Guyton and Hall Textbook of Medical Physiology, 12th Ed


Red Blood Cells, Anemia, and Polycythemia

imageWith this chapter we begin discussing the blood cells and cells of the macrophage system and lymphatic system. We first present the functions of red blood cells, which are the most abundant cells of the blood and are necessary for the delivery of oxygen to the tissues.

Red Blood Cells (Erythrocytes)

A major function of red blood cells, also known as erythrocytes, is to transport hemoglobin, which in turn carries oxygen from the lungs to the tissues. In some lower animals, hemoglobin circulates as free protein in the plasma, not enclosed in red blood cells. When it is free in the plasma of the human being, about 3 percent of it leaks through the capillary membrane into the tissue spaces or through the glomerular membrane of the kidney into the glomerular filtrate each time the blood passes through the capillaries. Therefore, hemoglobin must remain inside red blood cells to effectively perform its functions in humans.

The red blood cells have other functions besides transport of hemoglobin. For instance, they contain a large quantity of carbonic anhydrase, an enzyme that catalyzes the reversible reaction between carbon dioxide (CO2) and water to form carbonic acid (H2CO3), increasing the rate of this reaction several thousandfold. The rapidity of this reaction makes it possible for the water of the blood to transport enormous quantities of CO2 in the form of bicarbonate ion (image) from the tissues to the lungs, where it is reconverted to CO2 and expelled into the atmosphere as a body waste product. The hemoglobin in the cells is an excellent acid-base buffer (as is true of most proteins), so the red blood cells are responsible for most of the acid-base buffering power of whole blood.

Shape and Size of Red Blood Cells

Normal red blood cells, shown in Figure 32-3, are biconcave discs having a mean diameter of about 7.8 micrometers and a thickness of 2.5 micrometers at the thickest point and 1 micrometer or less in the center. The average volume of the red blood cell is 90 to 95 cubic micrometers.


Figure 32-3 Genesis of normal red blood cells (RBCs) and characteristics of RBCs in different types of anemias.

The shapes of red blood cells can change remarkably as the cells squeeze through capillaries. Actually, the red blood cell is a “bag” that can be deformed into almost any shape. Furthermore, because the normal cell has a great excess of cell membrane for the quantity of material inside, deformation does not stretch the membrane greatly and, consequently, does not rupture the cell, as would be the case with many other cells.

Concentration of Red Blood Cells in the Blood

In healthy men, the average number of red blood cells per cubic millimeter is 5,200,000 (±300,000); in women, it is 4,700,000 (±300,000). Persons living at high altitudes have greater numbers of red blood cells, as discussed later.

Quantity of Hemoglobin in the Cells

Red blood cells have the ability to concentrate hemoglobin in the cell fluid up to about 34 grams in each 100 milliliters of cells. The concentration does not rise above this value because this is the metabolic limit of the cell’s hemoglobin-forming mechanism. Furthermore, in normal people, the percentage of hemoglobin is almost always near the maximum in each cell. However, when hemoglobin formation is deficient, the percentage of hemoglobin in the cells may fall considerably below this value and the volume of the red cell may also decrease because of diminished hemoglobin to fill the cell.

When the hematocrit (the percentage of blood that is in cells—normally, 40 to 45 percent) and the quantity of hemoglobin in each respective cell are normal, the whole blood of men contains an average of 15 grams of hemoglobin per 100 milliliters of cells; for women, it contains an average of 14 grams per 100 milliliters.

As discussed in connection with blood transport of oxygen in Chapter 40, each gram of pure hemoglobin is capable of combining with 1.34 ml of oxygen. Therefore, in a normal man a maximum of about 20 milliliters of oxygen can be carried in combination with hemoglobin in each 100 milliliters of blood, and in a normal woman 19 milliliters of oxygen can be carried.

Production of Red Blood Cells

Areas of the Body That Produce Red Blood Cells

In the early weeks of embryonic life, primitive, nucleated red blood cells are produced in the yolk sac. During the middle trimester of gestation, the liver is the main organ for production of red blood cells but reasonable numbers are also produced in the spleen and lymph nodes. Then, during the last month or so of gestation and after birth, red blood cells are produced exclusively in the bone marrow.

As demonstrated in Figure 32-1, the bone marrow of essentially all bones produces red blood cells until a person is 5 years old. The marrow of the long bones, except for the proximal portions of the humeri and tibiae, becomes quite fatty and produces no more red blood cells after about age 20 years. Beyond this age, most red cells continue to be produced in the marrow of the membranous bones, such as the vertebrae, sternum, ribs, and ilia. Even in these bones, the marrow becomes less productive as age increases.


Figure 32-1 Relative rates of red blood cell production in the bone marrow of different bones at different ages.

Genesis of Blood Cells

Pluripotential Hematopoietic Stem Cells, Growth Inducers, and Differentiation Inducers

The blood cells begin their lives in the bone marrow from a single type of cell called the pluripotential hematopoietic stem cell, from which all the cells of the circulating blood are eventually derived. Figure 32-2 shows the successive divisions of the pluripotential cells to form the different circulating blood cells. As these cells reproduce, a small portion of them remains exactly like the original pluripotential cells and is retained in the bone marrow to maintain a supply of these, although their numbers diminish with age. Most of the reproduced cells, however, differentiate to form the other cell types shown to the right in Figure 32-2. The intermediate-stage cells are very much like the pluripotential stem cells, even though they have already become committed to a particular line of cells and are called committed stem cells.


Figure 32-2 Formation of the multiple different blood cells from the original pluripotent hematopoietic stem cell (PHSC) in the bone marrow.

The different committed stem cells, when grown in culture, will produce colonies of specific types of blood cells. A committed stem cell that produces erythrocytes is called a colony-forming unit-erythrocyte,and the abbreviation CFU-E is used to designate this type of stem cell. Likewise, colony-forming units that form granulocytes and monocytes have the designation CFU-GM and so forth.

Growth and reproduction of the different stem cells are controlled by multiple proteins called growth inducers. Four major growth inducers have been described, each having different characteristics. One of these, interleukin-3,promotes growth and reproduction of virtually all the different types of committed stem cells, whereas the others induce growth of only specific types of cells.

The growth inducers promote growth but not differentiation of the cells. This is the function of another set of proteins called differentiation inducers. Each of these causes one type of committed stem cell to differentiate one or more steps toward a final adult blood cell.

Formation of the growth inducers and differentiation inducers is itself controlled by factors outside the bone marrow. For instance, in the case of erythrocytes (red blood cells), exposure of the blood to low oxygen for a long time causes growth induction, differentiation, and production of greatly increased numbers of erythrocytes, as discussed later in the chapter. In the case of some of the white blood cells, infectious diseases cause growth, differentiation, and eventual formation of specific types of white blood cells that are needed to combat each infection.

Stages of Differentiation of Red Blood Cells

The first cell that can be identified as belonging to the red blood cell series is the proerythroblast, shown at the starting point in Figure 32-3. Under appropriate stimulation, large numbers of these cells are formed from the CFU-E stem cells.

Once the proerythroblast has been formed, it divides multiple times, eventually forming many mature red blood cells. The first-generation cells are called basophil erythroblasts because they stain with basic dyes; the cell at this time has accumulated very little hemoglobin. In the succeeding generations, as shown in Figure 32-3, the cells become filled with hemoglobin to a concentration of about 34 percent, the nucleus condenses to a small size, and its final remnant is absorbed or extruded from the cell. At the same time, the endoplasmic reticulum is also reabsorbed. The cell at this stage is called a reticulocytebecause it still contains a small amount of basophilic material, consisting of remnants of the Golgi apparatus, mitochondria, and a few other cytoplasmic organelles. During this reticulocyte stage, the cells pass from the bone marrow into the blood capillaries by diapedesis (squeezing through the pores of the capillary membrane).

The remaining basophilic material in the reticulocyte normally disappears within 1 to 2 days, and the cell is then a mature erythrocyte. Because of the short life of the reticulocytes, their concentration among all the red cells of the blood is normally slightly less than 1 percent.

Regulation of Red Blood Cell Production—Role of Erythropoietin

The total mass of red blood cells in the circulatory system is regulated within narrow limits, so (1) adequate red cells are always available to provide sufficient transport of oxygen from the lungs to the tissues, yet (2) the cells do not become so numerous that they impede blood flow. This control mechanism is diagrammed in Figure 32-4 and is as follows.


Figure 32-4 Function of the erythropoietin mechanism to increase production of red blood cells when tissue oxygenation decreases.

Tissue Oxygenation Is the Most Essential Regulator of Red Blood Cell Production

Any condition that causes the quantity of oxygen transported to the tissues to decrease ordinarily increases the rate of red blood cell production. Thus, when a person becomes extremely anemic as a result of hemorrhage or any other condition, the bone marrow begins to produce large quantities of red blood cells. Also, destruction of major portions of the bone marrow by any means, especially by x-ray therapy, causes hyperplasia of the remaining bone marrow, thereby attempting to supply the demand for red blood cells in the body.

At very high altitudes, where the quantity of oxygen in the air is greatly decreased, insufficient oxygen is transported to the tissues and red cell production is greatly increased. In this case, it is not the concentration of red blood cells in the blood that controls red cell production but the amount of oxygen transported to the tissues in relation to tissue demand for oxygen.

Various diseases of the circulation that cause decreased tissue blood flow, and particularly those that cause failure of oxygen absorption by the blood as it passes through the lungs, 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 glycoprotein with a molecular weight of about 34,000. In the absence of erythropoietin, hypoxia has little or no effect to stimulate 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

Normally, about 90 percent 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. Some studies suggest that erythropoietin is secreted mainly by fibroblast-like interstitial cells surrounding the tubules in the cortex and outer medulla secrete, where much of the kidney’s oxygen consumption occurs. It is likely that other cells, including the renal epithelial cells themselves, also secrete the erythropoietin in response to hypoxia.

Renal tissue hypoxia leads to increased tissue levels of hypoxia-inducible factor-1 (HIF-1), which serves as a transcription factor for a large number of hypoxia-inducible genes, including the erythropoietin gene. HIF-1 binds to a hypoxia response element residing in the erythropoietin gene, inducing transcription of mRNA and, ultimately, increased erythropoietin synthesis.

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 percent 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 from 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 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 B12 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 erythroblastic 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 mucosathat 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, decreases 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 and then released slowly as needed by the bone marrow. The minimum amount of vitamin B12required 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.

Formation of Hemoglobin

Synthesis of hemoglobin begins in the proerythroblasts and continues even into the reticulocyte stage of the red blood cells. Therefore, when reticulocytes leave the bone marrow and pass into the blood stream, they continue to form minute quantities of hemoglobin for another day or so until they become mature erythrocytes.

Figure 32-5 shows the basic chemical steps in the formation of hemoglobin. First, succinyl-CoA, formed in the Krebs metabolic cycle (as explained in Chapter 67), binds with glycine to form a pyrrole molecule. In turn, four pyrroles combine to form protoporphyrin IX, which then combines with iron to form the heme molecule. Finally, each heme molecule combines with a long polypeptide chain, a globinsynthesized by ribosomes, forming a subunit of hemoglobin called a hemoglobin chain (Figure 32-6). Each chain has a molecular weight of about 16,000; four of these in turn bind together loosely to form the whole hemoglobin molecule.


Figure 32-5 Formation of hemoglobin.


Figure 32-6 Basic structure of the hemoglobin molecule, showing one of the four heme chains that bind together to form the hemoglobin molecule.

There are several slight variations in the different subunit hemoglobin chains, depending on the amino acid composition of the polypeptide portion. The different types of chains are designated alpha chains, beta chains, gamma chains, and delta chains. The most common form of hemoglobin in the adult human being, hemoglobin A, is a combination of two alpha chains and two beta chains. Hemoglobin A has a molecular weight of 64,458.

Because each hemoglobin chain has a heme prosthetic group containing an atom of iron, and because there are four hemoglobin chains in each hemoglobin molecule, one finds four iron atoms in each hemoglobin molecule; each of these can bind loosely with one molecule of oxygen, making a total of four molecules of oxygen (or eight oxygen atoms) that can be transported by each hemoglobin molecule.

The types of hemoglobin chains in the hemoglobin molecule determine the binding affinity of the hemoglobin for oxygen. Abnormalities of the chains can alter the physical characteristics of the hemoglobin molecule as well. For instance, in sickle cell anemia, the amino acid valine is substituted for glutamic acid at one point in each of the two beta chains. When this type of hemoglobin is exposed to low oxygen, it forms elongated crystals inside the red blood cells that are sometimes 15 micrometers in length. These make it almost impossible for the cells to pass through many small capillaries, and the spiked ends of the crystals are likely to rupture the cell membranes, leading to sickle cell anemia.

Combination of Hemoglobin with Oxygen

The most important feature of the hemoglobin molecule is its ability to combine loosely and reversibly with oxygen. This ability is discussed in detail in Chapter 40 in relation to respiration because the primary function of hemoglobin in the body is to combine with oxygen in the lungs and then to release this oxygen readily in the peripheral tissue capillaries, where the gaseous tension of oxygen is much lower than in the lungs.

Oxygen does not combine with the two positive bonds of the iron in the hemoglobin molecule. Instead, it binds loosely with one of the so-called coordination bonds of the iron atom. This is an extremely loose bond, so the combination is easily reversible. Furthermore, the oxygen does not become ionic oxygen but is carried as molecular oxygen (composed of two oxygen atoms) to the tissues, where, because of the loose, readily reversible combination, it is released into the tissue fluids still in the form of molecular oxygen rather than ionic oxygen.

Iron Metabolism

Because iron is important for the formation not only of hemoglobin but also of other essential elements in the body (e.g., myoglobin, cytochromes, cytochrome oxidase, peroxidase, catalase), it is important to understand the means by which iron is utilized in the body. The total quantity of iron in the body averages 4 to 5 grams, about 65 percent of which is in the form of hemoglobin. About 4 percent is in the form of myoglobin, 1 percent is in the form of the various heme compounds that promote intracellular oxidation, 0.1 percent is combined with the protein transferrin in the blood plasma, and 15 to 30 percent is stored for later use, mainly in the reticuloendothelial system and liver parenchymal cells, principally in the form of ferritin.

Transport and Storage of Iron

Transport, storage, and metabolism of iron in the body are diagrammed in Figure 32-7 and can be explained as follows: When iron is absorbed from the small intestine, it immediately combines in the blood plasma with a beta globulin, apotransferrin, to form transferrin, which is then transported in the plasma. The iron is loosely bound in the transferrin and, consequently, can be released to any tissue cell at any point in the body. Excess iron in the blood is deposited especially in the liver hepatocytes and less in the reticuloendothelial cells of the bone marrow.


Figure 32-7 Iron transport and metabolism.

In the cell cytoplasm, iron combines mainly with a protein, apoferritin, to form ferritin. Apoferritin has a molecular weight of about 460,000, and varying quantities of iron can combine in clusters of iron radicals with this large molecule; therefore, ferritin may contain only a small amount of iron or a large amount. This iron stored as ferritin is called storage iron.

Smaller quantities of the iron in the storage pool are in an extremely insoluble form called hemosiderin. This is especially true when the total quantity of iron in the body is more than the apoferritin storage pool can accommodate. Hemosiderin collects in cells in the form of large clusters that can be observed microscopically as large particles. In contrast, ferritin particles are so small and dispersed that they usually can be seen in the cell cytoplasm only with the electron microscope.

When the quantity of iron in the plasma falls low, some of the iron in the ferritin storage pool is removed easily and transported in the form of transferrin in the plasma to the areas of the body where it is needed. A unique characteristic of the transferrin molecule is that it binds strongly with receptors in the cell membranes of erythroblasts in the bone marrow. Then, along with its bound iron, it is ingested into the erythroblasts by endocytosis. There the transferrin delivers the iron directly to the mitochondria, where heme is synthesized. In people who do not have adequate quantities of transferrin in their blood, failure to transport iron to the erythroblasts in this manner can cause severe hypochromic anemia (i.e., red cells that contain much less hemoglobin than normal).

When red blood cells have lived their life span of about 120 days and are destroyed, the hemoglobin released from the cells is ingested by monocyte-macrophage cells. There, iron is liberated and is stored mainly in the ferritin pool to be used as needed for the formation of new hemoglobin.

Daily Loss of Iron

A man excretes about 0.6 mg of iron each day, mainly into the feces. Additional quantities of iron are lost when bleeding occurs. For a woman, additional menstrual loss of blood brings long-term iron loss to an average of about 1.3 mg/day.

Absorption of Iron from the Intestinal Tract

Iron is absorbed from all parts of the small intestine, mostly by the following mechanism. The liver secretes moderate amounts of apotransferrin into the bile, which flows through the bile duct into the duodenum. Here, the apotransferrin binds with free iron and also with certain iron compounds, such as hemoglobin and myoglobin from meat, two of the most important sources of iron in the diet. This combination is called transferrin. It, in turn, is attracted to and binds with receptors in the membranes of the intestinal epithelial cells. Then, by pinocytosis, the transferrin molecule, carrying its iron store, is absorbed into the epithelial cells and later released into the blood capillaries beneath these cells in the form of plasma transferrin.

Iron absorption from the intestines is extremely slow, at a maximum rate of only a few milligrams per day. This means that even when tremendous quantities of iron are present in the food, only small proportions can be absorbed.

Regulation of Total Body Iron by Controlling Rate of Absorption

When the body has become saturated with iron so that essentially all apoferritin in the iron storage areas is already combined with iron, the rate of additional iron absorption from the intestinal tract becomes greatly decreased. Conversely, when the iron stores have become depleted, the rate of absorption can accelerate probably five or more times normal. Thus, total body iron is regulated mainly by altering the rate of absorption.

Life Span of Red Blood Cells is About 120 Days

When red blood cells are delivered from the bone marrow into the circulatory system, they normally circulate an average of 120 days before being destroyed. Even though mature red cells do not have a nucleus, mitochondria, or endoplasmic reticulum, they do have cytoplasmic enzymes that are capable of metabolizing glucose and forming small amounts of ATP. These enzymes also (1) maintain pliability of the cell membrane, (2) maintain membrane transport of ions, (3) keep the iron of the cells’ hemoglobin in the ferrous form rather than ferric form, and (4) prevent oxidation of the proteins in the red cells. Even so, the metabolic systems of old red cells become progressively less active and the cells become more and more fragile, presumably because their life processes wear out.

Once the red cell membrane becomes fragile, the cell ruptures during passage through some tight spot of the circulation. Many of the red cells self-destruct in the spleen, where they squeeze through the red pulp of the spleen. There, the spaces between the structural trabeculae of the red pulp, through which most of the cells must pass, are only 3 micrometers wide, in comparison with the 8-micrometer diameter of the red cell. When the spleen is removed, the number of old abnormal red cells circulating in the blood increases considerably.

Destruction of Hemoglobin

When red blood cells burst and release their hemoglobin, the hemoglobin is phagocytized almost immediately by macrophages in many parts of the body, but especially by the Kupffer cells of the liver and macrophages of the spleen and bone marrow. During the next few hours to days, the macrophages release iron from the hemoglobin and pass it back into the blood, to be carried by transferrin either to the bone marrow for the production of new red blood cells or to the liver and other tissues for storage in the form of ferritin. The porphyrin portion of the hemoglobin molecule is converted by the macrophages, through a series of stages, into the bile pigment bilirubin, which is released into the blood and later removed from the body by secretion through the liver into the bile; this is discussed in relation to liver function in Chapter 70.


Anemia means deficiency of hemoglobin in the blood, which can be caused by either too few red blood cells or too little hemoglobin in the cells. Some types of anemia and their physiologic causes are the following.

Blood Loss Anemia

After rapid hemorrhage the body replaces the fluid portion of the plasma in 1 to 3 days, but this leaves a low concentration of red blood cells. If a second hemorrhage does not occur, the red blood cell concentration usually returns to normal within 3 to 6 weeks.

In chronic blood loss a person frequently cannot absorb enough iron from the intestines to form hemoglobin as rapidly as it is lost. Red cells that are much smaller than normal and have too little hemoglobin inside them are then produced, giving rise to microcytic, hypochromic anemia, which is shown in Figure 32-3.

Aplastic Anemia

Bone marrow aplasia means lack of functioning bone marrow. For instance, a person exposed to high-dose radiation or chemotherapy for cancer treatment can damage stem cells of the bone marrow, followed in a few weeks by anemia. Likewise, high doses of certain toxic chemicals, such as insecticides or benzene in gasoline, may cause the same effect. In autoimmune disorders, such as lupus erythematosus, the immune system begins attacking healthy cells such as bone marrow stem cells, which may lead to aplastic anemia. In about half of aplastic anemia cases the cause is unknown, a condition called idiopathic aplastic anemia.

People with severe aplastic anemia usually die unless treated with blood transfusions, which can temporarily increase the numbers of red blood cells, or by bone marrow transplantation.

Megaloblastic Anemia

Based on the earlier discussions of vitamin B12, folic acid, and intrinsic factor from the stomach mucosa, one can readily understand that loss of any one of these can lead to slow reproduction of erythroblasts in the bone marrow. As a result, the red cells grow too large, with odd shapes, and are called megaloblasts. Thus, atrophy of the stomach mucosa, as occurs in pernicious anemia, or loss of the entire stomach after surgical total gastrectomy can lead to megaloblastic anemia. Also, patients who have intestinal sprue, in which folic acid, vitamin B12, and other vitamin B compounds are poorly absorbed, often develop megaloblastic anemia. Because in these states the erythroblasts cannot proliferate rapidly enough to form normal numbers of red blood cells, those red cells that are formed are mostly oversized, have bizarre shapes, and have fragile membranes. These cells rupture easily, leaving the person in dire need of an adequate number of red cells.

Hemolytic Anemia

Different abnormalities of the red blood cells, many of which are hereditarily acquired, make the cells fragile, so they rupture easily as they go through the capillaries, especially through the spleen. Even though the number of red blood cells formed may be normal, or even much greater than normal in some hemolytic diseases, the life span of the fragile red cell is so short that the cells are destroyed faster than they can be formed and serious anemia results.

In hereditary spherocytosis, the red cells are very small and spherical rather than being biconcave discs. These cells cannot withstand compression forces because they do not have the normal loose, baglike cell membrane structure of the biconcave discs. On passing through the splenic pulp and some other tight vascular beds, they are easily ruptured by even slight compression.

In sickle cell anemia, which is present in 0.3 to 1.0 percent of West African and American blacks, the cells have an abnormal type of hemoglobin called hemoglobin S, containing faulty beta chains in the hemoglobin molecule, as explained earlier in the chapter. When this hemoglobin is exposed to low concentrations of oxygen, it precipitates into long crystals inside the red blood cell. These crystals elongate the cell and give it the appearance of a sickle rather than a biconcave disc. The precipitated hemoglobin also damages the cell membrane, so the cells become highly fragile, leading to serious anemia. Such patients frequently experience a vicious circle of events called a sickle cell disease “crisis,” in which low oxygen tension in the tissues causes sickling, which leads to ruptured red cells, which causes a further decrease in oxygen tension and still more sickling and red cell destruction. Once the process starts, it progresses rapidly, eventuating in a serious decrease in red blood cells within a few hours and, in some cases, death.

In erythroblastosis fetalis, Rh-positive red blood cells in the fetus are attacked by antibodies from an Rh-negative mother. These antibodies make the Rh-positive cells fragile, leading to rapid rupture and causing the child to be born with serious anemia. This is discussed in Chapter 35 in relation to the Rh factor of blood. The extremely rapid formation of new red cells to make up for the destroyed cells in erythroblastosis fetalis causes a large number of early blast forms of red cells to be released from the bone marrow into the blood.

Effects of Anemia on Function of the Circulatory System

The viscosity of the blood, which was discussed in Chapter 14, depends largely on the blood concentration of red blood cells. In severe anemia, the blood viscosity may fall to as low as 1.5 times that of water rather than the normal value of about 3. This decreases the resistance to blood flow in the peripheral blood vessels, so far greater than normal quantities of blood flow through the tissues and return to the heart, thereby greatly increasing cardiac output. Moreover, hypoxia resulting from diminished transport of oxygen by the blood causes the peripheral tissue blood vessels to dilate, allowing a further increase in the return of blood to the heart and increasing the cardiac output to a still higher level—sometimes three to four times normal. Thus, one of the major effects of anemia is greatly increased cardiac output, as well as increased pumping workload on the heart.

The increased cardiac output in anemia partially offsets the reduced oxygen-carrying effect of the anemia because even though each unit quantity of blood carries only small quantities of oxygen, the rate of blood flow may be increased enough that almost normal quantities of oxygen are actually delivered to the tissues. However, when a person with anemia begins to exercise, the heart is not capable of pumping much greater quantities of blood than it is already pumping. Consequently, during exercise, which greatly increases tissue demand for oxygen, extreme tissue hypoxia results and acute cardiac failure may ensue.


Secondary Polycythemia

Whenever the tissues become hypoxic because of too little oxygen in the breathed air, such as at high altitudes, or because of failure of oxygen delivery to the tissues, such as in cardiac failure, the blood-forming organs automatically produce large quantities of extra red blood cells. This condition is called secondary polycythemia, and the red cell count commonly rises to 6 to 7 million/mm3, about 30 percent above normal.

A common type of secondary polycythemia, called physiologic polycythemia, occurs in natives who live at altitudes of 14,000 to 17,000 feet, where the atmospheric oxygen is very low. The blood count is generally 6 to 7 million/mm3; this allows these people to perform reasonably high levels of continuous work even in a rarefied atmosphere.

Polycythemia Vera (Erythremia)

In addition to those people who have physiologic polycythemia, others have a pathological condition known as polycythemia vera, in which the red blood cell count may be 7 to 8 million/mm3 and the hematocrit may be 60 to 70 percent instead of the normal 40 to 45 percent. Polycythemia vera is caused by a genetic aberration in the hemocytoblastic cells that produce the blood cells. The blast cells no longer stop producing red cells when too many cells are already present. This causes excess production of red blood cells in the same manner that a breast tumor causes excess production of a specific type of breast cell. It usually causes excess production of white blood cells and platelets as well.

In polycythemia vera, not only does the hematocrit increase, but the total blood volume also increases, on some occasions to almost twice normal. As a result, the entire vascular system becomes intensely engorged. Also, many blood capillaries become plugged by the viscous blood; the viscosity of the blood in polycythemia vera sometimes increases from the normal of 3 times the viscosity of water to 10 times that of water.

Effect of Polycythemia on Function of the Circulatory System

Because of the greatly increased viscosity of the blood in polycythemia, blood flow through the peripheral blood vessels is often very sluggish. In accordance with the factors that regulate return of blood to the heart, as discussed in Chapter 20, increasing blood viscosity decreases the rate of venous return to the heart. Conversely, the blood volume is greatly increased in polycythemia, which tends to increase venous return. Actually, the cardiac output in polycythemia is not far from normal because these two factors more or less neutralize each other.

The arterial pressure is also normal in most people with polycythemia, although in about one third of them, the arterial pressure is elevated. This means that the blood pressure–regulating mechanisms can usually offset the tendency for increased blood viscosity to increase peripheral resistance and, thereby, increase arterial pressure. Beyond certain limits, however, these regulations fail and hypertension develops.

The color of the skin depends to a great extent on the quantity of blood in the skin subpapillary venous plexus. In polycythemia vera, the quantity of blood in this plexus is greatly increased. Further, because the blood passes sluggishly through the skin capillaries before entering the venous plexus, a larger than normal quantity of hemoglobin is deoxygenated. The blue color of all this deoxygenated hemoglobin masks the red color of the oxygenated hemoglobin. Therefore, a person with polycythemia vera ordinarily has a ruddy complexion with a bluish (cyanotic) tint to the skin.


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