Purification of a Plasminogen Activator Inhibitor Indistinguishable from α₁-Antitrypsin and an Urokinase Inhibitor in Pregnancy Plasma

Abstract

An inhibitor of urokinase present in increased concentrations in plasma during pregnancy was purified. The inhibitor was identified by its pronounced effect on urokinase-induced fibrinolysis as opposed to the absence of effect on fibrinolysis induced by a tissue plasminogen activator. The inhibitor progressively inactivated urokinase upon incubation and was found to be indistinguishable from α₁-antitrypsin.

The primary plasminogen-activator inhibitors in endothelial cells, platelets, serum, and plasma are immunologically related.

“…Although PAI activities have been detected in a variety of human cells (7-9, 11, 36-40) and body fluids (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(33)(34)(35), only three of these have been characterized sufficiently to allow a direct comparison with the PAI activity measured here. These include protease nexin (38), the placenta-derived inhibitor (36), and the dexamethasone-induced PAI synthesized by rat hepatoma cells (39).…”

“…1; (Fig. 2) (11,(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(33)(34)(35). Thus, the residual antifibrinolytic activity remaining in the immunodepleted samples may be caused by plasmin inhibitors in addition to any PAIs not removed by the antiserum against the BAE PAT.…”

“…Conceptually, the activity of such plasminogen activators (PAs) may be regulated by specific inhibitors in the blood. Although plasminogen-activator inhibitor (PAI) activity has been detected in cultured endothelial cells (7)(8)(9), platelets (10,11), and serum (12,13), initial reports failed to demonstrate its presence in normal human plasma (14)(15)(16)(17)(18)(19)(20). However, several recent reports have now established the presence of such an activity in plasma from individuals at risk to develop thrombotic problems (21)(22)(23)(24)(25).…”

Differences in the Reactivities of Human Urokinase and the Porcine Tissue Plasminogen Activator

“…Particularly striking are the large differences in effect of 6-aminohexanoic acid or arantitrypsin on fibrinolysis caused by human urokinase or by porcine tissue plasminogen activator [18,34], while insignificant differences exist in the effect of a number of natural protease inhibitors on fibrinolysis caused by the two activators [32].…”