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. Hæmost., 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), ...

Fibrinogen, Lp(a), Microalbuminuria and Left Ventricular Mass Index: Cardiovascular Disease Risk factors in Diabetes

“…Lp(a) is antigenic variant of LDL having apo-a linked to apo B by disulfide bridge. Apo(a) is structural analogue of plasminogen so competes with it to bind fibrin and endothelial cell surface receptors thus inhibiting fibrinolysis [15]. Diabetic patients (group I) had high Lp (a) levels ([20 mg/dl) and presence of MAU in diabetics (group II) resulted in further significant increase in levels (P \ 0.01).…”

Vasculopatia livedoide: uma doença cutânea intrigante

“…21 LMWHs also show antiinflammatory effect, which is detected even with tissue levels 12 to 50 times lower. 21,98 Enoxaparin has an inhibitory action on the expression of P-selectin (CD-62P), reduces the expression of ICAM-1 in endothelial cells and decreases the expression of matrix metalloproteinases in a dose-dependent manner, thus exerting its anti-inflammatory functions. 21,99,100 The side effects of the use of enoxaparin are similar to those of unfractionated heparins.…”

“…Thus, high plasma concentrations of Lp (a) may represent a potential source of antifibrinolytic activity. 98 Heparins, particularly LMWHs, have antithrombotic effects: (i) via anti-Factor Xa effect of the coagulation cascade; (ii) by increasing fibrinolytic activity as they enhance the activity of tissue plasminogen activator (t-PA); and (iii) by releasing tissue factor pathway inhibitor ( TFPI). 21 LMWHs also show antiinflammatory effect, which is detected even with tissue levels 12 to 50 times lower.…”

Elusive proatherothrombotic role of Lp(a): a new direction?

“…Clinical studies [3] have demonstrated a role of elevated Lp(a) in thrombosis, and the apo(a) transgenic mice deficient in plasminogen had high incidence of thrombosis after vascular injury [6]. Lp(a) binding to fibrin(ogen) has been shown to have sites [10] unique from plasminogen and it may be these sites that alter the fibrin network structure.If apo(a) alters the structure of fibrin clots, it may also perturb the formation of extracellular matrix protein networks. The disruption of protein matrices and permeability may alter other important processes that take place within the extracellular matrices, such as degradation of matrix proteins, release of growth factors and cell migration.…”

“…Clinical studies [3] have demonstrated a role of elevated Lp(a) in thrombosis, and the apo(a) transgenic mice deficient in plasminogen had high incidence of thrombosis after vascular injury [6]. Lp(a) binding to fibrin(ogen) has been shown to have sites [10] unique from plasminogen and it may be these sites that alter the fibrin network structure.…”