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.