Chapter 32 Red Blood Cells, Anemia, and Polycythemia PDF

CHAPTER 32 UNIT VI Red Blood Cells, Anemia, and Polycythemia With this chapter we begin a thickness of 2.5 micrometers a...

CHAPTER 32 UNIT VI Red Blood Cells, Anemia, and Polycythemia With this chapter we begin a thickness of 2.5 micrometers at the thickest point and discussing the blood cells 1 micrometer or less in the center. The average volume of and cells of the macrophage the red blood cell is 90 to 95 cubic micrometers. system and lymphatic sys- The shapes of red blood cells can change remarkably tem. We first present the as the cells squeeze through capillaries. Actually, the red functions of red blood cells, blood cell is a “bag” that can be deformed into almost any which are the most abun- shape. Furthermore, because the normal cell has a great dant cells of the blood and are necessary for the delivery excess of cell membrane for the quantity of material inside, of oxygen to the tissues. deformation does not stretch the membrane greatly and, consequently, does not rupture the cell, as would be the case with many other cells. Red Blood Cells (Erythrocytes) Concentration of Red Blood Cells in the Blood. In A major function of red blood cells, also known as eryth- healthy men, the average number of red blood cells per rocytes, is to transport hemoglobin, which in turn carries cubic millimeter is 5,200,000 (±300,000); in women, it is oxygen from the lungs to the tissues. In some lower ani- 4,700,000 (±300,000). Persons living at high altitudes have mals, hemoglobin circulates as free protein in the plasma, greater numbers of red blood cells, as discussed later. not enclosed in red blood cells. When it is free in the plasma of the human being, about 3 percent of it leaks Quantity of Hemoglobin in the Cells. Red blood through the capillary membrane into the tissue spaces or cells have the ability to concentrate hemoglobin in the cell through the glomerular membrane of the kidney into the fluid up to about 34 grams in each 100 milliliters of cells. glomerular filtrate each time the blood passes through the The concentration does not rise above this value because capillaries. Therefore, hemoglobin must remain inside this is the metabolic limit of the cell’s hemoglobin-forming red blood cells to effectively perform its functions in mechanism. Furthermore, in normal people, the percent- humans. age of hemoglobin is almost always near the maximum in The red blood cells have other functions besides trans- each cell. However, when hemoglobin formation is defi- port of hemoglobin. For instance, they contain a large cient, the percentage of hemoglobin in the cells may fall quantity of carbonic anhydrase, an enzyme that catalyzes considerably below this value and the volume of the red the reversible reaction between carbon dioxide (CO2) and cell may also decrease because of diminished hemoglobin water to form carbonic acid (H2CO3), increasing the rate to fill the cell. of this reaction several thousandfold. The rapidity of this When the hematocrit (the percentage of blood that is reaction makes it possible for the water of the blood to in cells—normally, 40 to 45 percent) and the quantity of transport enormous quantities of CO2 in the form of bicar- hemoglobin in each respective cell are normal, the whole bonate ion (HCO3−) from the tissues to the lungs, where it blood of men contains an average of 15 grams of hemo- is reconverted to CO2 and expelled into the atmosphere globin per 100 milliliters of cells; for women, it contains as a body waste product. The hemoglobin in the cells is an average of 14 grams per 100 milliliters. an excellent acid-base buffer (as is true of most proteins), As discussed in connection with blood transport of so the red blood cells are responsible for most of the acid- oxygen in Chapter 40, each gram of pure hemoglobin is base buffering power of whole blood. capable of combining with 1.34 ml of oxygen. Therefore, in a normal man a maximum of about 20 milliliters of Shape and Size of Red Blood Cells. Normal red oxygen can be carried in combination with hemoglobin blood cells, shown in Figure 32-3, are biconcave discs in each 100 milliliters of blood, and in a normal woman having a mean diameter of about 7.8 micrometers and 19 milliliters of oxygen can be carried. 413 Unit VI Blood Cells, Immunity, and Blood Coagulation Production of Red Blood Cells except for the proximal portions of the humeri and tibiae, becomes quite fatty and produces no more red blood cells Areas of the Body That Produce Red Blood Cells. after about age 20 years. Beyond this age, most red cells In the early weeks of embryonic life, primitive, nucleated continue to be produced in the marrow of the membra- red blood cells are produced in the yolk sac. During the nous bones, such as the vertebrae, sternum, ribs, and ilia. middle trimester of gestation, the liver is the main organ Even in these bones, the marrow becomes less productive for production of red blood cells but reasonable num- as age increases. bers 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 Genesis of Blood Cells bone marrow. Pluripotential Hematopoietic Stem Cells, Growth As demonstrated in Figure 32-1, the bone marrow Inducers, and Differentiation Inducers. The blood cells of essentially all bones produces red blood cells until begin their lives in the bone marrow from a single type a person is 5 years old. The marrow of the long bones, of cell called the pluripotential hematopoietic stem cell, from which all the cells of the circulating blood are even- tually derived. Figure 32-2 shows the successive divisions 100 of the pluripotential cells to form the different circulating Cellularity (percent) 75 blood cells. As these cells reproduce, a small portion of Ver tebra them remains exactly like the original pluripotential cells 50 Sternu and is retained in the bone marrow to maintain a supply Tibia m Fe of these, although their numbers diminish with age. Most mu 25 Rib (sha sh of the reproduced cells, however, differentiate to form r aft) ( ft) 0 the other cell types shown to the right in Figure 32-2. The 0 5 10 15 20 30 40 50 60 70 intermediate-stage cells are very much like the pluripo- Age (years) tential stem cells, even though they have already become Figure 32-1 Relative rates of red blood cell production in the committed to a particular line of cells and are called bone marrow of different bones at different ages. committed stem cells. Erythrocytes CFU-B CFU-E (Colony-forming (Colony-forming unit–blast) unit–erythrocytes) Granulocytes (Neutrophils) (Eosinophils) (Basophils) Monocytes PHSC CFU-S CFU-GM (Pluripotent (Colony-forming (Colony-forming unit– hematopoietic unit–spleen) granulocytes, monocytes) Macrocytes stem cell) Megakaryocytes CFU-M Platelets (Colony-forming unit– megakaryocytes) T lymphocytes PHSC LSC B lymphocytes (Lymphoid stem cell) Figure 32-2 Formation of the multiple different blood cells from the original pluripotent hematopoietic stem cell (PHSC) in the bone marrow. 414  Chapter 32 Red Blood Cells, Anemia, and Polycythemia The different committed stem cells, when grown in Stages of Differentiation of Red Blood Cells culture, will produce colonies of specific types of blood The first cell that can be identified as belonging to the red cells. A committed stem cell that produces erythrocytes blood cell series is the proerythroblast, shown at the start- is called a colony-forming unit-erythrocyte, and the abbre- ing point in Figure 32-3. Under appropriate stimulation, UNIT VI viation CFU-E is used to designate this type of stem cell. large numbers of these cells are formed from the CFU-E Likewise, colony-forming units that form granulocytes and stem cells. monocytes have the designation CFU-GM and so forth. Once the proerythroblast has been formed, it divides Growth and reproduction of the different stem cells are multiple times, eventually forming many mature red controlled by multiple proteins called growth inducers. Four blood cells. The first-generation cells are called baso- major growth inducers have been described, each having phil erythroblasts because they stain with basic dyes; the different characteristics. One of these, interleukin-3, pro- cell at this time has accumulated very little hemoglobin. motes growth and reproduction of virtually all the different In the succeeding generations, as shown in Figure 32-3, types of committed stem cells, whereas the others induce the cells become filled with hemoglobin to a concen- growth of only specific types of cells. tration of about 34 percent, the nucleus condenses to a The growth inducers promote growth but not differ- small size, and its final remnant is absorbed or extruded entiation of the cells. This is the function of another set from the cell. At the same time, the endoplasmic reticu- of proteins called differentiation inducers. Each of these lum is also reabsorbed. The cell at this stage is called a causes one type of committed stem cell to differentiate reticulocyte because it still contains a small amount of one or more steps toward a final adult blood cell. basophilic material, consisting of remnants of the Golgi Formation of the growth inducers and differentiation apparatus, mitochondria, and a few other cytoplasmic inducers is itself controlled by factors outside the bone organelles. During this reticulocyte stage, the cells pass marrow. For instance, in the case of erythrocytes (red from the bone marrow into the blood capillaries by dia- blood cells), exposure of the blood to low oxygen for a pedesis (squeezing through the pores of the capillary long time causes growth induction, differentiation, and membrane). production of greatly increased numbers of erythrocytes, The remaining basophilic material in the reticulocyte as discussed later in the chapter. In the case of some of the normally disappears within 1 to 2 days, and the cell is then white blood cells, infectious diseases cause growth, differ- a mature erythrocyte. Because of the short life of the retic- entiation, and eventual formation of specific types of white ulocytes, their concentration among all the red cells of the blood cells that are needed to combat each infection. blood is normally slightly less than 1 percent. GENESIS OF RBC Proerythroblast Basophil erythroblast Microcytic, hypochromic anemia Sickle cell anemia Polychromatophil erythroblast Orthochromatic erythroblast Reticulocyte Erythrocytes Megaloblastic anemia Erythroblastosis fetalis Figure 32-3 Genesis of normal red blood cells (RBCs) and characteristics of RBCs in different types of anemias. 415 Unit VI Blood Cells, Immunity, and Blood Coagulation Regulation of Red Blood Cell Production—Role production, with a resultant increase in hematocrit and of Erythropoietin usually total blood volume as well. Erythropoietin Stimulates Red Cell Production, and The total mass of red blood cells in the circulatory system Its Formation Increases in Response to Hypoxia. The is regulated within narrow limits, so (1) adequate red cells principal stimulus for red blood cell production in low are always available to provide sufficient transport of oxy- oxygen states is a circulating hormone called erythro- gen from the lungs to the tissues, yet (2) the cells do not poietin, a glycoprotein with a molecular weight of about become so numerous that they impede blood flow. This 34,000. In the absence of erythropoietin, hypoxia has little control mechanism is diagrammed in Figure 32-4 and is or no effect to stimulate red blood cell production. But as follows. when the erythropoietin system is functional, hypoxia Tissue Oxygenation Is the Most Essential Regulator of causes a marked increase in erythropoietin production Red Blood Cell Production. Any condition that causes the and the erythropoietin in turn enhances red blood cell quantity of oxygen transported to the tissues to decrease production until the hypoxia is relieved. ordinarily increases the rate of red blood cell production. Role of the Kidneys in Formation of Erythro- Thus, when a person becomes extremely anemic as a result poietin. Normally, about 90 percent of all erythropoietin of hemorrhage or any other condition, the bone marrow is formed in the kidneys; the remainder is formed mainly begins to produce large quantities of red blood cells. Also, in the liver. It is not known exactly where in the kidneys destruction of major portions of the bone marrow by any the erythropoietin is formed. Some studies suggest that means, especially by x-ray therapy, causes hyperplasia of erythropoietin is secreted mainly by fibroblast-like inter- the remaining bone marrow, thereby attempting to supply stitial cells surrounding the tubules in the cortex and outer the demand for red blood cells in the body. medulla secrete, where much of the kidney’s oxygen con- At very high altitudes, where the quantity of oxygen in sumption occurs. It is likely that other cells, including the the air is greatly decreased, insufficient oxygen is trans- renal epithelial cells themselves, also secrete the erythro- ported to the tissues and red cell production is greatly poietin in response to hypoxia. increased. In this case, it is not the concentration of red Renal tissue hypoxia leads to increased tissue levels blood cells in the blood that controls red cell production of hypoxia-inducible factor-1 (HIF-1), which serves as a but the amount of oxygen transported to the tissues in transcription factor for a large number of hypoxia-induc- relation to tissue demand for oxygen. ible genes, including the erythropoietin gene. HIF-1 binds Various diseases of the circulation that cause decreased to a hypoxia response element residing in the erythropoie- tissue blood flow, and particularly those that cause failure tin gene, inducing transcription of mRNA and, ultimately, of oxygen absorption by the blood as it passes through increased erythropoietin synthesis. the lungs, can also increase the rate of red cell produc- At times, hypoxia in other parts of the body, but not in tion. This is especially apparent in prolonged cardiac the kidneys, stimulates kidney erythropoietin secretion, failure and in many lung diseases because the tissue which suggests that there might be some nonrenal sensor hypoxia resulting from these conditions increases red cell that sends an additional signal to the kidneys to produce this hormone. In particular, both norepinephrine and epinephrine and several of the prostaglandins stimulate Hematopoietic Stem Cells erythropoietin production. When both kidneys are removed from a person or Kidney when the kidneys are destroyed by renal disease, the per- Proerythroblasts son invariably becomes very anemic because the 10 per- Erythropoietin cent of the normal erythropoietin formed in other tissues Red Blood Cells (mainly in the liver) is sufficient to cause only one third to Decreases one half the red blood cell formation needed by the body. Effect of Erythropoietin in Erythrogenesis. When an Tissue Oxygenation animal or a person is placed in an atmosphere of low oxy- gen, erythropoietin begins to be formed within minutes to hours, and it reaches maximum production within 24 Decreases 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 Factors that decrease oxygenation the important effect of erythropoietin is to stimulate the 1. Low blood volume production of proerythroblasts from hematopoietic stem 2. Anemia cells in the bone marrow. In addition, once the proeryth- 3. Low hemoglobin 4. Poor blood flow roblasts are formed, the erythropoietin causes these cells 5. Pulmonary disease to pass more rapidly through the different erythroblastic Figure 32-4 Function of the erythropoietin mechanism to increase stages than they normally do, further speeding up the pro- production of red blood cells when tissue oxygenation decreases. duction of new red blood cells. The rapid production of 416  Chapter 32 Red Blood Cells, Anemia, and Polycythemia cells continues as long as the person remains in a low oxy- membranes of the mucosal cells in the ileum. (3) Then, gen state or until enough red blood cells have been pro- vitamin B12 is transported into the blood during the next duced to carry adequate amounts of oxygen to the tissues few hours by the process of pinocytosis, carrying intrinsic despite the low oxygen; at this time, the rate of erythro- factor and the vitamin together through the membrane. poietin production decreases to a level that will maintain Lack of intrinsic factor, therefore, decreases availability of UNIT VI the required number of red cells but not an excess. vitamin B12 because of faulty absorption of the vitamin. In the absence of erythropoietin, few red blood cells are Once vitamin B12 has been absorbed from the gastro- formed by the bone marrow. At the other extreme, when intestinal tract, it is first stored in large quantities in the large quantities of erythropoietin are formed and if there liver and then released slowly as needed by the bone mar- is plenty of iron and other required nutrients available, row. The minimum amount of vitamin B12 required each the rate of red blood cell production can rise to perhaps day to maintain normal red cell maturation is only 1 to 3 10 or more times normal. Therefore, the erythropoietin micrograms, and the normal storage in the liver and other mechanism for controlling red blood cell production is a body tissues is about 1000 times this amount. Therefore, 3 powerful one. to 4 years of defective B12 absorption are usually required to cause maturation failure anemia. Failure of Maturation Caused by Deficiency of Folic Maturation of Red Blood Cells—Requirement for Acid (Pteroylglutamic Acid). Folic acid is a normal con- Vitamin B12 (Cyanocobalamin) and Folic Acid stituent of green vegetables, some fruits, and meats (espe- Because of the continuing need to replenish red blood cially liver). However, it is easily destroyed during cooking. cells, the erythropoietic cells of the bone marrow are Also, people with gastrointestinal absorption abnormali- among the most rapidly growing and reproducing cells ties, such as the frequently occurring small intestinal in the entire body. Therefore, as would be expected, their disease called sprue, often have serious difficulty absorb- maturation and rate of production are affected greatly by ing both folic acid and vitamin B12. Therefore, in many a person’s nutritional status. instances of maturation failure, the cause is deficiency of Especially important for final maturation of the red intestinal absorption of both folic acid and vitamin B12. blood cells are two vitamins, vitamin B12 and folic acid. Both of these are essential for the synthesis of DNA Formation of Hemoglobin because each, in a different way, is required for the for- Synthesis of hemoglobin begins in the proerythroblasts mation of thymidine triphosphate, one of the essential and continues even into the reticulocyte stage of the red building blocks of DNA. Therefore, lack of either vitamin blood cells. Therefore, when reticulocytes leave the bone B12 or folic acid causes abnormal and diminished DNA marrow and pass into the blood stream, they continue to and, consequently, failure of nuclear maturation and cell form minute quantities of hemoglobin for another day or division. Furthermore, the erythroblastic cells of the bone so until they become mature erythrocytes. marrow, in addition to failing to proliferate rapidly, pro- Figure 32-5 shows the basic chemical steps in the for- duce mainly larger than normal red cells called macro- mation of hemoglobin. First, succinyl-CoA, formed in the cytes and the cell itself has a flimsy membrane and is often Krebs metabolic cycle (as explained in Chapter 67), binds irregular, large, and oval instead of the usual biconcave with glycine to form a pyrrole molecule. In turn, four pyr- disc. These poorly formed cells, after entering the circu- roles combine to form protoporphyrin IX, which then lating blood, are capable of carrying oxygen normally, but combines with iron to form the heme molecule. Finally, their fragility causes them to have a short life, one-half to each heme molecule combines with a long polypeptide one-third normal. Therefore, it is said that deficiency of chain, a globin synthesized by ribosomes, forming a sub- either vitamin B12 or folic acid causes maturation failure unit of hemoglobin called a hemoglobin chain (Figure in the process of erythropoiesis. 32-6). Each chain has a molecular weight of about 16,000; Maturation Failure Caused by Poor Absorption of four of these in turn bind together loosely to form the Vitamin B12 from the Gastrointestinal Tract—Pernicious whole hemoglobin molecule. Anemia. A common cause of red blood cell maturation failure is failure to absorb vitamin B12 from the gastroin- testinal tract. This often occurs in the disease pernicious A P anemia, in which the basic abnormality is an atrophic gas- tric mucosa that fails to produce normal gastric secretions. C C The parietal cells of the gastric glands secrete a glycopro- tein called intrinsic factor, which combines with vitamin I. 2 succinyl-CoA + 2 glycine HC CH B12 in food and makes the B12 available for absorption by N the gut. It does this in the following way: (1) Intrinsic II. 4 pyrrole protoporphyrin IX H factor binds tightly with the vitamin B12. In this bound III. protoporphyrin IX + Fe++ heme (pyrrole) state, the B12 is protected from digestion by the gastro- IV. heme + polypeptide hemoglobin chain (a or b) V. 2 a chains + 2 b chains hemoglobin A intestinal secretions. (2) Still in the bound state, intrinsic factor binds to specific receptor sites on the brush border Figure 32-5 Formation of hemoglobin. 417 Unit VI Blood Cells, Immunity, and Blood Coagulation CH2 in the body is to combine with oxygen in the lungs and H then to release this oxygen readily in the peripheral tissue CH C CH3 capillaries, where the gaseous tension of oxygen is much A B CH CH2 lower than in the lungs. H3C O2 Oxygen does not combine with the two positive bonds N (–)N of the iron in the hemoglobin molecule. Instead, it binds HC Fe CH loosely with one of the so-called coordination bonds of the iron atom. This is an extremely loose bond, so the N(–) N combination is easily reversible. Furthermore, the oxygen H3C D C CH3 does not become ionic oxygen but is carried as molecular oxygen (composed of two oxygen atoms) to the tissues, C where, because of the loose, readily reversible combina- CH2 H CH2 tion, it is released into the tissue fluids still in the form of molecular oxygen rather than ionic oxygen. CH2 CH2 COOH COOH Iron Metabolism Because iron is important for the formation not only of Polypeptide (hemoglobin chain–a or b) hemoglobin but also of other essential elements in the Figure 32-6 Basic structure of the hemoglobin molecule, show- body (e.g., myoglobin, cytochromes, cytochrome oxidase, ing one of the four heme chains that bind together to form the peroxidase, catalase), it is important to understand the hemoglobin molecule. 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 There are several slight variations in the different sub- 4 percent is in the form of myoglobin, 1 percent is in the unit hemoglobin chains, depending on the amino acid form of the various heme compounds that promote intra- composition of the polypeptide portion. The different cellular oxidation, 0.1 percent is combined with the pro- types of chains are designated alpha chains, beta chains, tein transferrin in the blood plasma, and 15 to 30 percent gamma chains, and delta chains. The most common form is stored for later use, mainly in the reticuloendothelial of hemoglobin in the adult human being, hemoglobin A, system and liver parenchymal cells, principally in the is a combination of two alpha chains and two beta chains. form of ferritin. Hemoglobin A has a molecular weight of 64,458. Because each hemoglobin chain has a heme prosthetic Transport and Storage of Iron. Transport, storage, group containing an atom of iron, and because there and metabolism of iron in the body are diagrammed in are four hemoglobin chains in each hemoglobin mole- Figure 32-7 and can be explained as follows: When iron cule, one finds four iron atoms in each hemoglobin mol- is absorbed from the small intestine, it immediately com- ecule; each of these can bind loosely with one molecule bines in the blood plasma with a beta globulin, apotrans- of oxygen, making a total of four molecules of oxygen ferrin, to form transferrin, which is then transported in (or eight oxygen atoms) that can be transported by each the plasma. The iron is loosely bound in the transferrin hemoglobin molecule. and, consequently, can be released to any tissue cell at The types of hemoglobin chains in the hemoglobin any point in the body. Excess iron in the blood is depos- molecule determine the binding affinity of the hemoglo- ited especially in the liver hepatocytes and less in the bin for oxygen. Abnormalities of the chains can alter the reticuloendothelial cells of the bone marrow. 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 Bilirubin (excreted) Tissues of the two beta chains. When this type of hemoglobin is Ferritin Hemosiderin exposed to low oxygen, it forms elongated crystals inside Macrophages Heme the red blood cells that are sometimes 15 micrometers in Free Degrading hemoglobin Enzymes length. These make it almost impossible for the cells to iron Free iron 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 Transferrin–Fe Red Cells Plasma Combination of Hemoglobin with Oxygen. The most important feature of the hemoglobin molecule is its ability to combine loosely and reversibly with oxygen. This Blood loss–0.7 mg Fe Fe++ absorbed Fe excreted–0.6 mg ability is discussed in detail in Chapter 40 in relation to daily in menses (small intestine) daily respiration because the primary function of hemoglobin Figure 32-7 Iron transport and metabolism. 418  Chapter 32 Red Blood Cells, Anemia, and Polycythemia In the cell cytoplasm, iron combines mainly with a the blood capillaries beneath these cells in the form of protein, apoferritin, to form ferritin. Apoferritin has a plasma transferrin. molecular weight of about 460,000, and varying quanti- Iron absorption from the intestines is extremely slow, ties of iron can combine in clusters of iron radicals with at a maximum rate of only a few milligrams per day. This this large molecule; therefore, ferritin may contain only a means that even when tremendous quantities of iron UNIT VI small amount of iron or a large amount. This iron stored are present in the food, only small proportions can be as ferritin is called storage iron. absorbed. Smaller quantities of the iron in the storage pool are Regulation of Total Body Iron by Controlling Rate of in an extremely insoluble form called hemosiderin. This Absorption. When the body has become saturated with is especially true when the total quantity of iron in the iron so that essentially all apoferritin in the iron storage body is more than the apoferritin storage pool can accom- areas is already combined with iron, the rate of additional modate. Hemosiderin collects in cells in the form of large iron absorption from the intestinal tract becomes greatly clusters that can be observed microscopically as large par- decreased. Conversely, when the iron stores have become ticles. In contrast, ferritin particles are so small and dis- depleted, the rate of absorption can accelerate probably persed that they usually can be seen in the cell cytoplasm five or more times normal. Thus, total body iron is regu- only with the electron microscope. lated mainly by altering the rate of absorption. When the quantity of iron in the plasma falls low, some of the iron in the ferritin storage pool is removed Life Span of Red Blood Cells is About 120 Days easily and transported in the form of transferrin in the plasma to the areas of the body where it is needed. A When red blood cells are delivered from the bone mar- unique characteristic of the transferrin molecule is that row into the circulatory system, they normally circu- it binds strongly with receptors in the cell membranes of late an average of 120 days before being destroyed. Even erythroblasts in the bone marrow. Then, along with its though mature red cells do not have a nucleus, mitochon- bound iron, it is ingested into the erythroblasts by endo- dria, or endoplasmic reticulum, they do have cytoplas- cytosis. There the transferrin delivers the iron directly to mic enzymes that are capable of metabolizing glucose the mitochondria, where heme is synthesized. In people and forming small amounts of ATP. These enzymes also who do not have adequate quantities of transferrin in (1) maintain pliability of the cell membrane, (2) maintain their blood, failure to transport iron to the erythroblasts membrane transport of ions, (3) keep the iron of the cells’ in this manner can cause severe hypochromic anemia hemoglobin in the ferrous form rather than ferric form, (i.e., red cells that contain much less hemoglobin than and (4) prevent oxidation of the proteins in the red cells. normal). Even so, the metabolic systems of old red cells become When red blood cells have lived their life span of about progressively less active and the cells become more and 120 days and are destroyed, the hemoglobin released more fragile, presumably because their life processes from the cells is ingested by monocyte-macrophage cells. wear out. There, iron is liberated and is stored mainly in the fer- Once the red cell membrane becomes fragile, the ritin pool to be used as needed for the formation of new cell ruptures during passage through some tight spot hemoglobin. 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 tra- Daily Loss of Iron. A man excretes about 0.6 mg of beculae of the red pulp, through which most of the cells iron each day, mainly into the feces. Additional quantities must pass, are only 3 micrometers wide, in comparison of iron are lost when bleeding occurs. For a woman, addi- with the 8-micrometer diameter of the red cell. When the tional menstrual loss of blood brings long-term iron loss spleen is removed, the number of old abnormal red cells to an average of about 1.3 mg/day. circulating in the blood increases considerably. Absorption of Iron from the Intestinal Tract Destruction of Hemoglobin. When red blood cells Iron is absorbed from all parts of the small intestine, burst and release their hemoglobin, the hemoglobin is mostly by the following mechanism. The liver secretes phagocytized almost immediately by macrophages in moderate amounts of apotransferrin into the bile, which many parts of the body, but especially by the Kupffer cells flows through the bile duct into the duodenum. Here, the of the liver and macrophages of the spleen and bone mar- apotransferrin binds with free iron and also with certain row. During the next few hours to days, the macrophages iron compounds, such as hemoglobin and myoglobin release iron from the hemoglobin and pass it back into from meat, two of the most important sources of iron the blood, to be carried by transferrin either to the bone in the diet. This combination is called transferrin. It, in marrow for the production of new red blood cells or to turn, is attracted to and binds with receptors in the mem- the liver and other tissues for storage in the form of ferri- branes of the intestinal epithelial cells. Then, by pinocy- tin. The porphyrin portion of the hemoglobin molecule is tosis, the transferrin molecule, carrying its iron store, is converted by the macrophages, through a series of stages, absorbed into the epithelial cells and later released into into the bile pigment bilirubin, which is released into 419 Unit VI Blood Cells, Immunity, and Blood Coagulation the blood and later removed from the body by secretion cells rupture easily, leaving the person in dire need of an through the liver into the bile; this is discussed in relation adequate number of red cells. to liver function in Chapter 70. Hemolytic Anemia. Different abnormalities of the red blood cells, many of which are hereditarily acquired, Anemias make the cells fragile, so they rupture easily as they go through the capillaries, especially through the spleen. Anemia means deficiency of hemoglobin in the blood, Even though the number of red blood cells formed may which can be caused by either too few red blood cells or be normal, or even much greater than normal in some too little hemoglobin in the cells. Some types of anemia hemolytic diseases, the life span of the fragile red cell is so and their physiologic causes are the following. short that the cells are destroyed faster than they can be formed and serious anemia results. Blood Loss Anemia. After rapid hemorrhage the In hereditary spherocytosis, the red cells are very small body replaces the fluid portion of the plasma in 1 to 3 and spherical rather than being biconcave discs. These days, but this leaves a low concentration of red blood cells. cells cannot withstand compression forces because they If a second hemorrhage does not occur, the red blood cell do not have the normal loose, baglike cell membrane concentration usually returns to normal within 3 to 6 structure of the biconcave discs. On passing through the weeks. splenic pulp and some other tight vascular beds, they are In chronic blood loss a person frequently cannot easily ruptured by even slight compression. absorb enough iron from the intestines to form hemoglo- In sickle cell anemia, which is present in 0.3 to 1.0 per- bin as rapidly as it is lost. Red cells that are much smaller cent of West African and American blacks, the cells have than normal and have too little hemoglobin inside them an abnormal type of hemoglobin called hemoglobin S, are then produced, giving rise to microcytic, hypochromic containing faulty beta chains in the hemoglobin molecule, anemia, which is shown in Figure 32-3. as explained earlier in the chapter. When this hemoglobin is exposed to low concentrations of oxygen, it precipitates Aplastic Anemia. Bone marrow aplasia means into long crystals inside the red blood cell. These crys- lack of functioning bone marrow. For instance, a person tals elongate the cell and give it the appearance of a sickle exposed to high-dose radiation or chemotherapy for can- rather than a biconcave disc. The precipitated hemoglo- cer treatment can damage stem cells of the bone marrow, bin also damages the cell membrane, so the cells become followed in a few weeks by anemia. Likewise, high doses highly fragile, leading to serious anemia. Such patients of certain toxic chemicals, such as insecticides or benzene frequently experience a vicious circle of events called a in gasoline, may cause the same effect. In autoimmune sickle cell disease “crisis,” in which low oxygen tension in disorders, such as lupus erythematosus, the immune sys- the tissues causes sickling, which leads to ruptured red tem begins attacking healthy cells such as bone marrow cells, which causes a further decrease in oxygen tension stem cells, which may lead to aplastic anemia. In about and still more sickling and red cell destruction. Once the half of aplastic anemia cases the cause is unknown, a con- process starts, it progresses rapidly, eventuating in a seri- dition called idiopathic aplastic anemia. ous decrease in red blood cells within a few hours and, in People with severe aplastic anemia usually die unless some cases, death. treated with blood transfusions, which can temporarily In erythroblastosis fetalis, Rh-positive red blood cells in increase the numbers of red blood cells, or by bone mar- the fetus are attacked by antibodies from an Rh-negative row transplantation. mother. These antibodies make the Rh-positive cells frag- ile, leading to rapid rupture and causing the child to be Megaloblastic Anemia. Based on the earlier discus- born with serious anemia. This is discussed in Chapter 35 sions of vitamin B12, folic acid, and intrinsic factor from in relation to the Rh factor of blood. The extremely rapid the stomach mucosa, one can readily understand that formation of new red cells to make up for the destroyed loss of any one of these can lead to slow reproduction of cells in erythroblastosis fetalis causes a large number of erythroblasts in the bone marrow. As a result, the red cells early blast forms of red cells to be released from the bone grow too large, with odd shapes, and are called megalo- marrow into the blood. blasts. 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 ane- Effects of Anemia on Function mia. Also, patients who have intestinal sprue, in which of the Circulatory System folic acid, vitamin B12, and other vitamin B compounds The viscosity of the blood, which was discussed in Chapter are poorly absorbed, often develop megaloblastic anemia. 14, depends largely on the blood concentration of red Because in these states the erythroblasts cannot prolifer- blood cells. In severe anemia, the blood viscosity may fall ate rapidly enough to form normal numbers of red blood to as low as 1.5 times that of water rather than the normal cells, those red cells that are formed are mostly oversized, value of about 3. This decreases the resistance to blood have bizarre shapes, and have fragile membranes. These flow in the peripheral blood vessels, so far greater than 420  Chapter 32 Red Blood Cells, Anemia, and Polycythemia normal quantities of blood flow through the tissues and some occasions to almost twice normal. As a result, the return to the heart, thereby greatly increasing cardiac out- entire vascular system becomes intensely engorged. Also, put. Moreover, hypoxia resulting from diminished trans- many blood capillaries become plugged by the viscous port of oxygen by the blood causes the peripheral tissue blood; the viscosity of the blood in polycythemia vera blood vessels to dilate, allowing a further increase in the sometimes increases from the normal of 3 times the vis- UNIT VI return of blood to the heart and increasing the cardiac cosity of water to 10 times that of water. output to a still higher level—sometimes three to four times normal. Thus, one of the major effects of anemia Effect of Polycythemia on Function is greatly increased cardiac output, as well as increased of the Circulatory System pumping workload on the heart. Because of the greatly increased viscosity of the blood in The increased cardiac output in anemia partially off- polycythemia, blood flow through the peripheral blood sets the reduced oxygen-carrying effect of the anemia vessels is often very sluggish. In accordance with the fac- because even though each unit quantity of blood carries tors that regulate return of blood to the heart, as discussed only small quantities of oxygen, the rate of blood flow in Chapter 20, increasing blood viscosity decreases the may be increased enough that almost normal quantities rate of venous return to the heart. Conversely, the blood of oxygen are actually delivered to the tissues. However, volume is greatly increased in polycythemia, which tends when a person with anemia begins to exercise, the heart is to increase venous return. Actually, the cardiac output in not capable of pumping much greater quantities of blood polycythemia is not far from normal because these two than it is already pumping. Consequently, during exer- factors more or less neutralize each other. cise, which greatly increases tissue demand for oxygen, The arterial pressure is also normal in most people extreme tissue hypoxia results and acute cardiac failure with polycythemia, although in about one third of them, may ensue. the arterial pressure is elevated. This means that the blood pressure–regulating mechanisms can usually offset the tendency for increased blood viscosity to increase periph- Polycythemia eral resistance and, thereby, increase arterial pressure. Beyond certain limits, however, these regulations fail and Secondary Polycythemia. Whenever the tissues hypertension develops. become hypoxic because of too little oxygen in the breathed The color of the skin depends to a great extent on the air, such as at high altitudes, or because of failure of oxygen quantity of blood in the skin subpapillary venous plexus. delivery to the tissues, such as in cardiac failure, the blood- In polycythemia vera, the quantity of blood in this plexus forming organs automatically produce large quantities of is greatly increased. Further, because the blood passes extra red blood cells. This condition is called secondary sluggishly through the skin capillaries before entering the polycythemia, and the red cell count commonly rises to 6 venous plexus, a larger than normal quantity of hemoglo- to 7 million/mm3, about 30 percent above normal. bin is deoxygenated. The blue color of all this deoxygen- A common type of secondary polycythemia, called ated hemoglobin masks the red color of the oxygenated physiologic polycythemia, occurs in natives who live at hemoglobin. Therefore, a person with polycythemia vera altitudes of 14,000 to 17,000 feet, where the atmospheric ordinarily has a ruddy complexion with a bluish (cyan- oxygen is very low. The blood count is generally 6 to otic) tint to the skin. 7 million/mm3; this allows these people to perform rea- sonably high levels of continuous work even in a rarefied atmosphere. Bibliography Alayash AI: Oxygen therapeutics: can we tame haemoglobin? Nat Rev Drug Polycythemia Vera (Erythremia). In addition to Discov 3:152, 2004. those people who have physiologic polycythemia, oth- Alleyne M, Horne MK, Miller JL: Individualized treatment for iron-deficiency anemia in adults, Am J Med 121:943, 2008. ers have a pathological condition known as polycythemia Claster S, Vichinsky EP: Managing sickle cell disease, BMJ 327:1151, 2003. vera, in which the red blood cell count may be 7 to 8 mil- de Montalembert M: Management of sickle cell disease, BMJ. 337:a1397, lion/mm3 and the hematocrit may be 60 to 70 percent 2008. instead of the normal 40 to 45 percent. Polycythemia Elliott S, Pham E, Macdougall IC: Erythropoietins: a common mechanism of vera is caused by a genetic aberration in the hemocyto- action, Exp Hematol 36:1573, 2008. Fandrey J: Oxygen-dependent and tissue-specific regulation of erythropoietin blastic cells that produce the blood cells. The blast cells gene expression, Am J Physiol Regul Integr Comp Physiol 286:R977, 2004. no longer stop producing red cells when too many cells Hentze MW, Muckenthaler MU, Andrews NC: Balancing acts: molecular are already present. This causes excess production of red control of mammalian iron metabolism, Cell 117:285, 2004. blood cells in the same manner that a breast tumor causes Kato GJ, Gladwin MT: Evolution of novel small-molecule therapeutics tar- excess production of a specific type of breast cell. It usu- geting sickle cell vasculopathy, JAMA 300:2638, 2008. Lappin T: The cellular biology of erythropoietin receptors, Oncologist ally causes excess production of white blood cells and 8(Suppl 1):15, 2003. platelets as well. Maxwell P: HIF-1: an oxygen response system with special relevance to the In polycythemia vera, not only does the hematocrit kidney, J Am Soc Nephrol 14:2712, 2003. increase, but the total blood volume also increases, on Metcalf D: Hematopoietic cytokines, Blood 111:485, 2008. 421 Unit VI Blood Cells, Immunity, and Blood Coagulation Nangaku M, Eckardt KU: Hypoxia and the HIF system in kidney disease, Pietrangelo A: Hereditary hemochromatosis—a new look at an old disease, J Mol Med 85:1325, 2007. N Engl J Med 350:2383, 2004. Percy MJ, Rumi E: Genetic origins and clinical phenotype of familial and Platt OS: Hydroxyurea for the treatment of sickle cell anemia, N Engl J Med acquired erythrocytosis and thrombocytosis, Am J Hematol 84:46, 2009. 27;358:1362, 2008. 422