Thrombosis is a multifactorial process that directly contributes to nearly half of the mortality in the United States. It is now widely appreciated that insulin resistance and Type 2 Diabetes Mellitus (DM), often in the setting of obesity, are frequently identified as contributors to the development of arterial thrombotic phenomena, and comprise a major theme of this application. All of the Projects include Aims that systematically investigate the impact of diabetes and/or insulin resistance on thrombosis. This is motivated by the most recent data estimate that 18.2 million individuals in the United States have DM and a further 40 million may have impaired glucose tolerance or "pre-diabetes". The component projects of this SCCOR address genetic, cellular and molecular mechanisms of thrombosis. In a mechanistic sense, this application targets three of the pre-eminent systems that contribute to the development of thrombosis, including platelet activation, thrombin biology and protease activated receptors (PARs), and the fibrinolytic system. This research program brings together investigators with diverse and complementary approaches to test hypotheses involving the mechanisms of thrombosis and how this process can be prevented. All of the Projects include Aims that directly involve human subjects. In fact, 12.5 of the 18 (69.4%) unique Specific Aims proposed in the five distinct Projects involve patient-oriented research. The combined skills of the investigators in fibrinolysis, the coupling of G-proteins to receptors, eicosanoid metabolism, platelet collagen receptors, and diabetes have been merged into a dynamic collaborative research group that will advance our understanding of the molecular mechanisms of arterial thrombosis in these high risk populations.