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10
Blood
Major Themes
The cellular elements of blood have a short life span and require continuous replacement. White blood cells play a critical role in defending the body against microbes and other foreign substances. Red blood cells transport oxygen from the lungs to tissues and return carbon dioxide. Platelets are cell fragments critical in the prevention and control of hemorrhage. Certain plasma proteins are important in body defenses, in the transport of essential substances, in maintaining blood volume, and in blood clotting. Numerous nutrient and waste substances are dissolved in plasma.
Chapter Objectives
Overview of Blood 376
1. List five functions of blood, and list the
blood component related to each function. Be as specific as possible.
4. Compare and contrast acute inflammation,

chronic inflammation, parasitic inflammation, and allergies, and list the cells involved in each.
Erythrocytes and Oxygen Transport

blood cells and explain the functional implications of each characteristic.
387
5. List three physical characteristics of red
2. Name the three types of plasma proteins

and roles of each.
Leukocytes, Inflammation, and Immunity 383

3. Classify leukocytes based on their
appearance and function.
6. Describe the structure and function of

hemoglobin.
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7. Describe the life cycle of a red blood cell. 8. Discuss the diagnosis and possible causes of
anemia.
12. Use flowcharts to illustrate the tissue factor

pathway, contact activation pathway, and common pathway of blood clotting, and explain how two different anticoagulants work.
9. Discuss the pathway that results in increased red

cell production in individuals living at high altitudes.
13. List three differences between coagulation and

thrombosis.
Platelets
392
Blood Groups and Transfusion
398
10. Describe the regulation and mechanism of

platelet synthesis and the problems associated with thrombocytopenia.
14. Determine which blood group can be transfused

into patients with A, B, O, or AB blood, and explain why agglutination reactions occur.
Hemostasis
393
Bone Marrow Failure: The Case of Eleanor B. 403

15. Use the case study to explain the central role of
bone marrow in blood cell production and to discuss the roles of erythrocytes, platelets, and leukocytes.
11. Use diagrams to explain the three steps of

hemostasis.
My life is running out of my nose!

As you read through the following case study, assemble a list of the terms and concepts you must learn in order to understand Eleanors case. Clinical History: Eleanor B., a 52-year-old professor of anthropology, presented to the emergency room of a large metropolitan hospital with a severe nosebleed. I never have nosebleeds. This takes the cake; it just wont stop. My life is running out of my nose! Questioning by hospital staff revealed that 8 years earlier she had surgery for breast cancer. Physicians had followed her closely until 3 years earlier, when she divorced and moved to her current job in a new city. Im embarrassed to admit that I havent seen a doctor in three years, she said. Ive just been too busy to have my regular checkups. Further questioning revealed nothing medically unusual. She mentioned, however, having felt unusually tired in the last few months. I seem to wear out at even the smallest tasks. Last week I stopped for a rest on a park bench on my way home. Thats never been necessary before. Physical examination and other data: Eleanor was pale, and her skin contained numerous pinpoint hemorrhages. Otherwise her physical examination was unremarkable. Blood analysis revealed a marked deficiency in red blood cells, white blood cells, and platelets. Her blood type was determined to be O positive. Clinical course: In the emergency room her nose was packed with cotton strips and she was transfused with platelets, which stopped the nosebleed. She was admitted to the hospital and transfused with red blood cells. Knowing that breast cancer has a tendency to spread to bones, the examining physician suspected that cancer cells had taken over her red bone marrow, the site of blood cell production. This theory was confirmed by a bone marrow biopsy, which showed nearly complete replacement of normal bone marrow by cancer cells.
375
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Need to Know
It is important to understand the terms and concepts listed below before tackling the new information in this chapter. Osmosis, cell structure, stem cells, properties of connective (Chapter 3) tissues Chemical signaling, hormone regulation (Chapter 4)
She was treated with additional chemotherapy but continued to need red blood cell transfusions to maintain hemoglobin near the normal level, and she required antibiotic treatment on several occasions for bacterial infectionspneumonia, skin abscesses, and recurrent diarrhea. Nine months later she was brought to the emergency room by ambulance for severe bloody vomiting. She was pale and confused, with blood pressure 60/20 mm Hg (normal: 120/80) and heart rate 140 beats per minute (normal: 70). Despite heroic efforts to save her, her heart stopped and could not be restarted. Lab studies from blood collected before her death showed the counts of red and white blood cells and platelets to be very low. Staphylococcus aureus, a bacterium, was cultured from her blood. At autopsy, the bone cavities normally containing red marrow were filled with tumor; little normal marrow remained. She was also found to have severe bacterial pneumonia and an extensive fungal infection in her esophagus. The latter had produced a large esophageal ulcer, which was the source of her fatal hemorrhage.
Our earliest ancestors recognized that blood was vital to life: whether gushing from man or mastodon, it was a warm, red, sticky fluid that carried away with it the victims life force. Honoring its importance, ancient peoples used blood in sacrificial rites, and the color of blood has come to symbolize valor and vitality. Eastern European folklore describes vampirescreatures who, by drinking fresh blood, could stave off death. Its not such a far-fetched ideaeven today we take blood from one person to give to another for that very purpose. So what, exactly, is this life-sustaining fluid that we hold so dear?
Dont worry; the bleeding always stops.

Advice from older surgeons to worried younger ones.
Overview of Blood
Blood is the fluid circulated by the heart through the blood vessels. Blood cells are made by the bone marrow and released into blood. Recall from Chapter 3 that we defined blood as liquid connective tissue. It fits that classification for two reasons: (1) functionally, it connects various parts of the body by carrying chemical signals, fluids, and nutrients from one place to another; (2) structurally, it contains cells and a large amount of extracellular matrix (plasma),
which in the case of blood, is liquid rather than solid. In addition, like cells in solid connective tissues, blood cells require nutrients, produce wastes, die, and are replaced by new cells. But although classified as connective tissue, blood has certain distinctive properties that set it apart from other tissues:
Blood cells are in continuous motion. The life span of blood cells is unusually short, varying
from a few hours to a few months.

Blood is redbright red if well oxygenated (on the
way to tissues from the lungs), dark reddish-blue if
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oxygen-depleted (on the way back to the lungs from tissues). Although it is a fluid, blood is thicker (more viscous) than water because it contains proteins and cells; it feels slightly oily and sticky for the same reason. Blood is slightly alkaline: pH averages about 7.40 (water is 7.0). Blood accounts for about 7% of body weightabout 5 kilograms (5 liters or 6 quarts of volume) in a 70-kg (155 lb) person. Before we explore the structure of blood in detail, lets take a look at its functions.
Blood elements form a clot to reduce blood loss.
Blood transfers heat to the skin surface to be lost. Blood elements defend against microbes entering body openings or wounds. Bloods hydraulic force sustains urine formation by kidneys.
Blood Has Five Main Functions

In the broadest sense, blood is a transportation system, truly an inner river that carries the essentials of life to tissues, returns metabolic wastes for elimination, and conveys chemical messages (Fig. 10.1). In particular, the functions of blood are:
Transport. Blood transports gases (such as oxygen),
nutrients, waste products, and chemical messages between organs, tissues, and cells. Hydraulic force. This is the pressure created by fluid flowing in a closed space. Blood propelled out of the heart into blood vessels creates a form of hydraulic pressure called blood pressure. Without adequate blood pressure, human life is impossiblethe vital substances blood transports will not reach distant tissues. Moreover, blood pressure enables the kidney to make urine and provides the hydraulic force for male and female erection. Defense. Blood cells and other blood-borne substances defend against threats originating both externally (microbes) and internally (cancer). Heat transfer. The circulation of blood through the skin exposes blood to skin temperature, which is normally much cooler than the core temperature of organs, where the metabolism of nutrients generates heat. Warm blood passes through skin, heat is lost, and cooler blood returns to the body core. Prevention of blood loss. Blood cells and elements form short-lived blockages in damaged vessels in order to prevent blood loss following tissue injury.
Blood transports oxygen, nutrients, wastes, and chemical messengers.
Figure 10.1. Blood functions. The many functions of blood, as illustrated by a wounded hiker. The hikers face is flushed, reflecting increased blood flow. How does this increased superficial blood flow help him?
healing. Sometimes this worsened the patients illness or led to the loss of the patients life, as we discuss in the accompanying History of Science box, titled The History of Blood Transfusion.
Blood Is Composed of Plasma and Cellular Elements

As we just noted, blood is composed of two main compartments: a fluid extracellular matrix called plasma and the solid cellular elements suspended within it. The cellular elements are whole blood cells and fragments of cells called platelets. Clinicians refer to plasma and its cellular components together as whole blood. Because the cellular elements are heavier (denser) than plasma, we can separate the two by centrifugation in a tubethe heavy cellular elements settle to the bottom of the tube
Until about 150 years ago, few physicians had more than a vague understanding of these functions and their relationship to health. Indeed, their fanciful theories of illness sometimes led them to bleed patients of large quantities of blood in a misguided effort to promote
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Human Form, Human Function: Essentials of Anatomy & Physiology
The History of Blood Transfusion

The circulation of blood in blood vessels through the body had been worked out correctly in the 13th century by an Arab physician named Ibn Al-Nafis. He rejected the prevailing view, originating in the second century with the Greek physician Galen, that bright red arterial blood originated in the heart and was consumed by the tissues, and that dark venous blood originated in the liver and served another purpose. Ibn Al-Nafiss findings were not known in Europe for centuries. Thus, the idea of blood flowing in blood vessels was not understood in the West until English physician William Harvey discovered the facts in 1628. Even before physicians understood the anatomy and physiology of the circulatory system, however, they made crude attempts to infuse blood into the sick. The first recorded attempt occurred in 1492, as Columbus was discovering the Americas. Pope Innocent VIII lay comatose in Rome and physicians attempted to rescue him by collecting blood from three 10-year-old boys and infusing it into the pope. Since the concept of blood circulating in veins had not yet been established, the blood was infused into his mouth. It was not a successthe Pope and all the boys died. In 1665, British physician Richard Lower devised instruments to shunt blood between surgically joined dogs. He observed that the ill effect of blood loss on one dog could be reversed by shunting the blood of a second dog into the first. A few years later, in 1668, Dr. Jean-Baptiste Denys, personal physician to King Louis XIV of France, transfused a small amount of sheeps blood into a 15year-old boy. The boy survived and the experiment was counted a success, but modern physicians recognize that his survival was likely due to the small amount of blood transfused. One of Dr. Denyss less fortunate patients survived two such transfusions but died after the third, amid great controversy. The first human-to-human intravascular blood transfusion would not occur for about another 150 years. In 1818, Dr. James Blundell, a British obstetrician caring for a woman who was hemorrhaging after
Blood transfusions. Direct person-to-person transfusions.
childbirth, recruited the patients husband as a donor and extracted four ounces (about 120 mL) of blood from the mans arm to transfuse into his wife. In the ensuing years, Dr. Blundell performed 10 additional transfusions, 5 of which were judged beneficial. For another 100 years, all attempts at blood transfusion were direct: from the body of one person directly into another. Two advancesblood banking and compatibility testingwere required before indirect blood transfusions could be widely used. In about 1918, perhaps stimulated by the awful carnage of World War I (19141918), it was discovered that blood could be anticoagulated, refrigerated, and stored (banked) for a few days before transfusion. But blood banking was of limited use until the concept of donor and recipient blood compatibility came to be understood. This leap forward can be attributed to the work of the Austrian scientist Karl Landsteiner. He discovered ABO blood groups in 1900, and, with his colleague Alexander Wiener, discovered the Rh blood group in 1937. With this discovery, all of the pieces were at last in place and modern transfusion practice spread widely.
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beneath the lighter liquid at the top (Fig. 10.2A). When we do this, heres what we see:
At the top of our tube is plasma, the liquid part of
automated machines, and the procedure is typically referred to as a complete blood count (CBC).
Case Notes
10.1. In Eleanors case, the initial blood analysis found that cellular elements accounted for about 27% of her blood volume. What percent of her blood volume was composed of plasma? 10.2. Based on the information in the previous case note, what was Eleanors approximate hematocrit?
blood, which accounts for about 55% of blood volume. It is a golden, syrupy mix composed mainly of water in which are dissolved proteins, nutrients, minerals, and other life essentials. At the bottom of the tube are red blood cells (clinically referred to as erythrocytes, erythro red), the heaviest and most numerous cells. They normally account for about 45% of blood volume, a percentage called the hematocrit (Greek haima blood; krites judge, as in someone who separates things, such as right from wrong). At the interface between plasma and red cells is a thin, tan layer, the buffy coat. This layer contains cells that are not as heavy as red cellswhite blood cells (clinically referred to as leukocytes, leuko white): these include monocytes, lymphocytes, neutrophils, eosinophils, and basophils. The buffy coat also contains platelets, fragments of a bone marrow cell called a megakaryocyte. The buffy coat normally accounts for less than 1% of blood volume.
Plasma Contains Water and Solutes

Plasma is the extracellular fluid of blood. It is nearly identical to the interstitial fluid of solid tissues (Chapter 5) except for the large amount of blood proteins it contains. Transparent and straw-colored, plasma is about 90% water; about 9% is composed of specialized proteins. There are three major types of plasma proteins:
Albumin. The most abundant (about 55%) of all plasma
Remember This! The two major compartments of blood are fluid (plasma) and solid matter (cellular elements).
The cellular elements of blood are easily visualized by microscopic examination of a blood smear. In this procedure, the lab technician spreads a drop of blood thinly over a microscope slide (Fig. 10.2B) and then stains the smear with Wrights stain, a mixture of blue and red dyes that impart colors to the various elements of the cells. It includes hematoxylin, a dark blue, alkaline dye, which stains the nucleus blue, and eosin, a bright red, acidic dye, which stains the cytoplasm pale red or pink. Cell organelles may stain a mixture of red, blue, or neutral tan. Based on the size and shape of the cells, the presence or absence of a nucleus, and the color of cytoplasmic granules (if any), the various cellular elements can easily be identified (see Table 10.1 on page 383). In addition to centrifugation to determine the hematocrit, other laboratory procedures can be employed to count the number of red blood cells, white blood cells, and platelets; measure the average size of the red blood cells; determine the amount of oxygen-carrying hemoglobin in the red blood cells; and determine the percentage of the various subtypes of white blood cells. Typically these measurements are done as a group by
proteins is albumin. Albumin accounts for most of the plasma osmotic pressure (Chapter 3), the force that tends to hold water in blood and draw water across the blood vessel wall from tissues into the bloodstream. This ability to keep water inside blood vessels is very important in maintaining blood volume. Albumin also acts as a binding protein that transports fatty acids, steroids, and other substances in blood. Fibrinogen. Somewhat over 5% of plasma protein is fibrinogen, a small protein involved in blood clotting, as explained later in the text. Globulins. Most of the other blood proteins are globulins, a catchall category that includes specialized binding (transport) proteins, enzymes, protein hormones, and clotting factors. For example, transferrin is a special globulin that transports iron, an important function discussed further on. Of particular interest is a subgroup of globulins, the gamma globulins, also called antibodies, made by specialized white blood cells to attack harmful microbes. About 1% of plasma is a rich mixture of other solutes. These include:

Glucose Cholesterol and other lipids Vitamins and other essential compounds Calcium, iron, sodium, potassium, and other minerals Metabolic wastes Dissolved gases such as oxygen, nitrogen, and carbon dioxide.
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380
1
Whole blood is withdrawn from a vein and transferred to a tube.
2
Centrifugation separates blood elements by their density.
Buffy coat: <1% Leukocytes
Plasma: 55% Water Proteins: Albumins Globulins Fibrinogen Other solutes: Nutrients Electrolytes Gases Wastes
Neutrophils
Lymphocytes
Monocytes
Erythrocytes: 44% Platelets Eosinophils
6 million/ l
Basophils Erythrocytes (a) Separation of blood elements using centrifugation Platelet
1
A blood droplet is transferred to a microscope slide.
Eosinophil
Lymphocyte
2
A second slide spreads out the droplet, forming a thin (one-cell thick) smear.
Neutrophil
Basophil
Monocyte
3
(b) Preparation of a blood smear The smear is stained with Wright stain to visualize cells.
Figure 10.2. Blood components. A. Centrifugation separates out the different blood elements to permit blood analysis. In a tube of centrifuged blood, cellular elements (erythrocytes, platelets, and white blood cells) constitute the bottom 45% (or so) and plasma constitutes the upper 55%. B. Blood smears are used to visualize the different cellular elements of a patients blood. The small insets show how monocytes, basophils, and eosinophils (which are few) would appear in a blood smear. Name the only cellular element that is not found in the buffy coat.
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Plasma is 90% water, 9% protein, 1% nonprotein solutes.
Remember This!
Cellular Elements Are Produced in the Bone Marrow

Like all cells, blood cells have a life cyclethey are produced, they work, and then they die by apoptosis. Compared with cells in most other tissues, the life span of all blood cells is short. Among blood cells, erythrocytes have by far the longest life span, about 120 days; leukocytes have life spans varying from a few hours to 2 weeks, and platelets live a week or two. Old blood cells and platelets die a natural death from apoptosis and are removed from circulation by the spleen. It is important to remember that the number of a particular type of cell in a blood sample depends upon its life span as well as its rate of productioncells with longer life spans and greater production will be present in greater numbers. The generation of blood cells is called hematopoiesis (Greek haima blood; poiesis formation). All blood cells arise from a common ancestor, a pluripotent hematopoietic stem cell, literally a blood cell with many powers (Fig. 10.3). It resides in the bone marrow. This master cell, in turn, gives rise to two types of specialized stem cells with narrower powers:
Lymphoid stem cells give rise to lymphocytes, a type
that white cells have much shorter life spans than red blood cells, so they must be replaced much more often. The production of cellular blood elements in the fetus differs materially from that in an adult. In the embryo and developing fetus, cellular elements of blood are produced primarily in the liver and spleen; but by the time of birth, production has gradually shifted to the red marrow. However, the liver and spleen retain their ability to produce cellular elements throughout life and will do so, even in older adults, under some circumstances. Blood cell production by the liver and spleen in an adult is called extramedullary hematopoiesis (hematopoiesis away from the medullary cavity of bones). It can occur in certain conditions that wipe out the bone marrow. For example, in Eleanors case, metastatic breast cancer in her bones replaced most of her red marrow, forcing the liver and spleen to take over hematopoiesis.
Case Note
10.3. At autopsy, Eleanor was found to have blood cell production in her liver and spleen. What is the name of this condition and what does it mean?
10.1 True or false: Blood, like cartilage, is classified as connective tissue. 10.2 List four substances transported by blood. 10.3 Explain why the hydraulic force of blood is important. 10.4 Name two types of threats that blood defends against. 10.5 True or false: Increasing the circulation of blood through skin warms the body. 10.6 Name the two main compartments of blood. 10.7 If you leave a tube of blood at room temperature, the red blood cells will settle to the bottom of the tube. Why? 10.8 Is a test result of 47% from a hematocrit or a blood smear? 10.9 Change the underlined term to make this statement true: Albumin is a specialized protein that transports iron. 10.10 If we wanted to make neutrophils in the test tube, which type of stem cell would we uselymphoid or myeloid? 10.11 Which blood element lives the longestred blood cells, white blood cells, or platelets?
of leukocyte. Myeloid stem cells give rise to all other blood cells the four other types of leukocytes as well as erythrocytes. They also produce megakaryocytes, which produce platelets. The harvesting of pluripotent stem cells holds great therapeutic promise if they can be collected in abundance and coaxed into forming new blood cells or perhaps other cells, such as heart or liver cells. It turns out that blood collected from the umbilical cord of a newborn infant is rich in pluripotent stem cells and can be frozen for future use or cultivated immediately for benefit to the infant itself or to someone else. Recall from our discussion of bones in Chapter 6 that bone marrow is either yellow (fatty) or red (hematopoietic). Red marrow actively produces blood cells; yellow marrow normally does not. In adults, most red marrow lies in the marrow cavity of bones of the spine, pelvis, ribs, cranium, and the proximal ends of long bones. Despite the fact that RBCs are 1,000 times more abundant than WBCs in blood, only about 25% of red marrow is composed of developing red cells; the remaining 75% consists of developing white cells. This owes to the fact
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Blood
Megakaryocyte
Platelets
Erythrocyte
Myeloid stem cell
Neutrophil
Basophil
Pluripotent hematopoietic stem cell Eosinophil
Leukocytes
Monocyte
Lymphoid stem cell
Lymphocyte
Figure 10.3. Hematopoiesis. All blood cells are the offspring of pluripotent hematopoietic stem cells that arise in the bone marrow. Numerous intermediate cell types between the stem cells and the mature blood cells are not illustrated. Which blood cell is not produced from a myeloid stem cell?
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Leukocytes, Inflammation, and Immunity

Leukocytes (white blood cells, or WBCs) defend the body against infections, airborne particulate matter, and newly hatched tumor cells; when tissue is damaged, WBCs clean up the debris and assist with repair. Such functions would not be possible for cells confined within blood vessels, but leukocytes are motile. In fact, their unique form of movement has its own name, diapedesis (Greek dia through pedan leap), which nicely captures their amebalike ability to crawl between adja-
cent cells in the walls of blood vessels and squirm out into the tissues. There, they roam at large, performing their tasks. Normal blood contains about 5,000 to 10,000 leukocytes per microliter (one thousandth of a milliliter, also defined as a cubic millimeter or mm3). Leukocytes are the only formed elements of blood that are complete cellseach one has a nucleus and a complete set of organelles. Their appearance varies considerably: some are large, others small; some have a prominent cytoplasm with visible organelles, others have minimal cytoplasm with few organelles; and some have a simple, round nucleus, whereas others have a multilobed nucleus (Table 10.1).
Table 10.1
Cell Type
Cellular Elements of Blood

Appearance (Wrights Stain) No nucleus or granules Cytoplasm: red Function Gas transport, acidbase balance Illustration
Erythrocytes (RBCs)
Leukocytes (white blood cells) Granulocytes Neutrophils (54% to 62% of WBCs)
Nucleus: lobed, dark purple Granules: fine, light tan or not visible Cytoplasm: pale pink
Phagocytosis of bacteria, other invaders
Eosinophils (1% to 3% of WBCs)
Nucleus: lobed, purple Granules: large, red Cytoplasm: pale pink
Allergic inflammatory reactions; defense against parasites Allergic inflammatory reactions
Basophils ( 1% of WBCs)
Nucleus: lobed, dark blue, often obscured by granules Granules: large, dark blue Cytoplasm: pink
Cells Without Granules Lymphocytes (25% to 38% of WBCs) Nucleus: unlobed, deep purple Granules: few if any Cytoplasm: scant, blue Nucleus: purplelarge and irregular Granules: few if any Cytoplasm: light blue Involved in specific immune responses
Monocytes (3% to 7% of WBCs)
Precursor to macrophages
In tissues
monocyte
macrophage
Platelets
Granules: purple or none Cytoplasm: light blue
Blood clotting
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Human Form, Human Function: Essentials of Anatomy & Physiology Less than 1% of all WBCs are basophils, granulocytes
Just as leukocytes are more complex than erythrocytes or platelets, their production (leukopoiesis) is more complex and depends heavily on cell-to-cell signaling by cytokines, large protein or glycoprotein molecules released by cells to influence the behavior of other cells locally or far away. Leukocytes release cytokines that stimulate the production and activity of other leukocytes. These WBC-to-WBC cytokines are called interleukins (literally between leukocytes). Dozens have been identified and named, such as IL-1, IL-2, and so on. Interleukins are discussed in more detail in Chapter 12. Leukocytes can be classified into three main groupings: granulocytes, lymphocytes, and monocytes (see Table 10.1).
with alkaline (basic) cytoplasmic granules that stain dark blue-black because of their affinity for hematoxylin (a blue dye). Basophils are important in allergic reactions: they release histamine, which dilates blood vessels, and heparin, a natural anticlotting (anticoagulant) compound that also has wide use as a drug, discussed further on. Other chemicals act as signals to recruit eosinophils and other cells to the site. The nuclei of basophils stain dark purple and are shaped somewhat like a long sausage bent into a C-shape.
Case Note
10.4. Eleanors bone marrow is not making adequate numbers of neutrophils, among other cells. Which process best describes neutrophil synthesis leukopoiesis or diapedesis?
Granulocytes Contain Large Cytoplasmic Granules

The majority of leukocytes, about 65%, are granulocytes, large WBCs with an irregularly shaped nucleus and abundant cytoplasm containing large cytoplasmic granules (lysosomes, Chapter 3). Granulocytes are actively mobile cells that defend the body against bacteria and other threats, such as inhaled particulate matter, and assist in cleaning up and repairing damaged tissue. Granulocytes are further classified according to the color of their cytoplasmic granules when stained with a standard red/blue dye mixture:
Most granulocytesabout 60% of all WBCsare neu-
Lymphocytes Are Cells of the Immune System

About 30% of WBCs are lymphocytes, cells of the immune system ( Chapter 12) that circulate in blood. However, they are also normally found in other tissues, especially lymph nodes, the spleen, and bone marrow. Lymphocytes are smaller and more uniform than granulocytes. They have round nuclei that stain dark blue and a small amount of light blue cytoplasm without granules (see Table 10.1). Lymphocytes defend against external threatsbacteria, viruses, and fungiand the internal threat of newly forming tumor cells. However, unlike granulocytes, they are only sluggishly mobile, are not phagocytes, and do not release packets of destructive chemicals. Instead, they defend the body by a group of highly specialized molecular mechanisms collectively called immunitythe subject of Chapter 12.
trophils, so called because their cytoplasmic granules stain a nearly colorless (that is, neutral) bluishtan. Neutrophils have an elongated, twisted, dark purple nucleus of five or six lobes shaped like a chain of linked sausages. Since their cytoplasmic granules contain packets of digestive enzymes, neutrophils are able to defend the body by phagocytizing and digesting bacteria, particulate matter, and other foreign threats. And in damaged tissue, they ingest and clear away cell debris to pave the way for tissue repair and healing. Their life span is the shortest of all blood cellsonly a few hours. About 3% of all WBCs are eosinophils, granulocytes that have eosin-loving cytoplasmic granules (eosin is a red dye), which stain bright red. These granules release packets of enzymes that defend against two types of threats: (a) they destroy parasites (multicellular microbes, such as intestinal worms), and (b) they neutralize offending agents in allergic reactions. The eosinophil nucleus stains dark purple and has two lobes somewhat like two sausage links.
Monocytes Develop into Macrophages

About 5% of WBCs are monocytes, which, like lymphocytes, do not contain granules. Monocytes are somewhat larger than granulocytes; they have large, darkly staining U-shaped nuclei and abundant light blue cytoplasm (see Table 10.1). After crawling out of the bloodstream, monocytes become highly mobile phagocytic cells called macrophages, with a gargantuan appetite for ingesting and destroying certain microbes and foreign material. Additionally, macrophages play a key role in helping lymphocytes do their job in the immune system.
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Remember This! The main task of WBCs is

to defend the body from microbes and foreign substances.
Leukocytes Are Involved in Inflammation

In the broadest sense, some type of injuryphysical trauma, molecular toxin, lack of oxygen, radiation, or infectioncauses every disease. Inflammation is the bodys collective cellular and vascular response to injury, and leukocytes play an important role in it (Table 10.2). Inflammation precedes and is intimately linked to the process of tissue repair, which was discussed in Chapter 5 (see Fig. 5.9). Repair begins as the immediate effects of injury begin to fade.
which are quite abundant in blood and can respond quickly. Moreover, neutrophils are attracted byand effectively defend againstthe bacteria that frequently enter the body through an injured barrier such as skin. In severe acute inflammation, neutrophils accumulate to form pus, the creamy white fluid for which leukocytes were originally given the name white blood cells. Depending on the degree and duration of injury, the tissue becomes distended, red, warm, and painful as it becomes engorged with blood and leaked plasma and as nerve endings become irritated by the process (Chapter 9).
Chronic Inflammation
Chronic inflammation is the result of longer-term, less intense injury, and can persist for weeks or years. In the case of certain chronic diseases, the injury itself is ongoing. In fact, injury, inflammation, and repair often coexist, sometimes indefinitely, as is the case with joints inflamed by chronic arthritis. The leukocytes most commonly involved in chronic inflammation are lymphocytes and macrophages, because chronic damage is often caused by slow-acting immune reactions ( Chapter 12) or by viruses, fungi, irritants, or other agents that do not attract neutrophils. Neutrophils, therefore, are rarely present. Although chronic inflammation is certainly painful and can be debilitating, it is usually not as intensely hot, swollen, red, or tender as acute inflammation. For example, rheumatoid arthritis is a chronic inflammatory condition of joints caused by faulty immune reactions. Smoking is another example: it damages and causes chronic inflammation in bronchial airways, which results in coughing, wheezing, and shortness of breath.
Acute Inflammation
Acute inflammation is the result of short-term, intense injury and persists for a few hours or days. In acute injury, inflammation fades gradually as the damaged tissue is regenerated from stem cells (Chapter 3) or, if regeneration is not possible, replaced by scar tissue. Injured cells or invading microbes release substances that cause blood vessels to dilate and become leaky. Plasma oozes from blood into the injured tissue, bringing nutrients and other molecules to assist with defense and repair. At the same time, leukocytes crawl out of blood vessels into the damaged tissue to attack and remove the offending agent, to clean up cell debris, and to initiate the repair process. The leukocytes most commonly involved in acute inflammation are neutrophils,
Table 10.2
Leukocytes and Inflammation

Cause Short-term, intense injury Long-term injury or chronic inflammatory disease Allergies (immune system hypersensitivity) End Result Repair or scarring Persistent inflammation and repair Varies from mild, local inflammation to systemic shock and death Parasite may be destroyed, or inflammation may harm the host Primary Leukocytes Involved Neutrophils Lymphocytes, macrophages
Type of Inflammation Acute Chronic
Allergic
Eosinophils, some basophils
Parasitic
Parasites
Eosinophils
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Intermediate Types of Inflammation

Falling somewhere between acute and chronic injury and inflammation are tissue injuries caused by parasites and allergic reactions, each of which attracts eosinophils and basophils. Hay fever is a common allergic condition; microscopic study of nasal mucus will reveal an abundance of eosinophils and some basophils. Or, if a complete blood count is done in a child with chronic abdominal pain, it may reveal large numbers of eosinophils; in that case intestinal parasites would rank high on the list of diagnostic considerations.
Leukemia and Lymphoma Are Malignant Diseases of Leukocytes

Recall from our discussion of the cells life cycle and cell growth in Chapter 3 that a malignancy is an uncontrolled growth of cells. Leukemia is malignant growth of any type of leukocyte, including lymphocytes, in which malignant leukocytes are present in blood. The total number of leukocytes in blood is increased and microscopic examination reveals increased numbers of abnormalappearing malignant leukocytes (Fig. 10.4). Lymphoma is a malignant growth of lymphocytes; however, no malignant cells are not detectable in blood. Instead, masses of malignant lymphocytes occur in lymph nodes, bone marrow, or other organs.
Case Note
10.5. We know that Eleanor, between hospital admissions, suffered from repeated bacterial infections. Lack of which blood cell is likely to blame?
Lymphocyte
Neutrophil
Infection Is a Risk with Low Numbers of Leukocytes

Recall that granulocytes attack invading bacteria and help to clean up damaged tissue; also that lymphocytes resist viral, fungal, and other nonbacterial infections. Given these roles, its not surprising that infection is a major risk for patients with low numbers of leukocytes or dysfunctional leukocytes. A low blood leukocyte count is called leukopenia (Greek penia poverty). Patients can be deficient in any particular type of WBC. Neutropeniaa deficiency in neutrophilsalso impairs wound healing, because neutrophils facilitate the healing process by removing debris. Eleanors body was unable to repair her esophageal ulcer because of neutropenia. The cardinal example of a disease marked by low lymphocyte counts is acquired immunodeficiency syndrome (AIDS), a condition in which the human immunodeficiency virus (HIV) virus kills lymphocytes, leaving the body vulnerable to recurrent infections and the development of malignant tumors. AIDS is discussed in greater detail in Chapter 12.
(a) Normal blood Malignant leukocytes
Case Note
(b) Blood from a patient with leukemia
10.6. Eleanors blood count revealed a low number of lymphocytes. Which term do you think describes this conditionlymphocytopenia or eosinopenia?
Figure 10.4. Leukemia. A. Normal blood, containing a normal neutrophil and lymphocyte. B. Blood from a patient with leukemia, showing numerous abnormal (cancerous) leukocytes. Which blood cell in part A is a granulocyte?
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10.12 Rank the following leukocytes from the most abundant to the least abundant: basophils, eosinophils, lymphocytes, neutrophils, monocytes. 10.13 Which of the above leukocytes are granulocytes? 10.14 What is the clinical term for a low blood leukocyte count? 10.15 Are neutrophils the major players in acute inflammation or chronic inflammation? 10.16 An adult patient has large numbers of malignant lymphocytes in her blood. What would you call the patients diseaselymphoma or leukemia?
the RBC count). Recall that only about 5,000 WBCs are present in the same volume.
Erythrocyte Form Contributes to Function

The physical characteristics of RBCs are perfectly suited to their function (Fig. 10.5). First, circulating RBCs have no nucleia nucleus would just occupy otherwise useful space for transporting oxygen. The RBC spits out its nucleus just before leaving the bone marrow. The net result is that a circulating RBC is essentially a sack of hemoglobina molecule to be discussed in more detail belowthat temporarily binds either oxygen or CO2 for transportation. RBCs also have few cytoplasmic organelles and a very low rate of metabolism. Without mitochondria, they must rely on anaerobic respiration, and without endoplasmic reticulum, they cannot synthesize most proteins. This almost lifeless state reflects their passive roletheir main job is to transport oxygen and carbon dioxide, not use it or generate it. Any oxygen used by a RBC is oxygen that doesnt reach tissues. Second, each RBC is shaped into a flattened, biconcave disc (Fig. 10.5A). This design is efficienta lot of membrane surface area and relatively little volume; it keeps the hemoglobin and its precious load of oxygen near the cell membrane for easy diffusion into tissues. Were RBCs spherical, the gases bound in the center of the cell would have a long way to diffuse before reaching the cell membrane. Third, RBCs are flexible and can safely travel through the tiniest capillaries. This ensures that, in a healthy person, even the most peripheral body tissues are perfused with blood.
Globin Heme Iron
Erythrocytes and Oxygen Transport

Erythrocytes (red blood cells, or RBCs) are workhorse transportation cellstheir major task is to transport oxygen from the lungs to tissues and carbon dioxide waste from tissues to the lungs. They are nonmotile cells that normally remain entirely within blood vessels; escape of erythrocytes from a blood vessel (hemorrhage) is abnormal. Erythrocytes are the most abundant cellular element in blood. A microliter (1 mm3) of blood contains about 5 million RBCs (a measurement called
0.451.16 m
2.312.85 m
7.28.4 m Sectional view (a) Red blood cells (b) Hemoglobin
Figure 10.5. Physical characteristics of RBCs. A. RBCs are biconcave discs without nuclei. B. Hemoglobin consists of four subunits, each containing a long protein chain (globin) and a complex organic molecule containing iron (heme). Why are RBCs biconcave instead of spherical?
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Case Note
10.7. When Eleanor bleeds, what type of cell is lost in the greatest abundance?
120 days before dying a natural death by apoptosis. The stages in an erythrocytes life cycle are diagrammed in Figure 10.6. 1. Marrow production of erythrocytes (or any other cell) requires raw materialamino acids, lipids, sugars, vitamins, and minerals. Synthesis of hemoglobin is critical to erythrocyte production, and hemoglobin cannot be synthesized without iron, zinc, copper, vitamin B12, vitamin B6, and folic acid. Iron is particularly important, because iron is a vital part of hemoglobin and virtually all of the bodys stores of iron are used to make the heme of hemoglobin. The body stores iron in the bone marrow, liver, and spleen, bound to a specialized iron storage protein called ferritin. 2. As RBCs near maturity in the bone marrow, they eject their nuclei and become reticulocytes, ready to enter the bloodstream. This name derives from the fact that reticulocytes retain a spidery (reticular) network of ribosomes. Once in circulation, reticulocytes mature in a day or two into adult erythrocytes and lose their distinctive appearance. The level of reticulocytes in normal blood is usually less than 1%. A reticulocyte percentage greater than about 1% indicates that the bone marrow is making new erythrocytes at a greater than normal pace because the oxygen-carrying capacity of the blood is too low. 3. Erythrocytes survive for about 120 days. Recall that they do not have any ribosomes, so they cannot make new proteins to repair themselves. Old (senescent) erythrocytes have been battered by their high-risk voyage through the tumult of the heart and the twisting, narrow passages of the capillaries; macrophages seek out these decrepit cells and destroy them. 4. Macrophages in the bone marrow, spleen, and liver phagocytose aged erythrocytes. 5. The iron atoms from metabolized heme (as well as dietary iron) are transported in blood by a specialized plasma protein, called transferrin, to the bone marrow, liver, and spleen for storage. 6. The noniron components of the heme molecule are metabolized into bilirubin, a bright yellow pigment that is removed from blood by the liver and excreted into the intestines. When present in excess, bilirubin accumulates in blood and imparts a yellow discoloration to skin, a condition called jaundice. 7. The amino acids in the globin part of hemoglobin are recycled to make other proteins.
Oxygen Is Bound to Hemoglobin

The effectiveness of oxygen transport by blood is directly proportional to the number of erythrocytes and the amount of hemoglobin they contain. Hemoglobin is a large iron-containing molecule that binds oxygen and carbon dioxide and completely fills the RBCs cytoplasm. Each molecule of hemoglobin is composed of four folded chains of globin, a large protein molecule, and four molecules of heme, a red pigment, each of which contains an iron ion (Fig. 10.5B). Each of these four ions of iron combines with one molecule of oxygen and each RBC contains about 250 million hemoglobin molecules; therefore, each RBC carries about a billion oxygen molecules. As discussed in Chapter 13, hemoglobin can also carry carbon dioxide and hydrogen ions in blood. Hemoglobin deficiency impairs oxygen transport to tissues, a condition called anemia, discussed in detail further on. Hemoglobin does not function well outside of RBCs. When released into plasma from damaged erythrocytes, it quickly diffuses out of the vascular system and is unavailable for O2/CO2 transport. Hemoglobin in the fetus (hemoglobin F) differs molecularly from adult hemoglobin (hemoglobin A): it has a greater affinity for oxygen than hemoglobin Aa fact of great physiological importance. The fetus gets its oxygen from its mother via the placenta, where a membrane separates fetal and maternal blood. Oxygen crosses this membrane by diffusion. The higher-affinity hemoglobin F lures the oxygen away from the maternal, lower-affinity hemoglobin A, just as a stronger magnet will lure a metal ball away from a weaker magnet. After birththat is, by the end of the third monthhemoglobin F is usually completely replaced by hemoglobin A.
Case Note
10.8. If Eleanor receives an infusion of plasma, will the amount of hemoglobin in her blood increase?
The Erythrocyte Life Cycle Spans 120 Days

Erythrocytes are produced by the bone marrow by a process called erythropoiesis; they circulate for about
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1
RBC building blocks (including iron) are absorbed from food. Iron is also obtained from stores in bone marrow, liver and spleen, where it is bound to ferritin.
2
Reticulocytes are released from bone marrow into blood, and mature into erythrocytes. Reticulocyte
Erythrocyte
6
The liver excretes bilirubin in bile, to be expelled in feces. + Transferrin
Amino acids
7
Globin is degraded into amino acids for further protein synthesis in bone marrow or other tissues.
Bilirubin
Globin
3
Degraded RBCs RBCs survive about 120 days in bloodstream.
Iron
Bilirubin
Heme
5
Transferrin transports iron (from heme) to storage sites or to the bone marrow. The rest of the heme molecule is converted into bilirubin.
Macrophage
4
Macrophages in spleen, liver and bone marrow phagocytize old RBCs.
Figure 10.6. Erythrocyte life cycle. Some components required for erythrocyte synthesis are recycled from old erythrocytes; others must be obtained from the diet. Name the binding protein that transports iron in blood.
Case Note
10.9. Recall that Eleanors bone marrow is not producing normal numbers of erythrocytes. In the absence of other problems, do you think her bilirubin level would be elevated or decreased?
Erythropoietin Stimulates Erythropoiesis

Erythropoiesis is stimulated by erythropoietin (EPO), a protein hormone produced by the kidneys. EPO is not stored; its production is regulated in a classic negative feedback loop based on the availability of oxygenproduction increases in response to hypoxia (low blood oxygen) and decreases as oxygen content rises (Fig. 10.7). People who live at high altitude have higher RBC counts (and higher hemoglobin and hematocrit, too) than
those who live at lower altitudes. This is because they are mildly hypoxic from the thin mountain air. Likewise, in anemic patients, the low level of transported oxygen stimulates the homeostatic production of EPO, rousing the bone marrow to pour out new erythrocytes to correct the anemia. Synthetic EPO is now available for the treatment of anemia and is especially useful in patients with chronic kidney disease, who cannot make enough natural EPO to avoid becoming anemic. Blood loss, be it the result of donating blood or hemorrhage, similarly activates EPO production because not enough erythrocytes are present to carry the expected amount of oxygen. The use of synthetic EPO injections to boost RBC production and oxygen-carrying capacity was especially prevalent in international cycling events in the 1980sthat is, until laboratory methods were devised to detect it. Some athletes then turned to blood doping, a practice in which blood is withdrawn and stored in advance of competition with the expectation of
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High or altitude Anemia
Case Note
10.10. If we measured Eleanors plasma erythropoietin, would we expect it to be low, normal, or high?
Corrects Hypoxia stimulates
O2 O2 O2
Anemia Is Too Little Hemoglobin in Blood

Anemia is too little hemoglobin in blood, which means that less oxygen is delivered to tissues. As a result, patients with anemia are pale from lack of red hemoglobin coloration. And because their cells are not provided with sufficient oxygen for normal function, they are at an increased risk for infection, tire easily, and cant think clearly. They also become easily short of breath, as their heart and lungs work overtime trying to make up the oxygen deficit. Anemia may be a manifestation of any of the following three basic conditions:
There are too few erythrocytes in the blood (the
O2
Epo
ia ox yp sh ve n-carrying capacity relie
O2
Epo
Epo
Epo
Erythropoietin stimulates
O2
O2
do xyge
Red bone marrow
erythrocyte count is low).

The size of the average erythrocyte is too small. The concentration of hemoglobin in the average eryth-
rea se
O2
rocyte (the amount of hemoglobin per unit of RBC volume) is too low. These measurements are the stuff of routine medical laboratory practice and offer valuable clues to the cause of anemia in any given patient. More about RBC measurements can be found on our website at https://lww. thepoint/McConnellandHull.com. When there are too few erythrocytes in blood or their size is too small, the erythrocyte volume absent from blood is replaced by plasma, usually within a few hours. This response expands blood volume back to normal, but of course it also dilutes the erythrocyte volume even further. This is why the most common initial clinical indication of anemia is a reduced hematocrit (Fig. 10.8A). Anemia is not a disease; rather, it is merely a sign, a clue, that something more fundamental is amiss. These more fundamental conditions include the following:
Hemolytic anemia: Abnormally rapid destruction of
In c
O2 Increased red blood cell production O2 O2
Figure 10.7. Erythropoietin stimulates erythropoiesis. Hypoxia stimulates EPO production by the kidneys, which increases the oxygen carrying capacity of blood by stimulating the production of RBCs. Completing the negative feedback loop, increased oxygen carrying capacity then decreases EPO production. What type of marrow is the target tissue for EPOyellow or red?
reinfusion immediately before competition. The depletion of RBCs renders the athlete temporarily anemic; however, this condition stimulates natural RBC production, which returns total circulating erythrocytes toward normal. Later, the stored blood is reinfused, giving the athlete an extra charge of oxygencarrying capacity and the expectation of improved performance. Blood doping is more difficult for athletic organizations to detect than EPO injections, but a hematocrit over 50% or hemoglobin in excess of 17 g/100 mL may be grounds for disqualifi cation. Blood doping is dangerous, too: unusually high numbers of erythrocytes can thicken blood to the point that it does not flow smoothly, which may cause blood vessel obstruction and a stroke or heart attack.
RBCs (life span of less than 120 days)

Hemorrhagic anemia: Bleeding Production failure anemia: Impaired production of new
RBCs or failure to produce enough hemoglobin in them.
Remember This!
Anemia is a sign of disease, not a disease itself. In all anemias, the missing RBC volume is replaced by plasma.
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100 Hematocrit (%)
100 Plasma
100
70 50 RBCs 30
100 70
Normal (45%)
Anemia (30%)
Absolute polycythemia (70%)
Relative polycythemia (70%) (b) Sickle-cell anemia
(a) Hematocrit disorders
Figure 10.8. Anemia and polycythemia. A. The hematocrit can diagnose anemia or polycythemia. B. Sickle cell anemia. Which tube represents the hematocrit of a dehydrated individual?
Hemolytic Anemia
Hemolytic anemia is due to the abnormal destruction of erythrocytes (before they die a natural death by apoptosis) a process known as hemolysis (Greek lysis loosening). For example, malaria is a parasitic infection of erythrocytes that destroys them as they circulate. Hemolysis is the cause of anemia in sickle cell anemia. The cells contain enough hemoglobin, but it is flawed because of a genetic defect of hemoglobin synthesis. The hemoglobin molecules tend to crystallize into long, thin rods that deform erythrocytes into elongated, pointy, curved, stiff cells that look like an ancient sickle (scythe) for harvesting wheat (Fig. 10.8 B). The life span of these inflexible cells is as short as 4 days, since macrophages detect their abnormal shape and destroy them. Sickle cells also tend to jam together and block blood flow, like sticks in a beaver dam. Such a blockage is painful and starves tissues of oxygen; it can lead to cell death.
anemia develops slowly and patients may become severely anemic without realizing it. The only symptom they may notice is that they tire or become short of breath easily. Because RBCs contain iron and iron is necessary for hemoglobin production, chronic bleeding may deplete the bone marrow of iron and impair hemoglobin production (discussed next).
Production Failure Anemia

Normally, all of the cellular elements of blood are made in the bone marrow and released into blood. Production failure anemia is due to failure of the bone marrow to produce normal erythrocytes in sufficient numbers to replace those dying a natural death (by apoptosis). Aplastic anemia (Greek awithout plasis formation) results from destruction of the marrow by drugs, toxins, radiation, or invasion by metastatic cancer. In iron deficiency anemia, the bone marrow is normal, but it lacks enough iron to synthesize a normal amount of heme for hemoglobin. There are two main causes of iron deficiency anemialack of dietary iron and iron loss due to chronic bleeding. Because they lose blood (and iron with it) normally with every menstrual period, women of childbearing age are especially vulnerable to iron deficiency anemia. Normal menstrual bleeding is usually not severe enough to produce anemia because dietary iron is usually adequate to keep up with the demand for replacement hemoglobin. But for women with sustained excessive menstrual bleeding, even oral iron supplementation may not suffice to prevent the development of iron deficiency and the anemia that accompanies it. After body iron stores are exhausted, the marrow cannot
Hemorrhagic Anemia
Hemorrhagic anemia is anemia due to the loss of RBCs by bleeding. It can take weeks or months for the bone marrow to replace all of the lost erythrocytes. For serious hemorrhage, transfusion or replacement erythrocytes is necessary to preserve life, as we saw with our case study of President Reagan in Chapter 1. Chronic blood loss, such as undetected intestinal bleeding, is a different matter. If bleeding is very slow, hemorrhagic anemia will not develop because newly produced erythrocytes can keep up with the loss. However, anemia will develop if bleeding exceeds the bodys capacity to produce new erythrocytes. In these cases,
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make normal RBCs, nor can it pack them with enough hemoglobin; iron deficiency anemia is the result.
Platelets
Platelets are not complete cellsthey are fragments of cytoplasm wrapped in cell membrane. About one-tenth the size of erythrocytes, platelets have no nuclei but retain a few organelles that impart a bluish cast with a standard red/blue stain (Table 10.1). They are produced by very large bone marrow cells called megakaryocytes (Greek megas great; karuon kernel or nucleus; -cyte cell). A microliter of normal blood contains about 200,000 to 500,000 platelets. Production of platelets, thrombopoiesis, is governed by thrombopoietin (TPO), a hormone made by the liver and to a lesser extent by the kidneys (Fig.10.9). Thrombopoietin stimulates megakaryocyte production by the bone marrow and megakaryocytes release platelets into blood. Platelets have a life span of about a week and they, too, are phagocytized by macrophages, mainly those in the spleen. Thrombopoietin levels are inversely related to the platelet count in a classic
Case Notes
10.11. Which two of the following terms best describe Eleanors anemia: aplastic, hemolytic, production failure. 10.12. Are Eleanors frequent nosebleeds and bleeding ulcer contributing to her anemia? If so, how?
Polycythemia Is Too Many RBCs

The opposite of anemia is polycythemia (poly- many; -cyte cell; Greek haima blood)too much hemoglobin in blood. As you might expect, measurements of hemoglobin, hematocrit, and RBC count are high (Fig. 10.8A). The most common cause of polycythemia is dehydration, which reduces plasma volumeerythrocytes are concentrated in less than a normal amount of plasma, a situation described as relative polycythemia. However, some people have increased RBC counts because there is an actual increase in the number of erythrocytes in the body. They are said to have absolute polycythemia. In many such people, this is a normal adaptation to life at a high altitude caused by increased erythropoietin production. A few patients with absolute polycythemia have a bone marrow malignancy called polycythemia vera (Greek vera true), an uncontrolled, malignant proliferation of primitive erythrocyte precursor cells in the bone marrow.
Corrects Thrombocytopenia stimulates
TPO
TPO
TPO
TPO
TP
TPO
10.17 What is the difference between a reticulocyte and an erythrocyte? 10.18 Fill in the blanks: Iron is transported by ____________ in blood and is stored attached to _____________ in tissues. 10.19 Identify three structural characteristics of RBCs that directly support their function. 10.20 True or false? A single molecule of hemoglobin can bind to about a billion molecules of oxygen. 10.21 Name the three categories of anemia.
TPO T
Thrombopoietin stimulates
10.22 If an anemic patient drinks a large volume of fluid and increases his plasma volume, will his hematocrit increase or decrease? 10.23 10.24 How can lung disease lead to polycythemia? Is EPO used to treat polycythemia or anemia?
Increased megakaryocyte production
Increased platelet count
Figure 10.9. Thrombopoietin stimulates thrombopoiesis. The platelet count is maintained at a relatively constant level by a negative feedback loop involving the hormone thrombopoietin. If platelet count were artificially increased by a platelet transfusion, what would happen to megakaryocyte production?
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PO
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negative homeostatic feedback mechanism: as the number of platelets declines, thrombopoietin levels rise and thrombopoiesis is stimulated. Platelets are very important in hemostasis: they help prevent hemorrhage and help stop it when it occurs. The role of platelets in hemostasis is discussed further on. An abnormally low number of platelets is called thrombocytopenia. Spontaneous hemorrhage becomes a danger when the platelet count falls below 50,000/ L.
to the interior of the heart and blood vessels (together known as the vascular space) and flows smoothly and clot-free. Disruption of this barrier allows blood to contact extravascular tissues, initiating the events of hemostasis.
Remember This!
Hemostasis, the control of hemorrhage, is different from homeostasis, the maintenance of a stable internal environment.
Case Note
10.13. What is the cause of Eleanors measles-like spots and nosebleed?
Blood Loss Threatens Life

Sudden blood loss, as with a serious wound, is an immediate threat to health and life. It has two ill effects. The loss of RBCs results in reduced oxygen transport capacity. At the same time, the loss of blood volume decreases blood pressure and results in low blood flow to tissues. Lack of oxygen transport and low blood flow combine to make severe hemorrhage a serious problem. Sudden loss of 10% of blood volume (about a pint, or 500 mL) will cause a drop of blood pressure, weakness or fainting, and fatigue with normal effort. Sudden loss of about 30% (1 quarts, or 1,500 mL) will dramatically reduce blood pressure and may be fatal if the lost blood volume is not replaced quickly by transfusion of either plasma or whole blood (discussed below).
10.25 Correct the italicized terms in the following statement to make it true: Erythropoiesis is the synthesis of platelets; leukopoiesis is the synthesis of RBCs. 10.26 Name the two cellular components of blood that do not have DNA. 10.27 True or false: A patient with thrombocytopenia is at increased risk of hemorrhage.
Case Note
10.14. If Eleanor receives a plasma transfusion, which blood function will be improved: oxygen carrying capacity or blood pressure?
Hemostasis
Hemostasis is the collective name for a group of activities that together prevent or stop bleeding. Blood clotting is the best known of these activities, but the formation of a blood clot is only one of many factors in the prevention and control of hemorrhage. Blood vessels play an important role in hemostasis. The diameter of small vessels, called arterioles, determines blood flow to a particular region (such as a small patch of skin). Contraction of smooth muscle in the vessel wall is vasoconstriction, which narrows the vessel diameter and reduces blood flow to a particular tissue or organ. Smooth muscle relaxation is vasodilation, which increases vessel diameter and blood flow. All blood vessels and the heart are lined by a smooth endothelial membrane, which prevents blood from touching any tissue or fluid outside the confines of the vascular system. Normally, therefore, blood is confined
Gradual loss of blood, as with a slowly bleeding intestinal tumor, has a less dramatic effect because the lost volume of whole blood is continually replaced in less than a day by an equal volume of cell-free fluid (plasma). Although the number of RBCs is diluted and the patients hemoglobin, hematocrit, and RBC count fall, the patients blood pressure may remain normal because of the increased production of plasma. But without adequate RBCs, the oxygen-transport function of blood remains impaired. Patients may fatigue easily but be able to go about their daily affairs. If blood loss stops and no erythrocytes are infused (transfused), it may take months for the bone marrow to produce enough RBCs for blood hematocrit, hemoglobin, and RBC count to return to normal. Oxygen-transport capacity can be improved by new RBCs, whether by natural production or transfusion.
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Remember This! Significant blood loss is associated with low oxygen transport capacity and low blood flow. Slow blood loss reduces oxygentransport capacity, but blood flow and pressure may remain stable.
Neither a stabilized sudden blood loss nor a gradual blood loss significantly reduces the other functions of blooddefense, heat transfer, and clotting. The leukocytes and other elements responsible for defense against microscopic invaders are quickly replaced. Heat transfer mainly depends on the volume of blood flowing to skin, and, as we have seen, after blood loss, the missing volume is usually restored within a day by plasma. Finally, clotting factors are so abundant in plasma that the amount lost in nonfatal blood loss is insignificant.
Injury ruptures vessel. Damaged endothelial cells release chemical signals. Vessel rupture RBC Platelet Smooth muscle Endothelial cell Extravascular tissue (collagen) Fibrinogen
1
Vasoconstriction. Smooth muscle contracts to constrict vessel lumen. Vessel lumens original size Contracted smooth muscle
Vasoconstriction Is the First Action in Hemostasis

Hemostasis has three components (Fig. 10.10): 1. Vasoconstriction 2. Formation of a platelet plug 3. Coagulation (blood clotting)
2
When a blood vessel is broken, damaged endothelial cells release local chemical signals (paracrine factors, Chapter 4). These chemical signals, along with reflex autonomic nerve signals, stimulate smooth muscle contraction in the vessel wall, which reduces the diameter of the lumen (Fig. 10.10, step 1). Vasoconstriction limits but does not stop blood loss from the ruptured vessel. The reaction is instantaneous but short-lived; nevertheless, it buys precious time for platelets and coagulation to effect a lasting solution.
Platelet plug formation. Platelets are activated by cytokines and by contact with collagen. They become sticky and attract more platelets. Platelet plug forms.
Platelet plug
3
Coagulation. Fibrinogen is converted into fibrin, which forms a clot with platelets and RBCs. Bleeding stops. Fibrin Fibrinogen
Platelets Slow Hemorrhage by Forming a Temporary Plug

When a blood vessel breaks, blood cells and plasma leave the vascular space and come into contact with collagen in the connective tissue surrounding the blood vessel (Fig.10.10, step 2). Platelets stick to the collagen and aggregate to form a platelet plug, which physically fills the break in the blood vessel wall. The plug may completely fill a small, capillary-size break and completely stop the bleeding, or it may limit the rate of hemorrhage from larger vessels. Chemicals released from damaged endothelial cells make platelets stickier, encouraging further platelet aggregation. Platelets in
Figure 10.10. The steps of hemostasis. Bleeding is stopped by sequentially vasoconstricting the vessel, forming a platelet plug and forming a clot. Which protein forms the clotfibrinogen or fibrin?
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the plug, in turn, release chemical signals that (a) stimulate further blood vessel contraction, (b) attract additional platelets, and (c) accelerate coagulation. In a patient with a bleeding problem, lab technicians can count the number of platelets and test for adequate platelet function. If the number of platelets is too low, a platelet plug cannot form. Whats more, low numbers of platelets cannot accelerate coagulation as they do when present in normal numbers. The bleeding time test examines the ability of platelets to form a plug and release their coagulation factors; it does so by determining the time it takes a tiny standardized pinprick wound to stop bleeding.
bruising or severe spontaneous hemorrhage, especially into joints, from otherwise minor trauma.
Coagulation Factors Interact in Pathways

The coagulation cascade can be divided into two initial pathways. The tissue factor pathway is most important. The contact activation pathway serves a secondary role (Fig. 10.11). These two initial pathways can be likened to two rivers joining to make a larger onethey merge into a single, final pathway called the common pathway. Each pathway involves a distinct set of coagulation factors. The tissue factor pathway is initiated when extravascular tissue or fluid, which ordinarily do not come into contact with blood, are exposed to plasma. The cell membrane of extravascular cells contains a protein called tissue factor (or thromboplastin), which initiates clotting when it comes into contact with plasma. When blood vessel damage exposes plasma to tissue factor, tissue factor activates a plasma clotting factor, factor VII. Factor VII then activates the common pathway, discussed below. The tissue factor pathway is fast, producing a clot in a few seconds. The contact activation pathway is so named because it is most often initiated by contact with foreign material, especially when blood is removed from the body (in vitro), as in laboratory testing. This pathway is initiated when plasma factor XII comes into contact with foreign substances, such as glass, plastic, or metal. Some of the chemical reactions of the contact activation pathway require calcium, which acts as a clotting factor itself (factor IV). Indeed, in laboratory practice, one way to prevent blood from clotting (anticoagulation, discussed further below) is to add a chemical that binds calcium and prevents its participation in the clotting process. The contact activation pathway is slow and takes a few minutes to produce a clot. This pathway can also be activated in vivo, but it is of secondary importance to the tissue factor pathway because individuals lacking one or more factors in this pathway do not necessarily have bleeding disorders. The common pathway begins with the activation of thrombokinase (factor X), an enzyme that converts another clotting factor, prothrombin (factor II), into thrombin. In the final step of coagulation, thrombin acts on fibrinogen (factor I) to convert it to the weave of fibrin that forms the clot. Clotting is a rapid homeostatic response that normally occurs only outside of the vascular space and is the consequence of normal physiological systems. However, in some pathological circumstances, blood clots inside blood
Case Note
10.15. Because of her thrombocytopenia, would Eleanor have a normal result in a bleeding time test?
Coagulation Results in a Fibrin Clot

Coagulation is a chain of events that produces a clot, a gel-like, semisolid web of fibrin filaments, platelets, and trapped blood cells that obstructs further escape of blood from an injured vessel (Fig.10.10, step 3). Fibrin is a long filamentous protein created by polymerization of fibrinogen, one of the three major types of plasma protein mentioned earlier.
Coagulation Factors Control Clot Formation

Coagulation is the result of interactions among about 50 blood coagulation factors, most of which circulate in plasma, although some are present in platelets, endothelial cells, and tissues. Most coagulation factors are proteins made by the liver; they are denoted by names and Roman numerals: factor I, factor II, and so on. These factors interact with one another in a cascade of steps: one reaction prompts another until the process is forced to its end pointa clot formed from a tangle of very long, thin strands of fibrin, which entrap blood cells and platelets and obstruct blood flow through the break. Absence of one factor can interrupt the entire process. For example, factor VIII is also called hemophilia factor because its absence is the cause of hemophilia, a sex-linked genetic condition found almost exclusively in males. The absence of factor VIII interrupts the coagulation cascade and prevents the production of fibrin. Platelets function normally, but platelets alone cannot stop hemorrhage, and blood loss continues. Hemophilia is associated with easy
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Extravascular cell
Tissue factor
Activated factor VII Inactive factor VII
Inactive factor XII
Activated factor XII
Test tube (or other foreign surface)
Other clotting factors Factor VII (a plasma protein) is activated by tissue factor, a receptor on extravascular cells. (a) Tissue factor (intrinsic) pathway
Factor XII activated by contacting test tube or foreign surface. (b) Contact activation (extrinsic) pathway
Active thrombokinase (active factor X) Slow
Prothrombin
Thrombin Fast Fibrinogen
Inactivates clotting cascade, dissolves clot
Fibrin
(c) Common pathway
Fibrin
(d) A clot.
Figure 10.11. The coagulation pathway. A. Exposure of clotting factor VII to tissue factor on extravascular cells activates the tissue factor pathway. B. The contact activation pathway is activated when clotting factor XII contacts collagen or a foreign surface such as glass. Activated factor XII initiates a series of enzymatic reactions. C. Activated factor VII or factors activated by the contact activation pathway activate the common pathway, which terminates in the formation of a web of fibrin fibers forming a clot. D. A photomicrograph of a blood clot. Which enzyme converts fibrinogen into fibrin?
vessels (intravascular coagulation) even if no hemorrhage is occurring. Intravascular coagulation is always secondary to some other serious disease and is often fatal. In a patient with a bleeding problem that might be due to faulty hemostasis, lab technicians can test the quality of coagulation by artificially activating each of
the clotting pathways in a blood specimen and measuring the time required to form a clot. A deficiency of any of the plasma factors will extend the time it takes to form a clot. By knowing which factors are involved in each pathway, the deficiency can be identified or narrowed to a few possibilities.
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Plasmin Dissolves Clots

After it forms, a clot slowly contracts, pulling together the wounded tissue and making the clot denser and more secure. Later, as the bodys repair process regenerates new tissue or scar tissue to provide permanent closure, the clot slowly dissolves. Dissolution is due to the action of another blood protein, plasmin, which digests the fibrin holding the clot together. Thrombin, the protein that stimulates clot formation, also promotes clot dissolution by stimulating plasmin production. As a clot contracts, it expresses a fluid called serum, which is identical to plasma except that it contains no fibrinogen or other clotting factors. Serum is the fluid that seeps, for example, from a fresh skin abrasion. Serum is also harvested from whole blood for laboratory analysis because it contains most of the constituents of plasma but does not form clots that could interfere with laboratory tests. For more detail about blood versus plasma versus serum, see the nearby Clinical Snapshot titled Serum? Plasma? Blood?
Anticoagulants Prevent Coagulation

Whether or not blood coagulates depends upon the balance of forces promoting or opposing coagulation.
Normally, blood is maintained in a smooth, clot-free state because circulating anticoagulants prevent clot formation. Clotting occurs when procoagulation forces prevail. Given that clotting is a chain reaction, it is reasonable to ask: Once it starts, why doesnt it proceed to coagulate the entire blood supply? The answer is that natural anticoagulants are released at the site of the clot and restrict clotting to the locality of the injury and hemorrhage. For example, basophils and other defensive cells release heparin, a polysaccharide that acts as a quick, short-lived anticoagulant by interfering with the action of prothrombin (factor II). Pharmaceutical anticoagulants are frequently administered as therapeutic drugs. For example, patients undergoing kidney dialysis are treated with a form of heparin to keep blood circulating through tubes that would otherwise cause activate the contact activation pathway. Warfarin (Coumadin) is a widely used anticoagulant that interferes with the action of vitamin K, which is required by the liver for the production of several coagulation factors, most notably prothrombin (II). Because it takes a few days for existing coagulation factors to disappear, warfarin anticoagulation takes a few days to develop. Finally, aspirin is a weak anticoagulantit interferes with the ability of platelets to become sticky and form
Serum? Plasma? Blood?

Serum is the fluid remaining after blood has clotted. Serum and plasma are identical in every respect except that plasma contains fibrinogen and serum contains noneall of the fibrinogen is consumed in forming fibrin to make the clot. For example, the bloody scab on a skin scrape is a dried clot, and the yellowish fluid that sometimes seeps from around the edges of the scab is serum. Plasma is tricky to use for laboratory analyses for two reasons:
Anticlotting chemicals must be added to blood in order
to obtain unclotted plasma.These chemicals alter plasma such that it no longer is an accurate representation of plasma as it was in the body. For example, most laboratory anticoagulants bind calcium to prevent clotting, and this prevents analysis of the plasmas calcium content. Anticlotting chemicals do not always work perfectly; small fibrin clots can develop and gum up delicate laboratory instruments.
Because serum contains no fibrinogen and cannot clot again, it is much more practical to use it for laboratory analyses of the constituents of plasma. Heres how its done. The lab technician collects blood into a glass or plastic tube, which activates the contact activation clotting pathway and allows the blood to clot. Just as a clot shrinks after formation in the body, it shrinks in a specimen tubeafter an hour, the clot is about half its original size. Serum is the remaining fluid, which can easily be harvested by centrifugation of the clot to the bottom of the tube. Because serum and plasma are identical for most purposes and laboratory analysis of serum so accurately reflects values in whole blood, the words serum, plasma, and blood are often used interchangeably. For example, when people speak of blood glucose or plasma glucose, the actual measurement was almost always done on serum.
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a platelet plug. As we have seen, aggregation of sticky platelets is a critical step in hemostasis. As we discuss next, platelet aggregation is also one of the initial steps in forming the cellular layers of a thrombusa risk factor in cardiovascular disease. For this reason a daily aspirin is effective in preventing some heart attacks and strokes caused by thrombus formation. Anticoagulants are also used for laboratory tests that require unclotted blood. More information can be found about this topic in the nearby Clinical Snapshot titled Serum? Plasma? Blood?
ried to the lungs. If such a thrombus is large enough, it can completely and fatally block blood flow to the lungs.
Remember This!
distinctly different.
A clot and a thrombus are
Case Note
10.16. The emergency room physicians advised Eleanor to stay away from aspirin. Why?
10.28 Which term describes the processes that stop bleeding hematopoiesis, hemostasis, or homeostasis? 10.29 Identify in order the three steps involved in hemostasis. 10.30 Which cellular elements of blood form a plug in broken blood vessels? 10.31 Which plasma protein is involved in blood clottingfibrinogen, albumin, or gamma globulin? 10.32 Which element is a clotting factorcalcium or iron? 10.33 True or false: Tissue factor is a soluble blood protein. 10.34 Fill in the blank: A deficiency in the ____________ pathway does not necessarily result in a bleeding disorder. 10.35 Do the following terms apply to thrombosis or clotting? Intravascular, organized structure, and pathological. 10.36 Do heparin and warfarin block the tissue factor pathway, contact activation pathway, or common pathway? Explain.
Coagulation and Thrombosis Differ

A thrombus is an abnormal, localized intravascular collection of platelets and blood cells, but it is not a clotcoagulation factors are not necessary for its formation. And whereas clotting is a normal process that occurs outside of blood vessels, a thrombus is always abnormal and occurs only within the lumen of a blood vessel. In the formation of a clot, blood cells are trapped in a rapidly developed, gelatinous weave of fibrin at a site of hemorrhage. By contrast, a thrombus forms inside a blood vessel at a point where the vessel lining is injured or blood flow as normalno vascular tear or hemorrhage is required. The injured lining of the blood vessel becomes sticky and platelets begin to accumulate slowly. Later, WBCs begin to accumulate and finally some RBCs become trapped in the growing mass. As cells accumulate, they do so in layers, creating a visible internal architecture that is distinctly different from a blood clot, which is a featureless red gel. Thrombi tend to occur in arteries damaged by atherosclerosis ( Chapter 11), an accumulation of cholesterol, other lipids, and scar tissue that occurs in damaged arteries. And because thrombi form inside blood vessels, they are capable of obstructing blood flow and are often a key element in a chain of events leading to heart attack or stroke. The danger of intravascular thrombus formation during long flights prompts airlines to urge passengers to keep their seatbelts loose and to move about the plane periodically. Tight seatbelts and lack of activity cause blood flow to stagnate in the legs, thus favoring thrombus formation. These can break away and be car-
Blood Groups and Transfusion

We noted at the beginning of this chapter that humankind has long associated loss of blood with illness or death and understood that blood was somehow vital to life. So it is no surprise that history is littered with attempts to restore health by transfusing blood. The nearby History of Science box, titled The Ancient Practice
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The Ancient Practice of Bloodletting

Skin and blood were the first body tissues to be recognized by the ancients: skin was constantly visible, whereas blood became visible following trauma. It was easy enough to see that injury produces bleeding, severe injury produces severe bleeding, and severe bleeding causes death. The conclusion necessarily followed that the life spirit must be in blood, and blood, therefore, must be important in maintaining life. But as civilizations evolved, ancient eastern and western traditions came to differ in their views about blood. Asian physicians recognized that the flow of blood transported energy to body parts. However, beginning with the Greeks, western physicians came to see blood as the carrier of harmful substances and thus practiced bloodletting, a therapy in which blood is drained from the body. Bloodletting was a recorded practice from at least the time of the Sumerians (1800 BCE) until the 19th century. For more than 1,000 years, Western physicians believed that the excess accumulation of certain humoursblack bile, yellow bile, phlegm, and blood itselfwas the cause of all illness. These physicians advocated and perpetuated the practice of bloodletting as a mainstay of treatment to rid the body of imagined excesses of humours. Two methods were common: bloodsucking leeches were applied to skin, or veins were sliced open. For example, in 1799, on what proved to be his deathbed, George Washington was repeatedly bled of perhaps a liter or two of blood by a series of physicians. His ailment: a severe throat infection, which leaves us to speculate that he might have survived but for the ministrations of his doctors. Bloodletting persisted well into the 19th century until it was largely displaced by treatments backed by empirical evidence of success. Nevertheless, it survives in a very narrow niche in modern medicine. Patients with a surprisingly common inherited condition called hemochromatosis (literally blood colored) accumulate
Bloodletting in the 19th century.
too much iron in their blood and other tissues, which can be toxic to the heart and other organs. RBCs contain large amounts of iron, and there is no good way to remove iron from the body except by draining away blood from time to time. In such cases, bloodletting is a very effective practice that allows patients to lead otherwise normal lives. Bloodletting is also used to treat a rare type of malignancy that produces an excess of certain blood proteins, which causes blood to become so thick that it cannot flow properly. However, in this instance, after patients are bled, the proteins are removed from the blood and the thinned blood is returned to the body.
of Bloodletting, offers an insight into the evolution of modern transfusion medicine. If youve ever donated blood, you know that its collected by venipuncture into sterile bags; but you might not be aware of the other steps that go on behind the
scenes. First, donated blood is mixed with anticoagulant to prevent clotting; then it is refrigerated for up to 35 days until used. Before its transfused, blood is tested to make sure that its free from any infectious microbes and to determine its blood group. Without these steps,
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transfusion would be a highly risky business because (a) any bacteria, viruses, or other microbes in the donor blood could be transferred to the recipient and (b), the body of the recipient will reject the transfused (donor) cells unless they contain certain special proteins that match the recipients own. We discuss the issues and challenges of safe transfusion in this section. Incidentally, whole blood and RBCs are not the only transfusable substances. Modern technique enables transfusion of selected components of plasma (e.g., coagulation factor VIII into hemophiliacs) or cellular elements (e.g., platelets).
Erythrocyte Antigens and Plasma Antibodies Determine Transfusion Compatibility

For the purposes of transfusion, each persons blood is distinctive from the blood of many but not all other people. Transfusion traits are due to antigens and antibodies, which are discussed in detail in Chapter 12. For now we will define an antigen as a molecule capable of provoking a defensive reaction by the immune system. An antibody is a specialized blood protein generated specifically to mount an attack against an antigen. The type of antigen important to our story of blood transfusion is a glycoprotein on the surface of red blood cell membranes. Persons possessing a certain RBC antigen are said to belong to a certain blood group (or blood type). For practical purposes, when the term blood group is commonly used, it refers to RBC blood groups. WBCs and platelets also have surface antigens that give them distinctive characteristics, but their numbers are so few that they are of little importance in most blood transfusions.
The Rh group, which is so named because the antigen group was originally discovered in rhesus monkeys, is determined by the presence or absence of a different antigen. There are eight antigens in the Rh group, but only one (antigen D) is important. About 80% of Americans have the Rh D antigen on their RBCs and are said to be Rh-positive; those without the Rh D antigen are said to be Rh-negative. The complete description of a persons blood type requires both ABO and Rh type. Thus a person may be O-positive (meaning type O, Rh-positive), AB-negative (meaning type AB, Rh-negative), and so on. By virtue of the presence of A and B antigens in bacteria, food, and other components of the environment, every person early in life develops antibodies against the A or B antigens not present in their own blood. Therefore:
The plasma of type A blood contains anti-B antibodies. The plasma of type B blood contains anti-A antibodies. The plasma of type O blood has both anti-A and
anti-B antibodies (recall that type O blood cells do not contain A or B antigens). The plasma of type AB blood has neither anti-A nor anti-B antibodies. The situation is quite different for the Rh D antigen. The environment does not contain Rh D antigen. Therefore, antibodies to the Rh D antigen develop only in an Rhnegative person who is exposed to large amounts of the Rh D antigensay, by transfusion with Rh-positive blood. The result is that anti-A and/or anti-B antibodies are present in almost everyone (except those with the rare AB blood type), and very, very few persons have anti Rh D antibodyonly those exposed in some way to RBCs containing Rh D antigen.
Remember This!
by RBC antigens.
Blood group is determined
Agglutination Reveals Blood Types

In the presence of the particular type of antigen they are designed to attack, antibodies attach to the antigens on the surface of RBCs and bind the RBCs together. The result is that interlocking chains of RBCs form in blood, a process called agglutination (Fig. 10.13). For example, agglutination occurs if type A blood is transfused into a recipient with type O blood because the type O patient has anti-A antibodies in plasma. Such a reaction is extremely serious. Agglutination of RBCs is visible to the naked eye and is used to choose correctly matched blood groups for safe transfusion. To determine a patients blood type, a procedure called blood typing is performed. Anticoagulated patient blood is placed on each of two slides. Anti-A
There are two main sets of RBC blood group antigens: the ABO group and the Rh group, both of which are inheritable. The ABO group is based on the presence or absence of two antigens, A and B (Fig. 10.12). Persons with neither A nor B antigen on their RBCs form blood group O (or blood type O). Persons with both A and B form blood group AB. Persons possessing only A antigen form group A; patients with only B form blood group B. Among Americans, the prevalence of the major RBC ABO blood groups, from most to least common, are blood types O, A, B, and AB.
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PATIENT BLOOD TYPE
PATIENT RBCs A antigens
PATIENT PLASMA
BLOOD TYPES PATIENT CAN RECEIVE
Type A
Anti-B antibodies
A, O
B antigens Anti-A antibodies B, O
Type B
A antigen
Type AB
Neither antibody
A, B, AB, O (Universal recipient)
B antigen Neither antigen A or B Type O (Universal donor) Anti-A antibody Anti-B antibody O
(a) The ABO antigen system
Rh D antigens
Rh positive
No anti-Rh D antibodies
Rh+ or Rh
No Rh D antigens Rh negative
Anti-Rh D antibodies (following exposure to Rh D antigen)
Rh (Only)
(b) The Rh antigen
Figure 10.12. Common blood groups. A. ABO blood groups. An individuals plasma contains antibodies against A or B antigens not present on his or her erythrocytes. B. Rh blood groups. Antibodies against antigen Rh D are present only in Rh-negative people who have been exposed to Rh-positive blood (perhaps from a transfusion). If you wanted plasma with both anti-A and anti-B antibodies in it, which blood group would you use?
401
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TRANSFUSION COMBINATION
DONOR (cells) No A or B antigens
RECIPIENT (plasma) A antibodies
RESULT
COMPATIBLE
(type O)
(type A)
No agglutination
A antigens
A and B antibodies
INCOMPATIBLE
+
Anti-A (type A) (type O) Agglutination
Figure 10.13. Cross-matching. Donor blood cells are mixed with the recipients plasma to check for compatibility. A compatible transfusion combination will not result in an agglutination reaction. In this example, someone with type A blood can receive a transfusion with type O blood, but not vice versa. In the incompatible transfusion, would the anti-B antibody of the recipient participate in the agglutination reaction?
plasma is added to one and anti-B to the other. If RBCs in both agglutinate, the patient belongs to blood group AB; if there is no agglutination on either slide, the patient is type O, and so on.
Case Note
10.17. Eleanors blood type is O-positive. What AB or Rh antigens do her RBCs have?
Safe Transfusion Requires Cross-Matching

Careful matching of RBC blood groups is essential to avoid agglutination. Thats why, in addition to blood typing, physicians routinely order a second, higherlevel lab test called cross-matching to be doubly sure that no agglutination will occur. The most important step in a cross-match involves mixing a sample of the proposed donors RBCs with a sample of the proposed recipients plasma to ensure that the two are actually,
not just theoretically, compatible (see Fig. 10.13). For example, we might propose to transfuse RBCs from a group O donor into a patient with group A RBCs. We expect the cross-match to be compatible because group O cells contain no A or B antigen to agglutinate with the anti-B antibody in the recipients plasma. If no agglutination occurs, the cross-match is said to be compatible. On the other hand, if agglutination does occur, the cross-match is said to be incompatible, which may indicate a laboratory mistake. Perhaps its not really group O donor blood we are usingor maybe we are testing the wrong recipient blood. In any case, if mismatched RBCs are transfused, agglutination will occur. An example of an incompatible transfusion combination is the reverse of our previous example; if we transfuse group A donor RBCs into a recipient with type O blood cells, agglutination occurs. The agglutinated RBCs will be destroyed (hemolysis), and their hemoglobin will be released into plasma in what is called an acute hemolytic reaction. This free hemoglobin must be cleansed (cleared) from plasma by the kidneys, but kidney capacity is limited and can easily
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be overwhelmed, resulting in kidney failure. In addition, even a small amount of agglutinated RBCs can clog blood vessels, thus severely reducing blood flow to tissues. The result is often fatal.
Case Note
10.18. Based on the information in the previous case note, could Eleanor be safely transfused with type A blood?
10.37 Which blood group does not have any of the A, B, or Rh antigens? 10.38 If someone has anti-A antibodies and Rh antibodies, what is his or her blood group? 10.39 If someone has anti-A antibodies but no Rh antibodies, can we be certain of his or her blood group? Explain. 10.40 Explain how an incompatible transfusion could cause the death of the patient.
The medical record does not indicate the counts of specific WBCs, but it is certain that the numbers of both neutrophils and lymphocytes (the most abundant blood leukocytes) were markedly decreased. Autopsy findings are confirmatory: bacterial infection of blood and lungs, which can be attributed to low neutrophil and lymphocyte counts, and fungal infection of her esophagus, which is sure to be a reflection of a low lymphocyte count. Moreover, healing of the ulcer, which had been caused by the fungal infection, was also impaired by neutropenia. Platelets Note that on Eleanors initial hospitalization, her platelet count was very low; she also had a severe nosebleed and tiny skin hemorrhages (petechiae, which are characteristic of platelet-induced bleeding). Physicians transfused her with platelets, which had the desired effect of stopping the bleeding. On her final admission with a massive gastrointestinal hemorrhage, the platelet count was again very low. The thrombocytopenia and bleeding esophageal ulcer combined to produce uncontrollable acute esophageal hemorrhage. Erythrocytes When she initially appeared with a nosebleed, Eleanor was significantly anemic, likely reflecting the failure of marrow production even before the nosebleed occurred. The nosebleed (and the later esophageal hemorrhage) introduced to the existing production-failure anemia a new problem of hemorrhagic anemia. Although Eleanors final blood hemoglobin level was extremely low, some patients with such low hemoglobin levels can survive if their blood volume is adequatethat is, if their bleeding is slow enough (or therapy quick enough) for their plasma volume to expand to make up for the lost blood volume. But Eleanors blood volume was not adequateshe bled so rapidly that both blood volume and blood pressure fell to undetectable levels and she expired from lack of oxygen (hypoxia).
Case Discussion
Bone Marrow Failure: The Case of Eleanor B.

E Eleanor died of bone marrow failurebreast cancer spread to f her h bones and replaced most of the bone marrow. At the time of her b death, every one of her major cell d lines was affected: platelet and leul kocyte cell counts were very low, and she was severely anemic even before her final, fatal hemorrhage. Lets discuss each of these elements in turn (Fig. 10.14).
Leukocytes When she first appeared in the emergency
Case Notes
room, Eleanors total white cell count was very low. From the time of her initial emergency room visit until the time of her death, she required antibiotic treatment for pneumonia, skin infections, and recurrent diarrhea, suggesting that the leukopenia impaired her resistance to disease. 10.19. On her final emergency room visit, why is Eleanors blood pressure low? 10.20. Eleanor is confused because her brain is not getting enough oxygen. In addition to her low blood pressure, can you think of a second reason?
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Breast cancer cells replaced Hematapoietic stem cells
Few lymphoid stem cells
Few myeloid stem cells
Few lymphocytes
Few megakaryocytes
Few reticulocytes
Few neutrophils
Lymphocytopenia
Thrombocytopenia
Low RBC count/ hemoglobin
Neutropenia
Viral, bacterial, fungal infections (including esophageal ulcer)
Acute esophageal hemorrhage
Anemia
Bacterial infections, impaired wound healing
Figure 10.14. Bone marrow failure and Eleanor H. Eleanors bone marrow can no longer produce enough blood cells to fight infection, prevent hemorrhage, and prevent anemia. The absence of which cell type increases Eleanors susceptibility to fungal infections?
Word Parts
Latin/Greek Word Parts -cyte -emia erythr/o hemat/o, hem/o leuk/o, leukocyt/o English Equivalents Cell Blood Red, red blood cell Blood White blood cell Examples Leukocyte: white blood cell Anemia: lack (an-) of red blood cells Erythropoietin: hormone stimulating red blood cell synthesis Hemostasis: maintenance of a constant Blood volume Leukocytopenia: too few white blood cells
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Word Parts (continued)

Latin/Greek Word Parts lymph/o macromonomyel/o -oxia -penia -poiesis prothromb/o, thrombocyto English Equivalents Lymphocyte Large One Bone marrow Oxygen Deficiency Synthesis Before, in front of Blood clot, platelet Examples Lymphopenia: lymphocyte deficiency Macrophage: large cell Monocyte: contains a single (unlobed) nucleus Myeloid stem cell: stem cell originating in bone marrow Hypoxia: low oxygen concentration (in blood) Thrombocytopenia: platelet deficiency Erythropoiesis: erythrocyte synthesis Prothrombin: a precursor to thrombin Thrombopoietin: hormone stimulating platelet synthesis
Chapter Challenge
CHAPTER RECALL
1. If you have 5 L of blood and cellular elements account for 40% of your blood volume, what is your total plasma volume? a. 5 L b. 4 L c. 3 L d. 2 L 2. Which of the following is not a role of albumin? a. Blood clotting b. Transportation of fatty acids c. Maintaining the osmotic pressure of blood d. None of the above 3. Serum contains a. RBCs. b. clotting factors. c. leukocytes. d. none of the above. 4. Which of the following cellular elements contains a nucleus? a. Erythrocyte b. Megakaryocyte c. Platelet d. All of the above 5. Hemoglobin a. is found in leukocytes. b. contains iron. c. transports fatty acids and other substances in blood. d. is an inorganic molecule. 6. Monocytes are a. granulocytes. b. the most abundant WBCs. c. the precursor to a type of phagocyte. d. the least abundant WBCs.
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Human Form, Human Function: Essentials of Anatomy & Physiology 15. The tissue factor pathway is a. initiated when cells that do not usually encounter blood proteins are exposed to plasma. b. stimulated by interactions between clotting factors and foreign substances. c. of secondary importance to the contact activation pathway in responding to tissue injury. d. the only clotting pathway that involves thrombin. 16. Thrombin a. converts fibrinogen into fibrin. b. binds tissue factor. c. forms a meshwork of fibers within the blood clot. d. is involved in the formation of thrombi but not of blood clots. 17. Transfusion reactions largely reflect the presence of antigens on a. RBCs. b. WBCs. c. platelets. d. all blood cells. 18. An individual with type A blood will have antibodies against a. B antigen. b. A antigen. c. both A and B antigens. d. neither A nor B antigens. 19. An individual with type O blood can safely receive a transfusion with a. type A blood. b. type B blood. c. type AB blood. d. none of the above.
7. The generation of blood cells is called a. hemostasis. b. homeostasis. c. hematopoiesis. d. hemolysis. 8. Erythropoietin is a. a clotting factor made by the liver. b. produced in response to hypoxia. c. produced by erythrocytes. d. the hormone that stimulates platelet synthesis. 9. Lymphoid stem cells produce a. all WBCs. b. only lymphocytes. c. only granulocytes. d. all blood cells. 10. Bilirubin is a. produced from globin degradation. b. recycled in the bone marrow into new hemoglobin molecules. c. excreted into the intestine by the liver. d. the protein that stores iron in tissues. 11. Which of the following cells is the most important player in acute inflammation and wound healing? a. Eosinophils b. Basophils c. Lymphocytes d. Neutrophils 12. Reticulocytes mature into a. basophils. b. macrophages. c. erythrocytes. d. platelets. 13. The increased hematocrit resulting from dehydration is called a. relative anemia. b. absolute anemia. c. relative polycythemia. d. absolute polycythemia. 14. You have just cut your finger. The bodys first physiological response to this trauma is the a. formation of a platelet plug. b. activation of clotting factors. c. formation of a thrombus. d. vasoconstriction.
CONCEPTUAL UNDERSTANDING
20. Name three structural characteristics of RBCs and explain the functional implications of each.
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APPLICATION
21. In a person who is experiencing chronic slow bleeding in the gastrointestinal tract, which of the following functions would be adversely affected? Defend your answers. a. Fighting off a cold b. Flushing red on a hot day c. Hemostasis of a paper cut d. oxygen transport 22. Your friend has recently learned that that 75% of her bone marrow is involved in leukocyte production, and she is worried that she might have leukemia. Is she right to worry? Explain.
23. The most common blood type in Norway is A . In an A individual, a. which antigens are present on RBCs? b. which antibodies are present in plasma? c. would a transfusion with A- blood induce agglutination? Explain why or why not.
You can find the answers to these questions on the student Web site at http://thepoint.lww.com/McConnellandHull
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4. Compare and contrast acute inflammation,

Erythrocytes and Oxygen Transport

5. List three physical characteristics of red

2. Name the three types of plasma proteins

Leukocytes, Inflammation, and Immunity 383

6. Describe the structure and function of

12. Use flowcharts to illustrate the tissue factor

9. Discuss the pathway that results in increased red

13. List three differences between coagulation and

Blood Groups and Transfusion

10. Describe the regulation and mechanism of

14. Determine which blood group can be transfused

Bone Marrow Failure: The Case of Eleanor B. 403

11. Use diagrams to explain the three steps of

My life is running out of my nose!

Dont worry; the bleeding always stops.

from a few hours to a few months.

way to tissues from the lungs), dark reddish-blue if

Blood elements form a clot to reduce blood loss.

Blood Has Five Main Functions

Blood transports oxygen, nutrients, wastes, and chemical messengers.

Blood Is Composed of Plasma and Cellular Elements

Human Form, Human Function: Essentials of Anatomy & Physiology

The History of Blood Transfusion

Blood transfusions. Direct person-to-person transfusions.

Plasma Contains Water and Solutes

Human Form, Human Function: Essentials of Anatomy & Physiology

Buffy coat: <1% Leukocytes

Erythrocytes: 44% Platelets Eosinophils

Basophils Erythrocytes (a) Separation of blood elements using centrifugation Platelet

Plasma is 90% water, 9% protein, 1% nonprotein solutes.

Cellular Elements Are Produced in the Bone Marrow

Human Form, Human Function: Essentials of Anatomy & Physiology

Myeloid stem cell

Pluripotent hematopoietic stem cell Eosinophil

Lymphoid stem cell

Leukocytes, Inflammation, and Immunity

Cellular Elements of Blood

Leukocytes (white blood cells) Granulocytes Neutrophils (54% to 62% of WBCs)

Phagocytosis of bacteria, other invaders

Eosinophils (1% to 3% of WBCs)

Nucleus: lobed, purple Granules: large, red Cytoplasm: pale pink

Allergic inflammatory reactions; defense against parasites Allergic inflammatory reactions

Monocytes (3% to 7% of WBCs)

Granules: purple or none Cytoplasm: light blue

Granulocytes Contain Large Cytoplasmic Granules

Lymphocytes Are Cells of the Immune System

Monocytes Develop into Macrophages

Remember This! The main task of WBCs is

Leukocytes Are Involved in Inflammation

Leukocytes and Inflammation

Type of Inflammation Acute Chronic

Eosinophils, some basophils

Human Form, Human Function: Essentials of Anatomy & Physiology

Intermediate Types of Inflammation

Leukemia and Lymphoma Are Malignant Diseases of Leukocytes

Infection Is a Risk with Low Numbers of Leukocytes

(a) Normal blood Malignant leukocytes

Erythrocyte Form Contributes to Function

Erythrocytes and Oxygen Transport

7.28.4 m Sectional view (a) Red blood cells (b) Hemoglobin