Modeling and Simulation of Procoagulant Circulating Tumor Cells in Flow

We describe a mathematical/computational model for thrombin concentration gradients generated by procoagulant circulating tumor cells (CTCs) in flow. We examine how CTCs enhance blood coagulation as they diffuse tissue factor-dependent coagulation enzymes in a flow environment with vessel walls. Concentration fields of various enzymes, such as prothrombin and thrombin, diffuse, to, and from CTCs, respectively, as they propagate through the bloodstream. The diffusion-dependent generation of these enzymes sets up complex time-dependent concentration fields. The CTCs are modeled as diffusing point particles in an incompressible fluid, and we exploit exact analytical solutions based on three-dimensional Green's functions for unbounded domains with one wall for high resolution numerical simulations. Time-dependent gradient trackers are used to highlight that concentration fields build-up (i) near boundaries (vessel walls), (ii) in regions surrounding the diffusing particles, and (iii) in complex time-dependent regions of the flow where fields associated with different particles overlap. Two flow conditions are modeled: no flow, and unidirectional constant flow. Our results indicate that the CTC-generated thrombin diffuses to and persists at the blood vessel wall, and that the spatial distribution of CTCs in flow determines local thrombin concentration. The magnitude of the diffusion gradient and local thrombin concentration is dependent upon bulk solution concentrations of coagulation factors within normal reported concentration ranges. Therefore, our model highlights the potential to determine patient-specific risks for CTC-induced hypercoagulability as a function of CTC number and individual patient concentration of coagulation factors.