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.
Highlights
Elevated plasma concentrations of lipoprotein (a) [Lp(a)] have been determined to be a causal risk factor for coronary heart disease, and may play a role in other atherothrombotic disorders
There has been considerable disagreement about whether elevated plasma concentrations of Lp(a) are a risk factor for purely thrombotic disorders, such as venous thromboembolism, and whether these findings in any way inform our understanding of atherothrombotic events in the arterial tree
Several of the kringles in plasminogen contain lysine binding sites (LBSs), defined structurally by a hydrophobic trough, lined by two or three key aromatic side chains, that binds the aliphatic backbone of the lysine side chain and that is flanked on either end by a cationic and anionic center [15, 16]
Summary
While acute coronary syndromes almost all feature thrombotic complications of atherosclerotic disease, it remains a mystery as to whether Lp(a) contributes to the former or latter processes, or both (Fig. 2). Addressing this question in a direct way is a nontrivial undertaking, not least because a comparatively large number of subjects need to be included in a study to achieve sufficient statistical power with respect to Lp(a). Some of the most dangerous lesions, vulnerable plaques, are not readily detectable by many imaging methods, and it cannot be excluded at this time that Lp(a) does not have a strong association with the development of vulnerable plaques In theory, though, it could be determined whether Lp(a) contributes directly to atherosclerosis, such as by detecting an association between Lp(a) concentrations and angiographically or ultrasonically detectable CAD. The rise of interventional cardiology likely means that larger prospective studies of the effect of Lp(a) on the evolution of coronary artery thrombosis will no longer be feasible, yet the available findings are a strong indicator that Lp(a) has an antifibrinolytic effect in arterial thrombosis in vivo
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