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Identification of heredity elevation or deficiency of plasminogen activator inhibitor type 1
Determination of risk for veno-occlusive disease associated with bone marrow transplantation
Differential diagnosis of impaired fibrinolysis
Prognostic marker of occurrence or recurrence of thrombosis
Plasminogen activator inhibitor type 1 (PAI-1) antigen is a single-chain glycoprotein (MW 50,000) produced by endothelial cells and hepatocytes and is also present in alpha granules of platelets. PAI-1 is a serine protein inhibitor that is secreted in response to inflammatory reactions. Platelet alpha granules contain large amounts of PAI-1, which is released during vascular injury and assists in fibrin clot stability. PAI-1 is synthesized in the active form but has marked functional instability and a functional half-life of about 2 hours in vivo. Circulating PAI-1 is bound to vitronectin, which protects the inhibitor from inactivation and may assist in targeting the inhibitor to sites of vascular injury. At least 4 different conformations of PAI-1 have been described: 1) the active form that reacts with plasminogen activator; 2) a latent form that is nonreactive; 3) a substrate form that can be cleaved by plasminogen activators but is noninhibitory; and 4) the inert form of PAI-1 generated by the cleavage of the reactive site.
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. 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).
Primary injury to the hepatic sinusoidal endothelium and hepatocytes induced by high-dose chemoradiotherapy is believed to be the key event in the pathogenesis of VOD. The clinical diagnosis of VOD is complex because the clinical signs and symptoms can occur as a result of other processes that can complicate the posttransplant period such as sepsis, graft-versus-host disease (GVHD), cyclosporine toxicity, other medications, hemolysis, or parenteral nutrition. Liver biopsy, although safer since the widespread introduction of transjugular procedures, remains hazardous in this thrombocytopenic population. A sensitive and specific assay would be invaluable in guiding management and avoiding potentially hazardous invasive diagnostic procedures. Along these lines several investigators have studied various markers of hypercoagulability for possible pathogenic and predictive relevance. Aside from serum bilirubin level, no laboratory marker has been standardized as a diagnostic marker of VOD and the severity of VOD remains retrospectively defined. Lee et al analyzed 115 patients after allogenic BMT in an attempt to identify diagnostic and severity markers of VOD. Of the 115 patients, 50 developed VOD.(1) Multiple logistic regression models were constructed that included recognized relevant clinical and hemostatic variables. Of the hemostatic variables, only PAI-1 antigen was identified as an independent marker for the occurrence of VOD. This confirmed findings of an earlier, smaller study, that PAI-1 is a powerful diagnostic marker of VOD during the early period post-BMT, and can distinguish VOD from other causes of hyperbilirubinemia post-BMT such as GVHD and drug toxicity. Furthermore, PAI-1 antigen and bilirubin were independent variables for predicting severe VOD.
Familial thrombosis has been associated with inherited elevation of plasma PAI-1 activity. Increased levels of PAI-1 have also been reported in a number of conditions including malignancy, liver disease, the postoperative period, septic shock, the second and third trimesters of pregnancy, obesity, and coronary heart disease.
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.
Increased levels of plasminogen activator inhibitor type 1 (PAI-1) are associated with a predisposition to thrombosis.
Decreased or absent levels of detectable functional PAI-1 will result in a life-long bleeding diathesis.
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.
1. 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;118:1087-1094
2. Stiko A, Hervio L, Loskutoff DJ: Plasminogen activator inhibitors. In Hemostasis and Thrombosis. Edited by RW Colman, J Hirsh, VJ Marder, et al. Philadelphia, Lippincott, 2001, pp 355-365
3. Vaughn DE, Declerck PJ: Regulation of fibrinolysis. In Thrombosis and Hemorrhage. Edited by J Loscalzo, AI Schager. Philadelphia, Lippincott, 2003, pp 389-396
4. Goodnight SH Jr, Hathaway WE: Fibrinolytic defects and thrombosis. In Disorders of Hemostasis and Thrombosis: A Clinical Guide. New York, McGraw-Hill Book Company, 2001, pp 389-396
5. 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
6. 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
7. Fay WP, Shapiro AD, Shih JL, et al: 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