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

Abstract

Summary. 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.

Platelet-lymphocyte ratio is a predictor of venous thromboembolism in cancer patients

“…What is more, our results provide coherent evidence that elevated PLR was of a strong predictor of thrombosis in patients with cancers [12]. In previous studies, the platelet counts alone have been reported as an independent risk factor for cancer related VTE [24,25]. Compared to the platelet alone, our study indicated that baseline evaluation of PLR might provide important information to predict higher risk of cancer related VET.…”

Investigation of Proposed Mechanisms of Chemotherapy-Induced Venous Thromboembolism

“…[7][8][9][10][11][12][13][14][15] In vitro, Swystun et al demonstrated that exposure of plasma to either doxorubicin-or epirubicin-treated endothelial cells resulted in an increase in plasma thrombin generation. 48 However, for the first time, in this study we have demonstrated that there is no increased endothelial response in VTEþ compared to VTEÀ patients.…”

Impact of Chemotherapy on Thrombin Generation and on the Protein C Pathway in Breast Cancer Patients

“…We previously demonstrated in vitro that anthracyclines (doxorubicin and epirubicin) have a greater 'prothrombotic potential' than antimetabolites do (methotrexate and 5-fluorouracil) [27] . Treatment of vascular endothelial cells with either doxorubicin or epirubicin increased thrombin generation in plasma exposed to these cells.…”