LIPOPROTEIN(A) - A KINETIC-STUDY OF ITS INFLUENCE ON FIBRIN-DEPENDENTPLASMINOGEN ACTIVATION BY PROUROKINASE OR TISSUE-PLASMINOGEN ACTIVATOR

Lipoprotein(a) [Lp(a)] has been postulated to inhibit fibrinolysis due to its structural homology to plasminogen. Indeed, it has been report ed that Lp(a) competitively inhibits the promotion by fibrin of tissue plasminogen activator (t-PA)-catalyzed plasminogen activation. Howeve r, it has also been reported that this inhibition is uncompetitive. No studies have been published, to our knowledge, of the effect of Lp(a) on prourokinase (pro-UK)-catalyzed plasminogen activation. Plasminoge n activation by pro-UK or a plasmin-resistant mutant pro-UK was previo usly shown to be promoted by fibrin fragment E2, whereas that by t-PA is promoted by fragment D. Therefore, the influence of Lp(a) on the ki netics of these two reactions was examined. When Lp(a) was added (90-6 00 nM), no change in the rate of plasmin generation by Ala158-pro-UK w as observed. Consistent with this, immobilized Lp(a) also failed to bi nd to fragment E2, whereas it did bind to D dimer. When t-PA-catalyzed plasminogen activation in the presence of D dimer was measured, uncom petitive inhibition by Lp(a) was found, but only at low concentrations of D dimer (<0.5 muM) or t-PA (0.05 nM). At higher concentrations of D dimer and t-PA, instead of inhibition, Lp(a) induced a 2.4-fold prom otion of plasminogen activation. Similarly, Lp(a) enhanced (up to 2.5- fold) plasminogen binding to immobilized fibrin in both buffer and pla sma milieus at the physiological concentration of plasminogen (2.0 muM ). In conclusion, Lp(a) had no effect on plasminogen activation by pro -UK and induced only limited inhibition of activation by t-PA. Since t his inhibition was of the uncompetitive type, it could not be attribut ed to competitive inhibition of plasminogen binding to fibrin by Lp(a) . These findings put into question the hypothesis that Lp(a) inhibits physiological fibrinolysis.