrand factor to support platelet aggregation and thrombus formation. These functions of ␣ IIb ␤ 3 have been targeted for antithrombotic therapy, and intravenous ␣ IIb ␤ 3 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 ␣ IIb ␤ 3 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 ␣ IIb ␤ 3 and platelets in the context of the new structural insights may explain its salutary and potential deleterious effects. n 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][4][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 (␤ 3 ), 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 ␣ IIb ␤ 3 , 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 ␣ IIb ␤ 3 could be an antithrombotic target.During the past 20 years, research on ␣ IIb ␤ 3 branched into 3 broad directions. First, fundamental analyses of the struc...

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Platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes

Cited by 58 publications

References 5 publications

Prevention of Platelet Glycoprotein IIb/IIIa Activation by 3,4-Methylenedioxy-β-Nitrostyrene, A Novel Tyrosine Kinase Inhibitor

Prevention of Platelet Glycoprotein IIb/IIIa Activation by 3,4-Methylenedioxy-β-Nitrostyrene, A Novel Tyrosine Kinase Inhibitor

The Usage Patterns of Cardiac Bedside Markers Employing Point‐of‐Care Testing for Troponin in Non‐ST‐Segment Elevation Acute Coronary Syndrome: Results from CRUSADE

Integrin α _IIb β ₃ and Its Antagonism

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Platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes

Cited by 58 publications

References 5 publications

Prevention of Platelet Glycoprotein IIb/IIIa Activation by 3,4-Methylenedioxy-β-Nitrostyrene, A Novel Tyrosine Kinase Inhibitor

Prevention of Platelet Glycoprotein IIb/IIIa Activation by 3,4-Methylenedioxy-β-Nitrostyrene, A Novel Tyrosine Kinase Inhibitor

The Usage Patterns of Cardiac Bedside Markers Employing Point‐of‐Care Testing for Troponin in Non‐ST‐Segment Elevation Acute Coronary Syndrome: Results from CRUSADE

Integrin α IIb β 3 and Its Antagonism

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Product

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Integrin α _IIb β ₃ and Its Antagonism