Membrane oxygenator failure during venovenous (V-V) extracorporeal membrane oxygenation (ECMO) can lead to life-threatening hypoxia, high replacement costs, and may be associated with a hyperfibrinolytic state and bleeding. The current understanding of the underlying mechanisms that drive this is limited. The primary aim of this study therefore is to investigate the hematological changes that occur before and after membrane oxygenator and circuit exchanges (ECMO circuit exchange) in patients with severe respiratory failure managed on V-V ECMO. We analyzed 100 consecutive V-V ECMO patients using linear mixed-effects modeling to evaluate hematological markers in the 72 hours before and 72 hours after ECMO circuit exchange. A total of 44 ECMO circuit exchanges occurred in 31 of 100 patients. The greatest change from baseline to peak were seen in plasma-free hemoglobin (42-fold increase p < 0.01) and the D-dimer:fibrinogen ratio (1.6-fold increase p = 0.03). Bilirubin, carboxyhemoglobin, D-dimer, fibrinogen, and platelets also showed statistically significant changes (p < 0.01), whereas lactate dehydrogenase did not (p = 0.93). Progressively deranged hematological markers normalize more than 72 hours after ECMO circuit exchange, with an associated reduction in membrane oxygenator resistance. This supports the biologic plausibility that ECMO circuit exchange may prevent further complications such as hyperfibrinolysis, membrane failure, and clinical bleeding.