Clinical Information

Plasminogen activator inhibitor type 1 (PAI-1) antigen is a single-chain glycoprotein (molecular weight 43 kDa) produced by endothelial cells and hepatocytes. It 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 non-inhibitory

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 and urokinase plasminogen activator 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 due to 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 the findings of a previous, 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 many 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.