Recognition of Plasminogen Activator Inhibitor Type 1 as the Primary Regulator of Fibrinolysis.
Plasminogen activator inhibitor type 1 (PAI-1)
fibrinolysis
fibrinolysis shutdown
fibrinolytic
potential
tissue-type plasminogen activator (tPA)
trauma.
Journal
Current drug targets
ISSN: 1873-5592
Titre abrégé: Curr Drug Targets
Pays: United Arab Emirates
ID NLM: 100960531
Informations de publication
Date de publication:
2019
2019
Historique:
received:
10
05
2019
revised:
17
06
2019
accepted:
24
06
2019
pubmed:
17
7
2019
medline:
15
9
2020
entrez:
17
7
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31309890
pii: CDT-EPUB-99611
doi: 10.2174/1389450120666190715102510
pmc: PMC7696651
mid: NIHMS1644722
doi:
Substances chimiques
Plasminogen Activator Inhibitor 1
0
Tissue Plasminogen Activator
EC 3.4.21.68
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
1695-1701Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL013423
Pays : United States
Organisme : NHLBI NIH HHS
ID : R37 HL013423
Pays : United States
Informations de copyright
Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.
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