Background: Blood damage induced by mechanical circulatory support (MCS) devices has become the biggest shackles in clinical. Non-physiological shear stress in MCS devices is considered to be an important trigger. Although researchers have been conducting in vitro studies, the major factor of blood damage is still unclear. Methods: In this study, 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. Results: The quantitative correlation between the hemolysis index and the two flow-dependent parameters was found following the power law mathematical model under high shear stress and instantaneous exposure time. The degradation of high molecular weight VWF was not obviously under high shear stress factor and did not satisfy the power law mathematical model. Besides, the degradation of high molecular weight VWF was found as the result of the accumulation over exposure time under non-physiological shear stress. Conclusions: Comparing to shear stress, exposure time has a greater effect on both red blood cell and VWF damage. To improve hemocompatibility of MCS devices, the slow even stagnant blood flow areas in these devices should be avoid as much as possible.