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ABSTRACT The fibrinolytic system comprises a series of serine proteases that interact to cleave fibrin into fibrin degradation products. Although all key components of the fibrinolytic system are present at birth, important age-dependent, quantitative and qualitative differences are present during childhood as compared to adults. These differences include decreased plasma concentrations of plasminogen, tissue-type plasminogen activator and alpha2-antiplasmin, increased plasma concentrations of plasminogen activator inhibitor-1, as well as a decrease in both plasmin generation and overall fibrinolytic activity. Increasing evidence suggests that these age-dependent differences may contribute to the development of specific childhood diseases and influence the course of fibrinolytic therapy, particularly in newborns. This review aims to summarize the available information on the age-dependent features of the fibrinolytic system in newborns and children in healthy and disease states and the impact of these features on fibrinolytic therapy.