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Venous thromboembolism (VTE), defined as deep vein thrombosis and/or pulmonary embolism is the second leading cause of mortality in cancer patients, second only to cancer itself. A number of reports suggest that circulating extracellular vesicles (EVs) may be increased in cancer patients with VTE. The aim of this study was to examine circulating EVs in high-risk ambulatory cancer patients, determine if levels are associated with hematological outcomes (VTE, major bleeding event), and to assess the impact of prophylactic antithrombotic therapy (Apixaban). We hypothesized that elevated levels of circulating large EVs will be predictive of cancer associated VTE and/or bleeding events and that treatment with Apixaban will reduce EV levels and incidence of cancer VTE. Plasma samples from patients at baseline, and 90-days follow-up from the Apixaban for the Prevention of Venous Thromboembolism in High-Risk Ambulatory Cancer patients (AVERT) trial were investigated. Total EVs were quantified by their pro-coagulant activity using the Zymuphen MP-Activity kit. Platelet, endothelial and tissue-factor EV levels were quantified by flow cytometry. We observed that circulating EVs exhibited significant associations with sex, age, and cancer type, however we did not observe any relationships with clinical outcomes. Thus, it appears that circulating EVs may not have a role in risk stratification for VTE in in high-risk ambulatory cancer patients.

Pulmonary arterial hypertension (PAH) is a progressive disease that results in increased pulmonary vasculature resistance, causing right ventricular (RV) remodeling, which eventually progresses into right heart failure and mortality. New and emerging therapeutic strategies involve regenerative approaches to repair the underlying vascular pathology using regenerative cell therapy and methods to alleviate RV dysfunction in the setting of fixed RV afterload. In the first section of the thesis, we investigated the role of EPC paracrine mechanisms in the treatment of PAH. We characterized the paracrine function of EPCs by demonstrating that EPC conditioned medium enhances endothelial cell migration, survival and angiogenesis in vitro. We further examined the role of secreted extracellular vesicles in the paracrine function of EPCs, which played a minor role in promoting wound healing. However, using the monocrotaline rat model of PAH, we did not demonstrate a consistent benefit on RV pressures or remodeling with EPCs or EPC conditioned medium. The lack of effect may be related to the advanced phenotype observed in our model of PAH. Survival in severe pulmonary arterial hypertension (PAH) is related to the ability of the right ventricle (RV) to adapt to increased afterload. Therefore, we explored the effect of genetic background on right ventricular adaptation and survival in a rat model of severe (PAH). Compared to the conventional Sprague-Dawley rat strain, we observed high mortality in the Fischer SUHx model of severe PAH. This was related to a strain-dependent failure of RV adaptation, as evidenced by RV dilatation, RV contractile dysfunction, decreased cardiac ouptut and decreased exercise capacity. Further analysis by gene expression microarrays and fluorescence microangiography demonstrate that failure of RV adaptation is due at least in part due to lack of adequate microvascular angiogenesis in the hypertrophied RV. This work lays the foundation for the section on RV-specific therapy that follows. Using the Fischer model of maladaptive RV remodeling, we tested whether cardiotrophin-1 (CT-1), a pro-angiogenic and cardioprotective cytokine, could improve RV adaptation. We demonstrated that as a rescue treatment, CT-1 reduced RV dilatation and function without influencing RV afterload, which suggests improved RV adaptation. These changes were associated with an increase in RV capillary density. As an early-stage preventative treatment, in addition to improving RV remodeling, CT-1 also reduced pulmonary pressures. These hemodynamic changes suggest that CT-1 may also have a direct impact on vascular tone or the underlying pulmonary vascular pathology.