ABSTRACT Cardiovascular disease remains the main cause of death in the world, where 17.9 million people die every year. Platelet activation plays a primary role in the pathophysiology of cardiovascular disease, especially in atherosclerosis, and the inability to regulate platelet function leads to atherothrombotic events resulting in myocardial infarction and stroke. Currently available antiplatelet agents inhibit platelet aggregation at the great risk of bleeding. In our lab, we have identified the 12-LOX derived DGLA product, 12-HETrE, to potently inhibit platelet activation ex vivo and significantly prevented occlusive thrombus formation in vivo. Interestingly, due to its potent antithrombotic activities of 12-HETrE, investigations on its impact on normal hemostasis uncovered that there were no differences in bleeding occurrences between treated and control groups. Further studies revealed that 12-HETrE mediated its antiplatelet effects in part through the prostacyclin receptor and possibly through other G⍺s-linked G-protein-coupled receptors. These studies highlight the potential for further studies into the mechanisms of 12-HETrE which could lead to further discoveries of potential targets for the development of antiplatelet therapies that will not lead to unnecessary bleeding risks. Previously, we have identified bioactive synthetic high-density lipoprotein (sHDL) as a mediator of platelet activation, where it was internalized by platelets and inhibited platelet aggregation in vitro and inhibited thrombus growth in vivo. Therefore, in this present study we will be further investigating the mechanisms of 12-HETrE in combination with the sHDL nanocarriers in its interactions with platelets to prevent thrombosis. The successful completion of this present study will provide robust mechanistic insight into how sHDL is able to improve 12-HETrE's antiplatelet properties and where or not it will increase its affinity for the IP receptor.