A MATHEMATICAL MODEL OF PLATELET AGGREGATION IN AN EXTRAVASCULAR INJURY UNDER FLOW.

We present the first mathematical model of flow-mediated primary hemostasis in an extravascular injury which can track the process from initial deposition to occlusion. The model consists of a system of ordinary differential equations (ODEs) that describe platelet aggregation (adhesion and cohesion), soluble-agonist-dependent platelet activation, and the flow of blood through the injury. The formation of platelet aggregates increases resistance to flow through the injury, which is modeled using the Stokes-Brinkman equations. Data from analogous experimental (microfluidic flow) and partial differential equation models informed parameter values used in the ODE model description of platelet adhesion, cohesion, and activation. This model predicts injury occlusion under a range of flow and platelet activation conditions. Simulations testing the effects of shear and activation rates resulted in delayed occlusion and aggregate heterogeneity. These results validate our hypothesis that flow-mediated dilution of activating chemical adenosine diphosphate hinders aggregate development. This novel modeling framework can be extended to include more mechanisms of platelet activation as well as the addition of the biochemical reactions of coagulation, resulting in a computationally efficient high throughput screening tool of primary and secondary hemostasis.

A density-dependent FEM-FCT algorithm with application to modeling platelet aggregation.

Upon injury to a blood vessel, flowing platelets will aggregate at the injury site, forming a plug to prevent blood loss. Through a complex system of biochemical reactions, a stabilizing mesh forms around the platelet aggregate forming a blood clot that further seals the injury. Computational models of clot formation have been developed to a study intravascular thrombosis, where a vessel injury does not cause blood leakage outside the blood vessel but blocks blood flow. To model scenarios in which blood leaks from a main vessel out into the extravascular space, new computational tools need to be developed to handle the complex geometries that represent the injury. We have previously modeled intravascular clot formation under flow using a continuum approach wherein the transport of platelet densities into some spatial location is limited by the platelet fraction that already reside in that location, i.e., the densities satisfy a maximum packing constraint through the use of a hindered transport coefficient. To extend this notion to extravascular injury geometries, we have modified a finite element method flux-corrected transport (FEM-FCT) scheme by prelimiting antidiffusive nodal fluxes. We show that our modified scheme, under a variety of test problems, including mesh refinement, structured vs unstructured meshes, and for a range of reaction rates, produces numerical results that satisfy a maximum platelet-density packing constraint.