ALL blood-wetted devices, without exaggeration, are susceptible to unintended thrombosis and bleeding – with dire consequences. In spite of decades of clinical experience, basic research, and computational fluid dynamics modeling, it is still virtually impossible to avoid deleterious hematological effects without anticoagulation, or experimental trail-and-error. The unfortunate consequence is an unacceptable rate of debilitating adverse events such as stroke and hemorrhage. This abiding challenge has driven the PIs over the past 25+ years to pursue a deterministic, multi-scale, multi-constituent, convection-diffusion-reaction model of thrombosis that embraces the principle elements of Virchow’s Triad: properties of blood, character of flow, and surface chemistry. We have made significant progress in the previous phase of this project, and now able to predict platelet deposition with remarkable accuracy at multiple scales: from small crevices to full-sized ventricular assist devices. We now wish to extend the thrombosis model to include thrombus stabilization, and remodeling. Specific Aim 1 will be to extend the model to include fibrin cross-linking, endothelialization and pannus formation. We hypothesize that these improvements will enhance the utility of the model for simulating the stability of adherent thrombus, hence risk of embolization, the effects of thrombolysis and the development of neointimal surface and/or pannus growth. Specific Aim 2 will be to incorporate biochemical pathways to simulate commonly used anticoagulation, and greatly improve its clinical translation. Specific Aim 3 will be to demonstrate the performance of the enhanced thrombosis model with macro-scale devices over a range of clinically relevant conditions, including a rotary blood pump with blood-immersed bearing, a catheter blood pump, a mechanical heart valve, and a ventricular cannula. We will perform simulations parametrically, over a range of conditions to produce a map of “Thrombosis Threat Level” within the device as a function of hemodynamic and hematological independent variables: flow rate, platelet reactivity/count/pre-activation, and anticoagulation. We further intend to package the model in a user-friendly, publicly available application to promote dissemination of this resource for both designers and practitioners to ameliorate one of the most pernicious and abiding complications of cardiovascular devices.