In vitro inhibition of fibrinolysis by apolipoprotein(a) and lipoprotein(a) is size- and concentration-dependent.

Lipoprotein(a) (Lp(a)) is considered an independent risk factor for atherosclerotic heart and circulatory diseases. The unique, polymorphic character of Lp(a) is based on its apolipoprotein(a) (apo(a)), which has remarkable structural analogies with plasminogen, an important protein for fibrinolysis. The formation of plasmin from plasminogen is a fundamental step in the dissolution of fibrin. Repression of this step may lead to a deceleration of fibrinolysis. It has been suggested that Lp(a) has antifibrinolytic properties through apo(a) and that the apo(a)-size polymorphism has a distinct influence on the pro-thrombotic properties of Lp(a). However, the results on this topic are controversial. Therefore we used a standardized in vitro fibrinolysis model to provide further information on the influence of Lp(a) on plasmin formation. Monitoring the time-course of plasmin formation, we investigated the inhibition of plasmin formation through dependence on Lp(a), respectively, free apo(a) concentration. Furthermore, we investigated the influence of three Lp(a)/apo(a) phenotypes ( 22K Lp(a), 22 kringle-4 repeats; 30K Lp(a), 30 kringle-4 repeats; 35K Lp(a), 35 kringle-4 repeats). Adding varying amounts of Lp(a) to our model, we observed that the rate of plasmin formation was inversely related to the Lp(a) concentration. At 0.1 μmol/l 30K Lp(a), for example, the plasmin formation was reduced by 12.7% and decreased further by 40.7% at 0.25 μmol/l Lp(a). A similar but more distinct effect was observed when free 30K apo(a) was added to the model (25.3% at 0.1 μmol/l vs. 59.3% at 0.25 μmol/l). Comparing the antifibrinolytic influence of different apo(a) phenotypes we found that the reduction of plasmin generation advanced with the size of apo(a). At 0.1 μmol/l Lp(a) the reduction of the plasmin formation increased in the order 22K Lp(a), 30K Lp(a) and 35K Lp(a) from 3.7% to 10.7% and 22.3%, respectively. Experiments with different phenotypes of free apo(a) showed similar results (0.5 μmol/l: 22K apo(a), 56.4% vs. 30K Lp(a), 80.4%). Summarizing these results, our study indicates a distinct interrelation of Lp(a)/apo(a) phenotype and concentration with the formation of plasmin. From the antifibrinolytic Lp(a)/apo(a) effect in vitro it may be hypothesized that Lp(a)/apo(a) also has an inhibitory influence on in vivo fibrinolysis.