Ventricular assist devices (VAD) have become an indispensable treatment option for end-stage heart failure, but thromboembolic complications remain a central issue in the management of patients on mechanical circulatory support with stroke emerging as the leading cause of death. Numerical modeling of thrombosis could supplement benchtop testing and animal trials and possibly supplant multi-year clinical experience. Our group has been developing a multi-constituent model of thrombosis for over two decades, and this work presents the latest advances in this effort. First, we calibrate the existing model of thrombosis for common biomaterials in the context of platelet deposition in a micro-crevice. The simulations reproduced the platelet deposition patterns observed experimentally and elucidated the role of flow, shear rate, and surface chemistry in shaping the deposition. These results provide foundation for further development and application of the model. We next focus on the von Willebrand Factor (vWF), a mechanosensitive blood glycoprotein that mediates thrombosis under high-shear conditions. While the thrombogenic effect of vWF is well recognized, its conformational response in complex flows has largely been omitted from numerical models of thrombosis. Therefore, we propose a continuum model for the unfolding of vWF in flow and verify its performance against experiments featuring stenotic geometries. Next, we incorporate the model of vWF unfolding into the multi-constituent model of thrombosis and validate it using three benchmarks: in vitro model of atherothrombosis, a stagnation point flow, and the PFA-100®, a clinical blood test commonly used for screening for von Willebrand Disease. The simulations reproduced the key aspects of vWF-mediated thrombosis observed in these experiments, such as the thrombus location, thrombus growth dynamics, and the effect of blocking platelet-vWF interactions. The model was able to account for qualitative and quantitative hemostatic deficiencies in patient blood. Lastly, we design a stator stage for a pediatric VAD using automated CFD-driven design optimization and apply the numerical model of thrombosis to assess and compare the best design candidates. While the optimized stator blades yielded major gains in pump performance, the simulations revealed an increased risk of thrombosis in one of the designs, demonstrating the practical utility of the model.