Hemorrhagic complications, especially mucosal bleedings, are very common for using continuous-flow mechanical circulatory supports (CF-MCS) including Extracorporeal Membrane Oxygenation (ECMO). CF-MCS could impact platelets by exposing this key player in primary hemostasis to high shear stress. A proteolytic cleavage (shedding) of platelet adhesion receptors GpIb and GpVI has been described under high shear stress and could contribute to the hemorrhagic complications in patients with CF-MCS. To assess whether CF-MCS promotes GpIb and GpVI shedding in vitro and in vivo and determine the kinetic evolution during the CF-MCS. First platelet shedding was investigated in vitro using a CF-MCS (Impella-CP®, Abiomed) loop model. Plasma with normal platelet count (plasma-NPC) was obtained by dilution of platelet-rich plasma collected from healthy donors in fresh frozen plasma. Sampling was performed before and after 2, 5, 30, 60 and 180 min perfusion of plasma-NPC in the loop model ( n = 4 runs). Platelet shedding was also investigated for the blood samples collected from 20 ECMO patients (WITECMO-h trial). Platelets of 20 healthy volunteers were evaluated as a control. GpIbα and GpVI shedding was analyzed by flow cytometry. A significant time-dependent decrease of GpIbα ( P < 0.001) and GpVI ( P < 0.001) MFI was observed after 180 min in the Impella®-CP loop model. In vivo baseline GpIbα and GpVI MFIs has been significantly decreased before ECMO implantation compared to the healthy subjects ( P < 0.001). After ECMO implantation, no significant variation of GpIbα and GpVI MFI was observed. CF-MCS induces platelet GpIb and GpVI shedding in vitro. Increased GpIb and GpVI shedding is already present before ECMO implantation and remain significantly elevated after the implantation. Loss of the platelet receptors GPIbα and GPVI in patients with CF-MCS may contribute to hemorrhagic complications observed in these patients.