Les effets pléiotropes d’un inhibiteur réversible de récepteurs P2Y12

RésuméLe cangrelor actif par voie injectable a été le premier inhibiteur réversible des récepteurs P2Y12, et maintenant, le ticagrelor, premier inhibiteur réversible actif par voie orale, ouvre une ère nouvelle dans l’inhibition de la voie de l’ADP: en effet, ils n’ont ni la même pharmacocinétique ni la même pharmacodynamie que les inhibiteurs irréversibles que sont les métabolites actifs des thiénopyridines auxquels nous étions accoutumés. La molécule agit par sa concentration plasmatique et non par son affinité pour son récepteur. L’activité de la molécule va donc pouvoir se porter:-sur des sites P2Y12 extra-plaquettaires qui n’étaient que peu ou pas accessibles aux inhibiteurs irréversibles, et ainsi dévoiler au niveau vasculaire des effets vasodilatateurs;-sur des sites récepteurs transporteurs de moindre affinité. C’est ainsi que le ticagrélor inhibe l’« erythrocyte equilibrative nucleoside transporter », transporteur situé à la membrane des globules rouges et responsable de l’incorporation rapide et active de l’adénosine dans les globules. L’inhibition de l’ENT induit une accumulation d’adénosine avec toute une série d’effets possibles, « les effets adénosine », qui peuvent potentiellement renforcer l’effet primaire: l’adénosine a une activité directe d’anti-agrégant plaquettaire et pas seulement inhibitrice de l’agrégation plaquettaire; l’adénosine a des effets vasculaires: vasodilatateurs mais aussi de pré- et de post-conditionnement en protection contre l’ischémie-reperfusion, et des effets anti-inflammatoires au niveau local. Mais c’est aussi cet effet adénosine qui peut expliquer certains effets secondaires notés lors des études avec le ticagrélor (dyspnée, augmentation des taux plasmatiques d’acide urique et de créatinine, bradycardie en particulier). L’observation que ces patients présentant ces effets secondaires tirent un bénéfice même supérieur du traitement est un argument fort pour indiquer que l’effet adénosine participe de manière significative au bénéfice global net du traitement par le ticagrélor.SummaryCangrelor, administered intravenously, was the first reversible inhibitor of P2Y12 receptors. More recently, ticagrelor is the first oral reversible inhibitor of P2Y12 receptors. These drugs act through their extracellular concentration, in contrast to thienopyridines, which act through irreversible binding of their active metabolite to P2Y12 receptors. These drugs also differ in terms of their pharmacokinetics, pharmacodynamics and modes of action (direct vs indirect). Besides inhibition of platelet P2Y12 receptors, ticagrelor also acts on P2Y12 receptors of other cells. These receptors are much less accessible to the high affinity and short plasma survival of the active metabolites of thienopyridines. At the vascular level, inhibition of P2Y12 receptors on smooth muscle cells prevents vasoconstriction induced by adenosine diphosphate. Ticagrelor also inhibits the erythrocyte equilibrative nucleoside transporter (ENT) (which is responsible for the rapid and active incorporation of adenosine into erythrocytes), and therefore leads to extra-cellular adenosine accumulation. Adenosine, a potent cellular mediator responsible for the ‘adenosine effects’of ticagrelor, can reinforce the primary effect of ticagrelor (adenosine has a direct inhibitory effect on platelet activation/aggregation and is not only an inhibitor of the ADP pathway of platelet activation/aggregation). Adenosine exerts multiple vascular effects – vasodilatation and protection against ischaemic – reperfusion lesions (pre-conditioning and post-conditioning effects) – and these effects can explain some of the secondary effects observed during clinical studies in patients receiving ticagrelor (dyspnoea, increase in plasma concentrations of uric acid and creatinine, bradycardia). The observation that patients affected by such side-effects benefit to a greater extent than patients who do not, provides substance to the argument that the adenosine effect of ticagrelor is significantly implicated in the net global benefit of treatment in patients with acute coronary syndromes

Eptifibatide provides additional platelet inhibition in Non–ST-Elevation myocardial infarction patients already treated with aspirin and clopidogrel Results of the platelet activity extinction in Non–Q-Wave myocardial infarction with aspirin, clopidogrel, and eptifibatide (PEACE) study

AbstractObjectivesThe present study hypothesis was that eptifibatide offered further antiplatelet efficacy above clopidogrel in non–ST-elevation myocardial infarction (NSTEMI) patients before an expeditive coronary intervention.BackgroundAlthough thienopyridines and glycoprotein (GP) IIb/IIIa antagonists are often co-prescribed in the context of NSTEMI, the antiplatelet interaction of these agents is poorly described and the superiority of GP IIb/IIIa antagonists above thienopyridine treatment alone is not clear.MethodsThirty-two NSTEMI patients treated with aspirin and enoxaparin were studied using flow cytometry to define parameters of platelet activation with a panel of agonists before clopidogrel, after clopidogrel, and during an eptifibatide infusion following the clopidogrel load.ResultsAfter platelet activation with adenosine diphosphate, thrombin receptor-activating peptide, or U46-619, relative reductions in conformationally activated GP IIb/IIIa receptor expression (evaluated with PAC-1) of 48%, 43%, and 33%, respectively (all p < 0.0001), were seen with clopidogrel, but further 80%, 78%, and 72% (all p < 0.0001) reductions were seen with eptifibatide. With the same agonists, fibrinogen binding was significantly reduced after clopidogrel by 70%, 64%, and 81% (all p < 0.0001) and again further reduced with eptifibatide by 90%, 95%, and 69% (all p < 0.0001). The total number of GP IIb/IIIa receptors (measured as P2 expression) and P-selectin expression fell after clopidogrel, after ex vivo stimulation with the same agonists; however, both parameters increased slightly during the eptifibatide infusion.ConclusionsThe activated GP IIb/IIIa expression and fibrinogen binding findings indicate that eptifibatide provides significant potent antiplatelet activity above aspirin and clopidogrel, suggesting additive immediate protection in the treatment of NSTEMI. The P2 and P-selectin findings suggest the possibility of a partial agonist and/or pro-inflammatory effect

A Randomized Comparison of High Clopidogrel Loading Doses in Patients With Non–ST-Segment Elevation Acute Coronary Syndromes The ALBION (Assessment of the Best Loading Dose of Clopidogrel to Blunt Platelet Activation, Inflammation and Ongoing Necrosis) Trial

ObjectivesWe sought to compare the antiplatelet effects of three clopidogrel loading doses (LDs).BackgroundAdministration of a 300-mg clopidogrel LD is beneficial in situations requiring rapid platelet inhibition. Whether higher LDs can provide further benefits remains unknown.MethodsPatients (n = 103) with non–ST-segment elevation acute coronary syndromes were randomized to receive a 300-mg, 600-mg, or 900-mg clopidogrel LD, given on top of other standard therapy (including acetylsalicylic acid). The main outcome measure was inhibition of adenosine diphosphate-induced inhibition of platelet aggregation (IPA); inhibition of platelet activation, inflammatory markers, troponin I release, and major adverse cardiac events also were evaluated; all measures were blindly evaluated.ResultsCompared with the 300-mg LD, greater doses were associated with significantly greater platelet inhibition, with dose-effect relationships observed for onset of action, maximal plateau, 24-h areas under the curves of IPA, and rates of low IPA (<10% at 6 h), using 20 μmol/l major adverse cardiac events. A significant dose-response was also observed for the vasodilator-stimulated phosphoprotein index, a measure of P2Y12receptor inhibition. Similar but nonsignificant trends were observed for troponin release and major adverse cardiac events. Bleeding rates were similar in each group.ConclusionsIn low-to-moderate risk patients with non–ST-elevation acute coronary syndromes, clopidogrel LDs >300 mg provide a faster onset of action, a higher IPA plateau, and greater reductions in platelet activation during the first 24 h. A 900-mg LD may induce a greater antiplatelet effect than 600 mg, when compared with the standard 300-mg regimen. These findings require further clinical confirmation

Platelet thrombin receptor antagonism and atherothrombosis

Clinical manifestations of atherothrombotic disease, such as acute coronary syndromes, cerebrovascular events, and peripheral arterial disease, are major causes of mortality and morbidity worldwide. Platelet activation and aggregation are ultimately responsible for the progression and clinical presentations of atherothrombotic disease. The current standard of care, dual oral antiplatelet therapy with aspirin and the P2Y12 adenosine diphosphate (ADP) receptor inhibitor clopidogrel, has been shown to improve outcomes in patients with atherothrombotic disease. However, aspirin and P2Y12 inhibitors target the thromboxane A2 and the ADP P2Y12 platelet activation pathways and minimally affect other pathways, while agonists such as thrombin, considered to be the most potent platelet activator, continue to stimulate platelet activation and thrombosis. This may help explain why patients continue to experience recurrent ischaemic events despite receiving such therapy. Furthermore, aspirin and P2Y12 receptor antagonists are associated with bleeding risk, as the pathways they inhibit are critical for haemostasis. The challenge remains to develop therapies that more effectively inhibit platelet activation without increasing bleeding complications. The inhibition of the protease-activated receptor-1 (PAR-1) for thrombin has been shown to inhibit thrombin-mediated platelet activation without increasing bleeding in pre-clinical models and small-scale clinical trials. PAR-1 inhibition in fact does not interfere with thrombin-dependent fibrin generation and coagulation, which are essential for haemostasis. Thus PAR-1 antagonism coupled with existing dual oral antiplatelet therapy may potentially offer more comprehensive platelet inhibition without the liability of increased bleeding

Discovery of novel GPVI receptor antagonists by structure-based repurposing.

Inappropriate platelet aggregation creates a cardiovascular risk that is largely managed with thienopyridines and aspirin. Although effective, these drugs carry risks of increased bleeding and drug 'resistance', underpinning a drive for new antiplatelet agents. To discover such drugs, one strategy is to identify a suitable druggable target and then find small molecules that modulate it. A good and unexploited target is the platelet collagen receptor, GPVI, which promotes thrombus formation. To identify inhibitors of GPVI that are safe and bioavailable, we docked a FDA-approved drug library into the GPVI collagen-binding site in silico. We now report that losartan and cinanserin inhibit GPVI-mediated platelet activation in a selective, competitive and dose-dependent manner. This mechanism of action likely underpins the cardioprotective effects of losartan that could not be ascribed to its antihypertensive effects. We have, therefore, identified small molecule inhibitors of GPVI-mediated platelet activation, and also demonstrated the utility of structure-based repurposing

Vitamine K

Subclasses of vitamin K, their origins, their differential characteristics of absorption and metabolism, their relative effects on gammacarboxylation of various proteins implicated in hemostasis andcoagulation, in bone calcification are not well known even by experts in these fields. These misunderstandings explain errors in recommendations for public and for patients. This review will not expose again the fundamentals on vitamins K as presented in the paper by Marc Guillaumont published in 2000 in this same journal. This 2011 review will try to update our actual knowledge and most of all will insist on their practical implications especially on the management of oral anticoagulant treatments since until recently vitamin K antagonist was the only available type of such a treatment. Several examples illustrate the need for a better understanding of this subject. The fear that diet vitamin K could deregulate the equilibrium of oral vitamin K antagonist treatment leads to recommend a quite total suppression of vitamin K containing components in the diet of anticoagulated patients. This leads to an opposite effect: a high sensitivity to vitamin K and to disequilibrium of the anticoagulant treatment while a comprehensivemoderate and regular diet intake of vitamin K first facilitates the food choice of the patients but also helps to stabilise the treatment of chronically anticoagulated patients. Vitamin K plays a role in bone calcification and in osteoporosis prevention. Until recently the food supplementation with vitamin K in view of preventing osteoporosis in general population was strongly limited due to fear to affect the treatment equilibrium in anticoagulated patients. While an understanding that the effects of moderate supplementation in vitamin K has no or limited effect on anticoagulation and on the long run could at the opposite help to stabilize the daily level of anticoagulation in patients chronically treated with vitamin K

À part le fibrinogène, les facteurs/marqueurs d'hémostase ont-ils aussi une place pour évaluer le risque d'accident cardiovasculaire ischémique ?

Dans leur grande majorité, les événements cardiovasculaires sont une complication thrombotique de lésions d'athérosclérose. En condition de flux sanguin artériel, comme dans les artères coronaires, les facteurs d'hémostase favorisent le risque thrombotique (surtout aux phases initiales), mais les facteurs de coagulation et de fibrinolyse interagissent également. S'il est admis que le fibrinogène est un marqueur/facteur de risque cardiovasculaire, la place, le rôle et l'intérêt des autres paramètres sont toujours controversés. Etant donnée la place des plaquettes (démontrée par l'efficacité préventive des antiplaquettaires dans cette pathologie), on s'attendrait à ce que les marqueurs plaquettaires présentent un intérêt. En fait, en dehors des augmentations du chiffre plaquettaire, il n'y a pas d'autre paramètre plaquettaire évident. Cette absence est due au moins en partie à la difficulté d'étudier les fonctions plaquettaires ex vivo. Plusieurs polymorphismes de glycoprotéines membranaires plaquettaires confèrent un excès modéré de risque, risque qui n'est retrouvé que chez les patients les plus jeunes. Pour la coagulation, il apparaît que la structure du caillot de fibrine est un paramètre important. Ce paramètre implique, outre le fibrinogène, la cinétique de génération de la thrombine, la fonctionnalité du facteur XIII et l'association aux cellules de la coagulation. Les facteurs de coagulation sont à l'évidence impliqués dans la vitesse de génération de la thrombine. L'activité du système fibrinolytique (et en particulier son déficit) est corrélée avec le risque cardiovasculaire. Les marqueurs globaux comme les D-dimères sont potentiellement utiles bien que faiblement corrélés avec la survenue d'événements cliniques. Tous les systèmes d'hémostase, de coagulation et de fibrinolyse sont impliqués dans la réactivité thrombotique (et certains dans l'athérogenèse elle-même). Il s'agit d'un système multifactoriel. Une meilleure prédictibilité des tests d'hémostase peut venir de la mise au point de tests plus représentatifs et de l'évaluation simultanée d'un grand nombre de paramètres (phénotypiques et génotypiques) qui permettraient d'aboutir à des scores de risque

Le fibrinogène a-t-il une place pour évaluer le risque d'accident cardiovasculaire ischémique ?

La plupart des événements cardiovasculaires sont une conséquence thrombotique de l'évolution d'une lésion d'athérosclérose. L'inflammation joue un rôle central tant dans le développement que dans la survenue des complications évolutives des lésions d'athérosclérose (en particulier de rupture de plaques). Les données épidémiologiques montrent de manière concordante que l'augmentation du fibrinogène (par rapport aux valeurs de contrôles appariés) est prédictive du risque d'accident cardiovasculaire aussi bien dans la population générale pour prédire le premier événement cardiovasculaire que chez les patients pour prédire le risque de récidive. La concentration plasmatique du fibrinogène est déterminée à la fois par une prédisposition génétique et par des facteurs acquis et environnementaux. C'est un exemple des interrelations gène-environnement. Il faut prendre conscience que l'augmentation du fibrinogène (responsable de l'augmentation significative du risque) est une augmentation très modérée (comprise dans les valeurs de référence du taux plasmatique). Cela permet de comprendre que ce facteur si prédictif lorsqu'il est considéré d'un point de vue épidémiologique, n'a aucune valeur pour établir le risque cardiovasculaire à un niveau individuel en pratique clinique quotidienne (sauf pour les très fortes augmentations qui ne sont rencontrées que très rarement)