The contribution of genetic factors to thrombotic and bleeding outcomes in coronary patients randomised to IIb/IIIa antagonists

Shields, Denis C.; Fitzgerald, Anthony P.; O’Neill, Paul; Muckian, Clare; Kenny, Dermot; Moran, Barry; Cannon, Christopher P.; Byrne, Connie E; Fitzgerald, Desmond J.

doi:10.1038/sj.tpj.6500100

Cited by 16 publications

(14 citation statements)

References 41 publications

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“…Likewise, polymorphisms have been shown to affect the variability of response to oral GPIIb/IIIa receptor antagonists as observed in patients with unstable coronary syndromes [37]. However, polymorphisms may also be the cause for the occurrence of treatment-related bleeding [38,39].…”

Section: Platelet Gpiib/iiia Receptor Antagonistsmentioning

confidence: 98%

Platelet GPIIb/IIIa Receptor Antagonists in Human Ischemic Brain Disease

Seitz¹,

Siebler

2008

CVP

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The goal of acute stroke therapy is to salvage brain tissue by rapid cerebral artery recanalization to improve microcirculation. A major drawback of fibrinolysis is the activation of platelets leading to a high rate of re-occlusion. Antagonists of the platelet GPIIb/IIIa-receptor inhibit the binding of fibrinogen to platelets counteracting secondary thrombus formation. Also, they were shown to suppress thrombembolus formation and to limit lesion development in cerebral ischemia. We review the literature concerning the use of intravenously administered GPIIb/IIIa-receptor antagonists abciximab, eptifibatide and tirofiban for the treatment of patients with acute ischemic brain infarction. In multicenter, prospective, randomized and placebo-controlled trials abciximab had a higher cerebral bleeding risk, while tirofiban did not increase hemorrhage. When combined with fibrinolysis, abciximab and tirofiban were found to improve cerebral artery recanalization and tissue reperfusion resulting in reduced infarct volumes and improved neurological outcome. Thus, GPIIb/IIIa-receptor antagonists have a great potential for the treatment of acute stroke.

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Section: Platelet Gpiib/iiia Receptor Antagonistsmentioning

confidence: 98%

Platelet GPIIb/IIIa Receptor Antagonists in Human Ischemic Brain Disease

Seitz¹,

Siebler

2008

CVP

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“…2 Platelets adhere to areas of injury through engagement of adhesion receptors (including glycoproteins VI, IB/V/IX, α IIb β 3 ) with adhesive proteins (collagen, von Willebrand factor, and fibrinogen, respectively), triggering activation and shape change. Secondary platelet activation is triggered by soluble agonists released or generated as a consequence of platelet activation, including thromboxane (TXA 2 ) and adenosine diphosphate (ADP) or the formation of thrombin locally.…”

Section: Platelet Activation and Coronary Thrombosismentioning

confidence: 99%

Aspirin and Clopidogrel Resistance

Fitzgerald

Maree²

2007

Hematology

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Aspirin and clopidogrel provide significant clinical benefit in patients with cardiovascular disease. However, given the complexity of platelet activation, it is not surprising that aspirin or clopidogrel prevent a small proportion of cardiovascular events. Of late, the terms aspirin and clopidogrel "resistance" have entered the physicians' lexicon, and infer a lack of therapeutic response and a single underlying mechanism, which is misleading. The incidence of "resistance" detected in studies varies with the definition applied and assay used to measure response. Rather than true resistance, however, there is a variable response that reflects the unique pharmacology and pharmacokinetics of each drug, the clinical significance of which remains to be established. True "aspirin resistance" implies that cyclooxygenase-1 is less sensitive to inactivation by aspirin. Despite 95% inhibition of serum thromboxane B(2) by aspirin, residual platelet aggregation is detected in some cases, the clinical significance of which is unknown. Heritable factors directly and indirectly related to platelet cyclooxygenase may influence aspirin response. In contrast to aspirin, the response to clopidogrel is highly variable and reflects the bioavailability of the active metabolite and not "resistance" of the receptor to inhibition.

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“…Atherothrombosis and CAD are the outcome of a complex interaction between genes and the environment, but it is clear that variations in platelet activity modulate thrombus formation. For example, large-scale clinical trials of oral "antiplatelet" drugs demonstrate that minor variations in platelet function can dramatically increase the risk of myocardial infarction (3). Evidence suggests that single nucleotide polymorphisms are associated with changes in platelet function (4,5); however, conflicting results have been obtained when these polymorphisms are tested for disease association (6).…”

Section: Introductionmentioning

confidence: 99%

Platelet genomics and proteomics in human health and disease

Macaulay

Carr²,

Gusnanto³

et al. 2005

Journal of Clinical Investigation

150

100

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Proteomic and genomic technologies provide powerful tools for characterizing the multitude of events that occur in the anucleate platelet. These technologies are beginning to define the complete platelet transcriptome and proteome as well as the protein-protein interactions critical for platelet function. The integration of these results provides the opportunity to identify those proteins involved in discrete facets of platelet function. Here we summarize the findings of platelet proteome and transcriptome studies and their application to diseases of platelet function.

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The contribution of genetic factors to thrombotic and bleeding outcomes in coronary patients randomised to IIb/IIIa antagonists

Cited by 16 publications

References 41 publications

Platelet GPIIb/IIIa Receptor Antagonists in Human Ischemic Brain Disease

Platelet GPIIb/IIIa Receptor Antagonists in Human Ischemic Brain Disease

Aspirin and Clopidogrel Resistance

Platelet genomics and proteomics in human health and disease

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