The role of coagulation and platelets in colon cancer-associated thrombosis

• Published in: American Journal of Physiology: Cell Physiology Vol. 316; no. 2; pp. C264 - C273
• Main Authors: Mitrugno, Annachiara, Tassi Yunga, Samuel, Sylman, Joanna L, Zilberman-Rudenko, Jevgenia, Shirai, Toshiaki, Hebert, Jessica F, Kayton, Robert, Zhang, Ying, Nan, Xiaolin, Shatzel, Joseph J, Esener, Sadik, Duvernay, Matthew T, Hamm, Heidi E, Gruber, András, Williams, Craig D, Takata, Yumie, Armstrong, Randall, Morgan, Terry K, McCarty, Owen J T
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.02.2019
• Subjects: Aspirin; Blood Coagulation - physiology; Blood Platelets - pathology; Blood Platelets - physiology; Cell interactions; Cell Line, Tumor; Coagulation; Colon cancer; Colonic Neoplasms - blood; Colonic Neoplasms - pathology; Colorectal cancer; Cross-Sectional Studies; Fibrin; Humans; Malignancy; Molecular modelling; Phenotypes; Platelets; Retrospective Studies; Thrombin; Thromboembolism; Thrombosis; Thrombosis - blood; Thrombosis - pathology; Thromboxane A2; Tissue factor; aspirin; cancer; thrombosis; coagulation; PAR4; platelets
• ISSN: 0363-6143; 1522-1563
• DOI: 10.1152/ajpcell.00367.2018

Cancer-associated thrombosis is a common first presenting sign of malignancy and is currently the second leading cause of death in cancer patients after their malignancy. However, the molecular mechanisms underlying cancer-associated thrombosis remain undefined. In this study, we aimed to develop a better understanding of how cancer cells affect the coagulation cascade and platelet activation to induce a prothrombotic phenotype. Our results show that colon cancer cells trigger platelet activation in a manner dependent on cancer cell tissue factor (TF) expression, thrombin generation, activation of the protease-activated receptor 4 (PAR4) on platelets and consequent release of ADP and thromboxane A2. Platelet-colon cancer cell interactions potentiated the release of platelet-derived extracellular vesicles (EVs) rather than cancer cell-derived EVs. Our data show that single colon cancer cells were capable of recruiting and activating platelets and generating fibrin in plasma under shear flow. Finally, in a retrospective analysis of colon cancer patients, we found that the number of venous thromboembolism events was 4.5 times higher in colon cancer patients than in a control population. In conclusion, our data suggest that platelet-cancer cell interactions and perhaps platelet procoagulant EVs may contribute to the prothrombotic phenotype of colon cancer patients. Our work may provide rationale for targeting platelet-cancer cell interactions with PAR4 antagonists together with aspirin and/or ADP receptor antagonists as a potential intervention to limit cancer-associated thrombosis, balancing safety with efficacy.