Grant: Travel Awards - Institute Community Support

Background: Thrombosis is the second leading cause of death in the cancer patient population. Lung cancer patients undergoing chemotherapy have an elevated risk for thrombosis. However, the mechanisms by which chemotherapy agents increase the risk for thrombosis remains unclear. Objectives: To determine the mechanism(s) by which lung cancer chemotherapy agents cisplatin, carboplatin, gemcitabine, and paclitaxel elicit increased tissue factor (TF) procoagulant activity healthy host cells (HUVEC, and monocytes) as well as lung tumour cells (A549). Results: Treatment of HUVECs, A549 cells, and monocytes with lung cancer chemotherapy significantly increased cell surface TF procoagulant activity. However, elevated TF antigen levels were observed only on cisplatin- and gemcitabine-treated monocytes. An increase in procoagulant activity without a corresponding increase in protein level suggested chemotherapy-dependent conversion (decryption) of existing TF from the inactive to active form. Our inhibition studies demonstrate that this decryption occurs via protein disulfide isomerase (PDI), an enzyme responsible for the formation and breakdown of disulfide bonds. We were able to inhibit as well as reverse chemotherapy-induced TF activity by blocking the formation of the disulfide bonds prior to formation or the disassociation of disulfide bonds post formation respectively. Conclusions: These studies provide insight into lung cancer chemotherapy-induced thrombissus and are the first to demonstrate that lung cancer chemotherapy agents increase procoagulant activity on endothelial cells, blood monocytes, and A549 cells by TF decryption through a disulfide bond formation in a PDI-dependent mechanism. These findings may lead to identification of novel targets for anti-coagluant therapy which would result in reduced chemotherapy-induced thrombosis mortalities.