PAI-1 is a serine protein inhibitor that is secreted in response to inflammatory reactions.
PAI-1 is the main inhibitor of tissue-type plasminogen activator (tPA) and urokinase plasminogen activator (uPA) and, as such, plays an important role in the regulation of fibrinolysis.
Plasminogen Activator Inhibitor (PAI-1) AG is useful to:
- aid in prognosis of occurrence or recurrence of thrombosis
- intentify heredity elevation or deficiency of plasminogen activator inhibitor type 1.
- determine the risk for veno-occlusive disease associated with bone marrow transplantation.
- aid diagnosis of impaired fibrinolysis
The plasminogen activator system plays a key role in a wide range of physiological and pathological processes, including coagulation, fibrinolysis, inflammation, wound healing, and malignancy. A crucial reaction of the plasminogen activator system is the conversion of plasminogen to plasmin by plasminogen activators.
Plasminogen activator inhibitor-1 (PAI-1) is a member of the superfamily of serine-protease inhibitors (or serpins), and the principal inhibitor of both the tissue-type and the urinary-type plasminogen activator, the two plasminogen activators able to activate plasminogen.
The main enzyme of the plasminogen activator system is plasmin. Plasmin is a serine protease playing a key role in the fibrinolysis cascade being responsible for the final degradation of fibrin and extracellular matrix proteins. Plasmin is similar to trypsin, and is generated from its precursor plasminogen by the plasminogen activators.
Plasminogen is primarily present in the plasma, and the liver represents its primary site of synthesis. However, plasminogen mRNA has been found in several mouse tissues, including adrenal, kidney, brain, testis, heart, lung, uterus, spleen, thymus, and gut, supporting the broad functional role played by the plasminogen activator system. The activation of plasminogen into plasmin is mediated by two types of activators, urokinase-type plasminogen activator (u-PA) and tissue-type plasminogen activator (t-PA).
The activity of both is regulated by specific plasminogen activator inhibitors (PAIs). The principal PAIs are PAI type 1 (PAI-1), initially called the endothelial cell PAI, PAI type 2 (PAI-2), also known as placental-type PAI, and PAI type 3 (PAI-3), which is identical to protein C inhibitor.
Among the inhibitory factors, the rapid acting PAI-1 is one of the most important inhibitors of the plasma fibrinolytic activity. PAI-1 is a single chain glycoprotein member of the superfamily of serine-protease inhibitors (or serpins). It is composed by 379 aminoacids with an apparent molecular weight of 48 kDa. PAI-1 (or serpin E1) is the principal inhibitor of both the tissue-type plasminogen activator (t-PA) and the urinary-type plasminogen activator (u-PA), which are able to activate plasminogen by cleaving a specific Arg-Val peptide bond located within the protease domain. Differently from t-PA (which is mainly involved in intravascular fibrinolysis), u-PA exerts proteolytic effects as well as intracellular signaling functions by binding to its high affinity receptor on the cell surface.
- The plasminogen activator inhibitor type 1 (PAI-1) level shows a diurnal variation with the highest levels occurring in the morning.
- The PAI-1 level increases during pregnancy and decreases rapidly after delivery.
- The extremely rare presence of antimouse antibodies in certain patients may lead to anomalous results.
- Inappropriate specimen collection and processing may lead to platelet activation and release of platelet PAI-1. Consequently, care must be taken to remove all platelets and minimize platelet activation during specimen collection and processing.
Cesari M, Pahor M, Incalzi RA. Plasminogen activator inhibitor-1 (PAI-1): a key factor linking fibrinolysis and age-related subclinical and clinical conditions. Cardiovasc Ther. 2010 Oct;28(5):e72-91. doi: 10.1111/j.1755-5922.2010.00171.x. Epub 2010 Jul 7. PMID: 20626406; PMCID: PMC2958211.
Lee JH, Lee KH, Lee JH, et al: Plasminogen activator inhibitor-1 is an independent diagnostic marker as well as severity predictor of hepatic veno-occlusive disease after allogeneic bone marrow transplantation in adults conditioned with busulphan and cyclophosphamide. Br J Haematol. 2002 Sep;118(4):1087-1094
Stiko A, Hervio L, Loskutoff DJ: Plasminogen activator inhibitors. In: Colman RW, Hirsh J, Marder VJ, et al, eds. Hemostasis and Thrombosis. Lippincott; 2001:355-365
Vaughn DE, Declerck PJ: Regulation of fibrinolysis. In: Loscalzo J, Schager A, eds. Thrombosis and Hemorrhage. Lippincott; 2003:389-396
Goodnight SH Jr, Hathaway WE: Fibrinolytic defects and thrombosis. In: Disorders of Hemostasis and Thrombosis: A Clinical Guide. McGraw-Hill Book Company; 2001:389-396
Kruithof EK, Gudinchet A, Bachman F: Plasminogen activator inhibitor-1 and plasminogen activator inhibitor-2 in various disease states. Thromb Haemostasis. 1988;59(1):7-12
Salat C, Holler E, Kolb HJ, et al: Plasminogen activator inhibitor-1 confirms the diagnosis of hepatic veno-occlusive disease in patients with hyperbilirubinemia after bone marrow transplantation. Blood. 1997;89:2184-2188
Fay WP, Shapiro AD, Shih JL, Schleef RR, Ginsburg D: Brief report: complete deficiency of plasminogen-activator inhibitor Type 1 due to a frame-shift mutation. N Engl J Med. 1992 Dec 10;327(24):1729-1733
Heiman M, Gupta S, Khan SS, et al: Complete plasminogen activator inhibitor 1 deficiency. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews 2017 www.ncbi.nlm.nih.gov/books/NBK447152/
Low plasma levels of the active form of PAI-1 have been associated with abnormal, clinically significant bleeding.
Complete deficiency of PAI-1, either congenital or acquired, is associated with bleeding manifestations that include hemarthroses, hematomas, menorrhagia, easy bruising, and postoperative hemorrhage.
Elevated levels of PAI-1 result in deficient plasminogen activation and are associated with a predisposition to thrombosis, including veno-occlusive disease (VOD) after bone marrow transplantation (BMT).
Familial thrombosis has been associated with inherited elevation of plasma PAI-1 activity. Increased levels of PAI-1 have also been reported in many conditions including malignancy, liver disease, the postoperative period, septic shock, the second and third trimesters of pregnancy, obesity, and coronary heart disease.
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