What is lipoprotein(a) (Lp‑a)?

What is Lipoprotein(a)?

Lipoprotein(a) [Lp(a)] is a genetically determined, modified LDL particle consisting of an LDL-like core containing apolipoprotein B-100 covalently linked by a disulfide bridge to a unique glycoprotein called apolipoprotein(a) [apo(a)], which structurally resembles plasminogen but lacks fibrinolytic activity. 1

Structural Composition

Lp(a) has a dual-component architecture that distinguishes it from standard LDL:

• The LDL-like core contains apolipoprotein B-100 (apoB-100) as its primary structural protein, with a lipid composition virtually indistinguishable from LDL—including phospholipids, free cholesterol, and a core of cholesteryl esters 1

• The apolipoprotein(a) component consists of repetitive protein segments called "kringles" (K) that are highly homologous to kringle-IV of plasminogen, plus one kringle-V domain and a protease-like domain that lacks enzymatic activity 1

• The disulfide bridge specifically links Cys4326 in apoB-100 with Cys4057 in apo(a), located in kringle-IV type 9 1

Genetic Basis and Size Heterogeneity

Lp(a) exhibits remarkable structural polymorphism driven entirely by genetics:

• Apo(a) contains a variable number of kringle-IV type 2 repeats—ranging from 3 to more than 40 copies—creating at least 30 genetically determined isoforms that differ substantially in molecular size 1, 2

• The smallest apo(a) isoform contains 11 kringle-IVs (types 1 and 3–10 occurring once each, plus two copies of type 2), one kringle-V, and the inactive protease domain 1

• Plasma Lp(a) concentrations are 70–90% genetically determined by the LPA gene locus encoding apo(a), with minor contributions from the APOE locus and PCSK9 R46L loss-of-function mutations 3, 4

• Lp(a) levels remain essentially constant throughout an individual's lifetime after reaching steady state within the first few months of life, are not influenced by dietary habits, and exhibit up to 1000-fold interindividual variation 4, 2

Pathophysiological Mechanisms

Lp(a) promotes cardiovascular disease through multiple distinct pathways that extend beyond simple cholesterol delivery:

• Atherogenic effects: Lp(a) particles are retained in the arterial intima and deposit cholesterol at sites of plaque formation; on a per-particle basis, Lp(a) is approximately 7-fold more atherogenic than LDL 5, 4

• Pro-inflammatory actions: Lp(a) carries oxidized phospholipids that induce vascular inflammation, promote M1-macrophage differentiation, and stimulate secretion of the antiangiogenic chemokine CXCL10 (IP10) 5, 6

• Pro-thrombotic/anti-fibrinolytic properties: The apo(a) component's structural similarity to plasminogen allows Lp(a) to competitively inhibit plasminogen binding and activation, favoring clot stability and impairing fibrinolysis 4, 6

• Calcification promotion: Lp(a) induces inflammation and calcification in aortic valve leaflet interstitium, causally linked to calcific aortic valve stenosis 3, 4

Clinical Significance and Cardiovascular Risk

Mounting evidence from prospective studies, meta-analyses, and Mendelian randomization establishes elevated Lp(a) as a causal, independent risk factor for atherosclerotic cardiovascular disease:

• The risk of developing coronary artery disease in Caucasians is more than two times higher in individuals with increased Lp(a) 1

• Elevated Lp(a) levels (>30–50 mg/dL or >75–125 nmol/L) affect approximately 20–30% of the global population, representing more than one billion people worldwide 3, 7

• Lp(a) confers residual cardiovascular risk even when LDL-C is optimally controlled; randomized trials demonstrate that when Lp(a) is elevated, cardiovascular event rates remain higher at any achieved LDL-C level 5, 3

• Risk increases progressively with higher Lp(a) levels, with particularly high risk at concentrations >100 mg/dL 5

Measurement Challenges

Quantification of Lp(a) remains technically problematic despite its clinical importance:

• Progress in Lp(a) research has been significantly slowed by the lack of generally accepted high-throughput methods to quantify plasma Lp(a) and determine apo(a) isoforms 1

• Large between-method variation exists due to lack of a common reference material, making comparisons between laboratories difficult 5

• Lp(a) comprises 30–45% cholesterol by mass, which is included in standard "LDL-C" laboratory measurements, potentially overestimating true LDL-C in patients with elevated Lp(a) 5, 8

• Different assays express Lp(a) levels either in mg/dL (mass) or nmol/L (molar concentration); a conversion factor of 3.17 can be used (1 mg/dL = 3.17 nmol/L), though molar concentrations are recommended 5, 8

Historical Context

Lp(a) was discovered by Kåre Berg in 1963 and was initially considered a genetic variant of β-lipoproteins (LDL), but was later recognized as a distinct lipoprotein class. 1, 2 Despite intensive research over six decades, the physiological function of Lp(a) remains elusive, though its pathological role in cardiovascular disease is now firmly established 1