Lipoprotein (a): truly a direct prothrombotic factor in cardiovascular disease?

Abstract

Elevated plasma concentrations of lipoprotein (a) [Lp(a)] have been determined to be a causal risk factor for coronary heart disease, and may similarly play a role in other atherothrombotic disorders. Lp(a) consists of a lipoprotein moiety indistinguishable from LDL, as well as the plasminogen-related glycoprotein, apo(a). Therefore, the pathogenic role for Lp(a) has traditionally been considered to reflect a dual function of its similarity to LDL, causing atherosclerosis, and its similarity to plasminogen, causing thrombosis through inhibition of fibrinolysis. This postulate remains highly speculative, however, because it has been difficult to separate the prothrombotic/antifibrinolytic functions of Lp(a) from its proatherosclerotic functions. This review surveys the current landscape surrounding these issues: the biochemical basis for procoagulant and antifibrinolytic effects of Lp(a) is summarized and the evidence addressing the role of Lp(a) in both arterial and venous thrombosis is discussed. While elevated Lp(a) appears to be primarily predisposing to thrombotic events in the arterial tree, the fact that most of these are precipitated by underlying atherosclerosis continues to confound our understanding of the true pathogenic roles of Lp(a) and, therefore, the most appropriate therapeutic target through which to mitigate the harmful effects of this lipoprotein.

Keywords: apolipoprotein (a); apolipoproteins; atherosclerosis; coagulation; fibrinolysis; lipoproteins; lipoproteins/kinetics; low density lipoprotein; thrombosis.

Fig. 1.

Structure of apo(a). The topologies of plasminogen and apo(a) are aligned to show regions of structural homology. The apo(a) lacks plasminogen kringles I–III and contains single copies of sequences similar to plasminogen KV and protease (P), although the protease domain of apo(a) is nonfunctional. The apo(a) contains 10 different types of kringle related to plasminogen KIV. The apo(a) KIV₂ is present in differing numbers of copies in different apo(a) alleles. The apo(a) KIV₉ contains a free cysteine (–SH) that mediates covalent coupling to apoB-100 in Lp(a). The apo(a) KIV₅–KIV₈ each contain a weak LBS (white asterisks) while KIV₁₀ contains a strong LBS (red asterisk).

Fig. 2.

Mechanistic basis of elevated Lp(a) as a risk factor for thrombosis as a complication of atherosclerosis. The Venn diagram depicts a series of factors that potentially contribute to venous thrombosis (left side) and arterial thrombosis in the setting of atherosclerosis (i.e., atherothrombosis; right side). Factors that are influenced by Lp(a) are contained in the filled circles; all the factors influenced by Lp(a) potentially contributing to both venous thrombosis and atherothrombosis are clustered in the center (orange zone), while those only influencing atherothrombosis are in the yellow zone. Factors influenced by Lp(a) that are directly prothrombotic/antifibrinolytic are italicized. Factors that contribute uniquely to venous thrombosis or atherosclerosis and are not influenced by Lp(a) are contained in the open circles. EC, endothelial cell; ECM, extracellular matrix; PL, phospholipids; SMC, smooth muscle cell. Adapted from reference (145).

Fig. 3.

Procoagulant and antifibrinolytic mechanisms of apo(a). The apo(a) binds to either free or cell-bound TFPI (A), thereby promoting prothrombin activation by Factor Xa formed by the tissue factor (TF)-Factor VIIa complex. The apo(a) promotes platelet aggregation and release of granule contents through the thrombin receptor (B), promoting both platelet plug formation and enhanced prothrombin activation. Thrombin formed from prothrombin cleaves fibrinopeptides (A, B) from soluble fibrinogen to form fibrin monomers, which then polymerize to form insoluble fibrin. The apo(a) forms a ternary complex with fibrin, plasminogen (Plg), and tPA to prevent activation of plasminogen to form plasmin (Pln) (C). Plasmin proteolyzes fibrin to form soluble fibrin degradation products (FDPs). The apo(a) prevents plasmin-mediated conversion of Glu-plasminogen to Lys-plasminogen (D), the latter of which is a better substrate for tPA. Lp(a) alters fibrin structure to yield thinner and more dense fibers, potentially by binding to the αC domain of fibrin and, hence, preventing lateral association of fibrin fibrils (E).