Chapter 33 PDF: Blood Cells and Their Functions

In 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 (RBCs), which are the most abundant cells of the blood and are necessary for the delivery of oxygen to the tissues. RED BLOOD CELLS (ERYTHRO...

In 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 (RBCs), 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 RBCs, also known as erythrocytes, is to transport hemoglobin, which, in turn, carries oxygen from the lungs to the tissues. In some animals, including many invertebrates, hemoglobin circulates as free protein in the circulatory fluids and is not enclosed in RBCs. When it is free in human plasma, about 3% 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. Terefore, hemoglobin must remain inside RBCs to perform its functions in humans effectively. Te RBCs have other functions besides transport of hemoglobin. For example, 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. Te 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 (HCO3 −) from the tissues to the lungs, where it is reconverted to CO2 and expelled into the atmosphere as a body waste product. Te hemoglobin in the cells is an excellent acid-base buffer (as is true of most proteins), so the RBCs are responsible for most of the acid-base buffering power of whole blood. Shape and Size of Red Blood Cells. Normal RBCs, shown in Figure 33-3, 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. Te average volume of the RBC is 90 to 95 cubic micrometers. Te shapes of RBCs can change remarkably as the cells squeeze through capillaries. Actually, the RBC resembles 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 RBCs per cubic millimeter is 5,200,000 (±300,000); in healthy women, it is 4,700,000 (±300,000). Persons living at high altitudes have greater numbers of RBCs, as discussed later. Quantity of Hemoglobin in the Cells. RBCs can concentrate hemoglobin in the cell fluid up to about 34 g/100 ml of cells. Te 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 RBC may also decrease because of diminished hemoglobin to fill the cell. When the hematocrit (the percentage of blood that is comprised of cells—normally, 40% to 45%) and the quantity of hemoglobin in each respective cell are normal, the whole blood of men contains an average of 15 g hemoglobin/100 ml; for women, it contains an average of 14 g hemoglobin/100 ml. As discussed in connection with blood transport of oxygen in Chapter 41, each gram of hemoglobin can combine with 1.34 ml of oxygen if the hemoglobin is 100% saturated. Terefore, in the average man, a maximum of about 20 milliliters of oxygen can be carried in combination with hemoglobin in each 100 milliliters of blood, and in 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 RBCs are produced in the yolk sac. During the middle trimester of gestation, the liver is the main organ for RBC production but reasonable numbers are also produced in the spleen and lymph nodes. Ten, during the last month or so of gestation and after birth, RBCs are produced exclusively in the bone marrow. As illustrated in Figure 33-1, the marrow of essentially all bones produces RBCs until a person is about 5 years old. Te marrow of the long bones, except for the proximal portions of the humeri and tibiae, becomes fatty and produces no more RBCs after about the age of 20 years. Beyond this age, most RBCs 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. Genesis of Blood Cells Multipotential Hematopoietic Stem Cells, Growth Inducers, and Differentiation Inducers. Te blood cells begin their lives in the bone marrow from a single type of cell called the multipotential hematopoietic stem cell, from which all the cells of the circulating blood are eventually derived. Figure 33-2 shows the successive divisions of the multipotential cells to form the different circulating blood cells. As these cells reproduce, a small portion of them remains exactly like the original multipotential cells and is retained in the bone marrow to maintain their supply, although their numbers diminish with age. Most of the reproduced cells, however, differentiate to form the other cell types, shown at the right in Figure 33-2. Te intermediatestage cells are very much like the multipotential stem cells, even though they have already become committed to a particular line of cells; these are called committed stem cells. Te 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 At least 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. Te growth inducers promote growth but not differentiation of the cells, which is the function of another set of proteins called differentiation inducers. Each of these differentiation inducers 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 controlled by factors outside the bone marrow. For example, in the case of RBCs, exposure of the blood to a low oxygen level for a long time causes growth induction, differentiation, and production of greatly increased numbers of RBCs, as discussed later in this 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 Te first cell that can be identified as belonging to the RBC series is the proerythroblast, shown at the starting point in Figure 33-3. 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 RBCs. Te first-generation cells are called basophil erythroblasts because they stain with basic dyes. Hemoglobin first appears in polychromatophil erythroblasts. In the succeeding generations, as shown in Figure 33-3, the cells become filled with hemoglobin to a concentration of about 34%, 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. Te cell at this stage is called a reticulocyte because 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). Te 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 RBCs is normally slightly less than 1%. Erythropoietin Regulates Red Blood Cell Production Te total mass of RBCs in the circulatory system is regulated within narrow limits, and thus (1) an adequate number of RBCs 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. Tis control mechanism is diagrammed in Figure 33-4 and is described in the following sections Tissue Oxygenation—Essential Regulator of Red Blood Cell Production. Conditions that decrease the quantity of oxygen transported to the tissues ordinarily increase the rate of RBC production. Tus, when a person becomes extremely anemic as a result of hemorrhage or any other condition, the bone marrow begins to produce large quantities of RBCs. Also, destruction of major portions of the bone marrow, especially by x-ray therapy, causes hyperplasia of the remaining bone marrow in an attempt to supply the body’s need for RBCs. At very high altitudes, where the quantity of oxygen in the air is greatly decreased, insufficient oxygen is transported to the tissues, and RBC production is greatly increased. In this case, it is not the concentration of RBCs in the blood that controls RBC production but the amount of oxygen transported to the tissues in relation to tissue demand for oxygen. Various diseases of the circulation that decrease tissue blood flow, particularly those that cause failure of oxygen absorption by the blood as it passes through the lungs, can also increase the rate of RBC production. Tis result is especially apparent in prolonged cardiac failure and in many lung diseases because the tissue hypoxia resulting from these conditions increases RBC production, with a resultant increase in hematocrit and, usually, total blood volume. Hypoxia Increases Formation of Erythropoietin Which Stimulates Red Blood Cell Production. Te principal stimulus for RBC production in a low oxygen state 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 RBC production. However, when the erythropoietin system is functional, hypoxia causes a marked increase in erythropoietin production and the erythropoietin, in turn, enhances RBC production until the hypoxia is relieved. Erythropoietin Is Formed Mainly in the Kidneys. Normally, about 90% of all erythropoietin is formed in the kidneys, and the remainder is formed mainly in the liver. It is not known exactly where in the kidneys the erythropoietin is formed. Some studies have suggested that erythropoietin is secreted mainly by fibroblast-like interstitial cells surrounding the tubules in the cortex and outer medulla, where much of the kidney’s oxygen consumption occurs. It is likely that other cells, including the renal epithelial cells, also secrete 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 hypoxiainducible genes, including the erythropoietin gene. HIF-1 binds to a hypoxia response element in the erythropoietin gene, inducing transcription of messenger RNA 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, 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. Tis is because the 10% of the normal erythropoietin formed in other tissues (mainly in the liver) is sufficient to cause only one third to half the RBC formation needed by the body. Erythropoietin Stimulates Production of Proerythroblasts From Hematopoietic Stem Cells. When an animal or 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 RBCs appear in the circulating blood until about 5 days later. From this, as well as from other studies, it has been determined that the important effect of erythropoietin is to stimulate 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 RBCs. Te rapid production of cells continues as long as the person remains in a low oxygen state or until enough RBCs have been produced to carry adequate amounts of oxygen to the tissues despite the low level of oxygen; at this time, the rate of erythropoietin production decreases to a level that will maintain the required number of RBCs but not an excess In the absence of erythropoietin, few RBCs are formed by the bone marrow. At the other extreme, when large quantities of erythropoietin are formed, and if plenty of iron and other required nutrients are available, the rate of RBC production can rise to perhaps 10 or more times normal. Terefore, the erythropoietin mechanism for controlling RBC production is a powerful one. Maturation of Red Blood Cells Requires Vitamin B12 (Cyanocobalamin) and Folic Acid Because of the continuing need to replenish RBCs, the erythropoietic cells of the bone marrow are among the most rapidly growing and reproducing cells in the entire body. Terefore, 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 RBCs are two vitamins, vitamin B12 and folic acid. Both these vitamins are essential for synthesis of DNA because each, in a different way, is required for formation of thymidine triphosphate, one of the essential building blocks of DNA. Terefore, lack of 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 RBCs called macrocytes, which have a flimsy membrane and are often irregular, large, and oval instead of the usual biconcave disc. Tese poorly formed cells, after entering the circulating blood, are capable of carrying oxygen normally, but their fragility causes them to have a short life, half to one-third normal. Terefore, deficiency of vitamin B12 or folic acid causes maturation failure in the process of erythropoiesis. Maturation Failure Anemia Caused by Poor Absorption of Vitamin B12 From the Gastrointestinal Tract— Pernicious Anemia. A common cause of RBC maturation failure is failure to absorb vitamin B12 from the gastrointestinal tract. Tis situation often occurs in the disease pernicious anemia, in which the basic abnormality is an atrophic gastric mucosa that fails to produce normal gastric secretions. Te 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 in the following way: 1. Intrinsic factor binds tightly with the vitamin B12. In this bound state, vitamin 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. Vitamin B12 is then 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. Te minimum amount of vitamin B12 required each day to maintain normal RBC maturation is only 1 to 3 micrograms, and the normal storage in the liver and other body tissues is about 1000 times this amount. Terefore, 3 to 4 years of defective vitamin B12 absorption are usually required to cause maturation failure anemia. Maturation Failure Anemia Caused by Folic Acid (Pteroylglutamic Acid) Deficiency. 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. Terefore, in many cases of maturation failure, the cause is deficiency of intestinal absorption of folic acid and vitamin B12. HEMOGLOBIN FORMATION Te synthesis of hemoglobin begins in polychromatophil erythroblasts and continues even into the reticulocyte stage of the RBCs. Terefore, 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 33-5 shows the basic chemical steps in the formation of hemoglobin. First, succinyl-CoA, which is formed in the Krebs metabolic cycle (as explained in Chapter 68), 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 globin synthesized by ribosomes, forming a subunit of hemoglobin called a hemoglobin chain (Figure 33-6). Each chain has a molecular weight of about 16,000; four of these chains, in turn, bind together loosely to form the whole hemoglobin molecule. Tere are several slight variations in the different subunit hemoglobin chains, depending on the amino acid composition of the polypeptide portion. Te different types of chains are designated as alpha (α) chains, beta (β) chains, (γ) gamma chains, and (δ) delta chains. Te most common form of hemoglobin in adults, 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. Te 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 example, 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 RBCs that are sometimes 15 micrometers in length. Tese crystals 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. Hemoglobin Combines Reversibly With Oxygen. Te most important feature of the hemoglobin molecule is its ability to combine loosely and reversibly with oxygen. Tis ability is discussed in detail in Chapter 41 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. Tis bond is extremely loose, 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, and catalase), it is important to understand the means whereby iron is used in the body. The total quantity of iron in the body averages 4 to 5 grams, about 65% of which is in the form of hemoglobin. About 4% is in the form of myoglobin, 1% is in the form of the various heme compounds that promote intracellular oxidation, 0.1% is combined with the protein transferrin in the blood plasma, and 15% to 30% 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 33-7 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. Te 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. 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 or a large amount of iron. Tis 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. Tis 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 an 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. Ten, along with its bound iron, it is ingested into the erythroblasts by endocytosis. Tere 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., RBCs that contain much less hemoglobin than normal). When RBCs have lived their life span of about 120 days and are destroyed, the hemoglobin released from the cells is ingested by monocyte-macrophage cells. Tere, 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. An average 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. Te 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. Tis combination is called transferrin. In turn, it is attracted to and binds with receptors in the membranes of intestinal epithelial cells. Ten, 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. Tis slow rate of absorption 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 Absorption Rate. When the body becomes 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 markedly decreases. Conversely, when the iron stores become depleted, the rate of absorption can probably accelerate five or more times normal. Tus, total body iron is regulated mainly by altering the rate of absorption. LIFE SPAN OF RED BLOOD CELLS IS ABOUT 120 DAYS When RBCs are delivered from the bone marrow into the circulatory system, they normally circulate an average of 120 days before being destroyed. Even though mature RBCs 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 adenosine triphosphate. Tese enzymes also do the following: (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 the ferric form; and (4) prevent oxidation of the proteins in the RBCs. Even so, the metabolic systems of old RBCs become progressively less active, and the cells become more and more fragile, presumably because their life processes wear out. Once the RBC membrane becomes fragile, the cell ruptures during passage through some tight spot of the circulation. Many of the RBCs self-destruct in the spleen, where they squeeze through the red pulp of the spleen. Tere, 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 RBC. When the spleen is removed, the number of old abnormal RBCs circulating in the blood increases considerably. Destruction of Hemoglobin by Macrophages. When RBCs 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 production of new RBCs or to the liver and other tissues for storage in the form of ferritin. Te 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. Tis process is discussed in relation to liver function in Chapter 71. ANEMIAS Anemia means deficiency of hemoglobin in the blood, which can be caused by too few RBCs or too little hemoglobin in the cells. Some types of anemia and their physiological causes are described in the following sections. Blood Loss Anemia. After rapid hemorrhage, the body replaces the fluid portion of the plasma in 1 to 3 days, but this response results in a low concentration of RBCs. If a second hemorrhage does not occur, the RBC concentration usually returns to normal within 3 to 6 weeks. When chronic blood loss occurs, a person frequently cannot absorb enough iron from the intestines to form hemoglobin as rapidly as it is lost. RBCs 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 33-3. Aplastic Anemia Due to Bone Marrow Dysfunction. Bone marrow aplasia means lack of functioning bone marrow. For example, exposure 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 they are treated with blood transfusions—which can temporarily increase the numbers of RBCs—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 RBCs grow too large, with odd shapes, and are called megaloblasts. Tus, 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, megaloblastic anemia often develops in patients who have intestinal sprue, in which folic acid, vitamin B12, and other vitamin B compounds are poorly absorbed. Because the erythroblasts in these states cannot proliferate rapidly enough to form normal numbers of RBCs, the RBCs that are formed are mostly oversized, have bizarre shapes, and have fragile membranes. Tese cells rupture easily, leaving the person in dire need of an adequate number of RBCs. Hemolytic Anemia. Different abnormalities of the RBCs, many of which are acquired through hereditary, make the cells fragile, so they rupture easily as they go through the capillaries, especially through the spleen. Even though the number of RBCs formed may be normal, or even much greater than normal in some hemolytic diseases, the life span of the fragile RBC is so short that the cells are destroyed faster than they can be formed, and serious anemia results. In hereditary spherocytosis, the RBCs are very small and spherical rather than being biconcave discs. Tese 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% 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 this chapter. When this hemoglobin is exposed to low concentrations of oxygen, it precipitates into long crystals inside the RBC. Tese crystals elongate the cell and give it the appearance of a sickle rather than a biconcave disc. Te 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 RBCs, which causes a further decrease in oxygen tension and still more sickling and RBC destruction. Once the process starts, it progresses rapidly, eventuating in a serious decrease in RBCs within a few hours and, in some cases, death. In erythroblastosis fetalis, Rh-positive RBCs in the fetus are attacked by antibodies from an Rh-negative mother. Tese antibodies make the Rh-positive cells fragile, leading to rapid rupture and causing the child to be born with a serious case of anemia. Tis condition is discussed in Chapter 36 in relation to the Rh factor of blood. Te extremely rapid formation of new RBCs to make up for the destroyed cells in erythroblastosis fetalis causes a large number of early blast forms of RBCs to be released from the bone marrow into the blood. EFFECTS OF ANEMIA ON CIRCULATORY SYSTEM FUNCTION Te viscosity of the blood, which was discussed in Chapter 14, depends largely on the blood concentration of RBCs. In persons with 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. Tis change 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. Tus, one of the major effects of anemia is greatly increased cardiac output, as well as increased pumping workload on the heart. Te increased cardiac output in persons with 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. POLYCYTHEMIA 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 RBCs. Tis condition is called secondary polycythemia, and the RBC count commonly rises to 6 to 7 million/mm3, about 30% above normal. A common type of secondary polycythemia, called physiological polycythemia, occurs in those who live at altitudes of 14,000 to 17,000 feet, where the atmospheric oxygen is very low. Te blood count is generally 6 to 7 million/mm3, which allows these people to perform reasonably high levels of continuous work, even in a rarefied atmosphere. Polycythemia Vera (Erythremia). In addition to physiological polycythemia, a pathological condition known as polycythemia vera exists, in which the RBC count may be 7 to 8 million/mm3 and the hematocrit may be 60% to 70% instead of the normal 40% to 45%. Polycythemia vera is caused by a genetic aberration in the hemocytoblastic cells that produce the blood cells. Te blast cells no longer stop producing RBCs when too many cells are already present. Tis causes excess production of RBCs 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, sometimes 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 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. Te arterial pressure is also normal in most people with polycythemia, although in about one-third of them, the arterial pressure is elevated. Tis 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. Te 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. Furthermore, because blood passes sluggishly through the skin capillaries before entering the venous plexus, a larger than normal quantity of hemoglobin is deoxygenated. Te blue color of all this deoxygenated hemoglobin masks the red color of the oxygenated hemoglobin. Terefore, a person with polycythemia vera ordinarily has a ruddy complexion, with a bluish (cyanotic) tint to the skin.