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11.1-11.4

The circulating fluid of the body is blood, a specialized con- nective tissue that contains cells suspended in a fluid matrix. 5p. 104 Blood has five major functions:

1. Transporting dissolved gases, nutrients, hormones, and

metabolic wastes. Blood carries oxygen from the lungs to the tissues, and carbon dioxide from the tissues to the lungs. It distributes nutrients that are either absorbed at the digestive tract or released from storage in adipose tissue or in the liver. Blood carries hormones from endocrine glands toward their target cells, and it absorbs and carries the wastes produced by active cells to the kidneys for excretion.

2. Regulating the pH and ion composition of interstitial

fluids throughout the body. Diffusion between interstitial fluids and blood eliminates local deficiencies or excesses of ions such as calcium or potassium. Blood also absorbs and neutralizes the acids generated by active tissues, such as lactic acid produced by skeletal muscle contractions.

3. Restricting fluid losses at injury sites. Blood contains enzymes and factors that respond to breaks in vessel walls by initiating the process of blood clotting. The resulting blood clot acts as a temporary patch that prevents further reductions in blood volume. 4. Defending against toxins and pathogens. Blood

transports white blood cells, specialized cells that

380

CARDIOVASCULAR

migrate into body tissues to fight infections or remove debris. Blood also delivers antibodies, special proteins that attack invading organisms or foreign compounds. 5. Stabilizing body temperature. Blood absorbs the heat generated by active skeletal muscles and redistributes it to other tissues. When body temperature is high, blood is directed to the skin surface, where heat is lost to the environment. When body temperature is too low, the flow of warm blood is restricted to crucial structures- to the brain and to other temperature-sensitive organs.

COMPOSITION OF BLOOD

Spotlight Figure 11-1 (pp. 382-383) describes the composi- tion of whole blood, which is made up of plasma and formed elements (blood cells and cell fragments). The components of whole blood may be separated, or fractionated, for analytical or clinical purposes.

Whole blood from any source-veins, capillaries, or arteries has the same basic physical characteristics:

• Temperature. The temperature of blood is roughly 38°C (100.4°F), slightly above normal body temperature.

⚫ Viscosity. Blood is five times as viscous as water-that is,

five times stickier, more cohesive, and resistant to flow than water. The high viscosity results from interactions among the dissolved proteins, formed elements, and water molecules in plasma.

pH. Blood is slightly alkaline, with a pH between 7.35 and 7.45 (average: 7.4). p. 36

BLOOD COLLECTION AND ANALYSIS

Fresh whole blood is usually collected from a superficial vein, such as the median cubital vein on the anterior surface of the elbow. This procedure is called venipuncture (VĒN-i-punk-chur; vena, vein + punctura, a piercing). It is a common sampling technique because superficial veins are easy to locate, the walls of veins are thinner than those of arteries of comparable size, and blood pressure in the venous system is relatively low, so the puncture wound seals quickly. The most common clinical procedures examine venous blood.

Blood from peripheral capillaries can be obtained by puncturing the tip of a finger, an ear lobe, or (in infants) the great toe or heel of the foot. A small drop of capillary blood can be used to prepare a blood smear, a thin film of blood on a microscope slide. The blood smear is then stained with special dyes to show different types of formed elements.

An arterial puncture, or "arterial stick," may be required for evaluating the efficiency of gas exchange at the lungs. Samples are usually drawn from the radial artery at the wrist or the brachial artery at the elbow.

CHECKPOINT

1. List five major functions of blood.

2. What two components make up whole blood?

3. Why is venipuncture a common technique for obtaining a

blood sample?

See the blue Answers tab at the back of the book.

11-2 Plasma, the fluid portion

of blood, contains significant quantities of plasma proteins

Plasma and interstitial fluid account for most of the volume of extracellular fluid (ECF) in the body. In this section we consider the composition of plasma and examine the proteins it contains.

THE COMPOSITION OF PLASMA

As shown in Spotlight Figure 11-1, plasma makes up the great- est volume of whole blood. The components of plasma include plasma proteins, other solutes, and water.

PLASMA PROTEINS

Plasma contains considerable quantities of dissolved proteins (Spotlight Figure 11-1). The three primary types of plasma pro- teins are albumins (al-BŪ-minz), globulins (GLOB-u-linz), and fibrinogen (fi-BRIN-o-jen). They make up more than 99 percent of the plasma proteins.

Albumins make up the majority of the plasma proteins. Their presence is important in maintaining the osmotic pres- sure of plasma. Globulins are the second most-abundant proteins in plasma. They include antibodies and transport proteins. Antibodies attack foreign proteins and pathogens. Transport proteins bind small ions, hormones, or compounds. that might otherwise be lost at the kidneys or that have very low solubility in water. One example is thyroid-binding globu- lin, which binds and transports thyroid hormones.

Both albumins and globulins can bind to lipids, such as triglycerides, fatty acids, or cholesterol. These lipids are not

themselves water soluble, but the protein-lipid combina- tion readily dissolves in plasma. In this way, the cardiovas- cular system transports insoluble lipids to peripheral tissues. Globulins involved in lipid transport are called lipoproteins (LĪ-pō-prō-tenz).

Fibrinogen, the third type of plasma protein, functions in blood clotting. Under certain conditions, fibrinogen molecules interact and convert to form large, insoluble strands of fibrin (FI-brin). These form insoluble fibers that provide the basic framework for a blood clot. If steps are not taken to prevent clotting in a blood sample, the conversion of fibrinogen (a soluble protein) to fibrin (an insoluble protein) will occur. This conversion removes the clotting proteins, leaving a fluid known as serum.

The BIG PICTURE

Approximately half of the volume of whole blood consists of cells and cell products. Plasma resembles interstitial fluid but it contains a unique mixture of proteins not found in other extracellular fluids.

The liver synthesizes more than 90 percent of the plasma proteins, including all albumins and fibrinogen and most of the globulins. Antibodies (immunoglobulins) are produced by plasma cells of the lymphatic system. Because the liver is the primary source of plasma proteins, liver disorders can alter the composition and functional properties of the blood. For example, some forms of liver disease can lead to uncontrolled bleeding due to the inadequate synthesis of fibrinogen and other plasma proteins involved in clotting.

✓CHECKPOINT

4. List the three major types of plasma proteins.

5. What would be the effects of a decrease in the amount of

plasma proteins?

See the blue Answers tab at the back of the book.

11-3 Red blood cells, formed by erythropoiesis, contain hemoglobin that can be recycled

Red blood cells (RBCs) are the most abundant blood cells, accounting for 99.9 percent of the formed elements. RBCs contain the pigment hemoglobin, which binds and transports oxygen and carbon dioxide.

Chapter 11 The Cardiovascular System: Blood 381

ABUNDANCE OF RED BLOOD CELLS

The number of RBCs in the blood of a normal individual staggers the imagination. A standard blood test reports the number of RBCs per microliter (μL) of whole blood as the red blood cell count. In adult males, 1 microliter, or 1 cubic millimeter (mm3), of whole blood contains roughly 5.4 million erythrocytes; in adult females, 1 microliter contains about 4.8 million. A single drop of whole blood contains some 260 million RBCs. RBCs account for roughly one-third of the 75 trillion cells in the human body.

The hematocrit is the percentage of whole blood volume occupied by formed elements (Spotlight Figure 11-1). The hematocrit is measured after a blood sample has been spun in a centrifuge so that all the formed elements come out of sus- pension. In adult males, it averages 46 percent (range: 40-54); in adult females, 42 percent (range: 37-47). Because whole blood contains roughly 1000 red blood cells for each white blood cell, the hematocrit closely approximates the volume of RBCs. For this reason, hematocrit values are often reported as the volume of packed red cells (VPRC), or simply the packed cell volume (PCV).

Many conditions can affect the hematocrit. The hematocrit increases, for example, during dehydration (owing to a reduction in plasma volume) or after erythropoietin (EPO) stimulation. p. 365 The hematocrit decreases as a result of internal bleeding or problems with RBC formation. So, the hematocrit alone does not provide specific diagnostic information. However, a change in hematocrit is an indication that more specific tests are needed.

STRUCTURE OF RBCs

Red blood cells are specialized to transport oxygen and carbon dioxide within the bloodstream. As Figure 11-2 (p. 384) shows, each RBC is a biconcave disc with a thin central region and a thick outer margin. This unusual shape has two important ef- fects on RBC function: (1) It gives each RBC a relatively large surface area to volume ratio that increases the rate of diffusion between its cytoplasm and the surrounding plasma, and (2) it enables RBCs to bend and flex to squeeze through narrow capillaries.

During their formation, RBCs lose most of their organelles, including mitochondria, ribosomes, and nuclei. Without a nucleus or ribosomes, RBCs can neither undergo cell divi- sion nor synthesize structural proteins or enzymes. Without mitochondria, they can obtain energy only through anaerobic metabolism, relying on glucose obtained from the surrounding

FIGURE 11-1

SPOTLIGHT The Composition of Whole Blood

A Fluid Connective Tissue

Blood is a fluid connective tissue with a unique composition. It consists of a matrix called plasma (PLAZ-muh) and formed elements (cells and cell fragments). The term whole blood refers to the combination of plasma and the formed elements together. The cardiovascular system of an adult male contains 5-6 liters (5.3-6.4 quarts) of whole blood; that of an adult

female contains 4-5 liters (4.2-5.3 quarts).

The sex differences in

blood volume primarily reflect differences in average body size.

PLASMA

Plasma, the matrix of blood, makes up about 55% of the volume of whole blood. In many respects, the composition of plasma resembles that of interstitial fluid. This similarity exists because water, ions, and small solutes are continuously exchanged between plasma and interstitial fluids across the walls of capillaries. The primary differences between plasma and interstitial fluid involve (1) the levels of respiratory gases (oxygen and carbon dioxide, due to the respiratory activities of tissue cells), and (2) the concentra- tions and types of dissolved proteins (because plasma proteins cannot cross capillary walls).

Sal N

Tima

Ward

Z Serum Ciol Activator

consists of

Plasma

Plasma Proteins

55% (Range: 46-63%)

Other Solutes

Water

Formed Elements

PIOC

45% (Range: 37-54%)

Platelets

White Blood Cells

Red Blood Cells

382

The hematocrit (he-MAT-ō-krit) is the percentage of whole

blood volume contributed by formed elements. The normal hematocrit, or packed cell volume (PCV), in adult males is 46 and in adult females is 42. The sex difference in hematocrit primarily reflects the fact that androgens (male hormones) stimulate red blood cell production, whereas estrogens (female hormones) do not.

Formed elements are blood cells and cell fragments that are suspended in plasma. These elements account for about 45% of the volume of whole blood. Three types of formed elements exist: platelets, white blood cells, and red blood cells. Formed elements are produced through the process of hemopoiesis (hem-o-poy-E-sis). Two populations of stem cells-myeloid stem cells and lymphoid stem cells-are responsible for the production of formed elements.

FORMED ELEMENTS

92%

<.1%

99.9%

Plasma Proteins

Plasma proteins are in solution rather than forming insoluble fibers like those in other connective tissues, such as loose connective tissue or cartilage. On average, each 100 mL of plasma contains 7.6 g of protein, almost five times the concentra- tion in interstitial fluid. The large size and globular shapes of most blood proteins prevent them from crossing capillary walls, so they remain trapped within the bloodstream. The liver synthesizes and releases more than 90% of the plasma proteins, including all albumins and fibrinogen, most globulins, and various prohormones.

Albumins

(al-BU-minz) constitute roughly 60% of the plasma proteins. As the most abundant plasma proteins, they are major contributors to the osmotic pressure of plasma.

Globulins

Fibrinogen (fi-BRIN-ō-jen) functions

in clotting, and normally accounts for roughly 4% of plasma proteins. Under certain conditions, fibrinogen molecules interact, forming large, insoluble strands of fibrin (Fi-brin) that form the basic framework for a blood clot.

(GLOB-ü-linz) account for approximately 35% of the proteins in plasma. Important plasma globulins include antibodies and transport globulins. Antibodies,

also called immunoglobulins (i-mü-no-GLOB-u-linz), attack foreign proteins and pathogens. Transport globulins bind small ions, hormones, and other compounds.

Plasma also contains enzymes and hormones whose concentrations vary widely.

Other Solutes

Other solutes are generally present in concentrations similar to those in the interstitial fluids. However, because blood is a transport medium there may be differences in nutrient and waste product concentrations between arterial blood and venous blood.

Organic Nutrients: Organic nutrients are used for ATP production, growth, and maintenance of cells. This

category includes lipids (fatty acids, cholesterol, glycerides), carbohydrates (primarily glucose), amino acids, and vitamins.

Electrolytes:

Normal extracellular ion

composition is essential for

vital cellular activities. The

major plasma electrolytes are Na+, K+, Ca2+, Mg2+, Cr, HCO3, HPO4, and SO42-

Organic Wastes: Waste products are

carried to sites of breakdown

or excretion. Examples of organic wastes include urea, uric acid, creatinine, bilirubin, and ammonium

ions.

Platelets

Platelets are small, membrane-bound cell fragments that contain enzymes and other substances important to clotting.

White Blood Cells

White blood cells (WBCs), or leukocytes (LOO-kō-sits; leukos, white+ -cyte, cell), participate in the body's defense

mechanisms. There are five classes of

leukocytes, each with slightly different

Neutrophils

Basophils

functions that will be explored later in the chapter.

Lymphocytes

Eosinophils

Monocytes

Red Blood Cells

Red blood cells (RBCs), or erythrocytes (e-RITH-ro-sits; erythros, red + -cyte, cell), are the most abundant blood cells. These specialized cells are essential for the transport of oxygen in the blood.

383

384

CARDIOVASCULAR

FIGURE 11-2 The Anatomy of Red Blood Cells.

0.45-1.16 pm

2.31-2.85 pm

Colorized SEM X 2100

b The three-dimensional shape of

RBCs.

7.2-8.4 μm

A sectional view of a mature RBC, showing the normal ranges for its dimensions.

Blood smear

LM X 477

RBCs

a When viewed in a standard blood

smear, RBCs appear as

two-dimensional objects, because they are flattened against the surface of the slide.

plasma. This characteristic makes RBCs relatively inefficient in terms of energy use, but it ensures that any oxygen they absorb will be carried to peripheral tissues, not "stolen" by mitochondria in the cytoplasm.

HEMOGLOBIN STRUCTURE AND FUNCTION

A mature red blood cell consists of a cell membrane enclos- ing a mass of transport proteins. Molecules of hemoglobin (HE-mō-glō-bin) (Hb) account for over 95 percent of an RBC's intracellular proteins. Hemoglobin is responsible for the cell's ability to transport oxygen and carbon dioxide.

Two pairs of globular proteins (each pair composed of slightly different polypeptide chains) combine to form a single hemoglobin molecule. p. 45 Each of the four subunits con- tains a single molecule of an organic pigment called heme. Each heme molecule holds an iron ion in such a way that it can interact with an oxygen molecule (O2). The iron-oxygen interaction is very weak, and the two can easily separate. RBCs containing hemoglobin with bound oxygen give blood a bright red color. The RBCs give blood a dark red, almost burgundy, color when oxygen is not bound to hemoglobin.

The amount of oxygen bound in each RBC depends on the conditions in the surrounding plasma. When oxygen is abun- dant in the plasma, hemoglobin molecules gain oxygen until all the heme molecules are occupied. As plasma oxygen levels decline, plasma carbon dioxide levels are usually rising. Under

these conditions, hemoglobin molecules release their oxygen reserves, and the globin portion of each hemoglobin molecule begins to bind carbon dioxide molecules in a process that is just as reversible as the binding of oxygen to heme.

As red blood cells circulate, they are exposed to varying concentrations of oxygen and carbon dioxide. At the lungs, where diffusion brings oxygen into the plasma and removes carbon dioxide, the hemoglobin molecules in red blood cells respond by absorbing oxygen and releasing carbon dioxide. In peripheral tissues, the situation is reversed; active cells consume oxygen and produce carbon dioxide. As blood flows through these areas, oxygen diffuses out of the plasma, and carbon dioxide diffuses in. Under these conditions, hemo- globin releases its bound oxygen and binds carbon dioxide.

Normal activity levels can be sustained only when tissue oxygen levels are kept within normal limits. The blood of a per- son who has a low hematocrit, or whose RBCs have a reduced hemoglobin content, has a reduced oxygen-carrying capacity. This condition is called anemia. Anemia causes a variety of symptoms, including premature muscle fatigue, weakness, and a general lack of energy.

RBC LIFE SPAN AND CIRCULATION

RBCs are exposed to severe physical stresses. A single round- trip from the heart, through the peripheral tissues and back to the heart takes less than a minute. In that time, an RBC is forced along vessels where it bounces off the walls, collides

Chapter 11 The Cardiovascular System: Blood 385

Clinical Note

Abnormal Hemoglobin

Several inherited disorders are characterized by the production of abnormal hemoglobin. Two of the best known are thalassemia and sickle cell anemia (SCA).

The various forms of thalassemia (thal-ah-SE-me-uh) result from an inability to produce adequate amounts of the globular

protein components of hemoglobin. As a result, the rate of RBC production is slowed, and mature RBCs are fragile and short lived. The scarcity of healthy RBCs reduces the oxygen-carrying capacity of the blood and leads to problems in growth and development. Individuals with severe thalassemia must undergo frequent transfusions-the administration of blood components- to maintain adequate numbers of RBCs in the blood.

Sickle cell anemia (SCA) results from a mutation affecting the amino acid sequence of one pair of the globular proteins of the hemoglobin molecule. When blood contains an abundance of oxygen, the hemoglobin molecules and the RBCs that carry them appear normal. But when the defective hemoglobin gives up enough of its stored oxygen, the adjacent hemoglobin molecules interact and the cells change shape, becoming stiff and markedly curved (Figure 11-3). This "sickling" does not affect the oxygen-carrying capabilities of the RBCs, but it makes them more fragile and easily damaged. The untimely breakdown of such "sickled" RBCs produces a characteristic hemolytic anemia.

Moreover, when an RBC that has folded to squeeze into a nar- row capillary delivers its oxygen to the surrounding tissue, the cell can become stuck as sickling occurs. This blocks blood flow, and nearby tissues become oxygen starved.

FIGURE 11-3 Sickling in Red Blood Cells. When fully oxygenated, the red blood cells of an individual with the sickling trait appear relatively normal. At lower oxygen concentrations, the RBCs change shape, becoming more rigid and sharply curved.

with other red blood cells, and is squeezed through tiny capil- laries. With all this wear and tear and no repair mechanisms, an RBC has a short life span-only about 120 days. The con- tinuous elimination of RBCs usually goes unnoticed because new ones enter the circulation at a comparable rate. About 1 percent of the circulating RBCs are replaced each day, and approximately 3 million new RBCs enter the circulation each second!

Hemoglobin Recycling

As red blood cells age or are damaged, some of them rupture. When this occurs, the hemoglobin breaks down in the blood, and the individual polypeptide chains are filtered from the blood by the kidneys and lost in the urine. When large num- bers of RBCs break down in the circulation, the urine can turn reddish or brown, a condition called hemoglobinuria.

Fortunately, only about 10 percent of RBCs survive long enough to rupture, or hemolyze (HE-mō-liz), within the bloodstream. Instead, phagocytic cells (macrophages) in the liver, spleen, and bone marrow usually recognize and engulf RBCs before they undergo hemolysis, in the process recycling hemoglobin and other components of RBCs. (Phagocytosis

and phagocytic cells were introduced in Chapter 3; additional details are given in Chapter 14. p. 67)

The recycling of hemoglobin and turnover of red blood cells is shown in Figure 11-4. Once a red blood cell has been engulfed and broken down by a macrophage, each component of a hemoglobin molecule has a different fate:

1. The four globular proteins of each hemoglobin

molecule are broken apart into their component amino acids. These amino acids are either metabolized by the cell or released into the circulation for use by other cells.

2. Each heme molecule is stripped of its iron and

converted to biliverdin (bil-i-VER-din), an organic compound with a green color. (Bad bruises commonly appear greenish because biliverdin forms in the blood-filled tissues.) Biliverdin is then converted to bilirubin (bil-i-ROO-bin), an orange-yellow pigment, and released into the bloodstream. Liver cells absorb the bilirubin and normally release it into the small intestine within the bile. If, however, the bile ducts are blocked (by gallstones, for example), bilirubin then diffuses into peripheral tissues, giving them a yellow

386

CARDIOVASCULAR

FIGURE 11-4 Recycling of Hemoglobin.

Events Occurring in Macrophages

Macrophages monitor the condition of circulating RBCs, engulfing them before they hemolyze (rupture), or removing hemoglobin molecules, iron, and cell fragments from the RBCs that hemolyze in the bloodstream.

Events Occurring in the Red Bone Marrow

Developing RBCs absorb amino acids and Fe2+ from the bloodstream and synthesize new Hb molecules.

Macrophages in liver,

spleen, and bone marrow

Fe2+

Amino acids

Heme

Biliverdin

Bilirubin

Bilirubin bound to albumin in bloodstream

Liver

Bilirubin

Excreted

in bile

90%

Fe2* transported in the bloodstream

by transferrin

Average life span of RBC is 120 days

Old and

10%

damaged RBCs

In the bloodstream, the rupture of RBCs is called hemolysis.

New RBCs released into

circulation

Hemoglobin that is not phagocytized breaks down,

and the polypeptide subunits are eliminated in urine.

RBC formation

Kidney

Absorbed into the bloodstream

Urobilins

Bilirubin

Urobilins, stercobilins

Events Occurring in the Liver

Bilirubin released from

macrophages binds to albumin and is transported to the liver for excretion in bile.

Events Occurring in the Large Intestine

Bacteria convert bilirubin to urobilins and

stercobilins. Feces are yellow-brown or brown due to the presence of urobilins and stercobilins in varying proportions.

Eliminated in feces

Eliminated

in urine

Events Occurring in the Kidney

The kidneys excrete some hemoglobin, as well as urobilins, which gives urine its yellow color.

color that is most apparent in the skin and the sclera of the eyes. This combination of signs (yellow skin and eyes) is called jaundice (JAWN-dis). Bilirubin reaching the large intestine is converted to related pigment molecules, called urobilins (ūr-o-BI-lins) and stercobilins (ster-kō-BI-lins). Some are absorbed into the bloodstream and excreted into urine. It is these bilirubin-derived pigments that produce the yellow color of urine and the brown color of feces.

3. Iron extracted from heme molecules may be stored

in the macrophage or released into the bloodstream, where it binds to transferrin (tranz-FER-in), a plasma transport protein. Red blood cells developing in the bone marrow absorb amino acids and transferrins from the bloodstream and use them in the synthesis of new hemoglobin molecules. Excess transferrins are removed in the liver and spleen, where the iron is stored in special protein-iron complexes.

In summary, most of the components of an individual red blood cell are recycled following hemolysis or phagocytosis. The entire process is remarkably efficient; although roughly mg of iron are incorporated into hemoglobin molecules each day, a dietary supply of 1-2 mg can keep pace with the incidental losses that occur in the feces and urine.

Gender and Iron Reserves

Any impairment in iron uptake or metabolism can cause seri- ous clinical problems because RBC formation will be affected. Women are especially dependent on a normal dietary supply of iron because their iron reserves are smaller than those of men. The body of a normal man contains around 3.5 g of iron in the ionic form Fe2+. Of that amount, 2.5 g is bound to the hemoglobin of circulating red blood cells, and the rest is stored in the liver and bone marrow. In women, total body iron content averages 2.4 g, with roughly 1.9 g incorporated into red blood cells. Thus, a woman's iron reserves consist of only 0.5 g, half that of a typical man. If dietary supplies of iron are inadequate, hemoglobin production slows, and symp- toms of iron deficiency anemia appear. The accumulation of too much iron in the liver and in cardiac muscle tissue can also cause problems. Excessive iron deposition in cardiac muscle cells has been linked to heart disease.

RBC FORMATION

Embryonic blood cells appear in the bloodstream during the third week of development. These cells divide repeatedly,

Chapter 11 The Cardiovascular System: Blood 387

rapidly increasing in number. The vessels of the embryonic yolk sac are the primary sites of blood formation for the first eight weeks of development. As other organ systems appear, some of the embryonic blood cells move out of the blood- stream and into the liver, spleen, thymus, and bone marrow. These embryonic cells differentiate into stem cells that divide to produce blood cells.

The liver and spleen are the primary sites of hemopoiesis from the second to fifth months of development, but as the skeleton enlarges, the bone marrow becomes increasingly important. In adults, red bone marrow is the only site of red blood cell produc- tion, as well as the primary site of white blood cell formation.

Red blood cell formation, or erythropoiesis (e-rith-rō- poy-Ē-sis), occurs only in red bone marrow, or myeloid tissue (MI-e-loyd; myelos, marrow). This tissue is located in the vertebrae, sternum, ribs, scapulae, pelvis, and proxi- mal limb bones. Other marrow areas contain a fatty tissue known as yellow bone marrow. Under extreme stimulation, such as a severe and sustained blood loss, areas of yellow marrow can convert to red marrow, increasing the rate of RBC formation.

Stages in RBC Maturation

Specialists in blood formation and function-hematologists (he-ma-TOL-o-jists)—give specific names to key stages in the maturation of the formed elements. Like all formed elements, RBCs result from the divisions of hemocytoblasts (multipotent stem cells) in red bone marrow (Figure 11-5). In giving rise to the cells that ultimately become RBCs, the hemocytoblasts produce myeloid stem cells, some of which proceed through a series of stages in their development to mature erythrocytes (see left side of Figure 11-5).

Erythroblasts are very immature red blood cells that are actively synthesizing hemoglobin. After roughly 4 days of dif- ferentiation, each erythroblast sheds its nucleus and becomes a reticulocyte (re-TIK-u-lō-sit). After 2 or 3 more days in the bone marrow synthesizing proteins, reticulocytes en- ter the bloodstream. At this time they can still be detected in a blood smear with stains that specifically combine with RNA. Normally, reticulocytes account for about 0.8 percent of the circulating erythrocytes. After 24 hours in circulation, the reticulocytes complete their maturation and become. indistinguishable from other mature RBCs.

The Regulation of Erythropoiesis

For erythropoiesis to proceed normally, the red bone mar- row must receive adequate supplies of amino acids, iron, and

388

CARDIOVASCULAR

FIGURE 11-5 The Origins and Differentiation of RBCs, Platelets, and WBCs. Hemocytoblast divisions give rise to myeloid stem cells or lymphoid stem cells. Lymphoid stem cells produce the various lymphocytes. Myeloid stem cells produce cells that ultimately become red blood cells, platelets, and the four other types of white blood cells. Hematologists use specific terms for the various key stages the formed elements pass through on the way to maturity. The targets of EPO and the four colony-stimulating factors (CSFs) are also indicated.

Red bone marrow

Myeloid Stem Cells

Multi-CSF

Hemocytoblasts

Progenitor Cells

EPO

GM-CSF

EPO

G-CSF

Proerythroblast

Myeloblast

Erythroblast stages

Reticulocyte

Ejection of nucleus

Megakaryocyte

Lymphoid Stem Cells

Blast Cells

M-CSF

Monoblast

Lymphoblast

Myelocytes

Band Cells

Erythrocyte

Platelets

Basophil

Red Blood Cells (RBCs)

Eosinophil

Granulocytes

Neutrophil

White Blood Cells (WBCs)

Promonocyte

Prolymphocyte

Monocyte

Lymphocyte

Agranulocytes

FIGURE 11-6 The Role of EPO in the Control of Erythropoiesis. Tissues deprived of oxygen release EPO, which accelerates division of stem cells and the maturation of erythroblasts. More red blood cells then enter the circulation, improving the delivery of oxygen to peripheral tissues.

Release of erythropoietin (EPO)

Red bone marrow

Increased mitotic rate

Stem cells

HOMEOSTASIS

Erythroblasts

DISTURBED

Tissue oxygen

Accelerated maturation

levels decline

HOMEOSTASIS

RESTORED

Tissue oxygen levels rise

Improved

охудел content of blood

Reticulocytes

Increased numbers of circulating RBCs

Chapter 11 The Cardiovascular System: Blood 389

cells that produce erythroblasts, and (2) it speeds up the maturation of red blood cells, primarily by accelerating the rate of hemoglobin synthesis. Under maximum EPO stimulation, the red bone marrow can increase the rate of RBC formation tenfold, to around 30 million cells per second.

This ability is important to a person recovering from a severe blood loss. However, if EPO is administered to a healthy person, the hematocrit may rise to 65 or more, and the resulting increase in blood viscosity increases the workload on the heart, which can lead to sudden death from heart failure. Similar risks result from blood doping, in which athletes reinfuse packed RBCs removed at an earlier date. The goal is to improve oxygen delivery to muscles, thereby enhancing performance.

The BIG PICTURE

Red blood cells (RBCs) are the most numerous cells in the body. They remain in circulation for approximately four months before being recycled; several million are produced each second. The hemoglobin inside RBCs transports oxygen from the lungs to peripheral tissues; it also carries carbon dioxide from those tissues to the lungs.

vitamins (including B12, B6, and folic acid) for protein syn- thesis. We obtain vitamin B12 from dairy products and meat, but its absorption requires the presence of intrinsic factor pro- duced in the stomach. If vitamin B12 is not obtained from the diet, normal stem cell divisions cannot occur, and pernicious anemia results. Erythropoiesis is stimulated directly by the hormone erythropoietin and indirectly by several hormones, including thyroxine, androgens, and growth hormone.

Erythropoietin (EPO), also called erythropoiesis-stimulating hormone, appears in the plasma when peripheral tissues- especially the kidneys-are exposed to low oxygen concen- trations (Figure 11-6). A low oxygen level in tissues is called hypoxia (hi-POKS-e-uh; hypo-, below + oxy-, presence of oxygen). EPO is released (1) during anemia, (2) when blood flow to the kidneys declines, (3) when the oxygen content of air in the lungs declines (due to disease or high altitude), and (4) when the respiratory surfaces of the lungs are damaged. Once in the bloodstream, EPO travels to red bone marrow, where it stimulates stem cells and developing RBCs.

Erythropoietin has two major effects: (1) It stimulates increased cell division rates in erythroblasts and in the stem

CHECKPOINT

6. Describe hemoglobin.

7. What effect does dehydration have on an individual's

hematocrit?

8. In what way would a disease that causes liver damage affect

the level of bilirubin in the blood?

9. What effect does a reduction in oxygen supply to the

kidneys have on levels of erythropoietin in the blood?

See the blue Answers tab at the back of the book.

11-4 The ABO blood types and Rh system are based on antigen-antibody responses

Antigens are substances (most often proteins) that can trigger a protective defense mechanism called an immune response. The plasma membranes of all your cells contain surface antigens, substances that your immune defenses recognize as "normal.” In other words, your immune system ignores these substances rather than attacking them as "foreign."

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Table 11-1

The Distribution of Blood Types in Selected Populations

Percentage with Each Blood Type Rh+

Population

U.S. (AVERAGE)

African American

Caucasian

Chinese American

100

Filipino American

100

Hawaiian

100

Japanese American

Korean American

100

NATIVE NORTH AMERICAN

100

NATIVE SOUTH AMERICAN

100

100

AUSTRALIAN ABORIGINE

100

0 100

The presence or absence of specific surface antigens in RBC membranes determines your blood type. Your genetic makeup determines which antigens occur on your RBCs. Although red blood cells have at least 50 kinds of surface antigens, three are of particular importance: A, B, and Rh (or D).

Based on RBC surface antigens, there are four blood types (Figure 11-7a). Type A blood has antigen A only, Type B has antigen B only, Type AB has both A and B, and Type O has neither A nor B. Variations in these values differ by ethnic group and by region (Table 11-1).

The term Rh positive (Rh) indicates the presence of the Rh antigen on the surface of RBCs. The term Rh nega- tive (Rh) indicates the absence of this antigen. When an individual's complete blood type is recorded, the term Rh is usually omitted, and the data are reported as O negative (0), A positive (A*), and so on. In the general U.S. popu- lation, blood types are distributed approximately as follows: O*, 38 percent; A*, 34 percent; B*, 9 percent; O", 7 per- cent; A, 6 percent; AB*, 3 percent; B, 2 percent; and AB ̄, 1 percent.

CROSS-REACTIONS IN TRANSFUSIONS

We noted previously that your immune system ignores the sur- face antigens also called agglutinogens (a-gloo-TIN-o-jenz)— on your own RBCs. However, your plasma contains antibodies, or agglutinins (a-GLOO-ti-ninz), that will attack surface anti- gens on RBCs of a different blood type (Figure 11-7a). Thus, the

plasma of individuals with Type A blood contains circulating anti-B antibodies, which will attack Type B surface antigens, and the plasma of Type B individuals contains anti-A antibod- ies, which will attack Type A surface antigens. Similarly, Type AB individuals lack antibodies against either A or B surface antigens, whereas the plasma of individuals with Type O blood contains both anti-A and anti-B antibodies.

The presence of these antibodies is why, before blood. is transfused, the blood types of donor and recipient are identified. If an individual receives blood of a different blood type, antibodies in the recipient's plasma meet their specific antigen on the donated RBCs, and a cross-reaction occurs (Figure 11-7b). Initially the binding of antigens and antibodies causes the foreign RBCs to clump together- a process called agglutination (a-gloo-ti-NA-shun). Sub- sequently, the RBCs may break up, or hemolyze. Clumps and fragments of RBCs under attack from antibodies form drifting masses that can plug small vessels in the kidneys, lungs, heart, or brain, damaging or destroying tissues. Such cross-reactions, or transfusion reactions, can be avoided by ensuring that the blood types of donor and recipient are compatible.

In practice, the surface antigens on the donor's cells are more important in determining compatibility than are the antibodies in the donor's plasma. Unless large volumes of whole blood or plasma are transferred, cross-reactions. between the donor's plasma and the recipient's blood cells will fail to produce significant agglutination. Packed RBCs, with a minimal amount of plasma, are commonly transfused. Even when whole blood is transfused, the plasma is diluted through mixing with the recipient's relatively large plasma volume.

Unlike the case for Type A and Type B individuals, the plasma of an Rh-negative individual does not normally contain anti-Rh antibodies. These antibodies are present only if the individual has been sensitized by previous exposure to Rh-positive RBCs. Such exposure can occur accidentally, during a transfusion, but it can also occur in a normal preg- nancy when an Rh-negative mother carries an Rh-positive fetus.

CHECKPOINT

10. Which blood type(s) can be safely transfused into a person

with Type AB blood?

11. Why can't a person with Type A blood safely receive blood

from a person with Type B blood?

See the blue Answers tab at the back of the book.

FIGURE 11-7 Blood Types and Cross-Reactions.

Chapter 11 The Cardiovascular System: Blood

Туре А

Type B

Type AB

Type A blood has RBCs with surface antigen A only.

Type B blood has RBCs with surface antigen B only.

Type AB blood has RBCs with both A and B surface antigens.

Surface antigen A

Surface antigen B

Type O

Type O blood has RBCs lacking both A and B surface antigens.

391

If you have Type A blood, your plasma contains anti-B antibodies, which will attack Type B surface antigens.

دل

If you have Type B blood, your plasma contains anti-A antibodies, which will attack Type A surface antigens.

If you have Type AB blood,

your plasma has neither anti-A nor anti-B antibodies.

XYYX

a Blood type depends on the presence of surface antigens (agglutinogens) on RBC surfaces. The plasma contains

antibodies (agglutinins) that will react with foreign surface antigens.

If you have Type O blood, your

plasma contains both anti-A and anti-B antibodies.

RBC

Surface antigens

Opposing antibodies

Agglutination (clumping)

b In a cross-reaction, antibodies react with their target antigens causing agglutination and hemolysis of the affected RBCs.

Hemolysis

Clinical Note

Hemolytic Disease of the Newborn

Genes controlling the presence or absence of any surface antigen in the membrane of an RBC are

provided by both parents, so a child's blood type can differ from that of either parent. During pregnancy, when fetal and maternal circulatory systems are closely intertwined, certain kinds of an- tibodies from the mother may cross the placenta, attacking and destroying fetal RBCs. The resulting potentially fatal condition is called hemolytic disease of the newborn (HDN).

The sensitization that causes this condition usually occurs during delivery, when bleeding at the placenta and uterus exposes an Rh-negative mother to an Rh-positive fetus's Rh antigens.

This event can trigger the production of anti-Rh antibodies in the mother. Because these antibodies are not produced in signifi cant amounts until after delivery, the first Rh-positive infant is not affected. However, a sensitized Rh- negative mother will respond to a second Rh-positive fetus by producing massive amounts of anti-Rh antibodies. These antibodies attack and hemolyze the fetal RBCs, producing a dangerous anemia, which increases the fetal demand for blood cells. The resulting RBCs leave the bone marrow and enter the circulation before completing their development. Because these immature RBCs are erythroblasts, HDN is also known as erythroblastosis fetalis (e-rith-rō-blas- TŌ-sis fe-TAL-is).

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Clinical Note

Testing for Blood Compatibility

Testing for blood compatibility normally involves two steps: a determination of blood type and a cross- match test. The standard test for blood type categorizes a blood sample on the basis of the three RBC surface antigens most likely to produce dangerous cross-reactions (Figure 11-8). The test involves mixing drops of blood with solutions containing anti-A, anti-B, and anti-Rh antibodies and noting any cross-reactions. For example, if the RBCs clump together when exposed to anti-A and anti-B, the individual has Type AB blood. If no reactions occur, the person must be Type O. The presence or absence of the Rh anti- gen is also noted, and the individual is classified as Rh-positive or Rh-negative. In the most common type-Type O-positive (0*)- the RBCs lack surface antigens A and B, but they do have the Rh antigen. Standard blood typing of both donor and recipient can be completed in a matter of minutes.

In an emergency (such as a severe gunshot wound), a patient may require 5 liters or more of blood before the damage can be repaired. Under these circumstances, Type O blood can be safely administered to a victim of any blood type because Type O RBCs lack A and B surface antigens. Because their blood cells are unlikely to produce severe cross-reactions in a recipient, Type O (especially O ̄) individuals are sometimes called universal donors. Type AB individuals were once called universal recipients because they lack anti-A or anti-B antibodies, which would attack donated RBCs. This term has been dropped from usage largely because reliable blood supplies and quick compatibility testing typically allow the administration of Type AB blood to Type AB recipients. With at least 48 other possible antigens on the cell surface, however, cross-reactions can occur, even to Type O blood. Whenever time and facilities permit, further testing is performed to ensure complete compatibility. Cross-match testing involves exposing the donor's RBCs to a sample of the recipient's plasma under controlled conditions. This procedure reveals the

FIGURE 11-8 Blood Type Testing. Test results for blood samples from four individuals. Drops of blood are mixed with solutions containing antibodies to the surface antigens A, B, and Rh (D). Clumping occurs when the sample contains the corresponding surface antigen(s). The blood types of the individuals are shown at right.

Anti-A

Anti-B

Blood

Anti-Rh

type

A+

B+

AB+

presence of significant cross-reactions involving other antigens and antibodies. Another way to avoid compatibility problems is to replace lost blood with synthetic blood substitutes, which do not contain surface antigens that can trigger a cross-reaction.

Other applications of blood compatibility-for example, paternity tests and crime detection-stem from the fact that blood groups are inherited. Results from such tests cannot prove that a particular individual is the criminal or the father involved, but it can prove that he is not involved. For example, a man with Type AB blood cannot be the father of an infant with Type O blood.

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