Inhibition of fibrinolysis by lipoprotein(a)

Abstract

A high plasma concentration of lipoprotein Lp(a) is now considered to be a major and independent risk factor for cerebro- and cardiovascular atherothrombosis. The mechanism by which Lp(a) may favour this pathological state may be related to its particular structure, a plasminogen-like glycoprotein, apo(a), that is disulfide linked to the apo B100 of an atherogenic LDL-like particle. Apo(a) exists in several isoforms defined by a variable number of copies of plasminogen-like kringle 4 and single copies of kringle 5 and the catalytic region. At least one of the plasminogen-like kringle 4 copies present in apo(a) (kringle IV type 10) contains a lysine binding site (LBS) that is similar to that of plasminogen. This structure allows binding of these proteins to fibrin and cell membranes. Plasminogen thus bound is cleaved at Arg561-Val562 by plasminogen activators and transformed into plasmin. This mechanism ensures fibrinolysis and pericellular proteolysis. In apo(a) a Ser-Ile substitution at the Arg-Val plasminogen activation cleavage site prevents its transformation into a plasmin-like enzyme. Because of this structural/functional homology and enzymatic difference, Lp(a) may compete with plasminogen for binding to lysine residues and impair, thereby, fibrinolysis and pericellular proteolysis. High concentrations of Lp(a) in plasma may, therefore, represent a potential source of antifibrinolytic activity. Indeed, we have recently shown that during the course of the nephrotic syndrome the amount of plasminogen bound and plasmin formed at the surface of fibrin are directly related to in vivo variations in the circulating concentration of Lp(a) (Arterioscler. Thromb. Vasc. Biol., 2000, 20: 575-584; Thromb. Haemost., 1999, 82: 121-127). This antifibrinolytic effect is primarily defined by the size of the apo(a) polymorphs, which show heterogeneity in their fibrin-binding activity--only small size isoforms display high affinity binding to fibrin (Biochemistry, 1995, 34: 13353-13358). Thus, in heterozygous subjects the amount of Lp(a) or plasminogen bound to fibrin is a function of the affinity of each of the apo(a) isoforms and of their concentration relative to each other and to plasminogen. The real risk factor is, therefore, the Lp(a) subpopulation with high affinity for fibrin. According to this concept, some Lp(a) phenotypes may not be related to atherothrombosis and, therefore, high Lp(a) in some individuals might not represent a risk factor for cardiovascular disease. In agreement with these data, it has been recently reported that Lp(a) particles containing low molecular mass apo(a) emerged as one of the leading risk conditions in advanced stenotic atherosclerosis (Circulation, 1999, 100: 1154-1160). The predictive value of high Lp(a) as a risk factor, therefore, depends on the relative concentration of Lp(a) particles containing small apo(a) isoforms with the highest affinity for fibrin. Within this context, the development of agents able to selectively neutralise the antifibrinolytic activity of Lp(a), offers new perspectives in the prevention and treatment of the cardiovascular risk associated with high concentrations of thrombogenic Lp(a).