Lipoprotein(a) (Lp(a))

The structure of lipoprotein(a)

Historically, the division of lipoproteins into different categories based on the different density of lipoprotein particles determined by ultracentrifugation:

1. chilomicrons
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))

Density of lipoprotein(a) (Lp(a)) is close to HDL. By electrophoretic mobility — to VLDL. Structurally same particles of Lp(a) is similar to LDL.

A particle of Lp (a) is composed of cholesterol, triglycerides, Apo-B, phospholipids and apolipoprotein Apo (a). They have a similar lipid composition to LDL, and, as well as LDL, contain one Apo-B protein molecule in each particle. But the protein part of Lp (a) also contains a special, peculiar only to these lipoproteins, protein - apolipoprotein Apo (a).

Apolipoprotein Apo(a) is a large, hydrophilic, and highly glycosylated protein, which composition is similar to plasminogen. Apolipoprotein Apo(a) consists of domains called "kringle", which, in fact, are similar to domains of plasminogen. Apolipoprotein Apo(a) consists of an inactive proteases domain, one kringle V domain and a different number of kringle IV domains.

In different individuals in the apolipoprotein Apo (a) encoding gene can be different (from 12 to 51) number of DNA fragments, encoding the domain of the apolipoprotein Apo (a).

The number of kringle domains in Apo(a), therefore, genetically predetermined and can vary from 12 to 51. As a result, there is a significant population polymorphism and the size of the protein, and particle size Lp(a). And therefore the molecular weight of the protein apolipoprotein Apo(a) in different individuals may range from ~280 to 800 kDa. Now known 34 isoforms of Lp (a).

It is assumed that the gene of apolipoprotein Apo(a) occurred as a result of repetition of some parts of the plasminogen gene, and both genes are closely related to each other.

Apolipoprotein Apo(a) is synthesized in the liver and is linked through disulfide bonds with the newly synthesized ApoB-100. Since both proteins interact by their C-terminal parts, ApoB loses the affinity to its receptor (LDL receptor). Catabolism of Lp(a), in contrast with other lipoproteins, occurs in the kidneys and not in the liver.

The apolipoprotein Apo (a) kringle domains are organized into a special protein "motive", consisting of three loop-like structures stabilized by three disulfide bonds. This "motive" is also contained in a large amount of proteins encoded by the genes of the family prothrombins, comprising the prothrombin, plasminogen, hepatocyte growth factor, urokinase, Factor XII, tissue plasminogen activator.

Plasminogen is a precursor (zymogen) of plasmin, the primary enzyme that breaks down fibrin clots. It turned out that the size of apolipoprotein (a) determine the Lp(a) concentration in plasma. The smaller the apolipoprotein Apo(a), i.e. the smaller the domains of "kringle IV", the higher the level of Lp(a) plasma and Vice versa, the longer the molecule of apolipoprotein Apo(a) – the smaller the Lp(a) concentration.

Overall, the level of synthesis of apolipoprotein Apo(a) is determined by how quickly its isoforms are secreted. Smaller isoforms of apolipoprotein Apo(a) secreted faster and therefore the level of Lp(a) in plasma is inversely proportional to the size of apolipoprotein Apo(a).

 

The level of lipoprotein(a) in different populations

Levels of Lp(a) in blood is genetically determined — by length of encoding apolipoprotein Apo(a) gene. As mentioned, in the human population there are many alleles (different variants) of the gene of apolipoprotein Apo(a) that encode a different number of kringle IV domains. In General, the concentration of Lp(a) different persons may be in the range from <0.1 to >200 mg/DL and to vary by 1,000 times. Africans have a high Lp(a) concentration, which is in average 7 times the level of Lp(a) in European and Asian populations.

Starting from early childhood, the Lp(a) concentration increases, reaches a plateau of maturity and then remains practically unchanged. Further increase in the level of Lp(a) is seen only in postmenopausal women.

 

The role of lipoprotein(a) in pathology

High levels of Lp(a) is a risk factor for coronary heart disease, atherosclerosis, thrombosis and stroke. High levels of Lp(a) is similar to a high level of LDL determines the risk of developing early atherosclerosis. Since Lp(a) is structurally very similar to plasminogen, Lp(a) has a high affinity to extracellular matrix and rapidly accumulates in the vascular wall. Further protein undergoes oxidation and partial proteolysis by the action of muscles that causes the development of atheromatous plaques.

Lp(a) has a greater affinity to fibronectin and forms complexes with proteoglycans and glycosaminoglycans of the extracellular matrix. This leads to selective accumulation of Lp(a) in the walls of blood vessels and induction of the inflammatory process. Moreover, Lp(a) is an adhesive substrate for monocytes and activates inflammatory cells. Also found mitogenic action of Lp(a) on smooth muscle cells, stimulating their growth. Also lipoprotein (a) competes with plasminogen for binding sites on the cell surface, reducing plasminogen activation and by inhibiting the lysis of blood clots.

In contrast to most lipid risk factors, the risk associated with elevated levels of Lp(a), does not depend on age or sex, or diet, or living conditions. However, as it turned out, factors that may increase the level of Lp(a), exist. As mentioned, the catabolism of Lp(a) occurs in the kidneys. Renal pathology increases the levels of Lp(a) due to reduced catabolism of its particles.

It was found that in patients suffering from chronic renal failure, nephrotic syndrome and diabetic nephropathy, as well as in patients on hemodialysis, the levels of Lp(a) significantly increased. It is natural that Lp (a) levels are lowered by remission of nephrotic syndrome.

It is essential that the apolipoprotein Apo(a) is a protein of acute phase of inflammation, and its concentration may increase after surgery, myocardial infarction, stroke and other tissue damage.

Despite decades of research, the normal physiological role of Lp(a) is still not determined for sure. It is believed that Lp(a) somehow involved in the metabolism of cholesterol and triglycerides (because, like LDL), or takes any part in the processes of coagulation, for apolipoprotein Apo(a) resembles plasminogen. Or both together. Lp(a) is not vital. Individuals with almost zero or vanishingly small concentrations have no significant abnormalities.

The levels of LP(a) different individuals can differ in 1000 times. It is assumed that LP(a), accelerates wound healing, helps to restore damaged tissues and damaged blood vessels. This is based on the hypothesis that Lp (a) - a positive acute phase reactant, it finds a large number of receptors located on the surface of endothelial cells, macrophages, fibroblasts and platelets. Lp (a) are also associated with various components of the subendothelial vessel wall and enhances matrix and smooth muscle cell proliferation.

Overall, Lp(a) is a risk factor and predictor of:

• hereditary predisposition to cardiovascular and micro vascular diseases
• genetically mediated acute coronary conditions
• genetically mediated ischemic strokes

Measuring the levels of Lp (a) must be:

• in patients with early cases of cardiovascular disease (CVD)
• for those who have a family history of frequent cases of CVD (suspected genetic predisposition)
• for those who are diagnosed with CVD and who have no traditional risk factors
• for those who have high cholesterol is not reduced by statin therapy
• in patients with real diseases
• in those to whom assigned angioplasty
• in those who are assigned to coronary artery bypass grafting
• in diabetes mellitus type 1 and 2

Lp (a) reference values:

• target level <14 mg/DL
• border risk 14-30 mg/DL
• high risk 31-50 mg/DL
• very high risk >50 mg/DL

Factors that increase the values:

• insulin deficiency
• low levels of free thyroxine

Factors that reduce the values:

• estrogens
• stanozolol
• niacin
• neomycin
• N-acetylcysteine
• omega-3 - fatty acids (fish oil)

 

Treatment

Due to the fact that levels of lipoprotein(a) genetically predetermined, lowering them is almost impossible: neither a change in diet, nor weight loss, nor commonly used drugs (statins).

Some positive effect was observed in the application of nicotinic acid and hormone replacement therapy, but these data need serious confirmation.

Drugs that reduce the levels of Lp(a), is not yet known, so it is unknown whether the lower levels of Lp(a) to lower cardiorisk.

It has been observed that elevated levels of Lp(a) have a certain efficiency of some vitamins and amino acids: Vit.C, Vit. B3, lysine, Proline, N-acetylcysteine, but certain treatments has not been developed and these methods of treatment require significant clinical confirmation.

Currently actively used such methods to reduce hyper-Lp(a), as a cascade plasma filtration and immunoadsorption.

 

Cascade plasma filtration

The principle of cascade plasma filtration procedures is that blood plasma separated in the primary plasmafilter, enters into the inner chamber of plasma fractionator. Molecules with a high molecular weight (atherogenic lipoproteins and very low density (VLDL), lipoprotein (a) (LP(a)), autoantibodies and circulating immune complexes, etc.) present in plasma, due to their large size are cut off by a porous filter located inside plasma fractionator.

Plasma components capable to pass through the pores of the filter, pass through the porous material, and combines with blood cells are returned to the patient.

Clinical effects of cascade plasma filtration procedures associated with the direct removal of pathogenic blood components and with significant improvement of microcirculation. Purified blood plasma (due to the difference of concentrations) contributes to the exit from the tissues of accumulated harmful substances, such as cholesterol from atherosclerotic plaques. Therefore, repeated procedures of cascade plasma filtration lead to a gradual cleansing of the blood and body tissues, dissolution of atherosclerotic plaques.

Cascade plasmafiltration procedure used in the treatment of atherosclerosis, complications of diabetes, maculopathy, sensorineural hearing loss, allergies, some forms of miscarriage, and other diseases.

 

Immunoadsorption

Immunoadsorption is binding and removing substances from blood by using of immunosorbents. The reaction of binding of certain molecules based on the antigen-antibody reaction.

Immuno sorption column with polyclonal and monoclonal antibodies to low-density lipoproteins and lipoprotein(a) applied for this purpose. This leads to the correction of dyslipidemia in patients with hereditary (homozygous and heterozygous) form of the disease and primary hypercholesterolemia (resistant to drug therapy) and hyperlipoproteinemy(a) cholesterolemia.

Immunosorbtion method principle is based on the use of antibodies specific to pathogenic component of human blood plasma. Column for immunosorbtion, containing antibodies, is included in the patient's extracorporeal circuit blood flow.

The patient's blood, separated in the plasma separator to the cells and the plasma, the plasma flows through the column and purified from pathogenic component. Purified plasma and blood cells are concatenated and returned again to the patient.

Plasma volume processed during immunoadsorption procedures is typically 1-1.5 of total volume of circulating plasma. Immunoadsorption procedure does not remove any of the plasma and blood components, besides that specifically adsorbed on the column. Loss of protein during immunosorption not exceed 7-15% (depending on the type of procedure), so use of plasma substitute solutions are not required.

Immunosorbtion column are designed for multiple personal uses. In the procedure of immunosorbtion typically used a pair of column that work alternately. This principle of "dual technologies" is a standard for all types of columns and is used to ensure maximum effectiveness of the treatments. Usually spend on each column 3-8 sorption cycles during one procedure. Between treatments immunosorbtion column are stored in a preservative buffer solution.