Erythrocytes

Formed Elements

The formed elements of blood include erythrocytes, leukocytes, and platelets. Red blood cells make up about 45% of blood volume, which is known as the hematocrit. The RBCs have no nuclei or organelles,meaning that they are not considered “true cells.” Platelets are only cell fragments. Only leukocytes are complete cells. Leukocytes and platelets make up less than 1%. The remainder is plasma. Most blood cells do not divide. Instead they are replaced when stem cells continuously divide in the bone marrow. All formed elements arise from the hematocytoblasts, also called hematopoietic stem cells, which are undifferen-tiated precursor cells in the red bone marrow. Most formed elements only survive in the bloodstream for a few days. Different modes of maturation of formed elements exist. Once a cell becomes committed to a certain blood cell pathway, it is unable to change. Membrane surface receptors appear, which signal the cell’s commitment to one blood cell pathway. The receptors respond to specific growth factors or hor-mones. These assist the cell in becoming even more specialized. In a healthy male adult the normal hema-tocrit value is 47%, plus or minus 5%. In a healthy female adult, it is 42%, plus or minus 5%. Less than 1% of blood volume consists of platelets and leukocytes. Most of the remaining 55% of whole blood is made up by the plasma (FIGURE 17- 2). The components that make up whole blood can be separated or fractionated to be clinically analyzed.

Erythrocytes

Erythrocytes or red blood cells (RBCs) have abiconcave shape, meaning they are basically round, with a center that is depressed in comparison withtheir edges. This shape helps them to transport gases by increasing the surface area of the cell, allow-ing more diffusion. This shape also ensures that the cell membrane is nearer to the hemoglobin, which carries oxygen, inside the cell. Erythrocytes, when mature, are bound by a plasma membrane. Red blood cells are about one-third hemoglobin, a protein that gives them their red color. Therefore, hemoglobin is the major protein in red blood cells. FIGURE 17-3 shows the various types of blood cells.

The formation of erythrocytes, called ­erythropoiesis, occurs only in the red bone mar-row or the myeloid tissue, the tissue that performs hematopoiesis. Erythropoiesis increases whenoxygen levels in the blood decrease. Erythrocytes have nuclei that are shed as they mature, allowing more room for hemoglobin. Lacking nuclei, mature RBCs cannot synthesize proteins or divide to form more cells. They produce adenosine triphosphate through glycolysis because they do not have mito-chondria and use none of the oxygen carried in their hemoglobin. Erythrocytes also have nearly no organelles and contain­ mostly antioxidant enzymes and structural proteins. The structural proteins allow them to change shape and return to their orig-inal shape afterward. A network of proteins,­ primar-ily one called spectrin, is attached to the cytoplasm of red blood cell plasma membranes. This maintains the biconcave shape. Spectrin forms a net that allows RBCs to bend, turn, and become more concave as needed to move through tiny capillaries. For exam-ple, in lung capillaries RBCs pick up oxygen and release it to tissue cells through other body capillar-ies. They also move approximately 20% of the car-bon dioxide from tissue cells back to the lungs. Red blood cells are highly efficient in these tasks because they generate adenosine triphosphate via anaerobic mechanisms and do not have mitochondria. This means they do not consume any of the oxygen they carry. Oxygen is picked up from the alveoli by the red blood cells, and it binds with hemoglobin. The RBCs carry oxygen to the tissue cells. They can form stacks called rouleaux.

Hemoglobin

Hemoglobin is responsible for the ability of the cells to transport oxygen and carbon dioxide, and most oxy-gen carried in the blood is bound to hemoglobin. It also aids in the process of blood clotting. Hemoglo-bin consists of the red heme pigment that is bound to the globin protein. Hemoglobin makes up more than 95% of the protein in a red blood cell. Globin has four polypeptide chains (two alpha and two beta) that each bind a ring-like heme group (FIGURE 17-4). Each heme group has an iron atom in its very center. One hemoglobin molecule can transport four molecules of oxygen, since each iron atom combines reversibly with one molecule of oxygen. One red blood cell consists of about 250 million hemoglobin molecules, meaning that each of them can contain approximately one bil-lion oxygen molecules. Because hemoglobin is inside erythrocytes, it does not break into fragments that could leak out of the bloodstream through capillary walls. The containment of hemoglobin by the eryth-rocytes also keeps it from making the blood more vis-cous and raising osmotic pressure.

When hemoglobin easily and reversibly binds with oxygen, oxyhemoglobin is formed. ­Oxyhemoglobin is bright red and has a three-dimensional structure. When oxygen is released, deoxyhemoglobin is formed. Deoxyhemoglobin is burgundy (darker red), andblood rich in deoxyhemoglobin may appear bluish when seen through blood vessels. Deoxyhemoglobin is also known as reduced hemoglobin.

Approximately 20% of the carbon dioxide that is transported by the blood is combined with hemoglobin. However, the carbon dioxide binds to the amino acids of the globin portion of hemo-globin instead of the heme portion. This forms carbaminohemoglobin­, and the process occursmore easily when the hemoglobin is dissociated from oxygen. This is known as its reduced state . The loading of carbon dioxide occurs in the tissues, with transport occurring from the tissues to the lungs, where it is eliminated from the body.

Mature RBCs contain an adult-type of hemoglo-bin called HbA. In an embryo or fetus, a different form of hemoglobin, known as fetal hemoglobin or HbF, is contained in the RBCs. This binds oxygen more readily than adult hemoglobin. Therefore, a developing fetus can “steal” oxygen from the mother’s bloodstream via the placenta. Fetal hemoglobin begins to convert to adult hemoglobin shortly before birth and continues over the next year.

The way hemoglobin is contained in the RBCs prevents two major occurrences. The hemoglo-bin does not break into fragments and therefore does not leak out of the bloodstream through the walls of the capillaries. Also, the hemoglobin is prevented from increased blood viscosity and rais-ing osmotic pressure. The viscosity of the blood is mostly determined by the erythrocytes. When the number of RBCs exceeds the normal range, blood flows more slowly because it has become more vis-cous. ­Oppositely, blood becomes thinner and flows more quickly when the RBC count drops below the normal range.

A red blood cell count is the number of RBCs in a microliter of blood. Normal ranges are as follows:

■■ Adult males: 4.7 million to 6.1 million cells per microliter

■■ Adult females: 4.2 million to 5.4 million cells per microliter Increased numbers of circulating RBCs increase the blood’s oxygen-carrying capacity, which can affect health positively. Red blood cell counts are taken to diagnose many diseases and evaluate their courses.

Erythropoiesis

In humans, RBCs are mostly developed in spaces within bones that are filled with red bone marrow. Erythrocytes usually live for 120 days, with replace-ment cells created to maintain a relatively stable RBC count. The rate of RBC formation is controlled by neg-ative feedback via the hormone erythropoietin. It is released by the kidneys and liver in response to pro-longed oxygen deficiency (FIGURE 17-5).

The formation of all types of blood cells is known as hematopoiesis and occurs in the red bone mar-row. In this bone marrow, there is a soft network of reticular connective tissue. This tissue bordersbloodsinusoids, which are wide blood capillaries. The net-work contains immature blood cells, fat cells, mac-rophages, and reticular cells. Blood reticulocyte counts provide information regarding the rate of erythrocyte formation. The reticular cells secrete the connective tissue fibers. In an adult, red bone mar-row is mostly found in the axial skeleton bones and girdles and in the proximal epiphyses of the femur and humerus.

Production of RBCs continues at a heightened rate until the amount of them in the blood circulation is enough to supply oxygen to the body tissues. The stages of formation of RBCs and other types of blood cells from hemocytoblasts are shown in ­FIGURE 17-6. These stages have been individually named by hema-tologists. Approximately 1 ounce of new blood is ­created every day. This ounce of blood contains approximately 100 billion new cells.

The stages of RBC maturation are described briefly, as follows:

■■ Hemocytoblasts or multipotent stem cells, in the red bone marrow, produce myeloid stem cells; myeloid stem cell division creates progenitor cells, from which all formed elements derive, except for lymphocytes.

■■ The myeloid stem cells divide, producing RBCs and several types of WBCs.

■■ Lymphoid stem cells divide to produce varioustypes of lymphocytes.

■■ Cells that will become RBCs initially differentiate into proerythroblasts.

■■ These cells then mature through several erythro blast stages, actively synthesizing hemoglobin.

■■ After approximately four days, the erythroblasts are then called normoblasts and shed their nuclei to become reticulocytes; the reticulocytes ­contain 80% of the hemoglobin of a mature RBC and are immature cells found in the peripheral blood.

■■ Hemoglobin synthesis continues for up to three more days; the cytoplasm of these cells still contains RNA.

■■ The reticulocytes move from the bone marrow into the bloodstream.

■■ Twenty-four hours later, the reticulocytes are fully matured and cannot be distinguished from other mature RBCs.

B-complex vitamins such as vitamin B₁₂ and folic acid greatly influence RBC production and are nec-essary for DNA synthesis. Hematopoietic or bloodcell–forming tissue is very vulnerable to deficiency ofboth of these vitamins. Iron is required for normal RBC production and for hemoglobin synthesis. Iron is slowly absorbed from the small intestine, and the body reuses much of the iron released by decomposi-tion of hemoglobin from damaged RBCs. Only small amounts of iron must be taken in via the diet.

Breakdown of Erythrocytes

Red blood cells bend as they move through blood vessels, but aging causes them to become more fragile. Cells called macrophages phagocytize and destroy damaged RBCs, mostly in the liver and spleen. Hemoglobin from RBCs is broken down into heme, which contains iron, and the protein globin.The heme then decomposes into iron and biliverdin­, a green pigment­. The iron may be transported by the blood to synthesize new hemoglobin, with about 80% of the iron stored in the liver as an iron–protein complex. Biliverdin is converted into bilirubin, an orange pigment that is excreted along with biliverdin in the bile. The life cycle of RBCs is summarized in FIGURE 17-7.

Erythropoietin Regulation

Especially during hypoxia, the kidneys produce erythropoietin, which is also called erythropoiesis-­ stimulating hormone. Erythropoietin stimulates pro-duction of erythroblasts from bone marrow. Therefore, bone marrow can increase the rate of RBC formation by approximately 10 times—about 30 million cells per second. This process aids the patient during recovery from a severe loss of blood.

Erythropoietin is actually a glycoprotein hormone.If certain kidney cells are deficient in oxygen, enzymes that are oxygen-sensitive cannot function normally. Hypoxia-inducible factor is an intracellular signalingmolecule that accumulates as a result, increasing the synthesis and release of erythropoietin. This condi-tion may be caused by iron deficiency, in which there is insufficient hemoglobin in each RBC; high altitudes or pneumonia, which cause reduced availability of oxygen; excessive destruction of RBCs; or hemor-rhage, which results in reduced numbers of RBCs. Oppositely, erythropoietin production is depressed by excessive oxygen or excessive erythrocytes in the bloodstream. In the bloodstream, erythropoietin stimulates red bone marrow cells that are already committed to forming erythrocytes, causing them to mature more quickly.

Iron

Amino acids, lipids, and carbohydrates are required for erythropoiesis to occur. Hemoglobin synthesis requires iron, which is available in the diet. The cells of the intestines accurately control iron absorption into the bloodstream as a result of changing amounts of iron that are stored in the body. Hemoglobin con-tains approximately 65% of the body’s supply of iron, which is about 4,000 mg. The liver and spleen store most of the rest of body iron, with small amounts also stored in the bone marrow. Iron is stored inside cells as protein–iron complexes called ferritin and hemo-siderin,because free iron ions are toxic to the body.

Iron is loosely bound to a transport protein called a metalloprotein, which transports globulin. Erythro-cytes that are developing take up iron as required to form hemoglobin. Every day we lose small amounts of iron via the feces, perspiration, and urine. Men lose approximately 0.9 mg per day, and women lose approximately 1.7 mg per day. Menstruation is the rea-son for additional average daily loss of iron in women.

As erythrocytes age they become less flexible and more fragile and rigid. The hemoglobin degenerates, with these RBCs fragmenting and becoming trapped in the smaller vessels, mostly those of the spleen. They are engulfed and destroyed by macrophages, with the heme portion of their hemoglobin being split from the globin portion. The iron core is saved and bound to ferritin or hemosiderin for future use.

1. Describe the function of hemoglobin.

2. Explain how RBCs produce adenosine triphosphate.

3. Which hormone is required for the formation of erythrocytes?