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U N I T
Hematopoietic
Function
F
rom ancient times, the importance of blood as a determinant of
health was recognized. Its life-affecting powers are well described in
the written treatises of Greek physician Galen (AD 130–200). Galen,
who reigned as the foremost medical authority for nearly 1500 years,
believed that an individual stayed healthy as long as four body fluids—blood, phlegm, yellow bile, and black bile—remained in the
right proportion. He also believed that the four humors determined
one’s basic temperament. Whether an individual was sanguine, sluggish and dull, quick to anger, or melancholy was determined by the
degree to which one or another of the humors predominated. The
most desirable personality type was achieved when blood was
thought to predominate, yielding a warm and cheerful person.
The workings of blood were traced by Galen from its creation,
which he believed took place in the liver, throughout the body. He
came to believe that disease manifested itself if any one of the fluids
was in excess or deficient and was carried in the blood. The theory
led to bloodletting—the drawing of blood from the vein of a sick person so the disease could flow out with the blood. For many centuries,
bloodletting was the standard treatment for a myriad of ills.
IV
CHAPTER
14
Hematopoietic System
Kathryn J. Gaspard
COMPOSITION OF BLOOD
AND FORMATION OF BLOOD CELLS
Plasma
Plasma Proteins
Blood Cells
Erythrocytes
Leukocytes
Thrombocytes
Hematopoiesis
Blood Cell Precursors
Regulation of Hematopoiesis
DIAGNOSTIC TESTS
Blood Count
Erythrocyte Sedimentation Rate
Bone Marrow Aspiration and Biopsy
When blood is removed from the circulatory system,
it clots. The clot contains the blood cells and fibrin strands
formed from the conversion of the plasma protein fibrinogen. It is surrounded by a yellow liquid called serum. Blood
that is kept from clotting by the addition of an anticoagulant (e.g., heparin, citrate) and then centrifuged separates
into layers (Fig. 14-1). The lower layer (approximately 42%
to 47% of the whole-blood volume) contains the erythrocytes, or red blood cells, and is referred to as the hematocrit.
The intermediate layer (approximately 1%) containing the
leukocytes is white or gray and is called the buffy layer.
Above the leukocytes is a thin layer of platelets that is not
discernible to the naked eye. The translucent, yellowish
fluid that forms on the top of the cells is the plasma, which
comprises approximately 55% of the total volume.
PLASMA
B
lood consists of blood cells (i.e., red blood cells,
thrombocytes or platelets, and white blood cells) and
the plasma in which the cells are suspended. Blood
cells have a relatively short life span and must be continually replaced. The generation of blood cells takes place in
the hematopoietic (from the Greek haima “blood” and
poiesis “making”) system. The hematopoietic system encompasses all of the blood cells and their precursors, the
bone marrow where blood cells have their origin, and the
lymphoid tissues where some blood cells circulate as they
develop and mature.
The plasma component of blood carries the cells that transport gases, aid in body defenses, and prevent blood loss. It
transports nutrients that are absorbed from the gastrointestinal tract to body cells and delivers the waste products
from cellular metabolism to the kidney for elimination; it
transports hormones and permits the exchange of chemical messengers; it facilitates the exchange of body heat; and
it participates in electrolyte and acid-base balance and the
osmotic regulation of body fluids. Plasma is 90% to 91%
water by weight, 6.5% to 8% proteins by weight, and 2%
other small molecular substances (Table 14-1).
PLASMA PROTEINS
Composition of Blood
and Formation of Blood Cells
After completing this section of the chapter, you should be able to
meet the following objectives:
✦ Describe the composition of plasma
✦ Name the formed elements of blood and cite their
function and life span
✦ Trace the process of hematopoiesis from stem cell to
mature blood cell
The plasma proteins are the most abundant solutes in
plasma. Most proteins are formed in the liver and serve a
variety of functions. The major types are albumin, globulins, and fibrinogen. Albumin is the most abundant and
makes up approximately 54% of the plasma proteins. It does
not diffuse through the vascular endothelium and therefore
contributes to plasma osmotic pressure and the maintenance of blood volume (see Chapter 33). Albumin also
serves as a carrier for certain substances and acts as a blood
buffer. The globulins comprise approximately 38% of
plasma proteins. There are three types of globulins: the
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UNIT IV
Hematopoietic Function
not divide and thus must be continually renewed by the
process of hematopoiesis in the bone marrow.
Erythrocytes
The erythrocytes, or red blood cells, are the most numerous of the formed elements. They are small, biconcave
disks with a large surface area and can easily deform in
small capillaries. They contain the oxygen-carrying protein, hemoglobin, that functions in the transport of oxygen. The erythrocytes are derived from the myeloid or
bone marrow stem cell and live approximately 120 days in
the circulation (see Chapter 16).
Plasma
(55% of
whole blood)
Buffy coat leukocytes
and platelets
(<1% of
whole blood)
Formed
elements
Erythrocytes
(45% of
whole blood)
Leukocytes
The leukocytes, or white blood cells, constitute only 1%
of the total blood volume. They originate in the bone
marrow and circulate throughout the lymphoid tissues of
the body. There they function in the inflammatory and
immune processes. They include the granulocytes, the
lymphocytes, and the monocytes (Fig. 14-2).
Granulocytes. The granulocytes are all phagocytic cells
FIGURE 14-1 Layering of blood components in an anticoagulated
and centrifuged blood sample.
alpha globulins that transport bilirubin and steroids, the
beta globulins that transport iron and copper, and the
gamma globulins that constitute the antibodies of the immune system. Fibrinogen makes up approximately 7% of
the plasma proteins and is converted to fibrin in the clotting
process. The remaining 1% of circulating proteins includes
hormones, enzymes, complement, and carriers for lipids.
BLOOD CELLS
The blood cells include the erythrocytes or red blood
cells, the leukocytes or white blood cells, and platelets
(Table 14-2). The blood cells, or formed elements, are not
all true cells, and most survive for only a few days in the
circulation or tissues as a result of their function. They do
COMPOSITION OF THE BLOOD
➤ Blood is a liquid that fills the vascular compartment and
serves to transport dissolved materials and blood cells
throughout the body.
➤ The most abundant of the blood cells, the erythrocytes or
red blood cells, function in oxygen and carbon dioxide
transport.
➤ The leukocytes, or white blood cells, serve various roles in
immunity and inflammation.
➤ Platelets are small cell fragments that are involved in blood
clotting.
and are identifiable because of their cytoplasmic granules.
These white blood cells are spherical and have distinctive
multilobar nuclei. The granulocytes are divided into three
types (neutrophils, eosinophils, and basophils) according
to the staining properties of the granules. Functionally, all
granulocytes are phagocytes.
Neutrophils. The neutrophils, which constitute 55% to
65% of the total number of white blood cells, have granules that are neutral and hence do not stain with an acidic
or a basic dye. Because these white cells have nuclei that
are divided into three to five lobes, they are often called
polymorphonuclear leukocytes.
The neutrophils are primarily responsible for maintaining normal host defenses against invading bacteria
and fungi, cell remains, and a variety of foreign substances.
The cytoplasm of mature neutrophils contains fine granules. These granules contain degrading enzymes that are
used in destroying foreign substances and correspond to
lysosomes found in other cells (see Chapter 4). Enzymes
and oxidizing agents associated with these granules are capable of degrading a variety of natural and synthetic substances, including complex polysaccharides, proteins, and
lipids. These enzymes are important in maintaining normal host defenses and in mediating inflammation.
The neutrophils have their origin in the myeloblasts
that are found in the bone marrow (Fig. 14-3). The myeloblasts are the committed precursors of the granulocyte
pathway and do not normally appear in the peripheral circulation. When they are present, it suggests a disorder of
blood cell proliferation and differentiation. The myeloblasts differentiate into promyelocytes and then myelocytes. Usually, a cell is not called a myelocyte until it has at
least 12 granules. The myelocytes mature to become metamyelocytes (Greek meta, “beyond”), at which point they
lose their capacity for mitosis. Subsequent development of
the neutrophil involves reduction in size, with transformation from an indented to an oval to a horseshoe-shaped
nucleus (i.e., band cell) and then to a mature cell with a
CHAPTER 14
TABLE 14-1
Plasma
Water
Proteins
Albumin
Globulins
Fibrinogen
Other substances
5
Plasma Components
Percentage of
Plasma Volume
Description
90–91
6.5–8
54% Plasma proteins
38% Plasma proteins
7% Plasma proteins
Hormones, enzymes, carbohydrates, fats, amino
acids, gases, electrolytes, excretory products
1–2
segmented nucleus. These mature neutrophils are often
referred to as segs because of their segmented nucleus.
Development from stem cell to mature neutrophil takes
approximately 2 weeks. It is at this point that the neutrophil enters the bloodstream.
After release from the marrow, the neutrophils spend
only approximately 4 to 8 hours in the circulation before
moving into the tissues. Their survival in the tissues lasts
approximately 4 to 5 days. They die in the tissues in discharging their phagocytic function or they die of senescence. The pool of circulating neutrophils (i.e., those that
appear in the blood count) is in closely maintained equilibrium with a similar-sized pool of cells marginating
along the walls of small blood vessels. These are the neutrophils that respond to chemotactic factors and migrate
into the tissues toward the offending agent. Epinephrine,
exercise, stress, and corticosteroid drug therapy can cause
rapid increases in the circulating neutrophil count by shifting cells from the marginating to the circulating pool. Endotoxins or microbes have the opposite effect, producing
a transient decrease in neutrophils by attracting neutrophils into the tissues.
Eosinophils. The cytoplasmic granules of the eosinophils
stain red with the acidic dye eosin. These leukocytes con-
TABLE 14-2
Hematopoietic System
stitute 1% to 3% of the total number of white blood cells
and increase in number during allergic reactions and parasitic infections. In allergic reactions, it is thought that they
release enzymes or chemical mediators that detoxify the
agents associated with allergic reactions. In parasitic infections, the eosinophils use surface markers to attach themselves to the parasite and then release hydolytic enzymes
that kill it.
Basophils. The granules of the basophils stain blue with
a basic dye. These cells constitute only approximately
0.3% to 0.5% of the white blood cells. The granules in the
basophils contain heparin, an anticoagulant, and histamine, a vasodilator. The basophils share properties of mast
cells and are thought to be involved in allergic and stress
responses.
Lymphocytes. The lymphocytes constitute 20% to 30%
of the white blood cell count. They originate in the bone
marrow from lymphoid stem cells. They have no identifiable granules in the cytoplasm and are also called agranulocytes. The lymphocytes play an important role in the
immune response. They move between blood and lymph
tissue, where they may be stored for hours or years. Their
function in the lymph nodes or spleen is to defend against
Blood Cell Counts
Blood Cells
Number of Cells/␮L
Red blood cell count
White blood cell count
Differential count
Granulocytes
Neutrophils
Segs
Bands
Eosinophils
Basophils
Lymphocytes
Monocytes
Platelet count
4.2–5.4 × 106, 3.6–5.0 × 106 *
4.40–11.3 × 103
150–400 × 103
*First value is for men and the second for women.
Percentage of
White Blood Cells
47–63
0–4
0–3
0–2
24–40
4–9
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UNIT IV
Hematopoietic Function
Granules
(lysosomes)
Promyelocyte
Myelocyte
Granulocyte
Myeloblast
Loss of capacity
for mitosis
Metamyelocyte
Lymphocyte
Lysosome
Band cell
Phagocytic
vacuole
Segmented neutrophil
Lysosome
Enters blood
Monocyte/Macrophage
FIGURE 14-2 White blood cells.
Enters tissues
(1-2 days)
FIGURE 14-3 Development of neutrophils. (Adapted from Cormack
D. H. [1993]. Ham’s histology [9th ed.]. Philadelphia: J. B. Lippincott)
microorganisms in the immune response (see Chapter 19).
There are two types of lymphocytes: B lymphocytes and
T lymphocytes. The B lymphocytes differentiate to form
antibody-producing plasma cells and are involved in
humoral-mediated immunity. The T lymphocytes activate other cells of the immune system and are involved
in cell-mediated immunity.
inert foreign bodies, such as talc or surgical sutures. Immune granulomas are caused by insoluble particles that
are capable of inciting a cell-mediated immune response.
The tubercle that forms in primary tuberculosis infections is an example of an immune granuloma (see Chapter 30).
Monocytes and Macrophages. Monocytes are the largest
Thrombocytes, or platelets, are circulating cell fragments of
the large megakaryocytes that are derived from the myeloid
stem cell. They function to form a platelet plug to control
bleeding after injury to a vessel wall (see Chapter 15). Their
cytoplasmic granules release mediators required for hemostasis. Thrombocytes have no nucleus, cannot replicate,
and, if not used, last approximately 8 to 9 days in the circulation before they are removed by the phagocytic cells of
the spleen.
of the white blood cells and constitute approximately 3%
to 8% of the total leukocyte count. The life span of the circulating monocyte is approximately 1 to 3 days, three to
four times longer than that of the granulocytes. These cells
survive for months to years in the tissues. The monocytes,
which are phagocytic cells, are often referred to as macrophages when they enter the tissues. The monocytes engulf
larger and greater quantities of foreign material than the
neutrophils. These leukocytes play an important role in
chronic inflammation and are also involved in the immune response by activating lymphocytes and by presenting antigen to T cells. When the monocyte leaves the
vascular system and enters the tissues, it functions as a
macrophage with specific activity. The macrophages are
known as histiocytes in loose connective tissue, microglial
cells in the brain, and Kupffer cells in the liver. Some macrophages function in the alveoli.
Granulomatous inflammation is a distinctive pattern
of chronic inflammation in which the macrophages form
a capsule around insoluble materials that cannot be digested. Foreign-body granulomas are incited by relatively
Thrombocytes
HEMATOPOIESIS
The generation of blood cells begins in the endothelial
cells of the developing blood vessels during the fifth week
of gestation and then continues in the liver and spleen.
After birth, this function is gradually taken over by the
bone marrow. The marrow is a network of connective tissue containing immature blood cells. At sites where the
marrow is hematopoietically active, it produces so many
erythrocytes that it is red, hence the name red bone marrow.
Fat cells are also present in bone marrow, but they are in-
CHAPTER 14
Hematopoietic System
Blood Cell Precursors
HEMATOPOIESIS
➤ Blood cells originate from pluripotent stem cells in the
bone marrow.
➤ The proliferation, differentiation, and functional abilities of
the various blood cells are controlled by hormone-like
growth factors called cytokines.
active in terms of blood cell generation. Marrow made up
predominantly of fat cells is called yellow bone marrow.
During active skeletal growth, red marrow is gradually replaced by yellow marrow in most of the long bones. In
adults, red marrow is largely restricted to the flat bones of
the pelvis, ribs, and sternum. As a person ages, the cellularity of the marrow declines. When the demand for red
cell replacement increases, as in hemolytic anemia, there
can be resubstitution of red marrow for yellow marrow.
Some hematopoiesis may also be generated in the spleen
and the liver.
The blood-forming population of bone marrow is made up
of three types of cells: self-renewing stem cells, differentiated progenitor (parent) cells, and functional mature blood
cells. All of the blood cell precursors of the erythrocyte
(i.e., red cell), myelocyte (i.e., granulocyte or monocyte),
lymphocyte (i.e., T lymphocyte and B lymphocyte), and
megakaryocyte (i.e., platelet) series are derived from a
small population of primitive cells called the pluripotent
stem cells (Fig. 14-4). Their lifelong potential for proliferation and self-renewal makes them an indispensable and
lifesaving source of reserve cells for the entire hematopoietic system. Several levels of differentiation lead to the development of committed unipotential cells, which are the
progenitors for each of the blood cell types. These cells are
referred to as colony-forming units or burst-forming units.
These progenitor cells lose their capacity for self-renewal
but retain the potential to differentiate in response to
lineage-specific growth factors. They develop into the precursor cells that give rise to mature erythrocytes, myelocytes, megakaryocytes, or lymphocytes.
Disorders of hematopoietic stem cells include aplastic
anemia and the leukemias. Today, potential cures for these
(committed stem cells)
Pluripotent stem cell
Myeloid stem cell
Lymphoid stem cell
T cell
progenitor
B cell
progenitor
Megakaryocyte
CFU
Granulocyte
CFU
Monocyte
CFU
Erythrocyte
CFU
thymus
Monoblast
B cell
(mature cells)
Megakaryocyte
T cell
7
Reticulocyte
Plasma cell
Monocyte
Eosinophil
Neutrophil
Basophil
Platelets
Erythrocyte
FIGURE 14-4 Major maturational stages of blood cells. CFU, colony forming units.
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UNIT IV
Hematopoietic Function
and many other disorders require hematopoietic stem cell
transplantation. Stem cell transplants correct bone marrow failure, immune deficiencies, hematologic defects and
malignancies, and inherited errors of metabolism. Sources
of the stem cells include bone marrow, peripheral blood,
and umbilical cord blood, all of which replenish the recipient with a normal population of pluripotent stem cells.
Bone marrow and peripheral blood transplants may be derived from the patient (autologous) or from a histocompatible donor (allogeneic). Autologous transplants are often
used to replenish stem cells after high-dose chemotherapy
or irradiation. Peripheral blood stem cells are harvested
from the blood after the administration of a cytokine
growth factor that increases the quantity and migration of
the cells from the bone marrow. Umbilical cord blood from
HLA-matched donors is a transplant option for children
and carries less risk for graft-versus-host disease. Methods
of collecting, propagating, and preserving stem cells are
still being investigated.
Regulation of Hematopoiesis
Under normal conditions, the numbers and total mass for
each type of circulating blood cell remain relatively constant. The blood cells are produced in different numbers
according to needs and regulatory factors. This regulation
of blood cells is thought to be at least partially controlled
by hormone-like growth factors called cytokines. The cytokines are a family of glycoproteins that stimulate the proliferation, differentiation, and functional activation of the
various blood cell precursors in bone marrow. Many cytokines are produced by bone marrow stromal cells that
include macrophages, endothelial cells, fibroblasts, and
lymphocytes and act locally in the bone marrow by binding to cell surface receptors. Other cytokines are produced
in the liver and kidney.
Some cytokines are colony-stimulating factors (CSFs)
that were named for their ability to promote growth of
blood cell colonies in culture. Major growth factors that
act on committed progenitor cells include: erythropoietin (EPO), which stimulates red blood cell production;
granulocyte-monocyte colony-stimulating factor (GM-CSF),
which stimulates progenitors for granulocytes, monocytes,
erythrocytes, and megakaryocytes; granulocyte colonystimulating factor (G-CSF), which promotes the proliferation of neutrophils; macrophage colony-stimulating factor
(M-CSF), which induces macrophage colonies, and thrombopoietin (TPO), which stimulates the differentiation of
platelets. The CSFs act at different points in the proliferation and differentiation pathway, and their functions
overlap. Other cytokines, such as the many interleukins,
the interferons, and tumor necrosis factor, support the proliferation of stem cells and the development of lymphocytes and act synergistically to aid the multiple functions
of the CSFs (see Chapter 19).
The genes for most hematopoietic growth factors have
been cloned, and their recombinant proteins have been
generated for use in a wide range of clinical problems. The
clinically useful factors include EPO, TPO, G-CSF, and GMCSF. They are used to treat bone marrow failure caused by
chemotherapy or aplastic anemia, the anemia of kidney
failure, hematopoietic neoplasms, infectious diseases such
as acquired immunodeficiency syndrome (AIDS), congenital and myeloproliferative disorders, and some solid tumors. Growth factors are used to increase peripheral stem
cells for transplantation and to accelerate cell proliferation
after bone marrow engraftment. Many of these uses are
still investigational.
In summary, blood is composed of plasma, plasma proteins, formed elements or blood cells, and substances such as
hormones, enzymes, electrolytes, and byproducts of cellular
waste. The blood cells consist of erythrocytes or red blood
cells, leukocytes or white blood cells, and thrombocytes or
platelets. Blood cells are generated from pluripotent stem cells
located in the bone marrow. Blood cell production is regulated
by chemical messengers called cytokines and growth factors.
Diagnostic Tests
After completing this section of the chapter, you should be able to
meet the following objectives:
✦ Cite information gained from a complete blood count
✦ State the purpose of the erythrocyte sedimentation rate
✦ Describe the procedure used in bone marrow aspiration
Blood specimens can be obtained through skin puncture (capillary blood), venipuncture, arterial puncture, or
bone marrow aspiration.
BLOOD COUNT
Tests of the hematologic system provide information regarding the number of blood cells and their structural and
functional characteristics. A complete blood count (CBC)
is a commonly performed screening test that determines
the number of red blood cells, white blood cells, and platelets per unit of blood. The white cell differential count is
the determination of the relative proportions (percentages)
of individual white cell types. Measurement of hemoglobin, hematocrit, mean corpuscular volume (MCV), mean
corpuscular hemoglobin concentration (MCHC), and mean
cell hemoglobin (MCH) is usually included in the CBC. Inspection of the blood smear identifies morphologic abnormalities such as a change in size, shape, or color of cells.
Specific tests of red blood cell function are found in Chapter 16 and of white blood cell function in Chapter 17.
ERYTHROCYTE SEDIMENTATION RATE
The erythrocyte sedimentation rate (ESR) is a screening
test for monitoring the fluctuations in the clinical course
of a disease. In anticoagulated blood, red blood cells aggregate and sediment to the bottom of a tube. The rate of
fall of the aggregates is accelerated in the presence of fib-
CHAPTER 14
Hematopoietic System
9
rinogen and other plasma proteins that are often increased
in inflammatory diseases. The ESR is the distance in millimeters that a red cell column travels in 1 hour. Normal
values are 1 to 13 mm/hour for men and 1 to 20 mm/hour
for women.
REVIEW EXERCISES
BONE MARROW ASPIRATION AND BIOPSY
A. Explain why stem cells are used rather than mature
lymphocytes. You might want to refer to Figure 14-4.
Tests of bone marrow function are done on samples obtained using bone marrow aspiration or bone marrow
biopsy. Bone marrow aspiration is performed with a special needle inserted into the bone marrow cavity, and a
sample of marrow is withdrawn. Usually, the posterior
iliac crest is used in all persons older than 12 to 18 months
of age. Other sites include the anterior iliac crest, sternum, and spinous processes T10 through L4. The sternum
is not commonly used in children because the cavity is
too shallow and there is danger of mediastinal and cardiac perforation. Because aspiration disturbs the marrow
architecture, this technique is used primarily to determine the type of cells present and their relative numbers.
Stained smears of bone marrow aspirates are usually subjected to several studies: determination of the erythroid
to myeloid cell count (i.e., normal ratio is 1⬊3); differential
cell count, search for abnormal cells, evaluation of iron
stores in reticulum cells, and special stains and immunochemical studies.
Bone marrow biopsy is done with a special biopsy needle inserted into the posterior iliac crest. Biopsy removes
an actual sample of bone marrow tissue and allows study
of the architecture of the tissue. It is used to determine the
marrow-to-fat ratio and the presence of fibrosis, plasma
cells, granulomas, and cancer cells. The major hazard of
these procedures is the slight risk for hemorrhage. This risk
is increased in persons with a reduced platelet count.
In summary, diagnostic tests of the blood include the complete blood count, which is used to describe the number and
characteristics of the erythrocytes, leukocytes, and platelets.
The erythrocyte sedimentation rate is used to detect inflammation. Bone marrow aspiration is used to determine the function of the bone marrow in generating blood cells.
Many of the primary immunodeficiency disorders in
which there is a defect in the development of immune
cells of T or B lymphocyte origin can be cured with allogeneic stem cell transplantation from an unaffected
donor.
B. Describe how the stem cells would go about the
process of repopulating the bone marrow.
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