ORIGINAL ARTICLESLung cancer chemotherapy agents increase procoagulant activity via protein disulfide isomerase-dependent tissue factor decryptionLysov, Zakhara,d; Swystun, Laura L.e; Kuruvilla, Sarab; Arnold, Andrewb; Liaw, Patricia C.c,dAuthor Information aDepartment of Medical Sciences bDepartment of Oncology cDepartment of Medicine dThrombosis and Atherosclerosis Research Institute (TaARI), McMaster University, Hamilton, Ontario, Canada eDepartment of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario, Canada Correspondence to Patricia Liaw, PhD, Thrombosis and Atherosclerosis Research Institute (TaARI), 237 Barton St. E., Hamilton, Ontario L8L 2X2, Canada Tel: +1 905 521 2100x40788; e-mail: [email protected] Received 20 January, 2014 Revised 22 March, 2014 Accepted 16 April, 2014 Blood Coagulation & Fibrinolysis: January 2015 - Volume 26 - Issue 1 - p 36-45 doi: 10.1097/MBC.0000000000000145 Buy Metrics Abstract 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. The aim of this study was to determine the mechanism(s) by which lung cancer chemotherapy agents cisplatin, carboplatin, gemcitabine, and paclitaxel elicit increased tissue factor activity on endothelial cells, A549 cells, and monocytes. Tissue factor activity, tissue factor antigen, and phosphatidylserine exposure were measured on chemotherapy-treated human umbilical vein endothelial cells (HUVEC), A549 cells, and monocytes. Cell surface protein disulfide isomerase (PDI) and cell surface free thiol levels were measured on HUVEC and A549 non-small cell lung carcinoma cells. Treatment of HUVECs, A549 cells, and monocytes with lung cancer chemotherapy significantly increased cell surface tissue factor activity. However, elevated tissue factor antigen levels were observed only on cisplatin-treated and gemcitabine-treated monocytes. Cell surface levels of phosphatidylserine were increased on HUVEC and monocytes treated with cisplatin/gemcitabine combination therapy. Chemotherapy also resulted in increased cell surface levels of PDI and reduced cell surface free thiol levels. Glutathione treatment and PDI inhibition, but not phosphatidylserine inhibition, attenuated tissue factor activity. Furthermore, increased tissue factor activity was reversed by reducing cysteines with dithiothreitol. These studies are the first to demonstrate that lung cancer chemotherapy agents increase procoagulant activity on endothelial cells and A549 cells by tissue factor decryption through a disulfide bond formation in a PDI-dependent mechanism. Copyright © 2015 YEAR Wolters Kluwer Health, Inc. All rights reserved.