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

Annachiara Mitrugno, Samuel Tassi Yunga, Joanna L. Sylman, Jevgenia Zilberman-Rudenko, Toshiaki Shirai, Jessica F. Hebert, Robert Kayton, Ying Zhang, Xiaolin Nan, Joseph J. Shatzel, Sadik Esener, Matthew T. Duvernay, Heidi E. Hamm, Andras Gruber, Craig D. Williams, Yumie Takata, Randall Armstrong, Terry Morgan, Owen McCarty

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)C264-C273
JournalAmerican journal of physiology. Cell physiology
Volume316
Issue number2
DOIs
StatePublished - Feb 1 2019

Keywords

  • aspirin
  • cancer
  • coagulation
  • PAR4
  • platelets
  • thrombosis

ASJC Scopus subject areas

  • Physiology
  • Cell Biology

Fingerprint Dive into the research topics of 'The role of coagulation and platelets in colon cancer-associated thrombosis'. Together they form a unique fingerprint.

  • Cite this

    Mitrugno, A., Tassi Yunga, S., Sylman, J. L., Zilberman-Rudenko, J., Shirai, T., Hebert, J. F., Kayton, R., Zhang, Y., Nan, X., Shatzel, J. J., Esener, S., Duvernay, M. T., Hamm, H. E., Gruber, A., Williams, C. D., Takata, Y., Armstrong, R., Morgan, T., & McCarty, O. (2019). The role of coagulation and platelets in colon cancer-associated thrombosis. American journal of physiology. Cell physiology, 316(2), C264-C273. https://doi.org/10.1152/ajpcell.00367.2018