Recognition of Plasminogen Activator Inhibitor Type 1 as the Primary Regulator of Fibrinolysis

Abstract

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.

Assessing plasminogen activation potential with global fibrinolytic assays

“…Supplementation with t‐PA to overcome PAI‐1 activity is one of these strategies and seems to be beneficial in evaluating the role of TAFI and α2AP. This method, however, is associated with difficulty in evaluating the potential to trigger the plasminogen activation step, which is regulated by the balance between t‐PA and PAI‐1 and is easily disrupted by t‐PA supplementation. Elimination of α2AP also successfully shortens the clot lysis time by abolishing the regulation at the second step and makes it possible to assess the plasminogen activation potential.…”

“…The euglobulin clot lysis time (ECLT) assay is one of the approaches in which α2AP and α2‐macroglobulin are eliminated from plasma by isoelectric precipitation at a pH of around 5.2 to 5.9. ECLT has a strong positive correlation with t‐PA activity and a negative correlation with either free or total PAI‐1 in plasma (Figure ) . The free t‐PA concentration, calculated on the basis of the assumption that PAI‐1 inactivates t‐PA by forming a high‐molecular‐weight complex even in plasma, showed a strong positive correlation with t‐PA activity and a negative correlation with ECLT.…”

A Novel Volume-Stable Collagen Matrix Induces Changes in the Behavior of Primary Human Oral Fibroblasts, Periodontal Ligament, and Endothelial Cells

“…The regulation of the two processes is achieved by the activity of a number of anti- and pro- fibrinolytic factors. Among them are thrombomodulin (encoded by the THBD gene) [ 31 ], thrombospondin 1 (encoded by THBS1) [ 32 , 33 , 34 ], thromboplastin, also known as tissue factor (encoded by F3) [ 35 ], plasminogen activator inhibitor type 1 (encoded by SERPINE1) [ 36 ], tissue plasminogen activator (encoded by PLAT) [ 31 ], urokinase-type plasminogen activator (encoded by PLAU) and its receptor (encoded by the PLAUR) [ 31 ], and the matrix metalloproteinase 14 (encoded by MMP14) [ 37 ]. Most of these factors also perform functions in cellular motility, adhesion, and differentiation [ 38 ].…”

DNA Methylation of the t-PA Gene Differs Between Various Immune Cell Subtypes Isolated From Depressed Patients Receiving Electroconvulsive Therapy

“…The enzyme t-PA (tissue-type plasminogen activator) and its inhibitor PAI-1 (plasminogen activator inhibitor-1) are implicated in the cleavage of extracellular pro-BDNF and are thus important for BDNF production (35,36). Both proteins have additional roles in the regulation of the immune system, as in macrophage migration (37) and NF-kB activation (38).…”