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Reelin is a secreted glycoprotein and essential for brain development and plasticity. Recent studies provide evidence that Reelin modifies platelet actin cytoskeletal dynamics. In this study we sought to dissect the contribution of Reelin in arterial thrombus formation. Here we analyzed the impact of Reelin in arterial thrombosis ex vivo and in vivo using Reelin deficient (reeler) and wildtype mice. We found that Reelin is secreted upon platelet activation and mediates signaling via glycoprotein (GP)Ib, the amyloid precursor protein (APP) and apolipoprotein E receptor 2 (ApoER2) to induce activation of Akt, extracellular signal-regulated kinase (Erk), SYK and Phospholipase Cγ2. Moreover, our data identifies Reelin as first physiological ligand for platelet APP. Platelets from reeler mice displayed attenuated platelet adhesion and significantly reduced thrombus formation under high shear conditions indicating an important role for Reelin in GPIb-dependent integrin αIIbβ3 activation. Accordingly, adhesion to immobilized vWF as well as integrin activation and the phosphorylation of Erk and Akt after GPIb engagement was reduced in Reelin deficient platelets. Defective Reelin signaling translated into protection from arterial thrombosis and cerebral ischemia/reperfusion injury beside normal hemostasis. Furthermore, treatment with an antagonistic antibody specific for Reelin protects wildtype mice from occlusive thrombus formation. Mechanistically, GPIb co-localizes to the major Reelin receptor APP in platelets suggesting that Reelin-induced effects on GPIb signaling are mediated by APP-GPIb interaction. These results indicate that Reelin is an important regulator of GPIb-mediated platelet activation and may represent a new therapeutic target for the prevention and treatment of cardio- and cerebrovascular diseases.