EFFECTS OF LIPOPROTEIN(A) ON THE BINDING OF PLASMINOGEN TO FIBRIN ANDITS ACTIVATION BY FIBRIN-BOUND TISSUE-TYPE PLASMINOGEN-ACTIVATOR

Molecular assembly of plasminogen and tissue-type plasminogen activato r (t-PA) at the surface of fibrin results in the generation of fibrin- bound plasmin and thereby in the dissolution of a clot. This mechanism is triggered by specific interactions of intra-chain surface lysine r esidues in fibrin with the kringle domains of plasminogen, and is furt her amplified via the interaction of plasminogen kringles with the car boxy-terminal lysine residues of fibrin that are exposed by plasmin cl eavage. By virtue of its marked homology with plasminogen, apo(a), the specific apolipoprotein component of Lp(a), may bind to the lysine si tes available for plasminogen on the surface of fibrin and thereby int erfere with the fibrinolytic process. A sensitive solid-phase fibrin s ystem, which allows the study of plasminogen activation at the plasma fibrin interface and makes feasible the analysis of products bound to fibrin, has been used to investigate the effects of Lp(a) on the bindi ng of plasminogen and its activation by fibrin-bound tPA. plasma sampl es from I human subjects with high levels of Lp(a) were studied. We ha ve established that Lp(a) binds to the fibrin surface and thereby comp etes with plasminogen (K-i = 44 nM) so as to inhibit its activation. W e have further shown that Lp(a) blocks specifically carboxy-terminal l ysine residues on the surface of fibrin. To further explore the role o f apo(a) on the Lp(a) fibrin interactions, we have performed ligand-bi nding studies using a recombinant form of apo(a) that contains 17 krin gle 4-like units. We have shown that recombinant apo(a) binds specific ally to fibrin (K-d = 26 +/- 8 nM, B-max = 26 +/- 2 fmol/well) and tha t this binding increases upon treatment of the fibrin surface with pla smin (K-d = 8 +/- 4 nM, B-max = 115 +/- 14 fmol/well). Altogether, our results indicate clearly that binding of native Lp(a) through this me chanism may impair clot lysis and may favor the accumulation of choles terol in thrombi at sites of vascular injury.