Venous thromboembolism (VTE) is caused by a combination of blood hypercoagulability, endothelial dysregulation, and blood stasis. This biologic dysregulation has environmental and inherited sources that interact to modulate thrombotic risk. Female sex-hormone-based oral contraceptives (OCs) are an important environmental cause of thrombosis in young women, increasing the risk of VTE 2 to 4-fold. The aim of this application is to elucidate mechanisms by which exogenous female sex hormones (OCs) increase the risk of VTE in premenopausal women. Our proposal has 4 aims, which will drive biologic discovery and functional experimentation. R61 Overview: Discovery. In the first 2 years of this proposal, we proposed to identify new genes, protein markers, and biologic pathways associated with OC use and VTE risk using “panomic” resources (genomic, transcriptomic, and proteomic) and functional cell biology and biochemistry techniques. Aim 1: Identify novel genes that contribute to VTE in premenopausal women using OCs in 3 well- characterized, case-control studies of VTE. We have accomplished this Aim. Aim 2: Characterize effects of OCs on endothelial cell (EC) transcriptomic and proteomic responses, EC procoagulant activity, and ability to promote clot formation. We have accomplished this Aim. R33 Overview: Validation and Functional Testing. In the next 3 years of this proposal, we will validate candidate genes and proteins identified in the R61 phase, characterizing their function in an in vitro cell-based model of coagulation. We will characterize interactions between EC dysregulation and plasma hypercoagulability to promote the formation of prothrombotic clots in a blood-endothelial interface model. Aim 3: Characterize candidate genes and proteins in human populations, focusing on Aim 2 discoveries. Aim 4: Characterize the novel candidate genes identified through discovery and validation in the aims above, and determine effects of each gene on EC procoagulant activity in normal and hypercoagulable plasmas. Collectively, these aims integrate discovery and functional-analysis information to identify biologic variation that promotes OC-induced VTE. This study will yield functionally-validated molecular signals and a blood-endothelial interface model for incorporation into VTE risk prediction tools in premenopausal women.