The thrombotic potential of circulating tumor microemboli: Computational modeling of circulating tumor cell-induced coagulation

Kevin G. Phillips, Angela M. Lee, Garth W. Tormoen, Rachel A. Rigg, Anand Kolatkar, Madelyn Luttgen, Kelly Bethel, Lyudmila Bazhenova, Peter Kuhn, Paul Newton, Owen J.T. McCarty

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

Thrombotic events can herald the diagnosis of cancer, preceding any cancer-related clinical symptoms. Patients with cancer are at a 4- to 7-fold increased risk of suffering from venous thromboembolism (VTE), with ∼7,000 patients with lung cancer presenting from VTEs. However, the physical biology underlying cancer-associated VTE remains poorly understood. Several lines of evidence suggest that the shedding of tissue factor (TF)-positive circulating tumor cells (CTCs) and microparticles from primary tumors may serve as a trigger for cancer-associated thrombosis. To investigate the potential direct and indirect roles of CTCs in VTE, we characterized thrombin generation by CTCs in an interactive numerical model coupling blood flow with advection-diffusion kinetics. Geometric measurements of CTCs isolated from the peripheral blood of a lung cancer patient prior to undergoing lobectomy formed the basis of the simulations. Singlet, doublet, and aggregate circulating tumor microemboli (CTM) were investigated in the model. Our numerical model demonstrated that CTM could potentiate occlusive events that drastically reduce blood flow and serve as a platform for the promotion of thrombin generation in flowing blood. These results provide a characterization of CTM dynamics in the vasculature and demonstrate an integrative framework combining clinical, biophysical, and mathematical approaches to enhance our understanding of CTCs and their potential direct and indirect roles in VTE formation.

Original languageEnglish (US)
Pages (from-to)C229-C236
JournalAmerican Journal of Physiology - Cell Physiology
Volume308
Issue number3
DOIs
StatePublished - 2015

Keywords

  • Advection-diffusion equation
  • Circulating tumor microemboli
  • Coagulation
  • Lung cancer
  • Navier-Stokes equation
  • Tissue factor
  • Venous thromboembolism

ASJC Scopus subject areas

  • Physiology
  • Cell Biology

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    Phillips, K. G., Lee, A. M., Tormoen, G. W., Rigg, R. A., Kolatkar, A., Luttgen, M., Bethel, K., Bazhenova, L., Kuhn, P., Newton, P., & McCarty, O. J. T. (2015). The thrombotic potential of circulating tumor microemboli: Computational modeling of circulating tumor cell-induced coagulation. American Journal of Physiology - Cell Physiology, 308(3), C229-C236. https://doi.org/10.1152/ajpcell.00315.2014