BIOCHEMISTRY: A TEXTBOOK FOR HIGHER EDUCATION - E. S. Severin - 2004

CHAPTER 14. BLOOD BIOCHEMISTRY

IV. Plasma Proteins

Blood Plasma contains 7% of all body Proteins at a concentration of 60 — 80 g/L. Plasma Proteins perform a multitude of Functions. One of them is the maintenance of osmotic pressure, as proteins bind Water and retain it within the vascular bed.

✵ Plasma Proteins form the crucial blood buffer system and maintain blood pH within the range of 7.37 — 7.43.

✵ Albumin, transthyretin, transcortin, transferrin, and several other proteins (Table 14-2) serve a transport function.

✵ Plasma proteins determine blood viscosity and, consequently, play a major role in the hemodynamics of the Circulatory system.

✵ Blood plasma proteins act as an amino acid reserve for the Organism.

✵ IMMUNOGLOBULINS, blood clotting proteins, α1-antitrypsin, and Complement system proteins carry out a protective function.

Using Cellulose acetate or agarose gel Electrophoresis, plasma Proteins can be separated into albumins (55 — 65%), α₁-globulins (2 — 4%), α₂-globulins (6 — 12%), β-globulins (8 — 12%), and γ-globulins (12 — 22%) (Fig. 14-19).

Class="center">Fig. 14-19. Electrophoretogram (A) and densitogram (B) of Serum proteins.

The application of other media for electrophoretic protein Separation makes it possible to detect a greater number of fractions. For instance, polyacrylamide or Starch gel electrophoresis resolves 16 — 17 protein fractions in blood plasma. Immunoelectrophoresis, combining electrophoretic and immunological Methods of Analysis, allows plasma proteins to be separated into more than 30 fractions.

Most serum proteins are synthesized in the Liver, though some are produced in other Tissues as well. For instance, γ-globulins are synthesized by B lymphocytes (see Chapter 4), Peptide Hormones are predominantly secreted by endocrine gland Cells, and the peptide hormone Erythropoietin is produced by Kidney cells.

Polymorphism is characteristic of many plasma proteins, such as albumin, α₁-antitrypsin, haptoglobin, transferrin, ceruloplasmin, α₂-macroglobulin, and immunoglobulins (see Chapter 4).

Nearly all plasma proteins, with the exception of albumin, are Glycoproteins. Oligosaccharides attach to proteins by forming glycosidic bonds with the hydroxyl group of Serine or Threonine, or by interacting with the carboxyl group of asparagine. In most cases, the terminal oligosaccharide residue is N-acetylneuraminic acid linked to galactose. The vascular endothelial enzyme neuraminidase hydrolyzes the bond between them, making galactose accessible to specific hepatocyte receptors. Through endocytosis, "aged" proteins enter liver cells, where they are degraded. The half-life (T¹_/2) of plasma proteins ranges from several hours to several weeks.

In A number of diseases, the relative distribution of protein fractions upon electrophoresis changes compared to the normal state (Fig. 14-20).

Fig. 14-20. Protein profiles of serum proteins. a — normal; b — Nephrotic Syndrome; c — hypogammaglobulinemia; d — liver cirrhosis; e — α1-antitrypsin deficiency; f — diffuse hypergammaglobulinemia.

Such alterations are referred to as dysproteinemias, though their interpretation often has relative diagnostic value. For example, the decrease in albumin, α₁-, and γ-globulins alongside an increase in α₂- and β-globulins, characteristic of nephrotic syndrome, is also observed in certain other conditions accompanied by protein loss. In humoral immunodeficiency, a reduction in the γ-globulin fraction indicates a decrease in the primary immunoglobulin component, IgG, but does not reflect the dynamics of IgA and IgM changes.

The levels of certain plasma proteins can increase dramatically during acute inflammatory processes and other pathological states (trauma, Burns, myocardial infarction). Such proteins are called acute-phase proteins because they participate in The Development of the body's inflammatory response. The primary inducer of the synthesis of most acute-phase proteins in hepatocytes is the polypeptide interleukin-1, released from mononuclear phagocytes. Acute-phase proteins include C-reactive protein (named for its interaction with the C-polysaccharide of pneumococci), α1-antitrypsin, haptoglobin, acid glycoprotein, and fibrinogen. C-reactive protein is known to stimulate The Complement System, and its blood concentration, for instance during an exacerbation of rheumatoid Arthritis, can increase up to 30-fold compared to normal. The blood plasma protein α₁-antitrypsin can inactivate certain proteases released during the acute phase of inflammation.

The levels of certain plasma proteins and their functions are presented in Table 14-2.

Table 14-2. Concentration and functions of selected plasma proteins

Albumin. The concentration of albumin in the blood is 40–50 g/L. Approximately 12 g of albumin is synthesized daily in the liver, and its half-life (T_1/2) is roughly 20 days. Albumin consists of 585 amino acid residues, contains 17 Disulfide Bonds, and has a Molecular Weight of 69 kDa. Because the albumin molecule is rich in dicarboxylic Amino Acids, it can bind Ca²⁺, Cu²⁺, and Zn²⁺ cations in the blood. About 40% of albumin is found in the blood and the remaining 60% in the extracellular fluid; however, its concentration in plasma is higher than in the interstitial fluid because the volume of the latter exceeds plasma volume by a factor of 4.

Due to its relatively small molecular mass and high concentration, albumin accounts for up to 80% of the plasma osmotic pressure. In hypoalbuminemia, plasma osmotic pressure drops, leading to an imbalance in the distribution of extracellular fluid between the vascular bed and the intercellular space, which clinically manifests as edema. A relative decrease in blood plasma volume is accompanied by reduced renal blood flow, triggering the renin-angiotensin-aldosterone system, which aims to restore blood volume (see Section 11). However, due to a shortage of albumin—which is supposed to retain Na⁺, other cations, and water—water leaks into the intercellular space, thereby exacerbating edema.

Hypoalbuminemia can also result from reduced albumin synthesis in liver diseases (such as cirrhosis), increased capillary permeability, protein loss due to extensive burns or catabolic states (severe Sepsis, malignancies), nephrotic syndrome accompanied by albuminuria, and starvation. Circulatory Disorders characterized by slowed blood flow lead to increased leakage of albumin into the intercellular space and the development of edema. A rapid increase in capillary permeability is accompanied by a sharp drop in blood volume, leading to a fall in blood pressure and clinical Shock.

Albumin is a critical transport protein. It transports free fatty acids (see Section 8), unconjugated bilirubin (see Section 13), Ca²⁺, Cu²⁺, Tryptophan, thyroxine, and triiodothyronine (see Section 11). Many drugs (such as aspirin, dicumarol, and sulfonamides) bind to blood albumin. This fact must be considered when treating conditions accompanied by hypoalbuminemia, as these cases show an increased concentration of free drug in the blood. In addition, it should be kept in mind that certain drugs may compete with bilirubin and with each other for binding sites on the albumin molecule.

Transthyretin (prealbumin) is also known as thyroxine-binding prealbumin and functions as an acute-phase protein. Belonging to the albumin fraction, transthyretin has a tetrameric molecular Structure. It is capable of binding a retinol-binding protein at one binding site and up to two molecules of thyroxine and triiodothyronine at another. The binding of these ligands occurs independently of each other. However, transthyretin plays a substantially lesser role in transporting the latter hormones compared to thyroxine-binding globulin.

α₁-Antitrypsin is classified as an α₁-globulin. It inhibits a range of proteases, including the enzyme Elastase, which is released from neutrophils and degrades the Elastin of lung alveoli. α₁-Antitrypsin deficiency can lead to pulmonary emphysema (see Section 15) and hepatitis resulting in liver cirrhosis. There are several polymorphic forms of α₁-antitrypsin, one of which is pathological. In individuals homozygous for two defective antitrypsin Gene alleles, the liver synthesizes an aberrant α₁-antitrypsin that forms aggregates, destroying hepatocytes. This disrupts the secretion of the protein by hepatocytes and reduces its blood concentration.

Haptoglobin accounts for approximately one-quarter of all α₂-globulins. During intravascular hemolysis of erythrocytes, haptoglobin forms a complex with hemoglobin that is subsequently degraded in the Cells of the reticuloendothelial system. While free hemoglobin, with a molecular mass of 65 kDa, can be filtered through renal glomeruli or aggregate within them, the hemoglobin-haptoglobin complex has a molecular mass that is too large (155 kDa) to pass through the glomeruli. Consequently, The formation of this complex prevents the loss of iron contained within hemoglobin. Determining haptoglobin levels is of diagnostic significance; for example, a decreased concentration of haptoglobin in the blood is observed in hemolytic anemia. This is explained by the fact that given a haptoglobin half-life of 5 days and a hemoglobin-haptoglobin complex half-life of about 90 minutes, an increased influx of free hemoglobin into the blood during erythrocyte hemolysis causes a sharp drop in free haptoglobin levels.

Haptoglobin is classified as an acute-phase protein; its blood concentration rises during acute Inflammatory Diseases.

Information regarding several other blood plasma proteins presented in Table 14-2 can be found in the respective sections of the textbook.