Lipoprotein(a) (Lp(a))

Lipoprotein(a) [Lp(a)] Overview

Lipoprotein(a), often abbreviated as Lp(a) and sometimes called "lipoprotein little a," is a unique type of lipoprotein particle found in the blood plasma of humans, other primates, and a few other animal species. Discovered by Kåre Berg in 1963, Lp(a) levels are primarily determined by genetics and are recognized as an independent risk factor for cardiovascular diseases.

Lp(a) particles consist of an LDL-like core containing cholesterol, triglycerides, and apolipoprotein B-100 (ApoB), attached to a distinctive, large glycoprotein called apolipoprotein(a) [apo(a)].

Structure of Lipoprotein(a)

Lipoproteins are generally classified based on their density, determined by ultracentrifugation:

1. Chylomicrons
2. Very Low-Density Lipoproteins (VLDL)
3. Intermediate-Density Lipoproteins (IDL)
4. Low-Density Lipoproteins (LDL)
5. High-Density Lipoproteins (HDL)
6. Lipoprotein(a) [Lp(a)]

While Lp(a)'s density is close to that of HDL and its electrophoretic mobility is similar to pre-beta lipoproteins (like VLDL), structurally, the core Lp(a) particle resembles LDL. It contains cholesterol, triglycerides, phospholipids, and one molecule of ApoB-100.

The defining feature of Lp(a) is the presence of apolipoprotein(a) [apo(a)], which is covalently linked to ApoB-100 via a disulfide bond. Apo(a) is a large, hydrophilic, highly glycosylated protein that shares significant structural homology with plasminogen, a key protein in the fibrinolytic (clot-dissolving) system.

Apo(a) is characterized by multiple repeating structural domains called "kringles," specifically kringle IV (KIV) repeats and one kringle V (KV) domain, followed by an inactive protease domain. The number of KIV repeats (specifically KIV type 2) within the apo(a) protein is highly variable among individuals, determined by the LPA gene. This variation in KIV repeats (ranging from fewer than 10 to over 40) accounts for the significant size polymorphism of apo(a) protein (molecular weight ranging from ~280 to 800 kDa) and, consequently, the size and density of Lp(a) particles.

The LPA gene, encoding apo(a), is closely linked to the plasminogen gene (PLG), suggesting it arose through duplication and modification events. Apo(a) is synthesized in the liver. When apo(a) binds to ApoB, it may alter the particle's interaction with the LDL receptor. Lp(a) catabolism (breakdown) is complex and less understood than LDL catabolism, potentially involving kidney pathways and scavenger receptors rather than primarily the liver LDL receptor pathway.

Lipoprotein(a) Levels and Genetics

Plasma Lp(a) concentrations are largely (over 90%) determined by inherited variations in the LPA gene, specifically the number of KIV type 2 repeats. There is a strong inverse correlation between the size of the apo(a) isoform (number of KIV repeats) and the plasma Lp(a) concentration:

• Smaller apo(a) isoforms (fewer KIV repeats) are generally secreted more efficiently from the liver, leading to higher plasma Lp(a) levels.
• Larger apo(a) isoforms (more KIV repeats) are secreted less efficiently, resulting in lower plasma Lp(a) levels.

Due to this genetic variability, Lp(a) levels can vary dramatically between individuals, ranging over 1,000-fold (from <0.1 mg/dL to >200 mg/dL or expressed in nmol/L). There are also significant population differences; individuals of African ancestry tend to have considerably higher average Lp(a) levels compared to European or Asian populations.

Lp(a) levels are established early in life (by age 1-2 years) and remain relatively stable throughout adulthood, largely unaffected by diet, lifestyle (except extreme changes), or most common lipid-lowering medications like statins. A slight increase may be observed in women after menopause.

Clinical Significance and Pathology

Elevated plasma Lp(a) concentration is recognized as an independent, causal risk factor for several cardiovascular conditions:

• Atherosclerotic Cardiovascular Disease (ASCVD), including Coronary Heart Disease (CHD) / Myocardial Infarction (Heart Attack)
• Ischemic Stroke
• Peripheral Artery Disease (PAD)
• Aortic Valve Stenosis
• Possibly Heart Failure

The risk associated with high Lp(a) is present even in individuals with otherwise normal LDL cholesterol levels. The mechanisms by which Lp(a) promotes disease are thought to be twofold:

1. Pro-atherogenic effects: Similar to LDL, the Lp(a) particle can penetrate the artery wall, become trapped in the extracellular matrix, undergo oxidation, and contribute to the formation of atherosclerotic plaques (atheroma). Its cholesterol content directly contributes to plaque buildup. Lp(a) may also promote inflammation and smooth muscle cell proliferation within the vessel wall.
2. Pro-thrombotic/Anti-fibrinolytic effects: Due to the structural similarity between apo(a) and plasminogen, Lp(a) can interfere with the fibrinolytic system. It competes with plasminogen for binding sites on cell surfaces (like endothelial cells) and fibrin clots, potentially impairing the activation of plasminogen to plasmin (the enzyme that dissolves clots). This interference can lead to reduced clot lysis and an increased tendency towards thrombosis.

Despite extensive research, the normal physiological function of Lp(a) remains unclear. Hypotheses suggest roles in wound healing or cholesterol transport, but individuals with very low or undetectable levels appear healthy.

Indications for Lp(a) Testing

Testing Lp(a) levels is recommended, according to various guidelines, in specific situations to assess cardiovascular risk:

• Individuals with a personal history of premature ASCVD (e.g., heart attack or stroke before age 55 in men, 65 in women) without traditional risk factors.
• Individuals with a strong family history of premature ASCVD or high Lp(a).
• Patients with familial hypercholesterolemia (FH).
• Patients with recurrent ASCVD events despite optimal management of other risk factors (especially LDL cholesterol).
• To help refine risk assessment in individuals considered at borderline or intermediate risk for ASCVD based on standard risk calculators.
• Patients with calcific aortic valve stenosis.

Reference Values / Risk Thresholds:

Lp(a) levels are often reported in mg/dL (mass) or nmol/L (particle number). The conversion factor depends on the apo(a) isoform size, making direct comparison difficult. However, commonly cited risk thresholds are:

• Desirable/Low Risk: < 30 mg/dL (or < 75 nmol/L)
• High Risk: ≥ 30 mg/dL (or ≥ 75 nmol/L)
• Very High Risk: ≥ 50 mg/dL (or ≥ 125 nmol/L)

Note: These thresholds are general guidelines; specific recommendations may vary. It's crucial to use assays standardized against WHO/IFCC reference materials, preferably reporting in nmol/L.

Factors Influencing Lp(a) Levels

As levels are primarily genetically determined, most lifestyle factors have minimal impact. However, certain conditions and factors can influence measured levels:

Factors that may Increase Lp(a):

• Genetics (primary determinant)
• Chronic Kidney Disease / End-Stage Renal Disease (due to reduced clearance)
• Nephrotic Syndrome
• Hypothyroidism (possibly mild increase)
• Acute Phase Response (Lp(a) may increase transiently after surgery, MI, stroke, inflammation)
• Certain hormonal changes (e.g., post-menopause)
• Growth hormone excess

Factors that may Decrease Lp(a):

• Estrogen therapy (e.g., hormone replacement therapy)
• Niacin (Vitamin B3) - moderate effect
• PCSK9 inhibitors (injectable cholesterol medications) - moderate effect
• Aspirin (possibly minor effect)
• Severe liver disease (impaired synthesis)
• Hyperthyroidism
• Certain medications (e.g., tamoxifen, L-carnitine - evidence less robust)

Note: Standard statin therapy generally does NOT lower Lp(a) levels and may sometimes slightly increase them.

Management of High Lp(a)

Currently, there are no widely approved pharmacologic therapies specifically designed to substantially lower Lp(a) levels and proven to reduce Lp(a)-mediated cardiovascular risk. Management focuses on aggressively controlling all other modifiable cardiovascular risk factors:

• Optimizing LDL cholesterol levels (often to lower targets using statins, ezetimibe, PCSK9 inhibitors).
• Managing blood pressure.
• Controlling diabetes.
• Smoking cessation.
• Maintaining a healthy lifestyle (diet, exercise, weight management).
• Considering aspirin therapy based on overall ASCVD risk.

Niacin and PCSK9 inhibitors can lower Lp(a) to some extent, but their impact on clinical outcomes specifically due to Lp(a) reduction is still under investigation. Several novel therapies targeting Lp(a) synthesis (e.g., antisense oligonucleotides, siRNA) are in late-stage clinical trials and show promise for significant Lp(a) lowering.

For selected patients with very high Lp(a) levels and progressive cardiovascular disease despite maximal medical therapy, lipoprotein apheresis may be considered.

Apheresis Techniques (Specialized Treatment)

Apheresis refers to procedures where blood is removed from the patient, passed through a machine to selectively remove a specific component, and the remaining blood is returned to the patient. For high Lp(a), specific apheresis techniques can be used.

Cascade Plasma Filtration

In cascade filtration (or double filtration plasmapheresis), blood is first separated into plasma and cells. The plasma then passes through a secondary filter (plasma fractionator) with specific pore sizes. Larger molecules, including VLDL, LDL, Lp(a), fibrinogen, immunoglobulins, and immune complexes, are retained by the filter, while smaller molecules (like albumin, HDL) pass through. The filtered plasma is then recombined with the blood cells and returned to the patient.

This technique can effectively lower levels of various large pathogenic molecules. Repeated sessions may help reduce atherosclerotic plaque burden by promoting cholesterol efflux from tissues into the plasma. It is used for various conditions beyond lipid disorders, including some autoimmune diseases.

Lipoprotein Apheresis / Immunoadsorption

This is a more specific form of apheresis targeting lipoproteins. Blood plasma is passed over a column containing materials that selectively bind and remove ApoB-containing lipoproteins (LDL, VLDL, Lp(a)).

• Methods: Techniques include dextran sulfate cellulose adsorption (DALI), heparin-induced extracorporeal LDL precipitation (HELP), immunoadsorption (using antibodies against ApoB or Lp(a)), and direct adsorption of lipoproteins (DALI).
• Specificity: Immunoadsorption columns using antibodies specific to ApoB or Lp(a) offer high selectivity.
• Procedure: Typically involves separating plasma from cells, passing the plasma over the adsorption column(s) (often used in pairs, alternating between adsorption and regeneration cycles), and returning the treated plasma and cells to the patient. The procedure removes the target lipoproteins without significant loss of other plasma proteins like albumin or immunoglobulins, often eliminating the need for replacement fluids.
• Use: Primarily used for patients with severe familial hypercholesterolemia resistant to medication, and increasingly considered for patients with very high Lp(a) and progressive ASCVD. Columns are typically patient-specific and reused multiple times after regeneration.

Lipoprotein apheresis requires specialized centers and is typically performed every 1-2 weeks.

The Lp(a) Blood Test Procedure

• Sample Type: Blood serum or plasma.
• Preparation: Fasting is generally NOT required for Lp(a) testing itself, as levels are not significantly affected by recent meals. However, if measured as part of a standard lipid panel, fasting (usually 8-12 hours) may be requested for accurate triglyceride and LDL-C measurement.
• Collection: Standard venipuncture to draw a blood sample from a vein in the arm.
• Analysis: Measured in a clinical laboratory using immunoassays. It's important that assays are standardized to reference materials and ideally report results in nmol/L due to the size heterogeneity.

References

1. Nordestgaard, B. G., Chapman, M. J., Ray, K., Borén, J., Andreotti, F., Watts, G. F., ... & European Atherosclerosis Society Consensus Panel. (2010). Lipoprotein(a) as a cardiovascular risk factor: current status. *European Heart Journal*, 31(23), 2844–2853. https://doi.org/10.1093/eurheartj/ehq386
2. Tsimikas, S. (2017). A Test in Context: Lipoprotein(a): Diagnosis, Prognosis, Controversies, and Emerging Therapies. *Journal of the American College of Cardiology*, 69(6), 692–711. https://doi.org/10.1016/j.jacc.2016.11.042
3. Wilson, D. P., Jacobson, T. A., Jones, P. H., Koschinsky, M. L., McNeal, C. J., Nordestgaard, B. G., & Orringer, C. E. (2019). Use of Lipoprotein(a) in clinical practice: A biomarker whose time has come. A scientific statement from the National Lipid Association. *Journal of Clinical Lipidology*, 13(3), 374–392. https://doi.org/10.1016/j.jacl.2019.04.010
4. Grundy, S. M., Stone, N. J., Bailey, A. L., Beam, C., Birtcher, K. K., Blumenthal, R. S., ... & Yeboah, J. (2019). 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. *Circulation*, 139(25), e1082–e1143. https://doi.org/10.1161/CIR.0000000000000625 (Mentions Lp(a) in risk assessment).
5. Thompson, G. R. (2010). Lipoprotein apheresis. *Current Opinion in Lipidology*, 21(6), 487–491. https://doi.org/10.1097/MOL.0b013e32833f0793