Role of tissue-factor bearing extracellular vesicles released from ovarian cancer cells in platelet aggregation in vitro and venous thrombosis in mice

Objective: Venous thromboembolism (VTE) contributes to morbidity and mortality in women with ovarian cancer. Underlying mechanisms of venous thrombosis in ovarian cancer are not well-understood. The aim of this study was to identify the potential role of tissue factor (TF)-bearing extracellular vesicles (EVs) originated from cancer cells in venous thrombosis in ovarian cancer models. Methods: We examined the expression of TF on EVs generated by ovarian cancer cells and the effect of TF-positive EVs on platelet aggregation. Furthermore, we performed TF-knockdown or induced TF-overexpression in ovarian cancer cell lines and examined the effects of EVs obtained from these cells on platelet aggregation. We examined the effect of TF-bearing EVs originated from ovarian cancer cells on venous thrombosis in a mouse model of inferior vena cava (IVC) stenosis. Results: TF was expressed in several ovarian cancer cell lines. EVs derived from ovarian cancer cell lines expressing TF promoted platelet aggregation. TF-knockdown in TF-high CAOV3 and OVCAR8 ovarian cancer cells delayed platelet aggregation induced by their EVs in vitro. Conversely, TF overexpression in TF-low A2780 and HeyA8 cells shortened platelet aggregation time induced by their EVs. EVs from TF-overexpressing A2780 ​cells enhanced thrombosis formation in the IVC stenosis model and resulted in a larger clot burden as compared to EVs from A2780 control cells. Conclusions: TF expression in ovarian cancer cell-derived EVs promoted platelet aggregation and thrombosis in preclinical models. These findings may have implications for reducing VTE rates in women with ovarian cancer.