Activators and inhibitors of the fibrinolytic enzyme system : a study of their interactions and influence on thrombolysis
The fibrinolytic system culminates in the formation of plasmin from its precursor plasminogen, through the action of agents termed activators. Neither the characterisation nor the role of inhibitors of plasminogen activators is defined. This study deals with the inhibitors of urokinase and tissue activator which are present in normal and pregnancy plasma, and amniotic fluid. It also describes the design and construction of an artificial circulatior which allowed the study of both activators at variable flow rate and pressure. Normal plasma contained at least three proteins with inhibitory activity against tissue activator and two which inhibited urokinase in fibrinolytic assays; one of those was capable of inhibiting both activators. Pregnancy plasma possessed increased anti-urokinase activity in fibrinolytic and amidolytic assays, which appeared to reside in a protein distinct from established protease inhibitors. Increased anti-tissue activator activity was also observed in pregnancy plasma but conclusive distinction of this inhibitor from α₂-antiplasmin was not achieved. Amniotic fluid inhibited the caseinolytic and amidolytic activities of plasmin. Removal of α₁-antitrypsin substantially reduced the antiplasmin activity but the anti-urokinase activity persisted. Preliminary experiments with the artificial circulation demonstrated that tissue activator was a much more efficient thrombolytic agent than urokinase in the presence of plasma. Variation in flow rate (10-40mls/min) also influenced the rate of lysis by both enzymes, but no significant differonce was observed when the pressure was altered between 10 and 30cm H₂0. It was concluded that this approach to the study of activators and inhibitors would increase the understanding of thrombolysis and would provide a background for the more rational use of thrombolytic agents.