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Platelets are anucleate fragments of megakaryocytes and have a central role in haemostasis responding to a variety of agents and stimuli initiating a series of events ending in activation and aggregation. At unstable plaques platelets can initiate atherothrombosis leading to complete occlusion of the vessel. Aspirin is a nonsteroidal anti-inflammatory drug and has been shown to reduce the risk of myocardial infarction and stroke in susceptible patients by approximately 25%. However, some patients, despite aspirin therapy, experience further vascular events suggesting that they aspirin 'resistant'. Clinical aspirin resistance refers to patients who, despite compliance with a therapeutic dose (?75 mg), continue to experience recurrent thrombotic events; biochemical aspirin resistance uses laboratory methods to indicate the failure of aspirin to inhibit platelet activity. In this study the human megakaryoblastic cell line (MEG-Ol) was used as a model, which exhibits both phenotypic and biochemical properties observed in pro-platelet megakaryopoiesis. In this study Meg-Ol cells were exposed to clinically relevant concentrations of aspirin and salicylate to observe the resultant global and sub- proteomes. As platelets are anucleate, proteornic techniques can investigate changes -\ .-i - •. in protein expression associated with aspirin resistance. This study also examined protein expression changes in response to therapeutic doses of aspirin in the global and sub-proteornes of platelets isolated from a healthy volunteer population classified as ASA·sensitive or AS A-resistant based on the PFA-lOO platelet functionality test. The findings of the present study show that the expression of important proteins in the well characterised megakaryocyte cell line, Meg-Ol , are modified following' exposure to both aspirin and salicylate. In addition the proteomes of platelets isolated from AS A-resistant and ASA-sensitive individuals differ in the expression of proteins. This study has shown that aspirin and salicylate treatment can alter the expression of numerous proteins independently of COX, which were directly or indirectly involved in platelet activation.

Au décours d'une première embolie pulmonaire (EP), certains patients présentent un syndrome post EP : un tiers des patients ont une obstruction persistante de la vascularisation pulmonaire, associée à la persistance d'une dyspnée et une limitation des performances à l'effort. Certains patients présenteront une récidive d'EP ou, plus rarement, une hypertension pulmonaire, dont les séquelles perfusionnelles sont un critère diagnostique indispensable. Le rôle et la physiopathologie des séquelles perfusionnelles au cours du syndrome post EP est incomprise. Ce travail a mis en évidence l'existence d'un risque majoré de récidive d'EP (odds ratio 1,9) chez les patients présentant des séquelles perfusionnelles >10% à la vascularisation pulmonaire. L'analyse des propriétés fonctionnelles du fibrinogène purifié à partir du plasma de patients suivis pour une première EP améliore la prédiction de séquelles perfusionnelles confirmant le rôle clé de celui-ci dans la physiopathologie de la maladie. Ainsi, une forte proportion de chaine Bβ porteuse d'un seul résidu acide sialique majore le risque de séquelles. L'étude des cellules endothéliales circulantes à la phase aigüe et après une EP montre que les patients qui développeront des séquelles mobilisent peu de cellules endothéliales, témoignant d'une forte altération des processus de réparation de l'endothélium pulmonaire. L'interaction de la fibrine avec les progéniteurs endothéliaux dans cette anomalie de la régulation est possible : les progéniteurs expriment le récepteur VLDLr dont l'épitope β15-42 de la fibrine est un ligand impliqué dans la régulation du cycle cellulaire et l'inhibition de l'angiogenèse. / Pulmonary vascular sequels after pulmonary embolism: prognosis, prediction and physiopathologyAbstract: Post Pulmonary Embolism (PE) syndrome is not rare after PE: one third of the patients presents residual pulmonary vascular obstruction (RPVO) traducing sequels associated with increased dyspnea and impaired exercise capacity. Some of these patients will suffer PE recurrence or, more rarely, chronic thromboembolic pulmonary hypertension, whose one the diagnosis criteria is persistent perfusion defect. Prognosis value and mechanisms underlying vascular sequels are still unclear. The present work shows that RPVO > 10% after a first PE is associated with an increased risk for venous thromboembolism recurrence (odds ratio 1.9). Secondly, fibrinogen properties were investigated in PE patients. Patients with RPVO >10% presented more monosialiated Bβchain form. Prediction models for RPVO that include fibrinogen analysis were more accurate than those without fibrinogen data; This results highlights the key role of fibrin in the pathophysiology of chronic venous thromboembolism. Interestingly, the present work shows that patient who will present RPVO had an impaired endothelial cells mobilization. Compared to patients without RPVO, patients with RPVO had lower circulating endothelial cells at the acute phase of PE. This endothelial dysfunction is probably triggered by endothelial progenitors that expressed the very low density lipoprotein receptor (VLDLr), implicated in the inhibition of angiogenesis and able to bind the β15-42 N terminal sequence of the fibrin Bβ chain.