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Three

Hematologic System

Alterations in

White Blood Cells

Hematopoietic and Lymphoid Tissue

Leukocytes (White blood cells)

Granulocytes

Lymphocytes

Monocytes and Macrophages

The Bone Marrow and Hematopoiesis

Lymphoid Tissues

Non-neoplastic Disorders of White Blood Cells

Neutropenia (Agranulocytosis)

Acquired Neutropenia

Congenital Neutropenia

Clinical Course

Infectious Mononucleosis

Pathogenesis

Clinical Course

Neoplastic Disorders of Hematopoietic and

Lymphoid Origin

Malignant Lymphomas

Hodgkin’s Disease

Non-Hodgkin’s Lymphomas

Leukemias

Classiﬁcation

Acute Leukemias

Chronic Leukemias

Multiple Myeloma

cells originate and mature function to protect the body

against invasion by foreign agents. Disorders of the white

blood cells include a deﬁciency of leukocytes (leukopenia) or

increased numbers as occurs with proliferative disorders. The

proliferative disorders may be reactive, such as occurs with

infection, or neoplastic, such as occurs with leukemias and

lymphomas.

HEMATOPOIETIC AND

LYMPHOID TISSUE

Blood consists of blood cells ( i.e., white blood cells, thrombo-

cytes or platelets [see Chapter 12], and red blood cells [see

Chapter 13]) and the plasma in which the cells are suspended.

The generation of blood cells takes place in the hematopoietic

(from the Greek haima for “blood” and poiesis for “making”)

system. 1 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.

191

UNIT

Alterations in the

CHAPTER

T he white blood cells and lymphoid tissues where these

192

Unit Three: Alterations in the Hematologic System

Leukocytes (White Blood Cells)

The leukocytes, or white blood cells, constitute only 1% of the

total blood volume. They originate in the bone marrow and cir-

culate throughout the lymphoid tissues of the body. There they

function in the inﬂammatory and immune processes. They in-

clude the granulocytes, the lymphocytes, and the monocytes

(Fig. 11-1).

other cells. Enzymes and oxidizing agents associated with these

granules are capable of degrading a variety of natural and syn-

thetic substances, including complex polysaccharides, proteins,

and lipids. The degradative functions of the neutrophil are im-

portant in maintaining normal host defenses and in mediating

the inﬂammatory response (see Chapter 9).

The neutrophils have their origin in the myeloblasts that are

found in the bone marrow (Fig. 11-2). 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 promyelo-

cytes and then myelocytes. Generally, a cell is not called a mye-

locyte until it has at least 12 granules. The myelocytes mature

to become metamyelocytes (Greek meta for “beyond”), at

which point they lose their capacity for mitosis. Subsequent de-

velopment 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 segmented nucleus. Mature neutrophils are often referred to

as segs because of their segmented nucleus. The development

from stem cell to mature neutrophil takes about 2 weeks. It is

at this point that the neutrophil enters the bloodstream.

After release from the marrow, the neutrophils spend only

about 4 to 8 hours in the circulation before moving into the tis-

sues. 2 Their survival in the tissues lasts about 4 to 5 days. They

die in the tissues while discharging their phagocytic function

or die of senescence. The pool of circulating neutrophils

( i.e., those that appear in the blood count) is in rapid equilib-

rium with a similar-sized pool of cells marginating along the

Granulocytes

The granulocytes are all phagocytic cells and are identiﬁable be-

cause of their cytoplasmic granules. These white blood cells are

spherical and have distinctive multilobar nuclei. The granulo-

cytes are divided into three types (neutrophils, eosinophils,

and basophils) according to the staining properties of the

granules.

Neutrophils. The neutrophils, which constitute 55% to 65% of

the total number of white blood cells, have granules that are

neutral and thus do not stain with an acidic or a basic dye.

Because their nuclei are divided into three to ﬁve lobes, they are

often called polymorphonuclear leukocytes (PMNs).

The neutrophils are primarily responsible for maintaining

normal host defenses against invading bacteria, fungi, products

of cell destruction, and a variety of foreign substances. The cy-

toplasm of mature neutrophils contains ﬁne granules. These

granules contain degrading enzymes that are used in destroy-

ing foreign substances and correspond to lysosomes found in

Granules

(lysosomes)

Promyelocyte

Granulocyte

Myelocyte

Myeloblast

Loss of capacity

for mitosis

Lymphocyte

Lysosome

Metamyelocyte

Band cell

Phagocylic

vacuole

Segmented neutrophil

Lysosome

Monocyte/Macrophage

Enters blood Enters tissues

(1-2 days)

■ FIGURE 11-2 ■ Development of neutrophils. (Adapted from

Cormack D.H. [1993]. Ham’s histology [9th ed.]. Philadelphia: J.B.

Lippincott)

■ FIGURE 11-1 ■ White blood cells—granulocyte, lymphocyte,

and monocyte.

Chapter 11: Alterations in White Blood Cells

193

walls of small blood vessels. These are the neutrophils that re-

spond to chemotactic factors and migrate into the tissues to-

ward the offending agent during an inﬂammatory response.

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 may have the opposite effect, by at-

tracting neutrophils to move out of the circulation and into the

tissues.

terial than do the neutrophils. These leukocytes play an im-

portant role in chronic inﬂammation and are also involved in

the immune response by activating lymphocytes and by pre-

senting antigen to T cells. When the monocyte leaves the

vascular system and enters the tissues, it functions as a macro-

phage with speciﬁc activity. The macrophages are known as his-

tiocytes in loose connective tissue, microglial cells in the brain,

and Kupffer’s cells in the liver.

Eosinophils. The cytoplasmic granules of the eosinophils stain

red with the acidic dye eosin. These leukocytes constitute 1%

to 3% of the total number of white blood cells and increase in

number during allergic reactions. They are thought to release

enzymes or chemical mediators that detoxify agents associated

with allergic reactions. Eosinophils are also involved in para-

sitic infections. Although most parasites are too large to be

phagocytized by eosinophils, the eosinophils attach them-

selves to the parasite by special surface molecules and release

hydrolytic enzymes and other substances from their granules

that kill the parasite.

The Bone Marrow and Hematopoiesis

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. 11-3).

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 stem cells, which are the progenitor for each of the

blood cell types. A committed stem cell that forms a speciﬁc

type of blood cell is called a colony-forming unit (CFU). 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 controlled

by a group of short-acting soluble mediators, called cytokines,

that stimulate the proliferation, differentiation, and functional

activation of the various blood cell precursors in bone mar-

row. 3 The cytokines that stimulate hematopoiesis are called

colony-stimulating factors (CSFs), based on their ability to pro-

mote the growth of the hematopoietic cell colonies from

bone marrow precursors. Lineage-speciﬁc CSFs that act on

committed progenitor cells include: erythropoietin (EPO),

granulocyte-monocyte colony-stimulating factor (GM-CSF),

and thrombopoietin (TPO). The major sources of the CSFs

are lymphocytes and stromal cells of the bone marrow. Other

cytokines, such as the interleukins, support the development of

lymphocytes and act synergistically to aid the functions of the

CSFs (see Chapter 8).

Basophils. The granules of the basophils stain blue with a

basic dye. These cells constitute only about 0.3% to 0.5% of

the white blood cells. The basophils in the circulating blood

are similar to the large mast cells located immediately outside

the capillaries in body tissues. Both the basophils and mast

cells release heparin, an anticoagulant, into the blood. The

mast cells and basophils also release histamine, a vasodilator,

and other inflammatory mediators. The mast cells and baso-

phils play an exceedingly important role in allergic reactions

(see Chapter 10).

Lymphocytes

The lymphocytes have their origin in the lymphoid stem cells

that are found in the bone marrow. The lymphocytes constitute

20% to 30% of the white blood cell count. They have no iden-

tiﬁable granules in the cytoplasm and are sometimes referred

to as agranulocytes. They move between blood and lymphoid

tissues, where they may be stored for hours or years. Their

function in the lymph nodes or spleen is to defend against for-

eign microbes in the immune response (see Chapter 8). There

are two types of lymphocytes: B lymphocytes and T lympho-

cytes. The lymphocytes play an important role in the immune

response. The B lymphocytes differentiate to form antibody-

producing plasma cells and are involved in humoral-mediated

immunity. The T lymphocytes are responsible for orchestrat-

ing the immune response (CD4 + T cells) and effecting cell-

mediated immunity (CD8 + T cells).

Lymphoid Tissues

The lymphoid tissues represent the structures where lympho-

cytes originate, mature, and interact with antigens. Lymphoid

tissues can be classiﬁed into two groups: the central or genera-

tive organs and peripheral lymphoid organs (see Chapter 8).

The central lymphoid structures consist of the bone marrow,

where all lymphocytes arise, and the thymus, where T cells ma-

ture and reach a stage of functional competence. The thymus is

also the site where self-reactive T cells are eliminated.

The peripheral lymphoid organs are the sites where mature

lymphocytes respond to foreign antigens. They include the

lymph nodes, the spleen, mucosa-associated lymphoid tissues,

and the cutaneous immune system. In addition, poorly deﬁned

aggregates of lymphocytes are found in connective tissues and

virtually all organs of the body.

Monocytes and Macrophages

Monocytes are the largest of the white blood cells and consti-

tute about 3% to 8% of the total leukocyte count. They have

abundant cytoplasm and a darkly stained nucleus, which has a

distinctive U or kidney shape. The circulating life span of the

monocyte is about 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 ma-

194

Unit Three: Alterations in the Hematologic System

Pluripotent stem cell

Myeloid stem cell

Lymphoid stem cell

T cell

progenitor

B cell

progenitor

Monocyte

CFU

Granulocyte

CFU

Megakaryocyte

CFU

Erythrocyte

CFU

thymus

Monoblast

B cell

Megakaryocyte

Reticulocyte

T cell

Plasma cell

Monocyte

Eosinophil

Neutrophil

Basophil

Platelets

Erythrocyte

■ FIGURE 11-3 ■ Major maturational stages of blood cells. CFU, colony-forming units.

KEY CONCEPTS

HEMATOPOIESIS

In summary, the hematopoietic system consists of a

number of cells derived from the pluripotent stem cells origi-

nating in the bone marrow. These cells differentiate into

committed cell lines that mature in red blood cells, platelets,

and a variety of white blood cells. The development of the

different types of blood cells is supported by chemical mes-

sengers called colony-stimulating factors. The lymphoid tis-

sues are found in the central lymphoid structures (bone mar-

row and thymus) where lymphocytes arise, mature, and

where self-reactive lymphocytes are eliminated and the peri-

pheral lymphoid structures (lymph nodes, spleen, mucosal-

associated lymphoid tissue, and the cutaneous immune

system) where lymphocytes respond to foreign antigens.

■

White blood cells are formed partially in the bone

marrow (granulocytes, monocytes, and some lym-

phocytes) and partially in the lymph system

(lymphocytes and plasma cells).

■

They are formed from hematopoietic stem cells that

differentiate into committed progenitor cells that in

turn develop into the myelogenous and lymphocytic

lineages needed for the formation of the different

types of white blood cell.

■

The growth and reproduction of the different stem

cells is controlled by CSFs and other cytokines and

chemical mediators.

NON-NEOPLASTIC DISORDERS

OF WHITE BLOOD CELLS

■

The life span of white blood cells is relatively short so

that constant renewal is necessary to maintain nor-

mal blood levels. Any conditions that decrease the

availability of stem cells or hematopoietic growth

factors produce a decrease in white blood cells.

L of

blood. The term leukopenia describes an absolute decrease in

white blood cell numbers. The disorder may affect any of the

The number of leukocytes, or white blood cells, in the periph-

eral circulation normally ranges from 5000 to 10,000/

Chapter 11: Alterations in White Blood Cells

195

speciﬁc types of white blood cells, but most often it affects the

neutrophils, which are the predominant type of granulocyte.

suppression of bone marrow function. The term idiosyncratic is

used to describe drug reactions that are different from the ef-

fects obtained in most persons and that cannot be explained in

terms of allergy. A number of drugs, such as chloramphenicol

(an antibiotic), phenothiazine tranquilizers, sulfonamides,

propylthiouracil (used in the treatment of hyperthyroidism),

and phenylbutazone (used in the treatment of arthritis), may

cause idiosyncratic depression of bone marrow function. Some

drugs, such as hydantoin derivatives and primidone (used in

the treatment of seizure disorders), can cause intramedullary

destruction of granulocytes and thereby impair production.

Many idiosyncratic cases of drug-induced neutropenia are

thought to be caused by immunologic mechanisms, with the

drug or its metabolites acting as antigens ( i.e., haptens) to in-

cite the production of antibodies reactive against the neutro-

phils. Neutrophils possess human leukocyte antigens (HLA)

and other antigens speciﬁc to a given leukocyte line. Antibodies

to these speciﬁc antigens have been identiﬁed in some cases of

d r ug-induced neutropenia. 4

Neutropenia (Agranulocytosis)

Neutropenia refers speciﬁcally to a decrease in neutrophils. It

commonly is deﬁned as a circulating neutrophil count of less

than 1500 cells/

L. 4

The reduction in granulocytes can occur because there is re-

duced or ineffective production of neutrophils or because there

is excessive removal of neutrophils from the blood. The causes

of neutropenia are summarized in Table 11-1.

Acquired Neutropenia

Granulopoiesis may be impaired by a variety of bone marrow

disorders, such as aplastic anemia or bone marrow depression

caused by cancer chemotherapy and irradiation, that interfere

with the formation of all blood cells. Overgrowth of neoplas-

tic cells in cases of nonmyelogenous leukemia and lymphoma

also may suppress the function of neutrophil precursors. In-

fections by viruses or bacteria may drain neutrophils from the

blood faster than they can be replaced, thereby depleting

the neutrophil storage pool in the bone marrow. 4 Because of the

neutrophil’s short life span of less than 1 day in the peripheral

blood, neutropenia occurs rapidly when granulopoiesis is im-

paired. Under these conditions, neutropenia usually is ac-

companied by thrombocytopenia ( i.e., platelet deﬁciency).

In aplastic anemia, all of the myeloid stem cells are affected,

resulting in anemia, thrombocytopenia, and agranulocytosis.

Autoimmune disorders or idiosyncratic drug reactions may

cause increased and premature destruction of neutrophils. In

splenomegaly, neutrophils may be trapped in the spleen along

with other blood cells. In Felty’s syndrome, a variant of rheu-

matoid arthritis, there is increased destruction of neutrophils

in the spleen.

Most cases of neutropenia are drug related. Chemother-

apeutic drugs used in the treatment of cancer ( e.g., alkylating

agents, antimetabolites) cause predictable dose-dependent

Congenital Neutropenia

A decreased production of granulocytes is a feature of a group

of hereditary hematologic disorders, including cyclic neutro-

penia and Kostmann’s syndrome. Periodic or cyclic neutropenia

is an autosomal dominant disorder with variable expression

that begins in infancy and persists for decades. It is character-

ized by periodic neutropenia that develops every 21 to 30 days

and lasts approximately 3 to 6 days. Although the cause is un-

determined, it is thought to result from impaired feedback

regulation of granulocyte production and release. Kostmann’s

syndrome, which occurs sporadically or as an autosomal reces-

sive disorder, causes severe neutropenia while preserving the

erythroid and megakaryocyte cell lineages that result in red

blood cell and platelet production. The total white blood cell

count may be within normal limits, but the neutrophil count

is less than 200/

L. Monocyte and eosinophil levels may be

elevated.

A transient neutropenia may occur in neonates whose

mothers have hypertension. It usually lasts from 1 to 60 hours

TABLE 11-1

Causes of Neutropenia

Cause

Mechanism

Accelerated removal ( e.g. , inﬂammation and infection)

Drug-induced granulocytopenia

Defective production

Cytotoxic drugs used in cancer therapy

Phenothiazine, thiouracil, chloramphenicol, phenylbutazone,

and others

Hydantoinates, primidone, and others

Immune destruction

Aminopyrine and others

Periodic or cyclic neutropenia (occurs during infancy and later)

Neoplasms involving bone marrow (e.g., leukemias and lymphomas)

Removal of neutrophils from the circulation exceeds production

Predictable damage to precursor cells, usually dose dependent

Idiosyncratic depression of bone marrow function

Intramedullary destruction of granulocytes

Immunologic mechanisms with cytolysis or leukoagglutination

Unknown

Overgrowth of neoplastic cells, which crowd out granulopoietic

precursors

Autoimmune reaction

Idiopathic neutropenia that occurs in the absence of other disease or

provoking inﬂuence

Felty’s syndrome

Intrasplenic destruction of neutrophils

L. Agranulocytosis, which denotes a severe

neutropenia, is characterized by a circulating neutrophil count

of less than 200 cells/

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