Blood platelets play a key role in hemostasis, which groups together all the mechanisms leading to the cessation of bleeding. Following a vascular breach, the platelets adhere to the proteins of the subendothelium, activate and form an aggregate that plugs the gap and stops bleeding. In pathological conditions, a platelet aggregate can form in a cerebral artery and lead to a severe ischemic disorder called stroke. In France, 130,000 new patients suffer from stroke each year, and about 32,000 die from it, making it the third leading cause of death. The treatment of ischemic stroke is based on thrombolysis, which involves injecting an agent that breaks down clots that clog the artery. This procedure is accompanied by a high bleeding risk and a very narrow therapeutic window, implying that only a minority of patients benefit from treatment (<10%). The combination of two antiplatelet agents, aspirin and a P2Y12 receptor antagonist, is the standard treatment for the management of acute coronary syndromes. This treatment is not recommended in ischemic brain diseases because of the risk of intracranial bleeding. Thrombectomy, which consists of removing the clot using a probe, has recently led to very encouraging preliminary results by allowing the vessels to be recanalized. However, several questions related to this gesture remain to be solved, such as the evaluation of the risk of haemorrhage, the risk of re-thrombosis and the interest of combining this technique with antiplatelet agents. The aim of the thesis will be to better understand the mechanisms involved by platelets in cerebral ischemia in order to identify targeting strategies without haemorrhagic risk. The project breaks down into three areas of research. The first axis will be to study the composition and structure of aggregates obtained after thrombectomy of patients with ischemic stroke by histology, confocal microscopy and transmission electron microscopy. Particular attention will be given to platelets to determine their proportion relative to other cells, their location and their degree of activation in order to understand their role. The second axis will identify platelet receptors whose targeting will limit cerebral thrombosis without causing hemorrhagic risks. Laboratory work has shown that the targeting of three platelet adhesion receptors, GPIb-V-IX GPIb subunit, GPVI and α6β1 integrin, inhibit experimental thrombosis in mice following lesions of the aorta, carotid artery or mesenteric arterioles, without prolonging the bleeding time. The relevance of the targeting of these receptors will be evaluated in two animal models of stroke based on an injury to FeCl3 of the middle cerebral artery or the injection of thrombin in the same vessel. An analysis of thrombi formation will be performed by a Doppler probe in real time, and the size of infarcted areas at D + 1 will be determined by MRI. Intracranial bleeding will be determined by histological analysis. The third axis will aim to develop an animal model of thrombectomy. The animal model will study the risk of bleeding and re-thrombosis related to this medical procedure, and evaluate the consequence of the combination of antiplatelet therapy to this promising technique. The prospects of this work are to identify new pharmacological strategies to combat cerebral ischemia with a low risk of intracranial hemorrhage.

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