Novel insights into Lp(a) physiology and pathogenicity: more questions than answers?

Lipoprotein(a) (Lp(a)) is of interest to both basic researchers who endeavour to understand the mechanism of action of this unique lipoprotein, as well as to clinicians who are interested in the contribution of Lp(a) to cardiovascular risk profiles. The Lp(a) particle contains a moiety that is indistinguishable from circulating LDL, covalently linked to the unique glycoprotein component apolipoprotein(a) (apo(a)). Since the 1970s, epidemiological data have been accumulated that, on balance, indicate that elevated plasma Lp(a) concentrations are an independent risk factor for vascular diseases. Apo(a) is highly homologous to the fibrinolytic proenzyme plasminogen, containing many tandemly-repeated kringle motifs similar to several of those found in the plasminogen molecule; the size of the kringle domain in apo(a) gives rise to Lp(a) isoform size heterogeneity which is a hallmark of this lipoprotein. The similarity between Lp(a) and plasminogen led to speculation of a bridging role for Lp(a) in atherothrombotic disease based on the duality of the structure of this lipoprotein. In this scenario, LDL would contribute to the proatherosclerotic properties of the particle, while apo(a) would interfere with the normal fibrinolytic functions of plasminogen, thereby inhibiting the breakdown of thrombi formed in the vasculature. Many in vitro and in vivo studies have suggested a prothrombotic role for Lp(a) which is attributable to the apo(a) component of the particle. However, there are a number of unique properties that apo(a) confers to Lp(a) which are independent of its similarity to plasminogen. These include the ability of apo(a)/Lp(a) to affect platelet function, to contribute to endothelial dysfunction, and to inhibit the clearance of chylomicron remnant particles in a transgenic mouse model. Very recent data have revealed a potential role for Lp(a) in the preferential binding of oxidized phospholipid adducts through one of the kringle motifs in apo(a). Many questions remain to be answered regarding the role of Lp(a) in atherothrombotic disease. This article will review the relevant literature concerning the contribution of Lp(a) to risk for both atherosclerotic and purely thrombotic disorders, as well as the proposed mechanisms of Lp(a) pathogenicity related to the structure of this lipoprotein. Emerging areas of interest in the field including the role of apo(a) isoform size as a risk factor for CHD - independent of Lp(a) levels - will also be discussed, as will speculation as to the possible physiological role of Lp(a). Future directions in the field as well as recommendations for the use of Lp(a) in clinical contexts will also be addressed.