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Role of blood platelets in ischemic stroke: identification of new safe antithrombotic targets

Research unit

UMR_S 949 - Biologie et pharmacologie des plaquettes sanguines : hémostase, thrombose, transfusion (BPPS)
10, rue Spielmann - BP 36 67065 Strasbourg Cedex

Group

Name: Biologie et pharmacologie des plaquettes

Group leader: GACHET Christian - christian.gachet@efs.sante.fr

Group leader's phone: 03 88 21 25 25

Website: Visit website

Group organization:
- Chercheurs: 4
- ITA: 8
- Doctorants: 2
- Post-Docs: 2
- Autres: 2

Publications of the team linked to the topic (3 last years):
1) Targeting platelet GPIbβ reduces platelet adhesion, GPIb signaling and thrombin generation and prevents arterial thrombosis. Maurer E, Tang C, Schaff M, Bourdon C, Receveur N, Ravanat C, Eckly A, Hechler B, Gachet C, Lanza F, Mangin PH.Arterioscler Thromb Vasc Biol. 2013 Jun;33(6):1221-9.
2) Integrin α6β1 is the main receptor for vascular laminins and plays a role in platelet adhesion, activation, and arterial thrombosis. Schaff M, Tang C, Maurer E, Bourdon C, Receveur N, Eckly A, Hechler B, Arnold C, de Arcangelis A, Nieswandt B, Denis CV, Lefebvre O, Georges-Labouesse E, Gachet C, Lanza F, Mangin PH. Circulation. 2013 Jul 30;128(5):541-52.

3) Fibrillar cellular fibronectin supports efficient platelet aggregation and procoagulant activity. Maurer E, Schaff M, Receveur N, Bourdon C, Mercier L, Nieswandt B, Dubois C, Jandrot-Perrus M, Goetz JG, Lanza F, Gachet C, Mangin PH. Thromb Haemost. 2015 Nov 25;114(6):1175-88.

About PhD

PhD Director: MANGIN Pierre - pierre.mangin@efs.sante.fr

Phone: 0687922254

Junior advisor: non

Co-tutely: non

Co-Director: non

About PhD topic :

Title: Role of blood platelets in ischemic stroke: identification of new safe antithrombotic targets

Project: Platelets play a key role in hemostasis, which represents the physiological mechanism leading to the arrest of bleeding. Following vascular injury, platelets adhere to subendothelial proteins, become activated and form an aggregate, which seals the breach 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, making it the third leading cause of mortality. Thrombolysis is a standard treatment of ischemic stroke. It consists in injecting an agent which breaks up clots within a cerebral artery. This treatment presents several limitations including a high risk of bleeding and a narrow therapeutic window, implying that only a limited number of patients is eligible to the treatment (<10%). The combination of two antiplatelet agents, aspirin and a P2Y12 receptor antagonist, which is the standard treatment for the management of acute coronary syndromes, is not recommended in the treatment of cerebral ischemic diseases due to elevated intracranial bleeding risks. Thrombectomy, a technique which involves removing the clot using a probe, has recently led to very encouraging preliminary results by allowing recanalization of brain vessels. A number of issues related to this medical procedure remains to be resolved including the risk of bleeding, the risk of re-thrombosis and the value of combining this technique with antiplatelet agents. The central aim of this PhD proposal is to better understand the role of platelets in ischemic stroke in order to identify novel antithrombotic strategies devoid of bleeding risk. The project is divided into three research axes. The first axis is to study the structure and composition of thrombi extracted from patients after thrombectomy, by using histology techniques, confocal microscopy and transmission electron microscopy. A particular attention will be paid to platelets to determine their proportion compared to other cells, their location and degree of activation in order to better understand their role. The second aim will be to identify platelet receptors whose targeting will efficiently inhibit cerebral thrombosis while causing no or low bleeding risks. Work carried out in our laboratory has shown that targeting three platelet adhesion receptors, the GPIbsubunit of the GPIb-V-IX complex, GPVI and integrin 61 inhibits experimental thrombosis in mice after injury of the aorta, carotid or mesenteric arteries, without prolonging the bleeding time. These will now be evaluated in two animal models of stroke based on a FeCl3 injury of the middle cerebral artery or thrombin injection into this vessel. An analysis of thrombus formation will be performed by a Doppler probe in real time, and the size of infarcted areas will be determined by MRI at D + 1. Intracranial bleeding will be assessed by histological analysis. The third research aim will be to develop an animal model of thrombectomy to study the risk of bleeding and re-thrombosis, and to evaluate the potential benefit of combining it with antiplatelet therapy. The perspective of this work is to identify new and innovative pharmacological strategies against cerebral ischemia with a low intracranial bleeding risk.

Wished skills: Dynamic, highly motivated and elevated scientific rigor. General knowledge in cellular biology.

Expertises which will be acquired during the training: Expertise in the field of platelet physiology. Technical expertise in imaging, cellular biology and various animal models