Dissertationen zum Thema „Syndrome des plaquettes grises“
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Delage, Laure. „Des déficiences génétiques comme modèles naturels pour l'étude de la régulation des checkpoints immunitaires et la caractérisation des réponses auto-immunes“. Electronic Thesis or Diss., Université Paris Cité, 2021. http://www.theses.fr/2021UNIP5190.
Der volle Inhalt der QuelleRecessive NBEAL2 mutations have been reported in patients with Gray Platelet Syndrome (GPS). This syndrome is characterized by a macro-thrombocytopenia, with platelets lacking alpha-granules, leading to bleeding disorders, often associated with splenomegaly. Thus, NBEAL2 plays a crucial role in the trafficking of alpha-granules in platelets. Moreover, our lab has also described NBEAL2 deficiencies in patients presenting clinical features of the autoimmune lymphoproliferative syndrome, suggesting a role of NBEAL2 in immune homeostasis and tolerance. A broader international cohort of GPS patients has been described, revealing immune system abnormalities (autoimmune diseases, autoantibodies, lymphopenia). If the role of NBEAL2 in the traffic of granules is often investigated, the exact mechanism leading to the development of autoimmune manifestations in GPS patients remains unknown. NBEAL2 belongs to a protein family involved in vesicular trafficking, all of which possess a conserved BEACH domain. Within this BEACH-domain containing proteins family, one of the closest members to NBEAL2 is LRBA. LRBA is involved in the recycling of CTLA-4, an inhibitory immune checkpoint. CTLA-4 plays a crucial role in the regulation of immune responses and tolerance. Recessive mutations of LRBA lead to similar clinical features as partial CTLA-4 deficiency: autoimmunity, lymphocytic infiltrations, and progressive B lymphopenia. Physiologically, LRBA prevents the lysosomal degradation of CTLA-4 and allows its recycling to the membrane. By analogy with LRBA, we investigated the importance of NBEAL2 in immune checkpoints intracellular trafficking and we brought new insights on its role in lymphocytes. Thus, NBEAL2 is a scaffold protein, binding LRBA, and involved in CTLA-4 trafficking as well as in vesicular trafficking in general. This work brings new knowledge to the regulation of CTLA-4 in activated T lymphocytes, a list of new partners for NBEAL2 protein and a new model of vesicular trafficking in which NBEAL2 is involved. Finally, a better understanding of the mechanisms leading to autoimmunity in patients with gray platelets syndrome could lead to better diagnosis and treatment management
Lauzière, Véronique. „Distribution subcellulaire de la protéine FMRP dans les plaquettes sanguines quiescentes et activées“. Mémoire, Université de Sherbrooke, 2011. http://hdl.handle.net/11143/5549.
Der volle Inhalt der QuelleTouat, Ziad. „Anévrysmes des aortes ascendante et abdominale chez l'homme : rôle des plaquettes dans ces pathologies“. Paris 7, 2007. http://www.theses.fr/2007PA077069.
Der volle Inhalt der QuelleAneurysms are defined by a dilation of the artery which leads to a loss of parallelism of the vascular wall. The implication of the blood component was neglected a long time in these pathologies. My work during my PhD concentrated on the study of a bond between aortic aneurysms of the aorta and the blood components. The abdominal aortic aneurysms are accompanied by a nonocclusive thrombus which forms an active interface between blood and arterial wall. We showed the active role for this thrombus in the AAA. The thrombi form a tank of proteases which attack the wall and prevent the cicatrization of the thrombus. I also showed that the renewal of these thrombi is responsible for enrichment in PMI1 via the constant exposure of P-selectin by activated platelets. These results were validated in vivo on an experimental model of aneurisms. I then showed for the first time a state of platelet activation and a generation of thrombin in patient with thoracic ascending aortic aneurysm, by detection of biomarkers. The development of these aneurisms is not accompanied by the formation of a thrombus. These original results suggest ; role for platelet activation and of the prothrombin on the evolution of this disease. In conclusion, my work highlights for the 1st time, the role of the platelets and coagulation cascade in the aneurysmal diseases. My results lead to a better understanding of this pathology whose inescapable evolution is the rupture, allowing to consider new clinical applications, into therapeutic and functional imagery
Tariket, Sofiane. „Investigation de la pathogenèse du syndrome de détresse respiratoire aiguë post-transfusionnel (TRALI) dans un modèle murin“. Thesis, Lyon, 2017. http://www.theses.fr/2017LYSES059/document.
Der volle Inhalt der QuelleBlood transfusion saves lives and reduces morbidity for many diseases and clinical conditions, but it is not without complications. A transfusion-related adverse event, also known as the Adverse Reaction (AR), is an incident occurring in a patient during or after a blood transfusion. Among them, TRALI is considered as one of the most critical inflammatory reactions. This pathology usually occurs within 6 hours after transfusion. Two types are recognized: immune TRALI and non-immune TRALI. In France, the first is almost completely prevented by a blood product safety policy, while the frequency of the second increases. The pathophysiology of TRALI remains poorly understood. While some scientists give an important function of patient blood platelets, others consider them dispensable. The aim of this thesis was, first, to investigate the inflammatory potential of blood platelets stored in platelet concentrates and its impact on the general vascular endothelium. Next, the role of patient blood platelets, including their secretory products, in the pathogenesis of this transfusion complication will be evaluated. For it, an ALI (mimicking a TRALI) was triggered, in an in vivo model, by an injection of anti-MHC I antibody in mice previously stimulated with LPS. Our results confirm the inflammatory potential of blood platelets in platelet concentrates, which can probably assume the entire responsibility for triggering a non-immune TRALI, and a secondary role for patient blood platelets in the amplification of the severity of this pathology. This thesis is the continuity of studies conducted in the laboratory GIMAP-EA3064, investigating the function of blood platelets in inflammation, thus opening up new perspectives in transfusion safety
Macchi, Laurent. „Etude de la caractérisation des anticorps anti-plaquettes dans différentes circonstances pathologiques et thérapeutiques“. Bordeaux 2, 1997. http://www.theses.fr/1997BOR28524.
Der volle Inhalt der QuelleLessard, Mandy. „Dosage quantitatif de la protéine FMRP développement d'un nouvel outil diagnostique pour le syndrome du X fragile“. Mémoire, Université de Sherbrooke, 2011. http://hdl.handle.net/11143/5560.
Der volle Inhalt der QuelleBellio, Marie. „La plaquette sanguine : un nouvel acteur du syndrome hémorragique de Noonan et du développement des maladies métaboliques“. Thesis, Toulouse 3, 2020. http://www.theses.fr/2020TOU30010.
Der volle Inhalt der QuelleBlood platelets play a major role in the maintenance of vascular integrity. They are the first blood cells recruited after vessel injury to stop bleeding by thrombus formation. Platelet hyper-activation is also a critical element in thrombotic events associated to several pathologies such as metabolic syndrome, which makes them major pharmacologic targets. My thesis work was focused on two main axis: (i) analysis of platelet activation in Noonan syndrome (NS) and Noonan syndrome with multiple lentigines (NSML) and (ii) characterization of the role of platelets in non-alcoholic fatty liver disease (NAFLD). Firstly, motivated by the occurrence of bleeding anomalies frequently reported in NS, we focused on characterizing platelet activation in NS and NSML caused respectively by a gain or a loss of function of the protein tyrosine phosphatase SHP2. We observed that platelets from NS patients display a defective in vitro aggregation to low concentrations of collagen, a GPVI agonist, associated to a decrease in thrombus growth ex vivo on a collagen surface under arterial shear stress. The mouse model phenocopying NS also exhibit a significant reduction in in vitro platelet aggregation induced by low concentrations of GPVI agonists, which is associated to a deficiency in GPVI signalling. The thrombus formation ex vivo under arterial shear stress as well as in vivo following a local carotid injury was also significantly affected. Primary haemostasis is also defective in NS mice as shown by a significant increase in mouse tail bleeding time. In contrast, NSML mouse platelets exhibited an increased activation after GPVI stimulation and an enhanced platelet thrombotic phenotype on collagen matrix under arterial shear stress. Interestingly, this platelet hyper-activation is also observed in blood samples from NSML patients ex vivo in arterial shear rate and exacerbated in high shear rate condition. This study allows the discovery of two new thrombopathies linked to platelet signalling defects and provides important information for the medical care of patient with NS or NSML in risk of bleeding or thrombosis situations. Besides, this study brings new insights into the understanding of SHP2 function in platelet activation. Secondly, I studied the role of platelets in NAFLD development. Using mouse models fed with different hyperlipidic diets mimicking different step of the NAFLD, we showed a protective role for platelets in hepatic glucidic and lipidic metabolism by inhibition of lipid storage. Furthermore, platelets protect against hepatic inflammation and fibrosis by decreasing inflammatory cells recruitment and fibrosis development. This protective role is associated to the presence of platelet aggregates in liver sinusoids. Interestingly, we demonstrate that platelet Vps34 deletion allows to slow down NAFLD development. Thereby, these innovative results highlight a new protective role of platelet in NAFLD development and could allow the identification of potential pharmacologic targets for preventing or limiting the disease. In conclusion, my thesis work brings new data on the role of platelets in different physiopathologic conditions: NS, NSML and NAFLD
Chappey, Olivier. „Intérêt de l'étude de l'incorporation de la sérotonine marquée par les plaquettes sanguines dans l'exploration biologique du syndrome d'Hermansky-Pudlak“. Paris 5, 1991. http://www.theses.fr/1991PA05P106.
Der volle Inhalt der QuelleRoussillon, Emmanuel. „Importance de la thrombopénie dans la prise en charge du Hellp syndrome : à propos de 62 cas“. Bordeaux 2, 1999. http://www.theses.fr/1999BOR23104.
Der volle Inhalt der QuellePellerin, David. „Correction de l’hyperactivité de la voie ERK par la lovastatine chez des individus avec syndrome du X fragile : potentiel des cascades signalétiques plaquettaires comme nouvelles mesures de la réponse clinique dans les essais thérapeutiques“. Mémoire, Université de Sherbrooke, 2016. http://hdl.handle.net/11143/11082.
Der volle Inhalt der QuelleAbstract: Background: Fragile X syndrome (FXS) results from loss of FMRP expression, which causes several signaling dysregulations, including the hyperactivation of the Mitogen-activated protein kinase (MAPK)/Extracellular signal-regulated kinase (ERK) pathway. Lovastatin, a drug used for the treatment of hypercholesterolemia, pleiotropically inhibits the MAPK/ERK cascade and has successfully corrected key pathological phenotypes in the FXS mouse model, underscoring its ‘disease-modifying’ potential. Thereby, we conducted in 2013 the first open-label clinical trial investigating the effect of a 12-week lovastatin regimen on cognitive and behavioral disabilities in FXS. Most individuals presented subtle positive cognitive changes as assessed by the Vineland-II Adaptive Behavior Scale (VABS-II) as well as behavior improvements using the widely used scale Aberrant Behavior Checklist-Community (ABC-C). The latter two scales are filled up by caregivers making them rater-dependent and prone to observer-expectancy effect. This might result in a placebo effect which is inherent to the open-label design of the trial. We therefore investigated whether blood platelets’ signaling cascades may be used as objective biomarkers to monitor treatment response. Methods: Blood samples were gathered from 15 FXS individuals during the trial in order to evaluate by quantitative Western Blotting the in vivo effect of lovastatin on ERK activity in blood platelets, and to correlate clinical and biological responses. The basal phosphorylation status of ERK was also assessed in platelets from a control cohort. Results: Our results showed a more than two-fold significant increase in FXS blood platelet basal ERK phosphorylation as compared to controls (p=0.002). Of note, we found that this hyperphosphorylation was normalized following the 12-week lovastatin trial (p=0.007) in 13 of the 15 FXS individuals enrolled in the trial. This represents the first evidence for a beneficial effect of lovastatin in human FXS. The extent of changes in ERK phosphorylation was also found to partly correlate with the clinical response scales’ scores, especially for the VABS-II. Indeed, the composite total score and the ‘daily living skills’ as well as the ‘socialization’ subscales scores of the VABS-II were correlated with the biological response (p=0.03). In comparison, no correlation was observed with the ABC-C scale. Conclusion: Broadly, these results suggest that platelets’ signaling cascades could be used as biomarkers to objectively assess treatment response during future clinical trials.
Colas, Romain. „Syndrome métabolique et diabète chez l'Homme : composition lipidique et oxydation des lipoprotéines de basse densité (LDL) plasmatiques en relation avec l'activation des plaquettes sanguines“. Phd thesis, INSA de Lyon, 2010. http://tel.archives-ouvertes.fr/tel-00587355.
Der volle Inhalt der QuelleEl, Mdawar Marie Belle. „Études des mécanismes cellulaires et moléculaires impliqués dans le développement du syndrome de détresse respiratoire post-transfusionnel (TRALI)“. Thesis, Strasbourg, 2018. http://www.theses.fr/2018STRAJ077.
Der volle Inhalt der QuelleImmunological TRALI is a rare acute respiratory distress syndrome induced by the presence of alloantibodies in transfused products. A mouse model using a monoclonal antibody against the major histocompatibility complex class I, anti-H-2d, is usually used to study its mechanisms. Nevertheless, there is a lack in our understanding regarding the course of events. In this thesis, I show that the inhibitions of the ATP-gated receptor P2X1 and of the TRPC6 channel reduce the development of periarteriolar pulmonary edema occurring during TRALI, pointing to a role of smooth muscles cells. Specific cell depletions show that platelets and neutrophils are dispensable for TRALI initiation, in contrast to previous reports. Monocytes and/or macrophages are however necessary. I also developed a model of immune TRALI using transgenic mice expressing the human receptor FcγRIIA, and a recombinant antibody with a human IgG1-Fc fragment. My work reveal a more severe TRALI response in transgenic mice, with enhanced activation of platelets and neutrophils. This model allow a finer study of mechanisms underlying TRALI, moving towards the human actors of the pathology. We can also use this novel approach to assess the contribution of human Fc fragment
JOLIMOY, CYRILLE. „Sensibilisation de la recherche des anticorps anti-idiotypes par absorption des anticorps anti-hla de classe i sur plaquettes : mise au point des cross-matches par cytometrie en flux“. Dijon, 1994. http://www.theses.fr/1994DIJOM088.
Der volle Inhalt der QuelleGrosdidier, Charlotte. „Anti-plaquettaires et risque hémorragique : rôle du CD40L“. Thesis, Aix-Marseille, 2014. http://www.theses.fr/2014AIXM5063/document.
Der volle Inhalt der QuelleAspirin and thienopyridine are the therapy for patients with percutaneous coronary intervention after ACS. The level of platelet inhibition by thienopyridine varies between patients, this variability, multifactorial, is associated with adverse clinical outcomes. Treatment efficacy was evaluated mainly on the association between poor thienopyridine response and thrombotic events but less on the principal side effect: bleeding complications. Platelet play a key role in atherosclerosis and thrombosis, notably via CD40L.I studied platelet factors that influence the bleeding risk in these patients and brought a new highlight on platelet function less known such as inflammation.P450 cytochrome genetic variants (2C19*2 and 2C19*17) influence platelet response to thienopyridines. There is a relation between platelet reactivity and bleeding events. A very low on-treatment platelet reactivity (VASP<10 %) is a predictor of bleeding and is mainly observed with prasugrel treatment. We then focussed on a marker of platelet inflammatory status, CD40L. Its release by platelets depends on P2Y12 signalling, whereas its surface expression is less dependent on this signalling pathway. A low platelet-CD40L surface expression is associated with bleeding events in these patients We show that genetic background on thienopyridine treatment efficacy is related to bleeding risk and that other platelet parameters influence the bleeding risk independently of platelet aggregation inhibition. Thus, a molecule of inflammation, CD40L, would be a link between inflammation and bleeding/thrombosis equilibrium
Egot, Marion. „Etude de la signalisation au cours de la rétraction du caillot : application à l'étude des anomalies de l'hémostase primaire dans le syndrome de Lowe“. Thesis, Paris 5, 2013. http://www.theses.fr/2013PA05P624.
Der volle Inhalt der QuellePrimary hemostasis is a mechanism allowing platelet clot formation that is thereafter stabilized by a fibrin network. Fibrin clot is also consolidated following post occupancy events, mainly clot retraction that decrease clot size and thus strengthen it. This phase is triggered by « outside-in » signaling. It is consecutive to αIIbβ3 integrin activation and platelet aggregation, dependent on cytoskeleton organization. Our first objective was to investigate signaling events underlying retraction, and particularly the involvement of ROCK, MLCK, Rac-1, and actin in MLC (Myosin Light Chain) phosphorylation. Indeed, MLC, involved in cytoskeleton rearrangement, is a key protein of this mechanism. We described a MLC biphasic phosphorylation profile, which second peak was dependent of Rac1 and actin polymerization. In a second part, we studied clot retraction signaling in patients with the Lowe syndrome. It is a rare genetic disease, caused by absence of OCRL (oculo cerebro renal of Lowe) protein in reference to the majority of affected organs. The rationale of this study was a previous observation of hemorrhagic events during and after surgeries, suggesting clot instability. A thrombopathy was suggested by a closure time lengthening in the PFA-100 system. The study enrolled 15 patients and 15 controls. Besides a defect of megakaryocyte maturation, we described a defect of « outside-in » signaling responsible for spreading and clot retraction abnormality. This retraction defect, caused by a MLC activity defect, could be partly responsible for hemorrhagic events reported in these patients
Cuisset, Thomas. „Variabilité de réponse au clopidogrel : bases biologiques, mécanismes, conséquences cliniques et alternatives thérapeutiques“. Thesis, Aix-Marseille 2, 2010. http://www.theses.fr/2010AIX20694/document.
Der volle Inhalt der QuelleAntiplatelet therapy is the cornerstone therapy for patients admitted for acute coronary syndrome and/or undergoing percutaneous coronary intervention. Dual antiplatelet therapy with aspirin and clopidogrel is now the gold standard therapy for these patients. In spite of this effective association, recurrent events still occur and low response to clopidogrel has been proposed as one of the responsible factors. Indeed, numerous biological studies have described a broad interindividual variability of platelet response to clopidogrel, assessed with various platelet function tests such as light transmittance aggregometry, VASP phosphorylation index and the bed-side Verify Now assay. Mechanisms underlying this variability of response remain unclear and probably multifactorial, but factors have been clearly identified: genetic polymorphisms, medications interactions and clinical factors (diabetes, weight…). More recently, the clinical impact of this biological entity has been described with worse clinical outcome in patients non responder to clopidogrel, presenting a higher rate of recurrent ischemic events, including stent thrombosis. Meanwhile, a higher rate of bleeding complications have been found in patients with the highest on-treatment platelet inhibition, suggesting a ‘soft’ therapeutic window to avoid both types of recurrent events. Thus, several strategies have been proposed to overcome this poor response to the drug such as higher clopidogrel doses or additional GPIIbIIIa inhibitors in non responders. However, benefit of tailored therapy has been yet established in properly sized, prospective, randomized trial, which are currently ongoing. New comers in the class of P2Y12 inhibitors, prasugrel and ticagrelor, might represent a good alternative for these high-risk patients
Kitsiouli, Eirini. „Etudes biochimique et immunochimique du liquide bronchoalvéolaire de patients atteints du syndrome de détresse respiratoire aigue͏̈. Développement d'une méthode fluorimétrique pour le dosage des activités phospholipase A2 et PAF-acétylhydrolase dans les fluides biologiques“. Bordeaux 2, 2000. http://www.theses.fr/2000BOR28720.
Der volle Inhalt der QuelleHaghighi, Fatemeh. „Prediction of ticagrelor's effect on the lipid composition and the P2Y12 receptor of platelet's membrane by molecular dynamic and docking“. Thesis, Bourgogne Franche-Comté, 2019. http://www.theses.fr/2019UBFCE019.
Der volle Inhalt der QuelleP2Y12 receptors are a major target of antiplatelet drugs in preventing thromboembolic events in patients with acute coronary syndrome. As such, ticagrelor, a selective and reversible P2Y12 receptor antagonist, has a place of choice in the therapeutic management. The aim of this work is to study the interactions between ticagrelor, ADP and P2Y12 receptors and platelet membrane lipids.Our data support the role of ticagrelor in the reorganization of membrane lipids and suggest specific interactions and a modification of the conformation between P2Y12 receptors, ADP, ticagrelor and its metabolites.In the first part of this work, our results showed that ticagrelor and ADP modify the composition, distribution and concentration of sphingomyelins in membrane microdomains related to platelet activation or inhibition.In the second part of this work, we described, for the first time, the interaction of P2Y12 receptors with the two metabolites of ticagrelor. In addition, we showed similar interactions between ADP and P2Y12 receptor antagonists with a difference in the binding pocket indicating the change in receptor conformation
Martel, Catherine. „Rôles physiopathologiques du complément dans le syndrome coronarien aigu et implications thérapeutiques“. Thèse, 2009. http://hdl.handle.net/1866/3639.
Der volle Inhalt der QuelleMany efforts have been made in lowering the risk of myocardial infarction in the general population. Most clinicians are knowledgeable of the several identified risk factors leading to the development of acute coronary syndromes (ACS), and in turn, insure a better follow-up for “at risk” patients [1]. Despite the fact that intensive efforts in controlling modifiable risk factors have led to a better management of new cases of ACS, myocardial infarction and its deleterious consequences are still a world plague. Because it as been shown that ACS can occur without the presence of traditional risk factors [3, 4], researchers have been interested in modifying new ACS biological pathways such as inflammation. Inflammation plays a key role in the initiation, progression, and complications of atherosclerosis [5, 6], but also in post-infarction situations [7, 8]. In the past years, inflammation markers have become important targets for the prevention and treatment of ACS. Despite intensive efforts, none of the yet tested drug was found to be effective in decreasing mortality. The complement system is mainly known for its fundamental role in innate and adaptive immunity [2]. However, excessive activation of the complement can lead to a significant number of deleterious effects such as inflammation, apoptosis, necrosis and cell lysis. Earlier findings have shown that complement is extensively activated in atherosclerotic lesions, particularly in vulnerable and ruptured plaques. The objective of my doctoral project was to establish the pathophysiological roles of complement in the axis inflammation-thrombosis of ACS with the ultimate goal of identifying new therapeutic targets leading to the development of new drugs for the prevention and treatment of these diseases. The main results obtained first suggest that the complement alternative pathway represents a potential therapeutic target in acute coronary disease since terminal complement activation occurs mainly by this specific pathway. Low MBL levels (mannan-binding lectin) in serum and negligible terminal complement activation rather characterize stable coronary artery disease. By comparing the relative activity of each pathway of the complement in patients treated or not by an antibody specific to the C5 protein of the complement (pexelizumab), other results show that an inhibition of C5 activation does not have a major beneficial effect on the inhibition of the sC5b-9 complex expression or on the subsequent clinical events. Consequently, we explored, using an in vitro model of endothelial cells, the reasons of this inefficiency. This work reveals that C5 inhibition by pexelizumab inhibits the production of the pro-inflammatory anaphylatoxin C5a and of the terminal complement complex without, however, effecting endothelial cell apoptosis induced by the serum of patients with STEMI. Finally, another section stipulates that atorvastatin decreases platelet-induced complement activation in hypercholesterolemic patients, highlighting the importance of statins in the reduction of the deleterious effects of platelets-induced complement activation. All together, the study of the specific role of the various pathways of complement activation in different pathological contexts, the analysis of the effects of a specific inhibition of the C5 complement protein in the progression of ACS and the highlighting of the interactions between complement and platelet activation contribute to the development of a better knowledge of the pathophysiological roles of the complement system in ACS.
Jabor, Bashar. „Lipoprotein-associated phospholipase A2 (Lp-PLA2) in acute coronary syndrome“. Thèse, 2014. http://hdl.handle.net/1866/13006.
Der volle Inhalt der QuelleLipoprotein associated phospholipase A2 (Lp-PLA2) is a biomarker of several inflammatory diseases and syndromes. An elevated Lp-PLA2 level is associated with unstable atherosclerotic plaques. Bound to plasma lipoproteins (LDL and HDL), Lp-PLA2 prevents the formation of biologically active oxidized phospholipids on their surface such as oxidized phosphatidylcholine (oxPC). Nevertheless, the products of Lp-PLA2 action, lysophosphatidylcholine (LPC) and non-esterified fatty acids (NEFA) are both known to aggravate inflammation. Thus, understanding the metabolism of Lp-PLA2 could help us better understand its role in plaque formation, as studies have shown high expression of Lp-PLA2 and LPCs in unstable plaques. Moreover, studies showed correlation between increased Lp-PLA2 mass and activity and increased risk of coronary artery disease, stroke, and death. The inhibition of Lp-PLA2 with a small molecule, Darapladib, has not demonstrated benefit in reduction of cardiovascular events in two clinical studies. Here, the first chapter will focus on Lp-PLA2 and cardiovascular disease in man, highlighting the latest updates in the literature. The second and third chapters will introduce experimental work on Lp-PLA2 in the setting of acute coronary syndrome.
Labarthe, Benoit. „Nouveaux paramètres d'exploration de la fonction plaquettaire en clinique : thrombose tardive, profilage micro-membranaire et détection de sous-populations cellulaires“. Thèse, 2008. http://hdl.handle.net/1866/2628.
Der volle Inhalt der QuelleBlood 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.