The features of atherothrombotic diseases are the rupture of atherosclerotic plaques and thrombosis.Platelet activation and aggregation play a pivotal role in the pathogenesis and clinical manifestation.Similar to neuronal and immunological synapse,synaptic structure is also formed between platelets during thrombus formation.The microenvironment of platelet synapse facilitates signal transduction that has been accepted as contact-dependent events due to their occurrence after platelet contact begins,which is believed to play a role in the thrombus formation and stability.Axonal guidance molecules(eg Ephrins and Semaphorins) have been found in platlet synapse.In addition to axonal guidance,axonal guidance molecules have been shown to participate in the pathophysiological processes,including immune response,tumor metastasis,angiogenesis,and thrombosis. Most recently,it was found that deletion of a semaphorin family member,Sema4D,attenuated platelet hyperreactivity in the setting of dyslipidemia and protected from the development of atherosclerotic plaques.This article summarizes the progress in the understanding of the molecular mechanisms by which axonal guidance molecules affect atherothrombosis.