Régulation plaquettaire : ciblage de la protéine kinase Syk dans les HIT et rôle du transporteur lipidique ABCA1 dans les fonctions plaquettaires

Les plaquettes sanguines jouent un rôle essentiel dans le maintien de l'intégrité vasculaire. Outre leur rôle physiologique conduisant à la formation du clou hémostatique en cas de brèche vasculaire, elles sont impliquées dans des pathologies thrombotiques comme l'athérothrombose ou les thrombopénies induites par l'héparine (TIH), ce qui en fait des cibles pharmacologiques de choix dans ces situations. Nous avons étudié les mécanismes mis en jeux par les plaquettes dans deux situations pathologiques ; les TIH avec la tyrosine kinase Syk comme acteur majeur et la maladie de Tangier résultant d'une mutation perte de fonction du transporteur de lipide ABCA1. Les TIH sont des complications rares mais graves des traitements à l'héparine dues au développement d'anticorps dirigés contre le complexe héparine-facteur 4 plaquettaire (PF4). Ces anticorps induisent la clairance des plaquettes (thrombopénie) et activent les récepteurs Fc à la surface des plaquettes (FcgRIIA) et des monocytes (FcgRI et FcgRII) conduisant à l'agrégation plaquettaire et l'expression du facteur tissulaire par les monocytes responsable des complications thrombotiques. Nous montrons que Syk est une kinase essentielle à l'activation des plaquettes (signalisation, sécrétion, agrégation, microparticules) par les anticorps dirigés contre le complexe héparine-PF4 présents dans le sérum de patients atteints de TIH. Parallèlement, l'inhibition de Syk bloque fortement l'expression du facteur tissulaire et l'activité procoagulante des monocytes induites par les anticorps TIH. Les inhibiteurs de Syk, en développement clinique avancé en immunothérapie, apparaissent donc prometteurs dans le traitement des TIH. ABCA1 est impliqué dans le transport réverse du cholestérol et de phospholipides vers les lipoprotéines de haute densité. Son déficit est associé à de profondes anomalies du bilan lipidique mais aussi à un phénotype hémorragique. Grâce à un modèle de souris déficientes en ABCA1, nous avons caractérisé son rôle dans l'activation plaquettaire. Contrairement à ce que l'on aurait pu penser, ABCA1 n'est pas impliqué dans l'exposition des phosphatidylsérines et l'activité procoagulante des plaquettes activées, et ne régule pas le contenu en cholestérol des membranes plaquettaires. Par contre, un défaut de taille des plaquettes et de leurs réponses fonctionnelles sont observés en son absence. ABCA1 apparaît comme un régulateur des mécanismes de signalisation pouvant expliquer le phénotype hémorragique rapporté dans la maladie de Tangier. L'ensemble de ces travaux a permis de caractériser des acteurs moléculaires de l'activation plaquettaire dans des situations pathologiques et de proposer de nouvelles stratégies thérapeutiques.Platelet activation at sites of vascular injury is essential for haemostasis. Next to this critical role in bleeding arrest, platelets are involved in thrombotic diseases such atherothrombosis or heparin-induced thrombocytopenia (HIT). Therefore, they are targets of antithrombotic therapies. We have studied the mechanisms of platelet activation in two pathological situations; HIT with the tyrosine kinase Syk as a key player and Tangier disease resulting of a loss of function of the ABCA1 lipid transporter. HIT is a prothrombotic and potentially devastating complication of heparin therapy due to formation of platelet-activating antibodies directed against complexes of platelet factor 4 (PF4) and heparin. These antibodies contribute to clear platelet from the circulation and activate, by their Fc fragment, Fc?RIIA receptors on platelet surface or FcgRI and FcgRII receptors on monocyte, leading to platelet aggregation and tissue factor expression by monocytes. We have shown that Syk activation is crucial for platelet activation (signalization, secretion, aggregation, microparticle generation) initiated by anti-PF4/heparin antibodies from sera of patients suffering from HIT. Interestingly, Syk inhibition also prevented tissue factor expression and procoagulant activity of moncytic cells induced by these antibodies. We propose that Syk inhibitors, initially developed as a potential treatment of autoimmune disease, may be of therapeutic interest in the treatment of HIT. ABCA1 has been demonstrated to be crucial in the reverse cholesterol transport pathway by loading cholesterol and phospholipids into ApoA-I to generate high density lipoproteins. Its defect is associated to circulating lipid disturbance but also to hemorrhagic diathesis. Surprisingly, using ABCA1 knock-out mice, we have demonstrated that this transporter is neither implicated in phosphatidyserine exposure, a mechanism leading to the procoagulant activity of activated platelets, nor in the control of platelet membranes cholesterol content. However, mouse platelets deficient for ABCA1 have an increased size and a defect in response to low doses of agonists such as thrombin and collagen. Our data indicate that ABCA1 is involved in the efficiency of platelet signal transduction, particularly in the activation of Akt. These studies have characterized key players of platelet activation and suggest new strategies in the development of antithrombotic therapies

0272: Unfractionated heparin addition during percutaneous coronary intervention in acute coronary syndrome patients previously treated with enoxaparin: biological impact

BackgroundThe benefit of anticoagulants (AC) to prevent thrombotic complications during percutaneous coronary intervention (PCI) is well established. In acute coronary syndrome (ACS) patients previously treated with enoxaparin, an additional bolus of AC is not recommended if the last injection was realized within 8 h. In this setting, many interventional cardiologists use unfractionated heparin (UFH) at the time of sheath insertion.ObjectivesThe aim of our study was to describe local current practices for AC use during PCI in patients already treated with enoxaparin and admitted for ACS and to assess the biological impact of UFH addition at the beginning of the procedure.MethodsA standardized survey was sent to the interventional cardiologists of the southwest of France to investigate their practice in terms of periprocedural AC use. In 2 centers, ACS patients previously treated with subcutaneous injection of enoxaparin within 8 h and who received intravenous UFH at the time of sheath insertion were prospectively included and their plasma anti-Xa activity was assessed at the sheath insertion and 30 min after UFH bolus. In-hospital bleeding and ischemic events were collected. The adequate therapeutic window was defined by anti Xa activity (range 0.5 to 0.9 IU/mL). Results: Among the 41 interventional cardiologists who replied, a large majority (75,6%) considered the addition of UFH in patients who received enoxaparin within 8 h as a valid option. 47 ACS patients were enrolled. The dose of the bolus of UFH was highly variable from 20 to 90 UI / kg. Anti-Xa activities were above 0.9 IU/mL in 14,9% of patients at the sheath insertion and in 72,3% of patients 30 min after UFH injection. 2 bleeding complications occurred, both in over-coagulated patients. No ischemic events were reported.ConclusionThe use of UFH in patients who already received enoxaparin may result in over-anticoagulation and lead to bleeding complications

Transcatheter heart valve selection and permanent pacemaker implantation in patients with pre-existent right bundle branch block

Background-Right bundle branch block is an established predictor for new conduction disturbances and need for a permanent pacemaker (PPM) after transcatheter aortic valve replacement. The aim of the study was to evaluate the absolute rates of transcatheter aortic valve replacement related PPM implantations in patients with pre-existent right bundle branch block and categorize for different transcatheter heart valves. Methods and Results-We pooled data on 306 transcatheter aortic valve replacement patients from 4 high-volume centers in Europe and selected those with right bundle branch block at baseline without a previously implanted PPM. Logistic regression was used to evaluate whether PPM rate differed among transcatheter heart valves after adjustment for confounders. Mean age was 83±7 years and 63% were male. Median Society of Thoracic Surgeons score was 6.3 (interquartile range, 4.1-10.2). The following transcatheter valve designs were used: Medtronic CoreValve (n=130; Medtronic, Minneapolis, MN); Edwards Sapien XT (ES-XT; n=124) and Edwards Sapien 3 (ES-3; n=32; Edwards Lifesciences, Irvine, CA); and Boston Scientific Lotus (n=20; Boston Scientific Corporation, Marlborough, MA). Overall permanent pacemaker implantation rate post-transcatheter aortic valve replacement was 41%, and per valve design: 75% with Lotus, 46% with CoreValve, 32% with ES-XT, and 34% with ES-3. The indication for PPM implantation was total atrioventricular block in 98% of the cases. Lotus was associated with a higher PPM rate than all other valves. PPM rate did not differ between ES-XT and ES-3. Ventricular paced rhythm at 30-day and 1-year follow-up was present in 81% at 89%, respectively. Conclusions-Right bundle branch block at baseline is associated with a high incidence of PPM implantation for all transcatheter heart valves. PPM rate was highest for Lotus and lowest for ES-XT and ES-3. Pacemaker dependency remained high during followup

Association of the PHACTR1/EDN1 genetic locus with spontaneous coronary artery dissection

Background: Spontaneous coronary artery dissection (SCAD) is an increasingly recognized cause of acute coronary syndromes (ACS) afflicting predominantly younger to middle-aged women. Observational studies have reported a high prevalence of extracoronary vascular anomalies, especially fibromuscular dysplasia (FMD) and a low prevalence of coincidental cases of atherosclerosis. PHACTR1/EDN1 is a genetic risk locus for several vascular diseases, including FMD and coronary artery disease, with the putative causal noncoding variant at the rs9349379 locus acting as a potential enhancer for the endothelin-1 (EDN1) gene. Objectives: This study sought to test the association between the rs9349379 genotype and SCAD. Methods: Results from case control studies from France, United Kingdom, United States, and Australia were analyzed to test the association with SCAD risk, including age at first event, pregnancy-associated SCAD (P-SCAD), and recurrent SCAD. Results: The previously reported risk allele for FMD (rs9349379-A) was associated with a higher risk of SCAD in all studies. In a meta-analysis of 1,055 SCAD patients and 7,190 controls, the odds ratio (OR) was 1.67 (95% confidence interval [CI]: 1.50 to 1.86) per copy of rs9349379-A. In a subset of 491 SCAD patients, the OR estimate was found to be higher for the association with SCAD in patients without FMD (OR: 1.89; 95% CI: 1.53 to 2.33) than in SCAD cases with FMD (OR: 1.60; 95% CI: 1.28 to 1.99). There was no effect of genotype on age at first event, P-SCAD, or recurrence. Conclusions: The first genetic risk factor for SCAD was identified in the largest study conducted to date for this condition. This genetic link may contribute to the clinical overlap between SCAD and FMD

Impact de la résistance biologique au clopidogrel au décours de l'angioplastie du tronc commun gauche (à propos d'un registre de monocentrique de 434 patients)

TOULOUSE3-BU Santé-Centrale (315552105) / SudocSudocFranceF

Le lipofilling cervico-facial en territoire irradié (étude anatomique, clinique et évaluation)

TOULOUSE3-BU Santé-Centrale (315552105) / SudocSudocFranceF

Alcoolisation septale dans la cardiomyopathie hypertrophique (expérience du CHU de Toulouse)

Objectif : Apprécier l'évolution clinique, hémodynamique et morphologique après alcoolisation septale (AS). Méthode : De février 2006 à juin 2008, nous avons inclus 12 patients présentant une cardiomyopathie hypertrophique obstructive et bénéficiant d'une AS. Un suivi clinique, échographique et par IRM a été réalisé. Résultats : Ce travail illustre la faisabilité de la technique avec une baisse immédiate du gradient intraventriculaire (94 +- 45 vs 22 +- 2 mmHg, p<0,05), une mortalité hospitalière nulle. Les complications immédiates sont dominées par le risque de troubles conductifs. A 1 an, il existe une amélioration fonctionnelle avec une diminution moyenne du stade NYHA de 1,5 [-1,94 -1,05] avec un maintien de la baisse du gradient par rapport à sa valeur de base -86% [-49%, -100%]. Aucune arythmie ventriculaire n'a été relevée après 1 an de suivi. Conclusion : L'AS semble une procédure efficace à moyen terme et peut donc être considérée comme une alternative valable à la myectomie.TOULOUSE3-BU Santé-Centrale (315552105) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF