Chapter 33 Red Blood Cells, Anemia, and Polycythemia PDF

CHAPTER 33 Red Blood Cells, Anemia, and UNIT VI Polycythemia In this cha...

CHAPTER 33 Red Blood Cells, Anemia, and UNIT VI Polycythemia In this chapter, we begin discussing the blood cells and Furthermore, because the normal cell has a great excess of cells of the macrophage system and lymphatic system. cell membrane for the quantity of material inside, defor- We first present the functions of red blood cells (RBCs), mation does not stretch the membrane greatly and, con- which are the most abundant cells of the blood and are sequently, does not rupture the cell, as would be the case necessary for the delivery of oxygen to the tissues. with many other cells.! Concentration of Red Blood Cells in the Blood. In RED BLOOD CELLS (ERYTHROCYTES) healthy men, the average number of RBCs per cubic mil- limeter is 5,200,000 (±300,000); in healthy women, it is A major function of RBCs, also known as erythrocytes, is 4,700,000 (±300,000). Persons living at high altitudes have to transport hemoglobin, which, in turn, carries oxygen greater numbers of RBCs, as discussed later.! from the lungs to the tissues. In some animals, including many invertebrates, hemoglobin circulates as free pro- Quantity of Hemoglobin in the Cells. RBCs can con- tein in the circulatory fluids and is not enclosed in RBCs. centrate hemoglobin in the cell fluid up to about 34 When it is free in human plasma, about 3% of it leaks g/100 ml of cells. The concentration does not rise above through the capillary membrane into the tissue spaces or this value because this is the metabolic limit of the cell’s through the glomerular membrane of the kidney into the hemoglobin-forming mechanism. Furthermore, in nor- glomerular filtrate each time the blood passes through mal people, the percentage of hemoglobin is almost al- the capillaries. Therefore, hemoglobin must remain inside ways near the maximum in each cell. However, when RBCs to perform its functions in humans effectively. hemoglobin formation is deficient, the percentage of The RBCs have other functions besides transport of hemoglobin in the cells may fall considerably below this hemoglobin. For example, they contain a large quantity of value, and the volume of the RBC may also decrease be- carbonic anhydrase, an enzyme that catalyzes the revers- cause of diminished hemoglobin to fill the cell. ible reaction between carbon dioxide (CO2) and water to When the hematocrit (the percentage of blood that is form carbonic acid (H2CO3), increasing the rate of this comprised of cells—normally, 40% to 45%) and the quan- reaction several thousandfold. The rapidity of this reaction tity of hemoglobin in each respective cell are normal, the makes it possible for the water of the blood to transport whole blood of men contains an average of 15 g hemo- enormous quantities of CO2 in the form of bicarbonate globin/100 ml; for women, it contains an average of 14 g ion (HCO3−) from the tissues to the lungs, where it is hemoglobin/100 ml. reconverted to CO2 and expelled into the atmosphere as As discussed in connection with blood transport of a body waste product. The hemoglobin in the cells is an oxygen in Chapter 41, each gram of hemoglobin can com- excellent acid-base buffer (as is true of most proteins), so bine with 1.34 ml of oxygen if the hemoglobin is 100% the RBCs are responsible for most of the acid-base buffer- saturated. Therefore, in the average man, a maximum of ing power of whole blood. about 20 milliliters of oxygen can be carried in combina- tion with hemoglobin in each 100 milliliters of blood, and Shape and Size of Red Blood Cells. Normal RBCs, in woman 19 milliliters of oxygen can be carried.! shown in Figure 33-3, are biconcave discs having a mean diameter of about 7.8 micrometers and a thickness of 2.5 PRODUCTION OF RED BLOOD CELLS micrometers at the thickest point and 1 micrometer or less in the center. The average volume of the RBC is 90 to Areas of the Body That Produce Red Blood Cells. In 95 cubic micrometers. the early weeks of embryonic life, primitive nucleated The shapes of RBCs can change remarkably as the cells RBCs are produced in the yolk sac. During the middle tri- squeeze through capillaries. Actually, the RBC resem- mester of gestation, the liver is the main organ for RBC bles a bag that can be deformed into almost any shape. production but reasonable numbers are also produced in 439 UNIT VI Blood Cells, Immunity, and Blood Coagulation the spleen and lymph nodes. Then, during the last month Genesis of Blood Cells or so of gestation and after birth, RBCs are produced ex- Multipotential Hematopoietic Stem Cells, Growth In- clusively in the bone marrow. ducers, and Differentiation Inducers. The blood cells As illustrated in Figure 33-1, the marrow of essentially begin their lives in the bone marrow from a single type of all bones produces RBCs until a person is about 5 years cell called the multipotential hematopoietic stem cell, from old. The marrow of the long bones, except for the proxi- which all the cells of the circulating blood are eventually mal portions of the humeri and tibiae, becomes fatty and derived. Figure 33-2 shows the successive divisions of the produces no more RBCs after about the age of 20 years. multipotential cells to form the different circulating blood Beyond this age, most RBCs continue to be produced in cells. As these cells reproduce, a small portion of them the marrow of the membranous bones, such as the ver- remains exactly like the original multipotential cells and tebrae, sternum, ribs, and ilia. Even in these bones, the is retained in the bone marrow to maintain their supply, marrow becomes less productive as age increases.! although their numbers diminish with age. Most of the re- produced cells, however, differentiate to form the other cell types, shown at the right in Figure 33-2. The intermediate- stage cells are very much like the multipotential stem cells, 100 even though they have already become committed to a par- Cellularity (percent) 75 ticular line of cells; these are called committed stem cells. Ver tebra The different committed stem cells, when grown in cul- 50 Sternu ture, will produce colonies of specific types of blood cells. Tibia m Fe A committed stem cell that produces erythrocytes is called mu 25 Rib (sha sh a colony-forming unit–erythrocyte, and the abbreviation r aft) ( ft) 0 CFU-E is used to designate this type of stem cell. Likewise, 0 5 10 15 20 30 40 50 60 70 colony-forming units that form granulocytes and mono- Age (years) cytes have the designation CFU-GM, and so forth. Figure 33-1. Relative rates of red blood cell production in the bone Growth and reproduction of the different stem cells marrow of different bones at different ages. are controlled by multiple proteins called growth inducers. Erythrocytes CFU-B CFU-E (Colony-forming (Colony-forming unit–blast) unit–erythrocytes) Granulocytes (Neutrophils) (Eosinophils) (Basophils) Monocytes MHSC CFU-S CFU-GM (Multipotent (Colony-forming (Colony-forming unit– hematopoietic unit–spleen) granulocytes, monocytes) Macrocytes stem cell) Megakaryocytes CFU-M Platelets (Colony-forming unit– megakaryocytes) T lymphocytes Figure 33-2. Formation of the mul- MHSC LSC B lymphocytes tiple different blood cells from the (Lymphoid stem cell) original multipotent hematopoietic stem cell in the bone marrow. 440  Chapter 33 Red Blood Cells, Anemia, and Polycythemia Genesis of RBCs Proerythroblast UNIT VI Basophil erythroblast Microcytic, hypochromic anemia Sickle cell anemia Polychromatophil erythroblast Orthochromatic erythroblast Reticulocyte Erythrocytes Megaloblastic anemia Erythroblastosis fetalis Figure 33-3. Genesis of normal red blood cells (RBCs) and characteristics of RBCs in different types of anemias. At least four major growth inducers have been described, The first-generation cells are called basophil erythroblasts each having different characteristics. One of these, because they stain with basic dyes. Hemoglobin first interleukin-3, promotes growth and reproduction of appears in polychromatophil erythroblasts. In the suc- virtually all the different types of committed stem cells, ceeding generations, as shown in Figure 33-3, the cells whereas the others induce growth of only specific types become filled with hemoglobin to a concentration of of cells. about 34%, the nucleus condenses to a small size, and its The growth inducers promote growth but not differen- final remnant is absorbed or extruded from the cell. At the tiation of the cells, which is the function of another set of same time, the endoplasmic reticulum is also reabsorbed. proteins called differentiation inducers. Each of these dif- The cell at this stage is called a reticulocyte because it still ferentiation inducers causes one type of committed stem contains a small amount of basophilic material, consisting cell to differentiate one or more steps toward a final of remnants of the Golgi apparatus, mitochondria, and a adult blood cell. few other cytoplasmic organelles. During this reticulocyte Formation of the growth inducers and differentiation stage, the cells pass from the bone marrow into the blood inducers is controlled by factors outside the bone marrow. capillaries by diapedesis (squeezing through the pores of For example, in the case of RBCs, exposure of the blood the capillary membrane). to a low oxygen level for a long time causes growth induc- The remaining basophilic material in the reticulocyte tion, differentiation, and production of greatly increased normally disappears within 1 to 2 days, and the cell is numbers of RBCs, as discussed later in this chapter. In the then a mature erythrocyte. Because of the short life of the case of some of the white blood cells, infectious diseases reticulocytes, their concentration among all the RBCs is cause growth, differentiation, and eventual formation of normally slightly less than 1%.! specific types of white blood cells that are needed to com- bat each infection.! Erythropoietin Regulates Red Blood Cell Production Stages of Differentiation of Red Blood The total mass of RBCs in the circulatory system is reg- Cells ulated within narrow limits, and thus (1) an adequate The first cell that can be identified as belonging to the RBC number of RBCs are always available to provide suffi- series is the proerythroblast, shown at the starting point in cient transport of oxygen from the lungs to the tissues, Figure 33-3. Under appropriate stimulation, large num- yet (2) the cells do not become so numerous that they bers of these cells are formed from the CFU-E stem cells. impede blood flow. This control mechanism is dia- Once the proerythroblast has been formed, it divides grammed in Figure 33-4 and is described in the follow- multiple times, eventually forming many mature RBCs. ing sections. 441 UNIT VI Blood Cells, Immunity, and Blood Coagulation Hematopoietic stem cells in erythropoietin production and the erythropoietin, in Kidney turn, enhances RBC production until the hypoxia is re- lieved.! Proerythroblasts Erythropoietin Erythropoietin Is Formed Mainly in the Kidneys. Nor- Red blood cells mally, about 90% of all erythropoietin is formed in the kid- Decreases neys, and the remainder is formed mainly in the liver. It is not known exactly where in the kidneys the erythropoietin is Tissue oxygenation formed. Some studies have suggested that erythropoietin is secreted mainly by fibroblast-like interstitial cells surround- ing the tubules in the cortex and outer medulla, where much Decreases of the kidney’s oxygen consumption occurs. It is likely that other cells, including the renal epithelial cells, also secrete Factors that decrease erythropoietin in response to hypoxia. oxygenation Renal tissue hypoxia leads to increased tissue lev- 1. Low blood volume els of hypoxia-inducible factor-1 (HIF-1), which serves 2. Anemia 3. Low hemoglobin as a transcription factor for a large number of hypoxia- 4. Poor blood flow inducible genes, including the erythropoietin gene. HIF-1 5. Pulmonary disease binds to a hypoxia response element in the erythropoietin Figure 33-4. Function of the erythropoietin mechanism to increase gene, inducing transcription of messenger RNA and, ulti- production of red blood cells when tissue oxygenation decreases. mately, increased erythropoietin synthesis. At times, hypoxia in other parts of the body, but not in Tissue Oxygenation—Essential Regulator of Red the kidneys, stimulates kidney erythropoietin secretion, Blood Cell Production. Conditions that decrease the which suggests that there might be some nonrenal sensor quantity of oxygen transported to the tissues ordinarily that sends an additional signal to the kidneys to produce increase the rate of RBC production. Thus, when a per- this hormone. In particular, norepinephrine and epineph- son becomes extremely anemic as a result of hemorrhage rine and several of the prostaglandins stimulate erythro- or any other condition, the bone marrow begins to pro- poietin production. duce large quantities of RBCs. Also, destruction of major When both kidneys are removed from a person, or portions of the bone marrow, especially by x-ray therapy, when the kidneys are destroyed by renal disease, the per- causes hyperplasia of the remaining bone marrow in an son invariably becomes very anemic. This is because the attempt to supply the body’s need for RBCs. 10% of the normal erythropoietin formed in other tissues At very high altitudes, where the quantity of oxy- (mainly in the liver) is sufficient to cause only one third to gen in the air is greatly decreased, insufficient oxygen is half the RBC formation needed by the body.! transported to the tissues, and RBC production is greatly increased. In this case, it is not the concentration of Erythropoietin Stimulates Production of Proeryth- RBCs in the blood that controls RBC production but the roblasts From Hematopoietic Stem Cells. When an amount of oxygen transported to the tissues in relation to animal or person is placed in an atmosphere of low oxy- tissue demand for oxygen. gen, erythropoietin begins to be formed within minutes Various diseases of the circulation that decrease tissue to hours, and it reaches maximum production within blood flow, particularly those that cause failure of oxygen 24 hours. Yet, almost no new RBCs appear in the cir- absorption by the blood as it passes through the lungs, culating blood until about 5 days later. From this, as can also increase the rate of RBC production. This result well as from other studies, it has been determined that is especially apparent in prolonged cardiac failure and in the important effect of erythropoietin is to stimulate many lung diseases because the tissue hypoxia resulting production of proerythroblasts from hematopoietic from these conditions increases RBC production, with a stem cells in the bone marrow. In addition, once the resultant increase in hematocrit and, usually, total blood proerythroblasts are formed, the erythropoietin causes volume.! these cells to pass more rapidly through the different erythroblastic stages than they normally do, further Hypoxia Increases Formation of Erythropoietin Which speeding up the production of new RBCs. The rapid Stimulates Red Blood Cell Production. The principal production of cells continues as long as the person re- stimulus for RBC production in a low oxygen state is a mains in a low oxygen state or until enough RBCs have circulating hormone called erythropoietin, a glycoprotein been produced to carry adequate amounts of oxygen with a molecular weight of about 34,000. In the absence to the tissues despite the low level of oxygen; at this of erythropoietin, hypoxia has little or no effect to stimu- time, the rate of erythropoietin production decreases to late RBC production. However, when the erythropoietin a level that will maintain the required number of RBCs system is functional, hypoxia causes a marked increase but not an excess. 442  Chapter 33 Red Blood Cells, Anemia, and Polycythemia In the absence of erythropoietin, few RBCs are formed Lack of intrinsic factor, therefore, decreases availabil- by the bone marrow. At the other extreme, when large ity of vitamin B12 because of faulty absorption of the quantities of erythropoietin are formed, and if plenty of vitamin. iron and other required nutrients are available, the rate Once vitamin B12 has been absorbed from the gastro- of RBC production can rise to perhaps 10 or more times intestinal tract, it is first stored in large quantities in the UNIT VI normal. Therefore, the erythropoietin mechanism for liver and then released slowly as needed by the bone mar- controlling RBC production is a powerful one.! row. The minimum amount of vitamin B12 required each day to maintain normal RBC maturation is only 1 to 3 Maturation of Red Blood Cells Requires micrograms, and the normal storage in the liver and other Vitamin B12 (Cyanocobalamin) and Folic body tissues is about 1000 times this amount. Therefore, 3 Acid to 4 years of defective vitamin B12 absorption are usually Because of the continuing need to replenish RBCs, the required to cause maturation failure anemia.! erythropoietic cells of the bone marrow are among the Maturation Failure Anemia Caused by Folic Acid most rapidly growing and reproducing cells in the entire (Pteroylglutamic Acid) Deficiency. Folic acid is a normal body. Therefore, as would be expected, their maturation constituent of green vegetables, some fruits, and meats and rate of production are affected greatly by a person’s (especially liver). However, it is easily destroyed during nutritional status. cooking. Also, people with gastrointestinal absorption Especially important for final maturation of the RBCs abnormalities, such as the frequently occurring small in- are two vitamins, vitamin B12 and folic acid. Both these testinal disease called sprue, often have serious difficulty vitamins are essential for synthesis of DNA because each, absorbing both folic acid and vitamin B12. Therefore, in in a different way, is required for formation of thymi- many cases of maturation failure, the cause is deficiency dine triphosphate, one of the essential building blocks of of intestinal absorption of folic acid and vitamin B12.! DNA. Therefore, lack of vitamin B12 or folic acid causes abnormal and diminished DNA and, consequently, fail- HEMOGLOBIN FORMATION ure of nuclear maturation and cell division. Furthermore, the erythroblastic cells of the bone marrow, in addition The synthesis of hemoglobin begins in polychromatophil to failing to proliferate rapidly, produce mainly larger erythroblasts and continues even into the reticulocyte than normal RBCs called macrocytes, which have a flimsy stage of the RBCs. Therefore, when reticulocytes leave membrane and are often irregular, large, and oval instead the bone marrow and pass into the blood stream, they of the usual biconcave disc. These poorly formed cells, continue to form minute quantities of hemoglobin for after entering the circulating blood, are capable of car- another day or so until they become mature erythrocytes. rying oxygen normally, but their fragility causes them Figure 33-5 shows the basic chemical steps in the to have a short life, half to one-third normal. Therefore, formation of hemoglobin. First, succinyl-CoA, which deficiency of vitamin B12 or folic acid causes maturation is formed in the Krebs metabolic cycle (as explained in failure in the process of erythropoiesis. Chapter 68), binds with glycine to form a pyrrole mole- cule. In turn, four pyrroles combine to form protoporphy- Maturation Failure Anemia Caused by Poor Absorp- rin IX, which then combines with iron to form the heme tion of Vitamin B12 From the Gastrointestinal Tract— molecule. Finally, each heme molecule combines with Pernicious Anemia. A common cause of RBC matu- a long polypeptide chain, a globin synthesized by ribo- ration failure is failure to absorb vitamin B12 from the somes, forming a subunit of hemoglobin called a hemo- gastrointestinal tract. This situation often occurs in the globin chain (Figure 33-6). Each chain has a molecular disease pernicious anemia, in which the basic abnormality weight of about 16,000; four of these chains, in turn, bind is an atrophic gastric mucosa that fails to produce normal together loosely to form the whole hemoglobin molecule. gastric secretions. The parietal cells of the gastric glands There are several slight variations in the different sub- secrete a glycoprotein called intrinsic factor, which com- unit hemoglobin chains, depending on the amino acid bines with vitamin B12 in food and makes the B12 available for absorption by the gut in the following way: A P 1. Intrinsic factor binds tightly with the vitamin B12. In this bound state, vitamin B12 is protected from C C digestion by the gastrointestinal secretions. 2. Still in the bound state, intrinsic factor binds to spe- I. 2 succinyl-CoA + 2 glycine HC CH cific receptor sites on the brush border membranes N of the mucosal cells in the ileum. II. 4 pyrrole protoporphyrin IX H 3. Vitamin B12 is then transported into the blood dur- III. protoporphyrin IX + Fe++ heme (pyrrole) ing the next few hours by the process of pinocytosis, IV. heme + polypeptide hemoglobin chain (α or β) carrying intrinsic factor and the vitamin together V. 2 α chains + 2 β chains hemoglobin A through the membrane. Figure 33-5. Formation of hemoglobin. 443 UNIT VI Blood Cells, Immunity, and Blood Coagulation CH2 Bilirubin (excreted) Tissues H CH C CH3 Ferritin Hemosiderin A B CH CH2 Macrophages Heme H3C O2 Degrading hemoglobin Free Enzymes N (–)N iron Free iron HC Fe CH N(–) N Hemoglobin Transferrin–Fe H3C D C CH3 Red Cells Plasma C CH2 H CH2 Blood loss: 0.7 mg Fe Fe++ absorbed Fe excreted: 0.6 mg daily in menses (small intestine) daily CH2 CH2 Figure 33-7. Iron transport and metabolism. COOH COOH and then to release this oxygen readily in the peripheral Polypeptide tissue capillaries, where the gaseous tension of oxygen is (hemoglobin chain α or β) much lower than in the lungs. Figure 33-6. Basic structure of the heme moiety, showing one of the Oxygen does not combine with the two positive bonds four heme chains that along with globin polypeptide, bind together to form the hemoglobin molecule. of the iron in the hemoglobin molecule. Instead, it binds loosely with one of the so-called coordination bonds of the iron atom. This bond is extremely loose, so the com- composition of the polypeptide portion. The different bination is easily reversible. Furthermore, the oxygen types of chains are designated as alpha (α) chains, beta (β) does not become ionic oxygen but is carried as molecular chains, (γ) gamma chains, and (δ) delta chains. The most oxygen (composed of two oxygen atoms) to the tissues, common form of hemoglobin in adults, hemoglobin A, is where, because of the loose, readily reversible combina- a combination of two alpha chains and two beta chains. tion, it is released into the tissue fluids still in the form of Hemoglobin A has a molecular weight of 64,458. molecular oxygen rather than ionic oxygen.! Because each hemoglobin chain has a heme prosthetic group containing an atom of iron, and because there are IRON METABOLISM four hemoglobin chains in each hemoglobin molecule, Because iron is important for the formation not only one finds four iron atoms in each hemoglobin molecule. of hemoglobin but also of other essential elements in Each of these can bind loosely with one molecule of oxy- the body (e.g., myoglobin, cytochromes, cytochrome gen, making a total of four molecules of oxygen (or eight oxidase, peroxidase, and catalase), it is important to oxygen atoms) that can be transported by each hemoglo- understand the means whereby iron is used in the bin molecule. body. The total quantity of iron in the body averages 4 The types of hemoglobin chains in the hemoglobin to 5 grams, about 65% of which is in the form of hemo- molecule determine the binding affinity of the hemoglo- globin. About 4% is in the form of myoglobin, 1% is in bin for oxygen. Abnormalities of the chains can alter the the form of the various heme compounds that promote physical characteristics of the hemoglobin molecule as intracellular oxidation, 0.1% is combined with the pro- well. For example, in sickle cell anemia, the amino acid tein transferrin in the blood plasma, and 15% to 30% is valine is substituted for glutamic acid at one point in each stored for later use, mainly in the reticuloendothelial of the two beta chains. When this type of hemoglobin is system and liver parenchymal cells, principally in the exposed to low oxygen, it forms elongated crystals inside form of ferritin. the RBCs that are sometimes 15 micrometers in length. These crystals make it almost impossible for the cells to Transport and Storage of Iron. Transport, storage, and pass through many small capillaries, and the spiked ends metabolism of iron in the body are diagrammed in Figure of the crystals are likely to rupture the cell membranes, 33-7 and can be explained as follows. When iron is ab- leading to sickle cell anemia. sorbed from the small intestine, it immediately combines in the blood plasma with a beta globulin, apotransferrin, Hemoglobin Combines Reversibly With Oxygen. The to form transferrin, which is then transported in the plas- most important feature of the hemoglobin molecule is ma. The iron is loosely bound in the transferrin and, con- its ability to combine loosely and reversibly with oxygen. sequently, can be released to any tissue cell at any point in This ability is discussed in detail in Chapter 41 in rela- the body. Excess iron in the blood is deposited especially tion to respiration because the primary function of hemo- in the liver hepatocytes and less in the reticuloendothelial globin in the body is to combine with oxygen in the lungs cells of the bone marrow. 444  Chapter 33 Red Blood Cells, Anemia, and Polycythemia In the cell cytoplasm, iron combines mainly with a Iron absorption from the intestines is extremely slow, protein, apoferritin, to form ferritin. Apoferritin has a at a maximum rate of only a few milligrams per day. This molecular weight of about 460,000, and varying quanti- slow rate of absorption means that even when tremen- ties of iron can combine in clusters of iron radicals with dous quantities of iron are present in the food, only small this large molecule; therefore, ferritin may contain only a proportions can be absorbed. UNIT VI small or a large amount of iron. This iron stored as ferritin is called storage iron. Regulation of Total Body Iron by Controlling Absorp- Smaller quantities of the iron in the storage pool are tion Rate. When the body becomes saturated with iron in an extremely insoluble form called hemosiderin. This so that essentially all apoferritin in the iron storage areas is especially true when the total quantity of iron in the is already combined with iron, the rate of additional iron body is more than the apoferritin storage pool can accom- absorption from the intestinal tract markedly decreases. modate. Hemosiderin collects in cells in the form of large Conversely, when the iron stores become depleted, the clusters that can be observed microscopically as large par- rate of absorption can probably accelerate five or more ticles. In contrast, ferritin particles are so small and dis- times normal. Thus, total body iron is regulated mainly by persed that they usually can be seen in the cell cytoplasm altering the rate of absorption.! only with an electron microscope. When the quantity of iron in the plasma falls low, some LIFE SPAN OF RED BLOOD CELLS IS of the iron in the ferritin storage pool is removed easily ABOUT 120 DAYS and transported in the form of transferrin in the plasma to When RBCs are delivered from the bone marrow into the areas of the body where it is needed. A unique charac- the circulatory system, they normally circulate an average teristic of the transferrin molecule is that it binds strongly of 120 days before being destroyed. Even though mature with receptors in the cell membranes of erythroblasts in RBCs do not have a nucleus, mitochondria, or endoplasmic the bone marrow. Then, along with its bound iron, it is reticulum, they do have cytoplasmic enzymes that are capa- ingested into the erythroblasts by endocytosis. There the ble of metabolizing glucose and forming small amounts of transferrin delivers the iron directly to the mitochondria, adenosine triphosphate. These enzymes also do the follow- where heme is synthesized. In people who do not have ing: (1) maintain pliability of the cell membrane; (2) main- adequate quantities of transferrin in their blood, failure tain membrane transport of ions; (3) keep the iron of the to transport iron to the erythroblasts in this manner can cells’ hemoglobin in the ferrous form rather than the ferric cause severe hypochromic anemia (i.e., RBCs that contain form; and (4) prevent oxidation of the proteins in the RBCs. much less hemoglobin than normal). Even so, the metabolic systems of old RBCs become pro- When RBCs have lived their life span of about 120 days gressively less active, and the cells become more and more and are destroyed, the hemoglobin released from the cells fragile, presumably because their life processes wear out. is ingested by monocyte-macrophage cells. There, iron is Once the RBC membrane becomes fragile, the cell liberated and is stored mainly in the ferritin pool to be ruptures during passage through some tight spot of the used as needed for the formation of new hemoglobin.! circulation. Many of the RBCs self-destruct in the spleen, where they squeeze through the red pulp of the spleen. Daily Loss of Iron. An average man excretes about 0.6 mg There, the spaces between the structural trabeculae of of iron each day, mainly into the feces. Additional quanti- the red pulp, through which most of the cells must pass, ties of iron are lost when bleeding occurs. For a woman, are only 3 micrometers wide, in comparison with the additional menstrual loss of blood brings long-term iron 8-micrometer diameter of the RBC. When the spleen is loss to an average of about 1.3 mg/day.! removed, the number of old abnormal RBCs circulating Absorption of Iron From the Intestinal in the blood increases considerably. Tract Destruction of Hemoglobin by Macrophages. When Iron is absorbed from all parts of the small intestine, RBCs burst and release their hemoglobin, the hemoglobin mostly by the following mechanism. The liver secretes is 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 of flows through the bile duct into the duodenum. Here, the the liver and macrophages of the spleen and bone marrow. apotransferrin binds with free iron and also with certain During the next few hours to days, the macrophages release iron compounds, such as hemoglobin and myoglobin iron from the hemoglobin and pass it back into the blood from meat, two of the most important sources of iron in to be carried by transferrin either to the bone marrow for the diet. This combination is called transferrin. In turn, it production of new RBCs or to the liver and other tissues is attracted to and binds with receptors in the membranes for storage in the form of ferritin. The porphyrin portion of of intestinal epithelial cells. Then, by pinocytosis, the the hemoglobin molecule is converted by the macrophages, transferrin molecule, carrying its iron store, is absorbed through a series of stages, into the bile pigment bilirubin, into the epithelial cells and later released into the blood which is released into the blood and later removed from the capillaries beneath these cells in the form of plasma body by secretion through the liver into the bile. This process transferrin. is discussed in relation to liver function in Chapter 71.! 445 UNIT VI Blood Cells, Immunity, and Blood Coagulation the number of RBCs formed may be normal, or even much ANEMIAS greater than normal in some hemolytic diseases, the life Anemia means deficiency of hemoglobin in the blood, span of the fragile RBC is so short that the cells are destroyed which can be caused by too few RBCs or too little hemo- faster than they can be formed, and serious anemia results. globin in the cells. Some types of anemia and their physi- In hereditary spherocytosis, the RBCs are very small ological causes are described in the following sections. and spherical rather than being biconcave discs. These cells cannot withstand compression forces because they Blood Loss Anemia. After rapid hemorrhage, the body do not have the normal loose, baglike cell membrane replaces the fluid portion of the plasma in 1 to 3 days, but structure of the biconcave discs. On passing through the this response results in a low concentration of RBCs. If a splenic pulp and some other tight vascular beds, they are second hemorrhage does not occur, the RBC concentra- easily ruptured by even slight compression. tion usually returns to normal within 3 to 6 weeks. In sickle cell anemia, which is present in 0.3% to 1.0% of When chronic blood loss occurs, a person frequently West African and American blacks, the cells have an abnor- cannot absorb enough iron from the intestines to form mal type of hemoglobin called hemoglobin S, containing hemoglobin as rapidly as it is lost. RBCs that are much faulty beta chains in the hemoglobin molecule, as explained smaller than normal and have too little hemoglobin inside earlier in this chapter. When this hemoglobin is exposed to them are then produced, giving rise to microcytic hypo- low concentrations of oxygen, it precipitates into long crys- chromic anemia, which is shown in Figure 33-3.! tals inside the RBC. These crystals elongate the cell and give Aplastic Anemia Due to Bone Marrow Dysfunction. it the appearance of a sickle rather than a biconcave disc. The Bone marrow aplasia means lack of functioning bone precipitated hemoglobin also damages the cell membrane, marrow. For example, exposure to high-dose radiation or so the cells become highly fragile, leading to serious anemia. chemotherapy for cancer treatment can damage stem cells Such patients frequently experience a vicious circle of events of the bone marrow, followed in a few weeks by anemia. called a sickle cell disease crisis, in which low oxygen tension Likewise, high doses of certain toxic chemicals, such as in the tissues causes sickling, which leads to ruptured RBCs, insecticides or benzene in gasoline, may cause the same which causes a further decrease in oxygen tension and still effect. In autoimmune disorders, such as lupus erythema- more sickling and RBC destruction. Once the process starts, tosus, the immune system begins attacking healthy cells it progresses rapidly, eventuating in a serious decrease in such as bone marrow stem cells, which may lead to aplas- RBCs within a few hours and, in some cases, death. tic anemia. In about half of aplastic anemia cases the cause In erythroblastosis fetalis, Rh-positive RBCs in the is unknown, a condition called idiopathic aplastic anemia. fetus are attacked by antibodies from an Rh-negative People with severe aplastic anemia usually die unless mother. These antibodies make the Rh-positive cells frag- they are treated with blood transfusions—which can tem- ile, leading to rapid rupture and causing the child to be porarily increase the numbers of RBCs—or by bone mar- born with a serious case of anemia. This condition is dis- row transplantation.! cussed in Chapter 36 in relation to the Rh factor of blood. The extremely rapid formation of new RBCs to make up Megaloblastic Anemia. Based on the earlier discussions for the destroyed cells in erythroblastosis fetalis causes a of vitamin B12, folic acid, and intrinsic factor from the large number of early blast forms of RBCs to be released stomach mucosa, one can readily understand that loss of from the bone marrow into the blood.! any one of these can lead to slow reproduction of eryth- EFFECTS OF ANEMIA ON CIRCULATORY roblasts in the bone marrow. As a result, the RBCs grow SYSTEM FUNCTION too large, with odd shapes, and are called megaloblasts. Thus, atrophy of the stomach mucosa, as occurs in perni- The viscosity of the blood, which was discussed in Chap- cious anemia, or loss of the entire stomach after surgical ter 14, depends largely on the blood concentration of total gastrectomy can lead to megaloblastic anemia. Also, RBCs. In persons with severe anemia, the blood viscosity megaloblastic anemia often develops in patients who have may fall to as low as 1.5 times that of water rather than the intestinal sprue, in which folic acid, vitamin B12, and other normal value of about 3. This change decreases the resis- vitamin B compounds are poorly absorbed. Because the tance to blood flow in the peripheral blood vessels, so far erythroblasts in these states cannot proliferate rapidly greater than normal quantities of blood flow through the enough to form normal numbers of RBCs, the RBCs that tissues and return to the heart, thereby greatly increas- are formed are mostly oversized, have bizarre shapes, and ing cardiac output. Moreover, hypoxia resulting from have fragile membranes. These cells rupture easily, leaving diminished transport of oxygen by the blood causes the the person in dire need of an adequate number of RBCs.! peripheral tissue blood vessels to dilate, allowing a further increase in the return of blood to the heart and increas- Hemolytic Anemia. Different abnormalities of the RBCs, ing the cardiac output to a still higher level—sometimes many of which are acquired through hereditary, make three to four times normal. Thus, one of the major effects the cells fragile, so they rupture easily as they go through of anemia is greatly increased cardiac output, as well as the capillaries, especially through the spleen. Even though increased pumping workload on the heart. 446  Chapter 33 Red Blood Cells, Anemia, and Polycythemia The increased cardiac output in persons with anemia that regulate return of blood to the heart, as discussed in partially offsets the reduced oxygen-carrying effect of the Chapter 20, increasing blood viscosity decreases the rate anemia because, even though each unit quantity of blood of venous return to the heart. Conversely, the blood vol- carries only small quantities of oxygen, the rate of blood ume is greatly increased in polycythemia, which tends to flow may be increased enough that almost normal quanti- increase venous return. Actually, the cardiac output in UNIT VI ties of oxygen are actually delivered to the tissues. However, polycythemia is not far from normal because these two when a person with anemia begins to exercise, the heart is factors more or less neutralize each other. not capable of pumping much greater quantities of blood The arterial pressure is also normal in most people than it is already pumping. Consequently, during exercise, with polycythemia, although in about one-third of them, which greatly increases tissue demand for oxygen, extreme the arterial pressure is elevated. This means that the blood tissue hypoxia results and acute cardiac failure may ensue.! pressure–regulating mechanisms can usually offset the tendency for increased blood viscosity to increase periph- eral resistance and, thereby, increase arterial pressure. POLYCYTHEMIA Beyond certain limits, however, these regulations fail, and hypertension develops. Secondary Polycythemia. Whenever the tissues be- The color of the skin depends to a great extent on the come hypoxic because of too little oxygen in the breathed quantity of blood in the skin subpapillary venous plexus. air, such as at high altitudes, or because of failure of oxy- In polycythemia vera, the quantity of blood in this plexus gen delivery to the tissues, such as in cardiac failure, the is greatly increased. Furthermore, because blood passes blood-forming organs automatically produce large quan- sluggishly through the skin capillaries before entering the tities of extra RBCs. This condition is called secondary venous plexus, a larger than normal quantity of hemoglo- polycythemia, and the RBC count commonly rises to 6 to bin is deoxygenated. The blue color of all this deoxygen- 7 million/mm3, about 30% above normal. ated hemoglobin masks the red color of the oxygenated A common type of secondary polycythemia, called phys- hemoglobin. Therefore, a person with polycythemia vera iological polycythemia, occurs in those who live at altitudes ordinarily has a ruddy complexion, with a bluish (cya- of 14,000 to 17,000 feet, where the atmospheric oxygen is notic) tint to the skin. very low. The blood count is generally 6 to 7 million/mm3, which allows these people to perform reasonably high lev- els of continuous work, even in a rarefied atmosphere.! Bibliography Polycythemia Vera (Erythremia). In addition to physi- Bizzaro N, Antico A: Diagnosis and classification of pernicious ane- ological polycythemia, a pathological condition known as mia. Autoimmun Rev 13:565, 2014. polycythemia vera exists, in which the RBC count may be Franke K, Gassmann M, Wielockx B: Erythrocytosis: the HIF pathway in control. Blood 122:1122, 2013. 7 to 8 million/mm3 and the hematocrit may be 60% to Green R: Vitamin B12 deficiency from the perspective of a practicing 70% instead of the normal 40% to 45%. Polycythemia vera hematologist. Blood 129:2603, 2017. is caused by a genetic aberration in the hemocytoblastic Kato GJ, Piel FB, Reid CD, Gaston MH et al: Sickle cell disease. Nat Rev cells that produce the blood cells. The blast cells no longer Dis Primers 2018 Mar 15;4:18010. doi: 10.1038/nrdp.2018.10 stop producing RBCs when too many cells are already Kato GJ, Steinberg MH, Gladwin MT: Intravascular hemolysis and the present. This causes excess production of RBCs in the pathophysiology of sickle cell disease. J Clin Invest 127:750, 2017 Koury MJ, Haase VH: Anaemia in kidney disease: harnessing hypoxia same manner that a breast tumor causes excess produc- responses for therapy. Nat Rev Nephrol 11:394, 2015. tion of a specific type of breast cell. It usually causes ex- Muckenthaler MU, Rivella S, Hentze MW, Galy B: A red carpet for cess production of white blood cells and platelets as well. iron metabolism. Cell 168:344, 2017. In polycythemia vera, not only does the hemato- Nolan KA, Wenger RH: Source and microenvironmental regulation of erythropoietin in the kidney. Curr Opin Nephrol Hypertens 27:277, crit increase, but the total blood volume also increases, 2018. sometimes to almost twice normal. As a result, the entire Piel FB, Steinberg MH, Rees DC: Sickle cell disease. N Engl J Med vascular system becomes intensely engorged. Also, many 376:1561, 2017. blood capillaries become plugged by the viscous blood; Renassia C, Peyssonnaux C: New insights into the links between hy- the viscosity of the blood in polycythemia vera sometimes poxia and iron homeostasis. Curr Opin Hematol. 26:125, 2019. Stabler SP: Clinical practice. Vitamin B12 deficiency. N Engl J Med increases from the normal of 3 times the viscosity of water 368:149, 2013. to 10 times that of water.! Telen MJ, Malik P, Vercellotti GM: Therapeutic strategies for sickle cell disease: towards a multi-agent approach. Nat Rev Drug Discov EFFECT OF POLYCYTHEMIA ON FUNCTION 18:139, 2019. OF THE CIRCULATORY SYSTEM Wang CY, Babitt JL: Liver iron sensing and body iron homeostasis. Blood 133:18, 2019. Because of the greatly increased viscosity of blood in poly- Weiss G, Ganz T, Goodnough LT: Anemia of inflammation. Blood cythemia, blood flow through the peripheral blood ves- 133:40, 2019. sels is often very sluggish. In accordance with the factors 447