Dr. Flaumenhaft studies platelet-mediated thrombus formation, the underlying pathology in myocardial infarction and stroke and the leading cause of mortality in the developed world. Two major focuses of the Flaumenhaft laboratory are to understand the molecular mechanisms of platelet granule release and to identify new strategies to inhibit platelet activation during thrombus formation using chemical genetics. High-speed, multicolor intravital microscopy is used to evaluate the role of platelet granule release during thrombus formation in vivo and to assess the efficacy of small molecule inhibitors as antithrombotics. His laboratory has identified several components of the platelet secretory machinery and demonstrated the importance of this machinery in thrombosis using intravital microscopy. Dr. Flaumenhaft has also applied high-throughput screening to identify small molecules directed at previously unexplored vascular targets. His laboratory has identified novel inhibitors of protein disulfide isomerase (PDI) and demonstrated their utility in blocking thrombus formation in vivo. One PDI inhibitor is presently in phase II/III clinical trials. In a second example, his laboratory has identified an allosteric binding site on the cytosolic face of protease-activated receptor 1 (PAR1). Engagement of this site by biased ligands inhibits prothrombotic signaling in platelets, while simultaneously stimulating a cytoprotective program in endothelial cells. The overarching goal of this work is to improve our fundamental knowledge of platelet function during thrombo-inflammatory processes in order to develop better therapeutic interventions for thrombotic and inflammatory disease.