Cartoon representation of the fibrinolytic system. After tissue injury (TI, yellow explosion), tPA (red rectangle) is extensively released from endothelial cells. If not cleared from the circulation or inhibited by plasminogen activator inhibitor 1 (PAI-1; light gray), tPA can, alongside plasminogen (Plg, dark green sphere), bind to fibrin. This results in the generation of plasmin (Plm, light green PacMan figure), which will degrade fibrin into fibrin degradation products (FDPs; gray pieces). Additionally, plasminogen can be activated by fibrin-independent uPA (marine blue rectangle). Plasmin is inhibited by circulating α2AP (orange diamond) by the formation of PAP complexes. Furthermore, α2AP can be crosslinked to the fibrin surface by activated FXIIIa (yellow oval), thereby inhibiting plasmin on the fibrin surface. C-terminal lysines (K; small blue spheres) that are exposed on partially degraded fibrin form binding sites for plasminogen and tPA. Activated thrombin-activatable fibrinolysis inhibitor (TAFIa; scissors) inhibits plasmin-mediated fibrin degradation by cleaving C-terminal lysine residues from partially degraded fibrin, thereby inhibiting binding of plasminogen and tPA to fibrin and thus inhibiting generation of plasmin. Adapted and extended from Wiman and Hamsten.¹