Beyond Heparin and Aspirin

Weitz, Jeffrey I.; Bates, Shannon M.

doi:10.1001/archinte.160.6.749

Cited by 35 publications

(9 citation statements)

References 51 publications

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“…The objective of anticoagulant/antithrombotic therapy in cardiovascular disease is to prevent further fibrin deposition and platelet aggregation, halting current and future ischemic episodes [6]. While the most commonly used agents (heparin, coumadin and aspirin) have well established biological actions, there are some limitations to their effectiveness and this has led to the development of new antithrombotic compounds [6]. The results described here suggest that specific RNA aptamers directed at exosite-2 of thrombin may be used for many different facets of therapeutic regulation of thrombin.…”

Section: Discussionmentioning

confidence: 99%

RNA aptamer to thrombin binds anion‐binding exosite‐2 and alters protease inhibition by heparin‐binding serpins

Jeter

Fortenberry

et al. 2004

FEBS Letters

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We studied the RNA aptamer Toggle-25/thrombin interaction during inhibition by antithrombin (AT), heparin cofactor II (HCII) and protein C inhibitor (PCI). Thrombin inhibition was reduced 3-fold by Toggle-25 for AT and HCII, but it was slightly enhanced for PCI. In the presence of glycosaminoglycans, AT and PCI had significantly reduced thrombin inhibition with Toggle-25, but it was only reduced 3-fold for HCII. This suggested that the primary effect of aptamer binding was through the heparin-binding site of thrombin, anion-binding exosite-2 (exosite-2). We localized the Toggle-25 binding site to Arg 98, Glu 169, Lys 174, Asp 175, Arg 245, and Lys 248 of exosite-2. We conclude that a RNA aptamer to thrombin exosite-2 might provide an effective clinical reagent to control heparin's anticoagulant action.

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Section: Discussionmentioning

confidence: 99%

RNA aptamer to thrombin binds anion‐binding exosite‐2 and alters protease inhibition by heparin‐binding serpins

Jeter

Fortenberry

et al. 2004

FEBS Letters

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“…127 Readministration of abciximab did not cause an increased risk of anaphylaxis, but 2.4% of patients did develop a severe thrombocytopenia. 128,130 No data are available on the safety of tirofiban readministration, but high antibody titers have been found in some patients who developed thrombocytopenia after tirofiban treatment. 131 It is believed that tirofiban binding induces a conformational change in αIIbβ3, and antibodies arise against the newly exposed epitopes in αIIbβ3.…”

Section: Side Effects Of αIibβ3 Inhibitorsmentioning

confidence: 99%

Integrin αIIbβ3

Błędzka

Smyth

Plow

2013

Circulation Research

141

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From the initial description of platelets in 1882, their propensity to aggregate and to contribute to thrombosis was apparent. Indeed, excessive platelet aggregation is associated with myocardial infarction and other thrombotic diseases whereas Glanzmann thrombasthenia, in which platelet aggregation is reduced, is a bleeding syndrome. Over the last half of the 20th century, many investigators have provided insights into the cellular and molecular basis for platelet aggregation. The major membrane protein on platelets, integrin αIIbβ3, mediates this response by rapidly transiting from its resting to an activated state in which it serves as a receptor for ligands that can bridge platelets together. Monoclonal antibodies, natural products, and small peptides were all shown to inhibit αIIbβ3 dependent platelet aggregation, and these inhibitors became the forerunners of antagonists that proceeded through preclinical testing and into large patient trials to treat acute coronary syndromes, particularly in the context of percutaneous coronary interventions. Three such αIIbβ3 antagonists, abciximab, eptifibatide, and tirofiban, received Food and Drug Administration approval. Over the past 15 years, millions of patients have been treated with these αIIbβ3 antagonists and many lives have been saved by their administration. With the side effect of increased bleeding and the development of new antithrombotic drugs, the use of αIIbβ3 antagonists is waning. Nevertheless, they are still widely used for the prevention of periprocedural thrombosis during percutaneous coronary interventions. This review focuses on the biology of αIIbβ3, the development of its antagonists, and some of the triumphs and shortcomings of αIIbβ3 antagonism.

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“…A glycoprotein IIb/IIIa receptor blocker is a most potent inhibitor of platelet aggregation, and is activated on platelets by collagen, thrombin and adenosine diphosphate, which act as a receptor for fibrinogen and von Willebrand factor, causing thrombus formation 18 , 19 ) . In a previous large-scale trial, blockade of this receptor by abciximab, a human-murine chimeric antibody Fab fragment, was shown to reduce the incidence of acute ischemic events by 35% among patients undergoing “high-risk” PCI 7 ) .…”

Section: Discussionmentioning

confidence: 99%

The Long-term Clinical Results of a Platelet Glycoprotein IIb/IIIa Receptor Blocker Abciximab: ReoProR Coated Stent in Patients with Coronary Artery Disease

Kim

Jeong²,

Hong³

et al. 2004

Korean J Intern Med

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Background :Previously, the inhibition of coronary restenosis with Abciximab (ReoPro®)-coated stent in a porcine model was reported. ReoPro® inhibits platelet aggregation, the proliferation of vascular smooth muscle cells and the inflammatory reaction.Methods :A prospective randomized trial was performed to compare two types of stent for revascularization in the native coronary artery. The primary effective end points were major adverse coronary events (MACE): cardiac death, acute myocardial infarction, target vessel revascularization (TVR) and restenosis at the 6-month clinical and angiographic follow-ups.Results :One hundred and fifty-five patients were enrolled between August 2001 and June 2003. The mean ages (56.0±10.0 vs. 56.9±10.8 years), baseline diameter of stenosis and minimal luminal diameter were no different between the two groups. There was one myocardial infarction and revascularization during the hospital stay in control stent group. During the clinical follow-up there were two myocardial infarctions in control group. Follow-up coronary angiograms were performed in 62.3% (48/77) and 65.4% (51/78) of the coated and control groups, respectively. The diameter of stenosis and late loss were significantly less in the ReoPro®-coated stent group compared with the controls (16.4±5.8% vs. 34.3±6.1%, p=0.009; and 0.33±0.28 mm vs. 0.88±0.41 mm; p=0.002). The restenosis and TVR rates of the ReoPro®-coated stent were relatively lower compared with the control stent [14.6% (7/48) vs. 29.4% (15/51), p=0.062; and 9.2% (7/76) vs. 14.7% (11/75); p=0.327].Conclusion :A ReoPro®-coated stent is safe, and may be effective in the prevention of coronary restenosis.

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Beyond Heparin and Aspirin

Cited by 35 publications

References 51 publications

RNA aptamer to thrombin binds anion‐binding exosite‐2 and alters protease inhibition by heparin‐binding serpins

RNA aptamer to thrombin binds anion‐binding exosite‐2 and alters protease inhibition by heparin‐binding serpins

Integrin αIIbβ3

The Long-term Clinical Results of a Platelet Glycoprotein IIb/IIIa Receptor Blocker Abciximab: ReoProR Coated Stent in Patients with Coronary Artery Disease

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