title: The thrombotic potential of circulating tumor microemboli: computational modeling of circulating tumor cell-induced coagulation.
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.
authors.affiliation: Department of Biomedical Engineering, School of Medicine, Oregon Health & Science University, Portland, Oregon;
authors.forename: Kevin G
authors.initials: KG
authors.lastname: Phillips
authors.affiliation: Department of Aerospace and Mechanical Engineering, Viterbi School of Engineering, University of Southern California, Los Angeles, California;
authors.forename: Angela M
authors.initials: AM
authors.lastname: Lee
authors.affiliation: Department of Biomedical Engineering, School of Medicine, Oregon Health & Science University, Portland, Oregon;
authors.forename: Garth W
authors.initials: GW
authors.lastname: Tormoen
authors.affiliation: Department of Biomedical Engineering, School of Medicine, Oregon Health & Science University, Portland, Oregon;
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Rigg
authors.affiliation: Department of Biological Sciences, University of Southern California, Los Angeles, California;
authors.forename: Anand
authors.initials: A
authors.lastname: Kolatkar
authors.affiliation: Department of Biological Sciences, University of Southern California, Los Angeles, California;
authors.forename: Madelyn
authors.initials: M
authors.lastname: Luttgen
authors.affiliation: Scripps Clinic Medical Group, Scripps Clinic, La Jolla, California;
authors.forename: Kelly
authors.initials: K
authors.lastname: Bethel
authors.affiliation: University of California San Diego Moores Cancer Center, San Diego, California; and.
authors.forename: Lyudmila
authors.initials: L
authors.lastname: Bazhenova
authors.affiliation: Department of Biological Sciences, University of Southern California, Los Angeles, California;
authors.forename: Peter
authors.initials: P
authors.lastname: Kuhn
authors.affiliation: Department of Aerospace and Mechanical Engineering, Viterbi School of Engineering, University of Southern California, Los Angeles, California;
authors.forename: Paul
authors.initials: P
authors.lastname: Newton
authors.affiliation: Department of Biomedical Engineering, School of Medicine, Oregon Health & Science University, Portland, Oregon; Department of Cell, Developmental and Cancer Biology, School of Medicine, Oregon Health & Science University, Portland, Oregon mccartyo@ohsu.edu newton@usc.edu pkuhnn@usc.edu.
authors.forename: Owen J T
authors.initials: OJ
authors.lastname: McCarty
mesh_terms: D000230:Adenocarcinoma / Q000097:blood* / Q000175:diagnosis / Q000601:surgery; D000077192:Adenocarcinoma of Lung; D001777:Blood Coagulation / Q000502:physiology*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008175:Lung Neoplasms / Q000097:blood* / Q000175:diagnosis / Q000601:surgery; D008875:Middle Aged; D009360:Neoplastic Cells, Circulating / Q000378:metabolism* / Q000473:pathology; D066230:Patient-Specific Modeling; D054556:Venous Thromboembolism / Q000097:blood* / Q000209:etiology
keywords: Navier-Stokes equation; advection-diffusion equation; circulating tumor microemboli; coagulation; lung cancer; tissue factor; venous thromboembolism