Effects of the chemotherapeutic agent doxorubicin on the protein C anticoagulant pathway

Abstract

Although chemotherapy treatment is associated with an increased risk of thrombosis, the pathogenic mechanisms for the thrombogenic effect of chemotherapeutic drugs are poorly understood. We hypothesize that exposure of vascular endothelial cells to chemotherapeutic agents results in the loss of a thromboresistant phenotype. In this study, we examined the effects of the chemotherapeutic agent doxorubicin on the endothelium-based protein C anticoagulant pathway. The endothelial cell protein C receptor (EPCR) and thrombomodulin are two endothelial cell surface receptors required for the conversion of zymogen protein C to the anticoagulant enzyme activated protein C. Exposure of human umbilical vein endothelial cells (HUVEC) to doxorubicin resulted in a dose-and time-dependent decrease in cell surface EPCR levels. This decrease occurred as a result of receptor shedding as well as from a down-regulation in EPCR mRNA levels. In contrast, doxorubicin treatment of HUVECs resulted in a dose-and time-dependent increase in cell surface thrombomodulin attributed to an up-regulation of thrombomodulin mRNA levels. The net effect of the doxorubicininduced changes in EPCR and thrombomodulin levels was a decrease in the capacity of HUVECs to convert protein C to activated protein C. Preliminary studies suggest that doxorubicin free radical metabolites mediate the doxorubicin-induced changes in EPCR expression but not those of thrombomodulin expression. In summary, these results suggest that doxorubicin alters the hemostatic balance of endothelial cells by down-regulating the endotheliumbased protein C anticoagulant pathway.

Venous thromboembolism (VTE) and glioblastoma

“…Chemotherapy can cause activation of the coagulation system through a variety of mechanisms [18][19][20][21][22][23]. Anti-angiogenic agents (such as bevacizumab) may also contribute to thrombosis through endothelial cell activation [24].…”

Endogenous activated protein C limits cancer cell extravasation through sphingosine-1-phosphate receptor 1–mediated vascular endothelial barrier enhancement

“…Interestingly, APC deficiency is observed in patients with cancer, especially in patients using certain types of chemotherapy. 31,32 Moreover, anticoagulant treatment, which is regularly prescribed to patients with cancer with thrombotic complications, may significantly affect endogenous APC generation. 33 Consequently, preservation or restoration of endogenous APC generation or both might thus be an interesting target for limiting cancer progression.…”

Tissue Factor and Cancer

“…Finally, a hypercoagulable state can emerge as a result of the chronic vascular damage or as a result of cancer-related deregulation of several haemostatic and fibrinolytic mechanisms. These include the release of cancer procoagulant [32,79] , downregulation of tissue factor pathway inhibitor (TFPI) [80][81][82][83] , upregulation of plasminogen activator inhibitor 1 (PAI-1), or cyclooxygenase 2 (COX-2) [84] , deregulation of the protein C system [85] and through a number of other scenarios [32] . At least in part, these procoagulant tendencies in cancer patients could be attributed to the prothrombotic conversion of cancer cells [32,86] , notably their increased levels of TF expression, as well as the elevation of TF found in circulating blood [31,32,45,75,77] .…”