Introduction: To understand the behavior of platelet volume indices and the von Willebrand factor (VWF), in vitro experiments using whole human blood were performed with extracorporeal circulation (ECC) circuits, including membrane oxygenators coated with acrylate copolymer (ACP) or immobilized heparin (IHP). Methods: Heparinized blood was circulated through two distinct experimental circuits: an ACP-coated reservoir and tubes, as well as membranes coated with either ACP or IHP (comprising five pieces of each type). The platelet distribution width, mean platelet volume (MPV), platelet large cell ratio (P-LCR), VWF quantity (VWFQ), and VWF activity (VWFA) were measured at 0, 8, 16, 24, and 32 h in each experiment. A two-way analysis of variance (ANOVA) was performed to determine whether the coating type or circulation duration affected the transition of each measurement. Results: Two-way ANOVA indicated that the transitions of MPV, P-LCR, and VWFA were significantly affected by the circulation duration ( p = 0.030, 0.001, and <0.001, respectively) and that the transitions of VWFQ and VWFA were significantly affected by the coating type ( p = 0.022 and 0.006, respectively). Factor interactions between the coating type and circulation duration were not observed for each transition ( p > 0.05). Conclusions: Our findings suggest that P-LCR is a good index for platelet activation in blood-circulating ECC and that VWFA and VWFQ are significantly attenuated in blood-circulating ECC with ACP-coated membranes, indicating the advantage of IHP coating regarding platelet activation.