Hormone therapies like oral contraception (OC) confer a heightened risk of venous thromboembolism (VTE) in premenopausal women. Until we gain mechanistic insights into why this happens, it is not possible to predict who is at risk for sex hormone-induced VTE. The long-term goal of this research is to identify the mechanisms by which sex hormones modulate hemostasis and thrombosis. The overall objective in this application is to determine how OC alter platelet function using a systems biology approach that combines ?omics technologies with computational models. Previous work on hormone-induced VTE have implicated several mechanisms related to platelet function including response to agonists, metabolism of arachidonic acid (AA), and gene expression. Systematic studies of these processes over different time scales and how they relate to each other is lacking and will be addressed here. The central hypothesis is that OC increase platelet reactivity over three time scales; (i) acutely (seconds-minutes) by potentiating calcium release from intracellular stores, (ii) metabolically (minutes-hours) by elevating thromboxane metabolism, and (iii) genomically (days-months) by altering the expression of adhesive receptors. This hypothesis is based on preliminary data that platelets incubated with physiologic concentrations of 17?-estradiol have higher intracellular calcium concentrations following adhesion to collagen and altered central metabolism. The rationale for the proposed research two- fold: (i) the development of new tools to study hormone-induced VTE over multiple time scales, and (ii) to measure the effects of exogenous hormones on platelet function over these time scales. This hypothesis will be tested by two specific aims: 1) Development of systems biology tools. 2) Measuring the effects of OC on platelet function over diverse time scales. Under the first aim, computational models of calcium dynamics and metabolism in platelets will be developed informed by experiments of platelet adhesion and metabolic flux analysis. Additionally, we will perform sequencing of gene variants known to affect platelet function and hormone receptors. Finally, existing microfluidic models of vascular injury will be refined to incorporate endothelial cells to measure platelet-endothelium interactions. Under the second aim, we will use the tools developed in the first aim to measure changes in platelet function following acute and chronic exposure to exogenous hormones. These studies will include tracking platelet function in a cohort of women prior to and after starting OC. The approach is innovative because it represents a new and substantive departure from the status quo by using a systems biology approach to measure and model the influence of sex hormones on platelet function over time scales of seconds to years. The proposed research is significant, because it will identify the mechanism(s) by which exogenous sex hormone confer a pro- and/or antiplatelet phenotype in premenopausal women by both non-genomic and genomic pathways. Ultimately, such knowledge has the potential to improve the safety of hormone therapies in the United States.

R61HL141794

2018-04-16

2020-03-31