Extracorporeal membrane oxygenation (ECMO) is a lifesaving therapy in patients with acute respiratory distress syndrome (ARDS). Hemostatic complications are frequently observed on ECMO and limit the success of this therapy. Platelets are key mediators of hemostasis enabling activation, aggregation and thrombus formation to exposed matrix proteins via their surface receptors such as glycoprotein (GP)VI or GPIb/V/IX. Recent research has elucidated a regulatory role of the GPV subunit. The cleaved soluble (s)GPV ectodomain was identified to spatio-temporally control fibrin formation through complex formation with thrombin. We aimed to decipher the impact of ECMO on platelet phenotype and function, including the role of GPV and plasmatic sGPV. We recruited 36 patients with ARDS in the wake of coronavirus disease 2019 (COVID-19) pneumonia and performed a longitudinal comparison of platelet phenotype and function in non-ECMO (n=23) versus ECMO (n=13) compared to healthy controls. Patients were assessed at up to three time points (t1=day 1-3; t2=day 4-6; t3=day 7-14 after cannulation/study inclusion). Agonist-induced platelet activation was assessed by flow cytometry and revealed decreased GPIIb/IIIa activation and α-granule release in all ARDS patients. During ECMO treatment, agonist-induced δ-granule release continuously decreased, which was independently confirmed by electron microscopy and associated with a prolonged in vitro bleeding time. GPV expression on the platelet surface markedly decreased in ECMO compared to non-ECMO patients. Plasma sGPV levels were increased in ECMO patients and associated with poor outcome. Our data demonstrate an ECMO-intrinsic platelet δ-granule deficiency and hemostatic dysfunction beyond the underlying ARDS.