The cells of the blood are classified as erythrocytes, leukocytes, or thrombocytes. The erythrocytes (red cells) carry oxygen to the tissues and are the most numerous cells in the blood. The leukocytes (white cells) are involved in defense against infection, and the thrombocytes (platelets) function in blood clotting. All of the cells in the blood can be generated from hematopoietic stem cells in the bone marrow on demand. For example, in response to infection, leukocytes secrete cytokines called interleukins that stimulate the production of additional leukocytes to fight the infection. Decreased supply of oxygen to the tissues signals the kidney to release erythropoietin, a hormone that stimulates the production of red cells.

The red cell has limited metabolic function, owing to its lack of internal organelles. Glycolysis is the main energy-generating pathway, with lactate production regenerating NAD⁺ for glycolysis to continue. The NADH produced in glycolysis is also used to reduce the ferric form of hemoglobin, methemoglobin, to the normal ferrous state. Glycolysis also leads to a side pathway in which 2,3-bisphosphoglycerate is produced, which is a major allosteric effector for oxygen binding to hemoglobin (see Chapter 7). The hexose monophosphate shunt pathway generates NADPH to protect red cell membrane lipids and proteins from oxidation, through regeneration of reduced glutathione. Heme synthesis occurs in the precursors of red cells and is a complex pathway that originates from succinyl coenzyme A (succinyl CoA) and glycine. Mutations in any of the steps of heme synthesis lead to a group of diseases known collectively as porphyrias.

The red cell membrane must be highly deformable to allow it to travel throughout the capillary system in the body. This is because of a complex cytoskeletal structure that consists of the major proteins spectrin, ankyrin, and band 3 protein. Mutations in these proteins lead to improper formation of the membrane cytoskeleton, ultimately resulting in malformed red cells, spherocytes, in the circulation. Spherocytes have a shortened lifespan, leading to loss of blood cells.

When the body does not have sufficient red cells, the patient is said to be anemic. Anemia can result from many causes. Nutritional deficiencies of iron, folate, or vitamin B12 prevent the formation of adequate numbers of red cells. Mutations in the genes that encode red cell metabolic enzymes, membrane structural proteins, and globins cause hereditary anemias. The appearance of red cells on a blood smear frequently provides clues to the cause of an anemia. Because the mutations that give rise to hereditary anemias also provide some protection against malaria, hereditary anemias are some of the most common genetic diseases known.

In humans, globin gene expression is altered during development, a process known as hemoglobin switching. The switch between the expression of one gene to another is regulated by transcription factor binding to the promoter regions of these genes. Current research is attempting to reactivate fetal hemoglobin genes to combat sickle cell disease and thalassemia.

THE WAITING ROOM

The blood, together with the bone marrow, makes up the organ system that makes a significant contribution to achieving homeostasis, the maintenance of the normal composition of the body’s internal environment. Blood can be considered a liquid tissue consisting of water, proteins, and specialized cells. The most abundant cells in the blood are the erythrocytes or red blood cells, which transport oxygen to the tissues and contribute to buffering of the blood through the binding of protons by hemoglobin (see the material in Chapter 4, Section IV.B, and Chapter 7, Section VII). Red blood cells lose all internal organelles during the process of differentiation. The white blood cells (leukocytes) are nucleated cells present in blood that function in the defense against infection. The platelets (thrombocytes), which contain cytoplasmic organelles but no nucleus, are involved in the control of bleeding by contributing to normal thrombus (clot) formation within the lumen of the blood vessel. The average concentration of these cells in the blood of normal individuals is presented in Table 42.1.

TABLE 42.1 Normal Values of Blood Cell Concentrations in Adults

The leukocytes can be classified either as polymorphonuclear leukocytes (granulocytes) or mononuclear leukocytes, depending on the morphology of the nucleus in these cells. The mononuclear leukocyte has a rounded nucleus, whereas the polymorphonuclear leukocytes have a multilobed nucleus.

Neutrophils are phagocytic cells that migrate rapidly to areas of infection or tissue damage. As part of the response to acute infection, neutrophils engulf foreign bodies and destroy them, in part, by initiating the respiratory burst (see Chapter 25). The respiratory burst creates oxygen radicals that rapidly destroy the foreign material found at the site of infection.

A primary function of eosinophils is to protect against parasites such as worms and to remove fibrin during inflammation. The eosinophilic granules are lysosomes containing hydrolytic enzymes and cationic proteins, which are toxic to parasitic worms. Increased eosinophils are also present in asthma and allergic responses, autoimmune diseases, and some cancers. Elucidating the function of eosinophils is currently an active area of research.

Basophils, the least abundant of the leukocytes, participate in hypersensitivity reactions, such as allergic responses. Histamine, produced by the decarboxylation of histidine, is stored in the secretory granules of basophils. Release of histamine during basophil activation stimulates smooth muscle cell contraction and increases vascular permeability. The granules also contain enzymes such as proteases, β-glucuronidase, and lysophospholipase. These enzymes degrade microbial structures and assist in the remodeling of damaged tissue.

2. Mononuclear Leukocytes

The mononuclear leukocytes consist of various classes of lymphocytes and the monocytes. Lymphocytes are small, round cells that were originally identified in lymph fluid. These cells have a high ratio of nuclear volume to cytoplasmic volume and are the primary antigen (foreign body)-recognizing cells. There are three major types of lymphocytes: T cells, B cells, and NK cells. The precursors of T cells (thymus-derived lymphocytes) are produced in the bone marrow and then migrate to the thymus, where they mature before being released to the circulation. Several subclasses of T cells exist. These subclasses are identified by different surface membrane proteins, the presence of which correlate with the function of the subclass. Lymphocytes that mature in the bone marrow are the B cells, which secrete antibodies in response to antigen binding. The third class of lymphocytes is the natural killer cells (NK cells), which target virally infected and malignant cells for destruction.

Circulatory monocytes are the precursors of tissue macrophages. Macrophages (“large eaters”) are phagocytic cells that enter inflammatory sites and consume microorganisms and necrotic host cell debris left behind by granulocyte attack of the foreign material. Macrophages in the spleen play an important role in maintaining the oxygen-delivering capabilities of the blood by removing damaged red blood cells that have a reduced oxygen-carrying capacity.

3. The Thrombocytes

Platelets are heavily granulated disk-like cells that aid in intravascular clotting. Like the erythrocyte, platelets lack a nucleus. Their function is discussed in the following chapter. Platelets arise by budding of the cytoplasm of megakaryocytes, multinucleated cells that reside in the bone marrow.

B. Anemia

The major function of erythrocytes is to deliver oxygen to the tissues. To do this, a sufficient concentration of hemoglobin in the red blood cells is necessary for efficient oxygen delivery to occur. When the hemoglobin concentration falls below normal values (Table 42.2), the patient is classified as anemic. Anemias can be categorized based on red cell size and hemoglobin concentration. Red cells can be of normal size (normocytic), small (microcytic), or large (macrocytic). Cells containing a normal hemoglobin concentration are termed normochromic; those with decreased concentration are hypochromic. This classification system provides important diagnostic tools (Table 42.3) that enable one to properly classify, diagnose, and treat the anemia.

TABLE 42.3 Classification of the Anemias on the Basis of Red Cell Morphology

To understand how the erythrocyte can carry out its major function a discussion of erythrocyte metabolism is required. Mature erythrocytes contain no intracellular organelles, so the metabolic enzymes of the red blood cell are limited to those found in the cytoplasm. In addition to hemoglobin, the cytosol of the red blood cell contains enzymes necessary for the prevention and repair of damage done by reactive oxygen species (see Chapter 25) and the generation of energy (Fig. 42.1). Erythrocytes can only generate adenosine triphosphate (ATP) by glycolysis (see Chapter 22). The ATP is used for ion transport across the cell membrane (primarily Na⁺, K⁺, and Ca⁺⁺), the phosphorylation of membrane proteins, and the priming reactions of glycolysis. Erythrocyte glycolysis also uses the Rapoport–Luebering shunt to generate 2,3-bisphosphoglycerate (2,3-BPG). Red cells contain 4 to 5 mM 2,3-BPG, compared with trace amounts in other cells. The trace amounts of 2,3-BPG found in cells other than erythrocytes are required for the phosphoglycerate mutase reaction of glycolysis, in which 3-phosphoglycerate is isomerized to 2-phosphoglycerate. As the 2,3-BPG is regenerated during each reaction cycle, it is required in only catalytic amounts. As has been discussed in more detail in Chapter 7, 2,3-BPG is a modulator of oxygen binding to hemoglobin that stabilizes the deoxy form of hemoglobin, thereby facilitating the release of oxygen to the tissues.

To bind oxygen, the iron of hemoglobin must be in the ferrous (+2) state. Reactive oxygen species can oxidize the iron to the ferric (+3) state, producing methemoglobin. Some of the NADH produced by glycolysis is used to regenerate hemoglobin from methemoglobin by the NADH-cytochrome b₅ methemoglobin reductase system. Cytochrome b₅ reduces the Fe³⁺ of methemoglobin. The oxidized cytochrome b₅ is then reduced by a flavin-containing enzyme, cytochrome b₅ reductase (also called methemoglobin reductase), using NADH as the reducing agent.

Approximately 5% to 10% of the glucose metabolized by red blood cells is used to generate NADPH by way of the hexose monophosphate shunt. The NADPH is used to maintain glutathione in the reduced state. The glutathione cycle is the red blood cell’s chief defense against damage to proteins and lipids by reactive oxygen species (see Chapter 25).

The enzyme that catalyzes the first step of the hexose monophosphate shunt is glucose 6-phosphate dehydrogenase (G6PD). The lifetime of the red blood cell correlates with G6PD activity. Lacking ribosomes, the red blood cell cannot synthesize new G6PD protein. Consequently, as the G6PD activity decreases, oxidative damage accumulates, leading to lysis of the erythrocyte. When red blood cell lysis (hemolysis) substantially exceeds the normal rate of red blood cell production, the number of erythrocytes in the blood drops below normal values, leading to hemolytic anemia.

B. The Erythrocyte Precursor Cells and Heme Synthesis

1. Heme Structure

Heme consists of a porphyrin ring coordinated with an atom of iron (Fig. 42.2). Four pyrrole rings are joined by methenyl bridges (==CH–) to form the porphyrin ring (see Fig. 7.12). Eight side chains serve as substituents on the porphyrin ring, two on each pyrrole. These side chains may be acetate (A), propionate (P), methyl (M), or vinyl (V) groups. In heme, the order of these groups is M V M V M P P M. This order, in which the position of the methyl group is reversed on the fourth ring, is characteristic of the porphyrins of the type III series, the most abundant in nature.

Heme is the most common porphyrin found in the body. It is complexed with proteins to form hemoglobin, myoglobin, and the cytochromes (see Chapters 7 and 24), including cytochrome P450 (see Chapter 25).

2. Synthesis of Heme

Heme is synthesized from glycine and succinyl CoA (Fig. 42.3), which condense in the initial reaction to form δ-aminolevulinic acid (δ-ALA) (Fig. 42.4). The enzyme that catalyzes this reaction, δ-ALA synthase, requires the participation of pyridoxal phosphate, as the reaction is an amino acid decarboxylation reaction (glycine is decarboxylated; see Chapter 37).

The next reaction of heme synthesis is catalyzed by δ-ALA dehydratase, in which two molecules of δ-ALA condense to form the pyrrole, porphobilinogen (Fig. 42.5). Four of these pyrrole rings condense to form a linear chain and then a series of porphyrinogens. The side chains of these porphyrinogens initially contain acetate (A) and propionate (P) groups. The acetyl groups are decarboxylated to form methyl groups. Then the first two propionyl side chains are decarboxylated and oxidized to vinyl groups, forming a protoporphyrinogen. The methylene bridges are subsequently oxidized to form protoporphyrin IX (see Fig. 42.3). Heme is red and is responsible for the color of red blood cells and of muscles that contain a large number of mitochondria.

In the final step of the pathway, iron (as Fe²⁺) is incorporated into protoporphyrin IX in a reaction catalyzed by ferrochelatase (also known as heme synthase).

3. Source of Iron

Iron, which is obtained from the diet, has a US Recommended Dietary Allowance (RDA) of 10 mg for men and postmenopausal women and 15 mg for premenopausal women. The average daily US diet contains 10 to 50 mg of iron. However, only 10% to 15% is normally absorbed, and iron deficiencies are fairly common. The iron in meats is in the form of heme, which is readily absorbed. The nonheme iron in plants is not as readily absorbed, in part because plants often contain oxalates, phytates, tannins, and other phenolic compounds that chelate or form insoluble precipitates with iron, preventing its absorption. Conversely, vitamin C (ascorbic acid) increases the uptake of nonheme iron from the digestive tract. The uptake of iron is also increased in times of need by mechanisms that are not yet understood. Iron is absorbed in the ferrous (Fe²⁺) state (Fig. 42.6) but is oxidized to the ferric state by a ferroxidase known as ceruloplasmin (a copper-containing enzyme) for transport through the body.

Because free iron is toxic, it is usually found in the body bound to proteins (see Fig. 42.6). Iron is carried in the blood (as Fe³⁺) by the protein apotransferrin, with which it forms a complex known as transferrin. Transferrin is usually only one-third saturated with iron. The total iron-binding capacity of blood, due mainly to its content of transferrin, is approximately 300 μg/dL. Transferrin, with bound iron, binds to the transferrin receptor on the cell surface and the complex is internalized into the cell. The internalized membrane develops into an endosome, with a slightly acidic pH. The iron is reduced by a membrane-bound oxidoreductase and the ferrous iron is transported out of the endosome into the cytoplasm via the divalent metal ion transporter 1 (DMT-1). Once in the cytoplasm, the iron is shunted to necessary enzymes, or can be oxidized and bind to ferritin for long-term storage.

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