Blood is made up of particulate cell forms suspended in a fluid medium called plasma, a very complicated mixture of inorganic, and simple and complex organic materials dissolved in water. If the blood is collected without anticoagulant, in vessels with siliconized or non polar surfaces, the fluid separating is referred to as native plasma. This approximates very closely the plasma actually present in circulating blood. It is the practice, however, to use such anticoagulants as oxalate, citrate, EDTA, and heparin to prepare specimens of plasma for study or analysis. This differs from native plasma because it is modified by the presence of the added chemicals and by the partial loss of calcium bound by oxalate, if this is used. If blood is permitted to clot, the fluid separating is referred to as serum. It lacks the protein fibrinogen present in plasma, the fibrinogen having been transformed into insoluble fibrin in the clotting process. The fibrinogen constitutes only some 3 to 6 per cent of the total plasma proteins. It is satisfactory and much more convenient to use serum rather than plasma in clinical chemical studies.
Some 92 to 93 per cent of plasma or serum is solvent water; of the 7 to 8 per cent of total solutes present, the proteins occur in the greatest concentration, roughly 6.8 to 8.8 (6.5 to 8.5) gm./100 ml. of plasma (serum) water. Because of the large molecular weight of proteins, however, their molar concentration calculates to about 0.80 to 1.10 mM/L. In clinical work, the concentration of proteins is given in terms of grams per 100 ml. of serum volume. It would be more precise to express it in terms of serum water. The latter value is 1.07 times the serum volume figure.
Plasma proteins serve a number of different functions in the organism. They play a nutritive role, inasmuch as they constitute a portion of the amino acid pool of the body; thus, the proteins are a form of storage amino acids. If needed, these proteins can be broken down in the liver to produce amino acids for use in building other proteins. Alternatively, they can be deaminated to give keto acids that can be mobilized to provide caloric energy or be transformed into carbohydrates and lipids. Plasma proteins also act as transport agents: many vital metabolites, metal ions, hormones, and lipids are transported about the body, bound to and carried by certain specific proteins. Some proteins have important special functions of their own, such as enzymes, the immune antibodies among the globulins, and the various proteins associated with blood coagulation.
Another important function of proteins is a physicochemical one. The plasma proteins, being large, colloidal molecules, are nondiffusible; i.e., they cannot move through the thin capillary wall membranes as can most other blood solutes. They are thus entrapped in the vascular system and exert a colloidal osmotic pressure, which serves to maintain a normal blood volume, and a normal water content in the interstitial fluid and the tissues. The albumin fraction is most important in maintaining this normal colloidal osmotic or oncotic pressure in blood. If the albumin falls to low levels, water will leave the blood vessels and enter the extracellular fluid and the tissues, thus producing edema.
The maintenance of the acid-base balance in blood also involves the plasma proteins. As amphoteric compounds, they function as buffers to minimize sudden, gross changes in the pH of the blood.
Despite their presence together, the various proteins of plasma do not originate from the same source. The liver is the main organ for the synthesis of albumins and alpha and beta globulins, and perhaps some nonimmune gamma globulins; among these these proteins are included the blood clotting and transport proteins. The cells of the reticuloendothelial system (spleen, bone marrow, lymph nodes) serve as the source of the antibody, immune gamma globulins and perhaps some beta globulins.
The level of total serum proteins found in healthy young and middle-aged adults is 6.0 to 8.2 gm./100 ml. of serum. In plasma, fibrinogen increases this value by an additional 0.2 to 0.4 gm./100 ml. A diurnal variation of 0.5 gm./100 ml. reflects small changes in the ratio of vascular to nonvascular fluid in the course of daily activity. In disease states both the total protein and the ratio of the individual protein fractions may change independently of one another. In states of dehydration, total protein may increase some 10 to 15 per cent, the rise being reflected in all protein fractions. Dehydration may result either from a decrease in water intake, as occurs in frank water deprivation (thirst), or from excessive water loss, as occurs in severe vomiting, diarrhea, Addison's disease, and diabetic acidosis. The absolute quantity of serum proteins is unaltered, but the concentration is increased because of the decreased volume of solvent water. In multiple myeloma, the total protein may increase to over 10 gm./100 ml., the increase being almost entirely due to the presence of markedly elevated levels of myeloma proteins (abnormal forms of gamma globulins). The quantities of other proteins are essentially unaltered.
Hypoproteinemia, characterized by total protein levels below 6.0 gm./100 ml., is encountered in many unrelated disease states. In the nephrotic syndrome large masses of albumin may be lost in the urine as a result of leakage of the albumin molecules through the damaged kidney. In salt retention syndromes, water is held back to dilute out the retained salt, resulting in the dilution of all protein fractions. Large quantities of proteins are lost in patients with severe burns, extensive bleeding, or open wounds. Water is replaced by the body more rapidly than is protein, effecting a decreased total protein concentration. A long period of low intake or deficient absorption of protein may affect the level and composition of serum proteins, as in sprue and in other forms of intestinal malabsorption, as well as in acute protein starvation (kwashiorkor). In these conditions the liver has inadequate raw material to synthesize serum proteins to replace those lost in the normal turnover (wear and tear) of proteins and amino acids.
In general, changes in total proteins may occur in one, several, or all fractions. It is also possible for significant changes to occur in different directions in different fractions, without changes in the total protein concentration.
The physician may occasionally request only a value for total protein in serum; however, more commonly he will ask for total protein, the values for the albumin, and total globulin fractions, and for the albumin-globulin (A/G) ratio. In healthy young and middle-aged adults, the albumin may vary from 3.8 to 4.7 gm./100 ml., and the total globulins from 2.3 to 3.5 gm./100 ml. The range found for the albumin-globulin ratio is 1.1 to 1.8, averaging 1.5. The globulins are usually separated by a salt fractionation procedure, but may be estimated from the sum of electrophoretically separated fractions. Albumins can be estimated separately by virtue of their ability to bind certain dyes such as methyl orange and hydroxyazobenzoic acid. These techniques will be discussed later.
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