BACKGROUND:: Extracorporeal membrane oxygenation (ECMO) is associated with a high risk of bleeding complications. The specific impact of ECMO on fibrinolysis remains unexplored. The objective of the current pilot observational prospective study was to investigate the longitudinal dynamics of fibrinolytic markers – i.e., changes over time - in the context of bleeding events in patients on ECMO. METHODS:: Longitudinal dynamics of contact phase components (kininogen and bradykinin) and fibrinolysis markers (tissue-type plasminogen activator [t-PA], plasminogen activator inhibitor-1 [PAI-1], their complexes [t-PA•PAI-1], plasmin-antiplasmin complexes, plasminogen, and D-dimer) were measured in patients undergoing veno-venous and veno-arterial ECMO, before implantation, at 0, 6, and 12 hours post-implantation, and daily thereafter. RESULTS:: The cohort consisted of 30 patients (214 ECMO-days). The concentrations of t-PA, D-dimer, plasmin-antiplasmin complexes, PAI-1 and t-PA•PAI-1 complexes were increased, whereas plasminogen decreased compared to normal values. A noteworthy divergence was observed between hemorrhagic and non-hemorrhagic patients: in bleeding patients, D-dimer, plasmin-antiplasmin, t-PA, PAI-1 and t-PA•PAI-1 followed an increasing kinetics before hemorrhage and then decreased to their baseline level; conversely non-bleeding patients showed a decreasing kinetics in these markers. Also, D-dimer and t-PA followed an increasing kinetics in bleeding patients compared to non-bleeding patients (median values for D-dimer dynamics: 1080 vs. -440 ng/mL, p=0.05; t-PA dynamics: 0.130 vs. 0.100 nM, p=0.038), and both markers significantly increased the day before hemorrhage. A t-PA concentration above 0.304 nM was associated with bleeding events (OR 4.92, 95% CI [1.01-24.08], p=0.049). CONCLUSION:: Contact activation induces fibrinolysis in ECMO patients, especially in patients experiencing bleeding. This finding supports the role of this mechanism as a possible causal factor for hemorrhages during ECMO and open new avenues for novel therapeutic perspectives.