Chemotherapeutic agents doxorubicin and epirubicin induce a procoagulant phenotype on endothelial cells and blood monocytes

Background: Although chemotherapy is associated with an increased risk of thrombosis, the pathogenic mechanisms by which chemotherapeutic agents exert prothrombotic effects are unclear. Objectives: In this study we explored the possibility that chemotherapeutic agents doxorubicin, epirubicin, 5-fluorouracil and methotrexate induce a procoagulant phenotype on vascular endothelial cells and/or on blood monocytes. Methods: Thrombin generation was measured in defibrinated plasma exposed to chemotherapy-treated human umbilical vein endothelial cells (HUVECs). Tissue factor activity assays were performed on chemotherapy-treated HUVECs and blood monocytes. The effects of chemotherapy drugs on phosphatidylserine exposure and the protein C pathway were also measured. Results: Exposure of defibrinated plasma to either doxorubicin- or epirubicin-treated HUVECs resulted in an increase in plasma thrombin generation. The procoagulant activity of doxorubicin- and epirubicin-treated HUVECs reflects an increase in tissue factor activity and phosphatidylserine exposure. Doxorubicin-mediated increase in tissue factor activity is related to increased levels of phosphatidylserine rather than to protein disulfide isomerase activity, and is likely to involve reactive oxygen species generation. Unlike doxorubicin, epirubicin does not have an impact on the protein C anticoagulant pathway. Interestingly, neither methotrextate nor 5-fluorouracil altered endothelial or monocyte hemostatic properties. Conclusions: These studies suggest that doxorubicin and epirubicin have the greatest 'prothrombotic potential' by virtue of their ability to alter endothelial and monocyte hemostatic properties.