Evidence that pre-existent variability in platelet response to ADP accounts for ‘clopidogrel resistance’: A rebuttal

Journal of Thrombosis and Haemostasis (Impact Factor: 5.72). 06/2007; 5(5):1087-8; author reply 1089-90. DOI: 10.1111/j.1538-7836.2007.02509.x
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Available from: Kevin P Bliden, Oct 02, 2014
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    ABSTRACT: Les plaquettes sanguines sont les principaux acteurs de l’hémostase primaire et de la thrombose, deux éléments majeurs de la physiopathologie vasculaire. Plusieurs médicaments régulent les fonctions plaquettaires mais peu de tests sont validés pour suivre leur efficacité en fonction de l’évolution clinique des patients. Mon doctorat a eu pour but de développer de nouvelles approches d’évaluation de la fonction plaquettaire. Deux essais cliniques réalisés sur des patients atteints de syndrome coronarien stable ont constitué la première partie de mon doctorat. La première étude met en évidence la nécessité d'une standardisation des tests biologiques pour la détection de patients répondant moins au clopidogrel, un inhibiteur du récepteur plaquettaire de l'ADP P2Y12. L’étude suivante montre le potentiel thérapeutique, chez ces patients, de l’inhibition conjointe de P2Y12 et du second récepteur plaquettaire de l'ADP P2Y1, sur la fonction plaquettaire. De plus, le suivi en temps réel par vidéomiscroscopie a permis de distinguer des effets précoces et tardifs des antiplaquettaires sur la formation du thrombus en chambre de perfusion. La seconde partie de mon doctorat concerne les microdomaines membranaires de type « lipid rafts » qui tiennent une place fondamentale dans les fonctions cellulaires et plaquettaires. Ainsi plusieurs récepteurs dépendent de ces microdomaines, régulant la fonction plaquettaire et les effets des médicaments antiplaquettaires. Cependant, les techniques d’étude de ces microdomaines sont complexes et peu adaptées aux études cliniques. Profitant de nouvelles sondes fluorescentes sensibles au niveau d’ordre liquide membranaire (OLM), nous avons développé une méthode de mesure de l’OLM par cytométrie de flux spectrale. Grâce à cette approche, nous avons montré que l’activation plaquettaire diminue l’OLM alors qu’il est augmenté chez des patients traités par un inhibiteur de la synthèse du cholestérol ou par le clopidogrel. Nous avons également mis en évidence, en condition de forces de cisaillement élevées correspondant à celles retrouvées au niveau de sténoses artérielles, une sous-population plaquettaire présentant un OLM plus bas. Le passage dans le domaine clinique de ces approches fondamentales qui privilégient l’étude dynamique des plaquettes pourrait permettre d’améliorer le diagnostique et le suivi de traitement de pathologies cardiovasculaires. Blood platelets play a central role in primary hemostasis and thrombosis, two major elements of vascular physiopathology. Although a number of drugs regulate platelet functions, there are no validated tests that monitor their efficacy on the basis of the patients' clinical course. This doctorate, therefore, aims to develop novel approaches to evaluate platelet function. The first part of my work consisted of two clinical trials involving patients with stable coronary syndrome. The first study demonstrated the need for standardized biological tests to screen for patients who respond less well to clopidogrel, an ADP P2Y12 receptor antagonist. The second study showed the therapeutic potential of the joint inhibition of P2Y12 and P2Y1 receptors on platelet adhesion, activation, and aggregation for these patients. Furthermore, a video microscopy model using perfusion chambers made it possible to monitor the course of thrombosis in real time, and enabled us to dissociate the early and late effects of the antiplatelet drugs. Lipid raft membrane microdomains play a pivotal role in many cell functions. At the platelet level, many receptors depend on these microdomains and thus modulate the function as well as the drug sensitivity of platelets. However, current techniques for the study of these microdomains are complex and limit their clinical applications. By taking advantage of new fluorescent probes that are sensitive to the level of the membrane order, we developed a method of measuring the membrane order using spectral flow cytometry. Through this approach we showed that platelet activation reduced the lipid order of the membranes, whereas it was increased in patients treated with a cholesterol synthesis inhibitor or clopidogrel. It was also possible for us to demonstrate the appearance, under shear stress similar to that of stenotic arteries, of a platelet sub-population with a very low membrane order. These approaches which privilege the dynamic study of thrombi and platelets could be applied to the clinical practice and thus widen the fields of clinical studies.
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    ABSTRACT: Clopidogrel is a widely used antithrombotic agent that inhibits the platelet P2Y(12) adenosine diphosphate (ADP) receptor. There is increasing interest in 'clopidogrel resistance'. To determine whether 'clopidogrel resistance' is accounted for by a pre-existent variability in platelet response to ADP. Platelet response to 20 microm ADP was analyzed by four independent whole blood flow cytometric assays: platelet surface activated GPIIb-IIIa, platelet surface P-selectin, monocyte-platelet aggregates and neutrophil-platelet aggregates. In 25 consecutive, non-aspirin-treated healthy subjects, we studied platelet response before and after clopidogrel administration. In addition, we studied the platelet response in 613 consecutive aspirinated patients with or without coronary artery disease (CAD, as determined by angiography) who had or had not been treated with clopidogrel. In these patients, we tested for homogeneity of variance across all durations of clopidogrel exposure and severity of CAD by estimating the 'goodness of fit' of two independent models. In the healthy subjects, pre-clopidogrel response to ADP predicted post-clopidogrel response to ADP. In the patients, clopidogrel, as expected, inhibited the platelet response to ADP. However, irrespective of the duration of clopidogrel administration, the severity of CAD, and the dose of aspirin, clopidogrel did not increase the variance in the platelet response to ADP in any of the four assays of platelet response. These studies provide evidence that 'clopidogrel resistance' is accounted for by a pre-existent variability in platelet response to ADP and this variability is not increased by clopidogrel administration.
    Full-text · Article · Feb 2007 · Journal of Thrombosis and Haemostasis
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    ABSTRACT: Despite the improvement in outcome observed with primary angioplasty compared with thrombolysis, there is still room for improvement. Indeed, despite restoration of optimal epicardial flow in the vast majority of patients, suboptimal myocardial reperfusion is observed in a relatively large proportion. The aim of this article is to provide an up-to-date review of adjunctive antithrombotic therapy for primary angioplasty for ST-segment elevation myocardial infarction (STEMI).The HORIZONS trial has shown a significant reduction in mortality and major bleeding complications in patients treated with bivalirudin compared with those treated with glycoprotein (GP) IIb-IIIa inhibitors. Thus, bivalirudin may be considered as an alternative strategy to heparin plus GPIIb-IIIa inhibitors in primary angioplasty, especially in patients at high risk for bleeding complications. However, despite the negative results of the FINESSE trial, a large amount of evidence has been observed in favour of early administration of GPIIb-IIIa inhibitors, which should still be considered a reasonable strategy.Non-responsiveness to aspirin and clopidogrel is relatively common. However, future trials are needed to evaluate whether the routine assessment for non-responsiveness and a consequent change in therapy (to higher dosages of clopidogrel or a switch to another adenosine diphosphate [ADP]-receptor antagonist) may improve clinical outcome. Even though not yet demonstrated, it is conceivable that the greatest benefits of clopidogrel may come from early administration, and that this might be considered as part of a pharmacological facilitation strategy, together with early administration of GPIIb-IIIa inhibitors. As a result of better and faster inhibition of platelet aggregation, further benefits might be expected from the early administration of one of the new oral platelet ADP-receptor antagonists.As a consequence of the very low mortality currently achieved by primary angioplasty, additional endpoints, such as infarct size and myocardial perfusion, should be considered when exploring the potential benefits of adjunctive antithrombotic therapies in future randomized trials among patients undergoing mechanical revascularization for STEMI.
    No preview · Article · Feb 2008 · Drugs
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