Physiological and pathological role of inhibitors of fibrinolysis
The activity of the fibrinolytic system is dependent on the activation of plasminogen to plasmin by the activators t-PA and u-PA. These proteases are regulated by plasminogen activator inhibitor 1 (PAI-1); 2-antiplasmin (2-AP) inhibits the plasmin generated by their action. Both PAI-1 and 2-AP occur in plasma and platelets. The relative importance of the plasma and platelet inhibitors of fibrinolysis was examined using a simple microtitre plate system to study fibrin clot lysis in vitro. Cross-linked fibrin clots contained plasminogen, fibrinogen and t-PA at concentrations close to physiological. Purified 2-AP and PAI-1 caused dose-dependent inhibition of clot lysis. The inhibition due to normal plasma, platelet-rich or platelet-poor, was neutralised only by antibodies to 2-AP. Isolated platelets, at a final concentration similar to that in blood, 2.5 x 108 platelets/ml, gave rise to marked inhibition of clot lysis. This inhibition was neutralised only by antibodies to PAI-1. At the normal circulating ratio of platelets to plasma, 2-AP was the dominant inhibitor. When the platelet to plasma ratio was elevated some 20-fold, platelet PAI-1 provided a significant contribution. At a platelet to plasma ratio of 50:1 the balance was shifted such that PAI-1 became the dominant inhibitor. These results indicate that the local concentration of platelet PAI-1 would have to be very high for this inhibitor to achieve a significant regulatory role relative to that of plasma 2-AP. The study was subsequently extended to examine the concentrations of these inhibitors, and other related components of the fibrinolytic system, in human thrombi formed in vivo and normal and diseased arteries.