The blood microenvironment is a dynamic system consisting of a diverse range of cells and plasma proteins that function together to maintain homeostasis. In my dissertation, I explored the intricate interplay amongst the different components of the blood microenvironment (e.g. endothelial cells, platelets, and coagulation factors) in studies ranging from in vitro experiments, to in vivo studies with nonhuman primates (NHPs), and clinical studies. My objective was to leverage knowledge of complex blood microenvironment interactions to develop tools targeting the intracellular and extracellular pathways that contribute to the manifestation of vascular diseases and responses to vascular devices.