The fibrinolytic system consists of a balance between rates of plasminogen activation and
fibrin degradation, both of which are finely regulated by spatio-temporal mechanisms. Three distinct
inhibitors of the fibrinolytic system that differently regulate these two steps are plasminogen activator
inhibitor type-1 (PAI-1), α2-antiplasmin, and thrombin activatable fibrinolysis inhibitor (TAFI). In
this review, we focus on the mechanisms by which PAI-1 governs total fibrinolytic activity to provide
its essential role in many hemostatic disorders, including fibrinolytic shutdown after trauma. PAI-1 is
a member of the serine protease inhibitor (SERPIN) superfamily and inhibits the protease activities of
plasminogen activators (PAs) by forming complexes with PAs, thereby regulating fibrinolysis. The
major PA in the vasculature is tissue-type PA (tPA) which is secreted from vascular endothelial cells
(VECs) as an active enzyme and is retained on the surface of VECs. PAI-1, existing in molar excess to
tPA in plasma, regulates the amount of free active tPA in plasma and on the surface of VECs by forming
a tPA-PAI-1 complex. Thus, high plasma levels of PAI-1 are directly related to attenuated fibrinolysis
and increased risk for thrombosis. Since plasma PAI-1 levels are highly elevated under a variety
of pathological conditions, including infection and inflammation, the fibrinolytic potential in
plasma and on VECs is readily suppressed to induce fibrinolytic shutdown. A congenital deficiency of
PAI-1 in humans, in turn, leads to life-threatening bleeding. These considerations support the contention
that PAI-1 is the primary regulator of the initial step of fibrinolysis and governs total fibrinolytic
activity.