Plasminogen activator inhibitor-1 (PAI-1) antigen

Abstract

Plasminogen activator inhibitor-1 (PAI-1) is a major inhibitor of the fibrinolytic system. PAI-1 exerts its activity through inhibition of the plasminogen activators (PA), t-PA (tissue-type PA) and /or u-PA (urokinase-type PA). Increased levels of PAI-1 are associated with various thrombotic diseases1. Up to now only a few cases of PAI-1 deficiencies have been reported, and were associated with an increased bleeding tendency2–v6. In addition transgenic mice, overexpressing human PAI-1, and PAI-1 deficient mice have further demonstrated the role of PAI-1 in thrombosis, thrombolysis, fibrin deposition and related events7,8. Initially the pathophysiological importance of PAI-1 was established using activity methods. However, over the past decade a number of immunological assays have been developed for the sensitive and accurate measurement of PAI-1 antigen2,9-15. Concomitant biochemical and structural research on PAI-1 revealed a unique conformational flexibility in this protein. To date at least three different conformations (with different functional properties) of intact PAI-1 have been identified: an active form, a latent form and a substrate form16–18. Yet the active and the latent conformations appear to be the most relevant free PAI-1 forms in biological fluids. The active form reacts with PA resulting in the formation of covalent complexes (i.e t-PA/PAI-1 or u-PA/PAI-1). In addition the active form binds to vitronectin, resulting in a stabilization of the protein19,20. Alternatively PAI-1 may occur as an inactive cleaved derivative (cleaved at P1P1). Taken together, the following forms should be considered in the evaluation of PAI-1 antigen in biological fluids: active PAI-1, latent PAI-1, complexed PAI-1 (t-PA/PAI-1 in plasma, u-PA/PAI-1 in tissue-derived samples), active PAI-1 associated to vitronectin (either in plasma or in the extracellular matrix).