Impact of chemotherapy on thrombin generation and on the protein C pathway in breast cancer patients

Although thromboembolism is a problematic complication of chemotherapy, the pathogenic mechanisms by which chemotherapeutic agents exert prothrombotic effects in vivo are unclear.The objective of this study was to examine the effects of adjuvant chemotherapy on thrombin generation, the protein C anticoagulant pathway, and microparticle tissue factor (MP TF) activity in 26 breast cancer patients (stages I to III). The patients received cyclophosphamide, 5-fluorouracil, and methotrexate, epirubicin, or doxorubicin. Plasma samples were collected on day 1 (baseline), day 2, and day 8 for the first 2 cycles of chemotherapy. Levels of thrombin-antithrombin (TAT) complexes, MP TF activity, and components of the protein C anticoagulant pathway, including protein C, activated protein C (APC), soluble thrombomodulin (sTM), and soluble endothelial protein C receptor (sEPCR), were measured. Compared to prechemotherapy baseline levels, plasma TAT, protein C, and APC were significantly different following the administration of chemotherapy (p < 0.01 for each). Plasma TAT was higher in cycle 1, day 2, and cycle 2, day 8, compared to baseline. Plasma protein C levels were lower in cycle 2, day 8, whereas plasma APC levels were lower in cycle 2, day 1, and cycle 2, day 8. No significant changes were found in plasma sEPCR, sTM, or MP TF activity. This study suggests that adjuvant chemotherapy in women with breast cancer increases thrombin generation and impairs the endothelium-based protein C anticoagulant pathway.