I

Factors that decrease oxygenation

1. Low blood volume

2. Anemia

3. Low hemoglobin

4. Poor blood flow

5. Pulmonary disease

Figure 32-4

Function of the erythropoietin mechanism to increase production of red blood cells when tissue oxygenation decreases.

can also increase the rate of red cell production. This is especially apparent in prolonged cardiac failure and in many lung diseases, because the tissue hypoxia resulting from these conditions increases red cell production, with a resultant increase in hematocrit and usually total blood volume as well.

Erythropoietin Stimulates Red Cell Production, and Its Formation Increases in Response to Hypoxia. The principal stimulus for red blood cell production in low oxygen states is a circulating hormone called erythropoietin, a gly-coprotein with a molecular weight of about 34,000. In the absence of erythropoietin, hypoxia has little or no effect in stimulating red blood cell production. But when the erythropoietin system is functional, hypoxia causes a marked increase in erythropoietin production, and the erythropoietin in turn enhances red blood cell production until the hypoxia is relieved.

Role of the Kidneys in Formation of Erythropoietin. In the normal person, about 90 per cent of all erythropoietin is formed in the kidneys; the remainder is formed mainly in the liver. It is not known exactly where in the kidneys the erythropoietin is formed. One likely possibility is that the renal tubular epithelial cells secrete the erythropoietin, because anemic blood is unable to deliver enough oxygen from the peritubular capillaries to the highly oxygen-consuming tubular cells, thus stimulating erythropoietin production.

At times, hypoxia in other parts of the body, but not in the kidneys, stimulates kidney erythropoietin secretion, which suggests that there might be some nonrenal sensor that sends an additional signal to the kidneys to produce this hormone. In particular, both norepinephrine and epinephrine and several of the prostaglandins stimulate erythropoietin production.

When both kidneys are removed from a person or when the kidneys are destroyed by renal disease, the person invariably becomes very anemic because the 10 per cent of the normal erythropoietin formed in other tissues (mainly in the liver) is sufficient to cause only one third to one half the red blood cell formation needed by the body.

Effect of Erythropoietin in Erythrogenesis. When an animal or a person is placed in an atmosphere of low oxygen, erythropoietin begins to be formed within minutes to hours, and it reaches maximum production within 24 hours. Yet almost no new red blood cells appear in the circulating blood until about 5 days later. From this fact, as well as other studies, it has been determined that the important effect of erythropoietin is to stimulate the production of proerythroblasts from hematopoietic stem cells in the bone marrow. In addition, once the proerythroblasts are formed, the erythropoietin causes these cells to pass more rapidly through the different erythroblastic stages than they normally do, further speeding up the production of new red blood cells. The rapid production of cells continues as long as the person remains in a low oxygen state or until enough red blood cells have been produced to carry adequate amounts of oxygen to the tissues despite the low oxygen; at this time, the rate of erythropoietin production decreases to a level that will maintain the required number of red cells but not an excess.

In the absence of erythropoietin, few red blood cells are formed by the bone marrow. At the other extreme, when large quantities of erythropoietin are formed available, and if there is plenty of iron and other required nutrients available, the rate of red blood cell production can rise to perhaps 10 or more times normal. Therefore, the erythropoietin mechanism for controlling red blood cell production is a powerful one.

Maturation of Red Blood Cells—Requirement for Vitamin B12 (Cyanocobalamin) and Folic Acid

Because of the continuing need to replenish red blood cells, the erythropoietic cells of the bone marrow are among the most rapidly growing and reproducing cells in the entire body. Therefore, as would be expected, their maturation and rate of production are affected greatly by a person's nutritional status.

Especially important for final maturation of the red blood cells are two vitamins, vitamin Bn and folic acid. Both of these are essential for the synthesis of DNA, because each in a different way is required for the formation of thymidine triphosphate, one of the essential building blocks of DNA. Therefore, lack of either vitamin B12 or folic acid causes abnormal and diminished DNA and, consequently, failure of nuclear maturation and cell division. Furthermore, the ery-throblastic cells of the bone marrow, in addition to failing to proliferate rapidly, produce mainly larger than normal red cells called macrocytes, and the cell itself has a flimsy membrane and is often irregular, large, and oval instead of the usual biconcave disc. These poorly formed cells, after entering the circulating blood, are capable of carrying oxygen normally, but their fragility causes them to have a short life, one half to one third normal. Therefore, it is said that deficiency of either vitamin B12 or folic acid causes maturation failure in the process of erythropoiesis.

Maturation Failure Caused by Poor Absorption of Vitamin B12 from the Gastrointestinal Tract—Pernicious Anemia. A

common cause of red blood cell maturation failure is failure to absorb vitamin B12 from the gastrointestinal tract. This often occurs in the disease pernicious anemia, in which the basic abnormality is an atrophic gastric mucosa that fails to produce normal gastric secretions. The parietal cells of the gastric glands secrete a glycoprotein called intrinsic factor, which combines with vitamin B12 in food and makes the B12 available for absorption by the gut. It does this in the following way: (1) Intrinsic factor binds tightly with the vitamin B12. In this bound state, the B12 is protected from digestion by the gastrointestinal secretions. (2) Still in the bound state, intrinsic factor binds to specific receptor sites on the brush border membranes of the mucosal cells in the ileum. (3) Then, vitamin B12 is transported into the blood during the next few hours by the process of pinocytosis, carrying intrinsic factor and the vitamin together through the membrane. Lack of intrinsic factor, therefore, causes diminished availability of vitamin B12 because of faulty absorption of the vitamin.

Once vitamin B12 has been absorbed from the gastrointestinal tract, it is first stored in large quantities in the liver, then released slowly as needed by the bone marrow. The minimum amount of vitamin B12 required each day to maintain normal red cell maturation is only 1 to 3 micrograms, and the normal storage in the liver and other body tissues is about 1000 times this amount. Therefore, 3 to 4 years of defective B12 absorption are usually required to cause maturation failure anemia.

Failure of Maturation Caused by Deficiency of Folic Acid (Pteroylglutamic Acid). Folic acid is a normal constituent of green vegetables, some fruits, and meats (especially liver). However, it is easily destroyed during cooking. Also, people with gastrointestinal absorption abnormalities, such as the frequently occurring small intestinal disease called sprue, often have serious difficulty absorbing both folic acid and vitamin B12. Therefore, in many instances of maturation failure, the cause is deficiency of intestinal absorption of both folic acid and vitamin B12.

I. 2 succinyl-CoA + 2 glycine-HC CH

IV. heme + polypeptide -► hemoglobin chain (a or b)

Figure 32-5

Formation of hemoglobin.

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