Systems and methods are provided for depleting platelets from blood. The system includes a multi-stage blood separation chamber in which blood is separated into red blood cells and platelet-rich plasma. The platelet-rich plasma is conveyed from a first stage of the chamber to a second stage, where it is separated into platelets and platelet-poor plasma. The platelet-poor plasma is conveyed out of the chamber while the platelets are allowed to accumulate in the second stage of the chamber. When a controller of the system has determined that the maximum chamber capacity of platelets has been accumulated in the second stage of the chamber, the platelets are conveyed out of the chamber to a waste container. The cycle of separating blood into its components, accumulating platelets in the chamber, and then flushing the platelets from the chamber is repeated until a target platelet concentration of the blood is achieved.
