Blood damage induced by mechanical circulatory support devices (MCSDs) remains a significant challenge to optimal clinical care. Although researchers have been conducting in vitro studies, the major determinant of blood damage is still unclear. An optimized capillary tube blood-shearing platform with custom designed parts was constructed to investigate the influence of two flow-dependent parameters (shear stress and exposure time) on the shear-induced damage of red blood cells and von Willebrand factor (VWF). Blood samples under different high shear stress and instantaneous exposure time were obtained by changing the flow rate and the length of capillary tube. Plasma free hemoglobin assay and immunoblotting of VWF were then performed on the sheared blood samples. The quantitative correlation between the hemolysis index and the two flow-dependent parameters was found following the power law mathematical model under the flow condition with high shear stress and instantaneous exposure time. The degradation of high molecular weight VWF was not obvious under high shear stress factor. However, the degradation of high molecular weight VWF was found as the result of the accumulation over exposure time under non-physiological shear stress, which was consistent with the different mechanism of VWF damage comparing to red blood cell damage. Compared to peak shear stress, exposure time has a greater effect on both red blood cell and VWF damage. To improve the hemocompatibility of MCSDs, it is more important to avoid regions of slow blood flow with non-physiological shear stress under laminar flow conditions.