To investigate the effects of blood pumps operated in different modes on nonphysiologic flow patterns, cell and protein function, and the risk of bleeding, thrombosis, and hemolysis, an extracorporeal blood pump (CentriMag) was operated in three clinical modalities including heart failure (HF), venous-venous (V-V) extracorporeal membrane oxygenation (ECMO), and venous-arterial (V-A) ECMO. Computational fluid dynamics (CFD) methods and coupled hemolysis models as well as recently developed bleeding and thrombosis models associated with changes in platelet and von Willebrand factor (vWF) function were used to predict hydraulic performance and hemocompatibility. The V-A ECMO mode had the highest flow losses and shear stress levels, the V-V ECMO mode was intermediate, and the HF mode was the lowest. Different nonphysiologic flow patterns altered cell/protein morphology and function. The V-A ECMO mode resulted in the highest levels of platelet activation, receptor shedding, vWF unfolding, and high molecular weight multimers vWF (HMWM-vWF) degradation, leading to the lowest platelet adhesion and the highest vWF binding capacity, intermediate in the V-V ECMO mode, and opposite in the HF mode. The V-A ECMO mode resulted in the highest risk of bleeding, thrombosis, and hemolysis, with the V-V ECMO mode intermediate and the HF mode lowest. These findings are supported by published experimental or clinical statistics. Further studies found that secondary blood flow passages resulted in the highest risk of blood damage. Nonphysiologic blood flow patterns were strongly associated with cell and protein function changing, blood damage, and complications.