I A P P R O A C H T O H E M AT O L O G I C
DISORDERS
David C. Dale, m.d.
Hematology deals with the normal functions and disorders of
the formed elements in the blood (i.e., erythrocytes, leukocytes,
and platelets) and the plasma factors governing hemostasis.
The blood sustains life by transporting oxygen and essential
nutrients, removing waste, and delivering the humoral and cel-
lular factors necessary for host defenses. Platelets and coagula-
tion factors, together with vascular endothelial cells, maintain
the integrity of this system. Some hematologic disorders such
as anemia, leukocytosis, and bleeding are quite common,
occurring secondary to infectious, inflammatory, nutritional,
and malignant diseases. Other disorders, including the hemato-
logic malignancies, are far less common. This subsection pre-
sents the general principles for understanding the hematopoiet-
ic system [see other subsections under Hematology for a more
detailed description of the pathophysiology of specific hematologic dis-
eases and their treatment].
Hematopoiesis
Hematopoiesis begins in the fetal yolk sac and later occurs
predominantly in the liver and the spleen.1 Recent studies
demonstrate that islands of hematopoiesis develop in these tis-
sues from hemangioblasts, which are the common progenitors
for both hematopoietic and endothelial cells.2 These islands then
involute as the marrow becomes the primary site for blood cell
formation by the seventh month of fetal development.3 Barring
serious damage, such as that which occurs with myelofibrosis
or radiation injury, the bone marrow remains the site of blood
cell formation throughout the rest of life. In childhood, there is
active hematopoiesis in the marrow spaces of the central axial
skeleton (i.e., the ribs, vertebrae, and pelvis) and the extremities,
extending to the wrists, ankles, and the calvaria. With normal
growth and development, hematopoiesis gradually withdraws
from the periphery. This change is reversible, however; distal
marrow extension can result from intensive stimulation, as oc-
curs with severe hemolytic anemias, long-term administration
of hematopoietic growth factors, and hematologic malignan-
cies. The term medullary hematopoiesis refers to the production
of blood cells in the bone marrow; the term extramedullary
hematopoiesis indicates blood cell production outside the mar-
row in the spleen, liver, and other locations.
organization of hematopoietic tissues
In its normal state, the medullary space in which hematopoi-
etic cells develop contains many adipocytes and has a rich vas-
cular supply [see Figure 1].4 Vascular endothelial cells, marrow
fibroblasts, and stromal cells are important sources of the ma-
trix proteins that provide structure to the marrow space; these
cells also produce the hematopoietic growth factors and
chemokines that regulate blood cell production.5 The vascular
endothelial cells also form an important barrier that keeps im-
mature cells in the marrow and permits mature hematopoietic
elements to enter the blood. The abundant adipocytes may in-
fluence hematopoiesis by serving as a localized energy source,
by synthesizing growth factors, and by affecting the metabo-
© 2003 WebMD Inc. All rights reserved.
June 2003 Update
lism of androgens and estrogens.6 Marrow macrophages re-
move effete or apoptotic cells and clear the blood of foreign ma-
terials when they enter the marrow. Osteoblasts and osteoclasts
maintain and remodel the surrounding cancellous bone and the
calcified lattice, which crisscrosses the marrow space.4
The thymus, lymph nodes, mucosa-associated lymphatic tis-
sues, and the spleen have multiple hematopoietic functions.
Early in development, they are major sites of hematopoiesis. In
adulthood, they are principally sites of lymphocyte develop-
ment, processing of antigens, development of effector T cells,
and antibody production [see 6 Immunology/Allergy]. In leu-
kemia and the myeloproliferative disorders, the size and cellu-
lar architecture of these tissues are deranged, leading to many
of the clinical manifestations of these disorders [see 12:XVI Acute
Leukemia and 12:XVII Chronic Myelogenous Leukemia and Other
Myeloproliferative Disorders].
Hematopoietic Stem Cells
All cells of the hematopoietic system are derived from com-
mon precursor cells, the hematopoietic stem cells.7 These cells
are difficult to identify, in part because they normally represent
only about 0.05% of marrow cells. Through self-renewal, this
population is maintained at a constant level.8 Through the use
of monoclonal antibodies that recognize specific cell surface
molecules expressed selectively on developing hematopoietic
cells and other specialized techniques, the stem cells can now
be separated from other marrow cells. With these methods,
very primitive hematopoietic stem cells have been found to be
positive for c-kit and thy-1 but negative for CD34, CD38, CD33,
and HLA-DR.8 For clinical purposes, CD34+ progenitor cell
populations, which contain stem cells and some more mature
cells, are often used for hematopoietic stem cell transplantation9
[see 5:XI Hematopoietic Stem Cell Transplantation].
Stem cells give rise to daughter cells, which undergo irre-
versible differentiation along various hematopoietic cell lin-
eages [see Figure 2].10 Many aspects of the earliest steps in this
differentiation process are not well understood. With lineage
commitment, however, differentiation, maturation, and release
of cells to the blood come under the control of well-defined
hematopoietic growth factors. In the early phases of differentia-
tion, the regulatory roles played by these growth factors over-
lap.11 Later in development, some growth factors are lineage
specific, meaning that they govern the maturation and deploy-
ment of single lineages. Erythropoietin (EPO) (erythrocytes),
thrombopoietin (TPO) (platelets), granulocyte colony-stimulat-
ing factor (G-CSF) (neutrophils), and macrophage colony-stim-
ulating factor (M-CSF) (monocytes) are the best-characterized
lineage-specific factors.
Hematopoietic Growth Factors
The hematopoietic growth factors, also referred to as
hematopoietic cytokines, are a family of glycoproteins pro-
duced in the bone marrow by endothelial cells, stromal cells, fi-
broblasts, macrophages, and lymphocytes; they are also pro-
duced at distant sites, from which they are transported to the
marrow through the blood [see Table 1]. The naming of these
factors is somewhat confusing. Erythropoietin and throm-
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HEMATOLOGY:I Approach to Hematologic Disorders–1
bopoietin derive part of their names from the Greek word
poiesis, meaning “to make.” The colony-stimulating factors
were first recognized because of their capacity to stimulate ear-
ly hematopoietic cells to grow into clusters and large colonies in
tissue culture systems. The term interleukin denotes factors that
are produced by leukocytes and that affect other leukocytes.
This is a large family of factors that predominantly govern lym-
phocytopoiesis, but many members also have broad effects on
other lineages. The discovery of new growth factors and of the
biologic consequences of deficiencies or excesses of these fac-
tors continues to evolve rapidly.
Hematopoietic cells have distinctive patterns of expression
of growth factor receptors, and the patterns evolve as the cells
differentiate [see Figure 2].11 Each growth factor binds only to its
specific receptor.12 It is now known that some growth factors
share components of the receptor (e.g., interleukin-3 [IL-3], IL-5,
and granulocyte-macrophage colony-stimulating factor [GM-
CSF] share a common β chain of their receptor); specificity
comes from other unique or private components of the recep-
tor. Binding of the ligand to the receptor leads to a conforma-
tional change, activation of intracellular kinases, and, ultimate-
ly, the triggering of cell proliferation.13,14 For some growth fac-
tors, these pathways are well defined; for others, the pathways
are still unclear [see Figure 3].
Hematopoietic growth factors not only stimulate cell prolif-
eration but also prolong cell survival; that is, they have anti-
apoptotic effects.15 For some lineages, such as neutrophils and
monocytes, growth factor receptors occur on fully mature cells;
exposure of these cells to the factors primes the cells for an en-
hanced responsiveness to bacteria or other stimulators of their
metabolic activity. Thus, for cells of the neutrophil lineage,
the growth factors G-CSF and GM-CSF can stimulate early
hematopoietic cell proliferation, increase the number of cells
produced by the marrow, prolong the life span of these cells,
and augment cell functions.16
Macrophage
Erythroblastic
Area
Lymphoblast
Erythroblast
Neutrophil
Myeloid Area
Megakaryocyte
Figure 1 The architecture of the bone marrow showing the various types of cells.
© 2003 WebMD Inc. All rights reserved.
June 2003 Update
Erythropoietin
The peritubular interstitial cells located in the inner cortex and
outer medulla of the kidney are the primary site for erythropoi-
etin production.17 In response to hypoxia, transcription of the ery-
thropoietin gene in these cells increases, resulting in increased se-
cretion of erythropoietin. The protein is then transported through
the blood to the marrow to stimulate erythropoiesis. With renal
failure, erythropoietin production is severely impaired. In infec-
tions and many chronic inflammatory conditions, the erythro-
poietin response is blunted, and erythropoietin levels are low.18
Erythropoietin is a glycosylated protein that modulates
erythropoiesis by affecting several steps in red cell develop-
ment. The most primitive identifiable erythroid cells, the burst-
forming unit–erythroid cells (BFU-E), are relatively insensitive
to erythropoietin. More mature cells, the colony-forming
unit–erythroid cells (CFU-E), are very sensitive. Erythropoietin
treatment prolongs survival of erythroid precursors, shortens
the time between cell divisions, and increases the number of
cells produced from individual precursors.19
Erythropoietin can be administered intravenously or subcu-
taneously for the treatment of anemia caused by inadequate en-
dogenous production of erythropoietin.20 Treatment is maxi-
mally effective when the marrow has a generous supply of iron
and other nutrients, such as cobalamin and folic acid.21 For pa-
tients with renal failure, who have very low erythropoietin lev-
els, the starting dosage is 50 to 100 units S.C. three times a week.
The most easily monitored immediate effect of increased en-
dogenous or exogenous erythropoietin is an increase in the
blood reticulocyte count. Normally, as red cell precursors ma-
ture, the cells extrude their nucleus at the normal blast stage.
The resulting reticulocytes, identified by the supravital stain of
their residual ribosomes, persist for about 3 days in the marrow
and 1 day in the blood. Erythropoietin shortens the transit time
through the marrow, leading to an increase in the number and
proportion of blood reticulocytes within a few days.
Arterial Capillary
Fat Cell
Sinus
Adventitial Cell
Endothelial Cells
Central Longitudinal Vein
Erythrocyte
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HEMATOLOGY:I Approach to Hematologic Disorders–2
 IL-1
IL-3 IL-1
IL-6 IL-6
SCF SCF
G-CSF Pluripotent FLT-3L
Stem Cell

Myeloid Lymphoid
Stem Cell Stem Cell
GM-CSF
IL-3

BFU-E CFU-Mega CFU-GM Pre–B Cell Prothymocyte

IL-3 GM-CSF GM-CSF GM-CSF IL-1 IL-5 IL-2

IL-3
IL-11 IL-3 IL-2 IL-6
EPO IL-3 IL-3 IL-3 IL-4
IL-4

Proerythroblast Megakaryocyte Monoblast Myeloblast Eosinophilic Basophilic B Lymphoblast T Lymphoblast

Myeloblast Myeloblast

GM-CSF GM-CSF GM-CSF IL-3 Antigen-

EPO TPO
M-CSF G-CSF IL-5 IL-4 Driven

Red Blood Cell Platelets Monocyte Neutrophil Eosinophil Basophil B Lymphocyte T Lymphocyte

Figure 2 The pattern for development of various types of blood cells in the bone marrow. (BFU-E—burst-forming
unit–erythroid; CFU-GM—colony-forming unit–granulocyte-macrophage; CFU-mega—colony-forming unit–megakaryocyte;
EPO—erythropoietin; EPOR—surface component of the erythropoietin receptor; FLT-3L—fms-like tyrosine kinase 3 ligand;
G-CSF—granulocyte colony-stimulating factor; GM-CSF—granulocyte-macrophage colony-stimulating factor; IL—
interleukin; M-CSF—macrophage colony-stimulating factor; TPO—thrombopoietin; SCF—stem cell factor)

In some conditions, particularly chronic inflammatory dis-
eases, the effectiveness of erythropoietin can be predicted
from measurement of the serum erythropoietin level by im-
munoassay.17,18 It may be cost-effective to measure the level
before initiating treatment in patients with anemia attribut-
able to suppressed erythropoietin production, such as pa-
tients with HIV infection, cancer, and chronic inflammatory
diseases. Several studies have shown that erythropoietin
treatment decreases the severity of anemia and improves the
quality of life for these patients. In patients with anemia
caused by cancer and cancer chemotherapy, current guide-
lines recommend erythropoietin treatment if the hemoglobin
level is less than 10 g/dl.22
Thrombopoietin
The development of megakaryocytes from hematopoietic
stem cells and the level of platelets in the blood are governed by
thrombopoietin.23 Thrombopoietin is produced primarily by
the liver and is similar to erythropoietin in structure. However,
thrombopoietin has broader biologic effects than erythropoi-
etin, stimulating the proliferation and release of hematopoietic
stem cells from the bone marrow and prolonging survival of
these cells.24 Thrombopoietin signals through its specific recep-
tor, called cMpL, expressed on hematopoietic cells. Plasma
thrombopoietin levels are inversely related to the blood platelet
count. Deficiencies in thrombopoietin cause thrombocytopenia,
and excesses in thrombopoietin cause thrombocytosis. Recom-
binant human thrombopoietin is being studied for use in the
treatment of thrombocytopenia of diverse causes. Thrombopoi-
etin is not yet approved for clinical use.24
Granulocyte Colony-Stimulating Factor
G-CSF is a glycosylated protein produced by monocytes,
macrophages, fibroblasts, stromal cells, and endothelial cells
throughout the body.25 It stimulates the growth and differentia-
tion of neutrophils both in vitro and in vivo. G-CSF levels are
normally very low or undetectable but increase with bacterial
infections or after administration of bacterial endotoxin.16 G-
CSF (the synthesized form is known as filgrastim or lenogras-
tim) administration causes a dose-dependent increase in the
blood neutrophil count in healthy persons. Studies in animals
have shown that G-CSF deficiency causes neutropenia.26 As
with erythropoietin, administration of G-CSF leads to an accel-
eration in the development of neutrophils in the bone marrow,
with the neutrophils shifting at an earlier stage than normal
from the marrow to the blood.27

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June 2003 Update HEMATOLOGY:I Approach to Hematologic Disorders–3
 Table 1 Hematopoietic Growth Factors
Chromosome
Factor Other Names Cell Source Function
Location

Stimulates erythrocyte formation and

EPO Erythropoietin Juxtaglomerular cells 7q
release from marrow

Thrombopoietin; megakaryocyte
Hepatocytes, renal and endothe- Stimulates megakaryocyte proliferation
TPO growth and development factor 3q27
lial cells, fibroblasts and platelet formation
(MGDF)

Granulocyte colony-stimulating Endothelial cells, monocytes, Stimulates formation and function of

G-CSF 17q11.2-q21
factor; filgrastim; lenograstim fibroblasts neutrophils

Granulocyte-macrophage colony- Stimulates formation and function of neu-

GM-CSF T cells, monocytes, fibroblasts 5q23-q31
stimulating factor trophils, monocytes, and eosinophils

Macrophage colony-stimulating
Endothelial cells, macrophages, Stimulates monocyte formation and
M-CSF factor; colony stimulating factor–1 5q33.1
fibroblasts function
(CSF-1)

IL-1α and Interleukin-1α and -1β, endogenous Monocytes, keratinocytes, Proliferation of T cells, B cells, and other
2q13
IL-1β pyrogen hemopoietin-1 endothelial cells cells; induces fever and catabolism

T cells (CD4+, CD8+), large

T cell proliferation, antitumor and anti-
IL-2 T cell growth factor granular lymphocytes (natural 4q
microbial effects
killer, or NK, cells)

Multi–colony stimulating factor; mast Activated T cells; large granular

IL-3 5q23-q31 Proliferation of early hematopoietic cells
cell growth factor lymphocytes (NK cells)

B cell growth factor; T cell growth Proliferation of B cells and T cells; enhances
IL-4 T cells 5q23-q31
factor II; mast cell growth factor II cytotoxic activities

Eosinophil differentiation factor; eo- Stimulates eosinophil formation; stimulates

IL-5 T cells 5q23.3-q32
sinophil colony-stimulating factor T cell and B cell functions

Monocytes, tumor cells, B cells

B cell stimulatory factor II; hepatocyte Stimulates and inhibits cell growth;
IL-6 and T cells, fibroblasts, endo- 7p
stimulatory factor promotes B cell differentiation
thelial cells

Lymphopoietin 1; pre–B cell growth

IL-7 Lymphoid tissues and cell lines 8q12-q13 Growth factor for B cells and T cells
factor

Stimulates proliferation of early hemato-

Fibroblasts, trophoblasts, cancer
IL-11 Plasmacytoma stimulating factor 19q13.3-q13.4 poietic cells; induces acute-phase protein
cell lines
synthesis

Stimulates T cell expansion and interferon-

5q31-q33;
IL-12 Natural killer cell stimulating factor Macrophages, B cells gamma; synergistically promotes early
3p12-q13.2
hematopoietic cell proliferation

Monocytes and lymphocytes;

LIF Leukemia inhibitory factor 22q Stimulates hematopoietic cell differentiation
stomal cells

Stimulates proliferation of early hematopoi-

SCF Stem cell factor; kit ligand; steel factor Endothelial cells; hepatocytes 4q11-q20
etic cells and mast cells

FLT-3 T cells, stromal cells, and Stimulates early hematopoietic cell differen-
fms-like tyrosine kinase 3; STK-1 19q13.3
ligand fibroblasts tiation; increases blood dendrite cells

G-CSF is approved for the treatment of neutropenia after
cancer chemotherapy, for acceleration of neutrophil recovery
after bone marrow transplantation, for mobilization of hemato-
poietic progenitor cells from the marrow to the blood in hema-
topoietic transplantation, and for the treatment of severe chron-
ic neutropenia. The usual dosage is 5 mg/kg S.C. daily; higher
doses are used to mobilize progenitor cells, and lower doses are
used for long-term treatment of neutropenia. A new formula-
tion of G-CSF, in which G-CSF is conjugated to polyethylene
glycol to reduce renal clearance, was recently approved for
marketing. Its principal advantage is that one injection is suffi-
cient to stimulate marrow recovery after standard doses of can-
cer chemotherapy. Side effects of either form of G-CSF are prin-
cipally musculoskeletal pain and headaches during the period
of rapid marrow expansion soon after therapy is initiated. Oth-
er side effects are uncommon.
Granulocyte-Macrophage Colony-Stimulating Factor
GM-CSF is a glycosylated protein produced by many types
of cells, including T cells.28 GM-CSF stimulates formation of
neutrophils, monocytes, and eosinophils and may also enhance
the growth of early cells of other lineages. In contrast to G-CSF,
GM-CSF levels generally do not increase with infections or
acute inflammatory conditions,29 and neutropenia does not re-
sult from deficiencies of GM-CSF.30 The marrow effects of G-
CSF and GM-CSF are similar, but GM-CSF is less potent in ele-
vating the blood neutrophil count.31 GM-CSF (the synthesized
form is known as sargramostim or molgramostim) is approved

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June 2003 Update HEMATOLOGY:I Approach to Hematologic Disorders–4

EPOR EPO
Y Y
Y Y
Y Y
JAK2
Y Y
Recruitment
Y mary, secondary, and tertiary granules), which are necessary for
Homodimerization
Y
SH2 Y
STAT5 Translocation
Nucleus
Figure 3 A model of how hematopoietic growth factors interact with
their receptors to initiate cell proliferation. (EPO—erythropoietin;
JAK2—Janus kinase 2; SH2—Src homology 2; STAT5—signal
transducer and activator of transcription 5)
in the United States for acceleration of marrow recovery after
bone marrow transplantation or chemotherapy and for mobi-
lization of progenitor cells from the marrow. The usual dosage
is 250 mg/m2/day S.C. Its side effects include bone and muscu-
loskeletal pain, myalgias, and injection-site reactions.
Interleukin-11
IL-11 (oprelvekin) is a pleiotropic cytokine that is expressed
by, and active in, many tissues.32 IL-11 acts synergistically with
other growth factors, including thrombopoietin, to stimulate
megakaryocyte development and platelet formation. It is ap-
proved for use in the prevention of severe thrombocytopenia
and for patients who need platelet transfusions after chemo-
therapy. The usual dosage is 50 mg/kg/day S.C. Its side effects
include edema, tachycardia, and dyspnea.
Other Growth Factors
Several other hematopoietic growth factors have potential
clinical uses. IL-3 acts at an early phase in hematopoiesis to
stimulate cell proliferation but has relatively little effect on pe-
ripheral counts. IL-3 has been molecularly coupled to other
growth factors, including GM-CSF, G-CSF, and TPO, to pro-
duce hybrid molecules that are under investigation. Stem cell
factor (SCF) and fms-like tyrosine kinase 3 (FLT-3) ligand are
other early-acting factors under investigation. M-CSF is a selec-
tive factor for monocytes and macrophage formation. IL-5 is a
similar selective factor for the generation of eosinophils.
It is presumed that normally, hematopoietic cell formation is
governed by combinations of factors, released in a cascade, that
closely coordinate the development of these cells. The details of
how this process occurs, however, are not yet clear. Numerous
laboratory and clinical studies have investigated combinations
of factors, but the therapeutic benefit of using multiple growth
factors is not yet proved.
© 2003 WebMD Inc. All rights reserved.
June 2003 Update
dynamics of hematopoiesis
In the marrow, blood cells develop in two phases, the prolif-
erative and the maturational phases. During cell proliferation,
the precursors of blood cells normally undergo cell division at
intervals of about 18 to 24 hours. In the maturational phase, cell
division ceases, but final features are added before the cells en-
ter the blood. During this phase, erythrocytes normally lose all
their nuclear material, acquire their biconcave shape, and de-
velop their final content of enzymes necessary for maintaining
the biconcave shape and resisting destruction by oxidative
stress. Normally, it takes 7 to 10 days for erythrocytes to devel-
op from their early precursors, but this process can be accelerat-
ed by erythropoietin therapy.33
Neutrophils acquire most of their granules (known as the pri-
their microbicidal activities, during the proliferative phase.34
During maturation, their nuclear chromatin condenses, the gly-
cogen content of the cytoplasm increases, and the surface prop-
erties governing the circulation, adherence, and migration to tis-
sues are added.35 Neutrophils reach a fully mature state in the
marrow before they are released into the blood. These mature
marrow cells are called the marrow neutrophil reserve. Quanti-
tatively, this neutrophil pool is substantially larger—probably
Table 2 Causes of Lymphadenopathy42
Infections
Bacterial: streptococci,* Staphylococcus aureus,* syphilis,*† cat-
scratch disease,* Mycobacterium tuberculosis and other my-
cobacteria,† brucellosis,† leptospirosis,† meliodiosis,† chan-
croid, plague, tularemia, rat-bite fever
Viral: adenovirus,* HIV,*† infectious mononucleosis,*† herpes
simplex,* measles,† rubella,† cytomegalovirus,† hepatitis,†
Kawasaki disease
Mycotic: sporotrichosis, histoplasmosis,† coccidioidomycosis†
Rickettsial: Rocky Mountain spotted fever,*† scrub typhus†
Chlamydial: Chlamydia trachomatis, lymphogranuloma
venereum
Protozoan: toxoplasmosis,† trypanosomiasis,† kala-azar†
Helminthic: filariasis,† onchocerciasis
Immunologic Causes
Stings and bites*
Drug reactions*†: phenytoin, hydralazine
Serum sickness*†
Collagen vascular diseases: rheumatoid arthritis,† dermato-
myositis,† angioimmunoblastic lymphadenopathy†
Malignancies
Hematologic: Hodgkin disease,* acute leukemia,† chronic lym-
phocytic leukemia,† chronic myelogenous leukemia,† lym-
phoma,† myelofibrosis†
Other: metastatic carcinoma, sarcomas
Endocrine Diseases
Hyperthyroidism†
Histiocytic Disorders
Lipid storage disease,† malignant histiocytosis,† Langerhans
(eosinophilic) histiocytosis
Miscellaneous
Sarcoidosis, amyloidosis,† chronic granulomatous disease, lym-
phomatoid granulomatosis, necrotizing lymphadenitis
*Most common causes in general practice in the United States.
†Usually cause generalized lymphadenopathy.
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HEMATOLOGY:I Approach to Hematologic Disorders–5
five to 10 times larger—than the total circulating supply of neu-
trophils. Normally, it takes 10 to 14 days for blood neutrophils to
develop from early precursors, but this process is accelerated in
the presence of infections and by treatment with G-CSF or GM-
CSF [see 5:VII Nonmalignant Disorders of Leukocytes].
Platelets form from the breaking apart of the cytoplasm of the
fully mature megakaryocytes, which are also derived from
hematopoietic stem cells.23 Megakaryocytes undergo reduplica-
tion of their nuclear chromatin without cell division, which re-
sults in the production of extremely large cells. When marrow
damage occurs from chemotherapeutic agents and after he-
matopoietic transplantation, the megakaryocytes are often the
slowest cells to recover, and thrombocytopenia is often the last
cytopenia to resolve.
There are important differences in the dynamics or kinetics
of erythrocytes, platelets, and leukocytes in the blood. For in-
stance, neutrophils have a blood half-life of only 6 to 8 hours;
essentially, a new blood population of neutrophils is formed
every 24 hours.35 Erythrocytes last the longest by far: the normal
life span is about 100 days.33 These differences partially account
for why neutrophils and their precursors are the predominant
marrow cells, whereas in the blood, erythrocytes far outnumber
neutrophils. Similarly, the short half-life and high turnover rate
of neutrophils account for why neutropenia is the most fre-
quent hematologic consequence when bone marrow is dam-
aged by drugs or radiation. Finally, transfusion of erythrocytes
and platelets is feasible because of their relatively long life span,
whereas the short life span of neutrophils has greatly impeded
efforts to develop neutrophil transfusion therapy.
Clinical Manifestations of Hematologic Disorders
The following signs and symptoms are frequently observed
in patients with hematologic diseases.
weakness, fatigue, and pallor
Weakness and fatigue are common complaints of patients
with anemia, especially if it is of recent onset, such as anemia
caused by recent blood loss or acute hemolysis.36 Anemia that
develops gradually, particularly in inactive persons, may cause
only fatigue. Fatigue is a very common complaint of patients
with infections, inflammatory diseases, and malignancies. Sev-
eral recent studies document that raising hemoglobin levels
with erythropoietin injection decreases fatigue in patients with
cancer or HIV infection.37,38 Other common causes of fatigue in-
clude chronic lung diseases, congestive heart failure, endocrine
disorders, and depression.
Pallor is recognized by examining the conjunctiva, mucous
membranes, nail beds, and palmar creases—tissues lacking
melanin pigmentation. The World Health Organization has de-
veloped a simple clinical scale to measure pallor for diagnosing
anemia when blood counts are not available. The sensitivity
and specificity of this scale vary between 70% and 90%, de-
pending on the population and severity of the anemia.39,40 Other
causes of pallor include edema (including myxedema) and
vasoconstriction caused by cold temperatures, hemorrhage, hy-
poglycemia, or shock.
pain
Pain, particularly bone pain, is an important marker of hema-
tologic disease. Pain is usually generalized in patients with
acute leukemia and multiple myeloma,41 but most frequently, it
© 2003 WebMD Inc. All rights reserved.
June 2003 Update
is felt in the back or pelvis. With metastatic breast, colon, or lung
cancer, the pain is more often localized and asymmetrical. In
sickle cell disease, severe bone pain and pain in many other tis-
sues occur with vascular obstruction and infarction caused by
obstruction of blood flow by the aggregation of abnormal cells
[see 5:IV Hemoglobinopathies and Hemolytic Anemias]. Bone pain
mimicking these disorders occurs with marrow expansion in re-
sponse to treatment with hematopoietic growth factors.
fatigue, pharyngitis, and fever
Fatigue, pharyngitis, and fever are a frequently observed se-
quence in patients with acutely developing neutropenia, occur-
ring as an idiosyncratic or toxic reaction to many drugs. In cases
of severe neutropenia, cough and respiratory symptoms, peri-
anal pain and tenderness, or acute abdominal pain often occurs
and necessitates immediate medical assessment [see 5:VII Non-
malignant Disorders of Leukocytes].
mouth ulcers, gingivitis, and cervical adenopathy
Mouth ulcers, gingivitis, and cervical adenopathy are com-
mon problems of patients with chronic neutropenia [see 5:VII
Nonmalignant Disorders of Leukocytes]. Gingivitis is a serious
problem, often leading to periodontal disease and tooth loss.
lymphadenopathy and splenomegaly
Lymphadenopathy is a common presentation of infectious,
inflammatory, and hematologic diseases, particularly the lym-
phomas and leukemias [see Table 2]. Lymphadenopathy may
occur without associated symptoms, but often, fatigue and in-
termittent fever (e.g., Pel-Ebstein fever) occur. In contrast to
acute infectious diseases leading to tender lymphadenopathy,
in most hematologic disorders the lymph nodes and spleen are
nontender, with a soft to rubbery consistency. Splenomegaly is
often more difficult to detect than lymphadenopathy; most of
the diseases causing lymphadenopathy can also cause splenic
enlargement.
bleeding
Bleeding occurs as a consequence of thrombocytopenia, defi-
ciencies of coagulation factors, or both [see 5:XIII Hemorrhagic Dis-
orders]. Thrombocytopenia usually presents as petechial bleeding
that is first observed in the lower extremities. Coagulation factor
deficiencies more often cause bleeding into the gastrointestinal
tract or joints. Intracranial bleeding, however, can occur with a de-
ficiency of platelets or coagulation factors and can be catastrophic.
thrombosis
Thrombosis can be either venous or arterial [see 5:XIV Throm-
botic Disorders]. With venous thrombosis, swelling, tenderness,
and pain beyond the obstruction usually occur, and emboliza-
tion to the lungs is a frequent concern. Venous thrombosis usu-
ally occurs after inactivity or obstruction of venous flow or with
imbalances of coagulation factors. On the other hand, arterial
thrombosis usually occurs because of abnormalities of the arte-
rial wall from atherosclerosis or acute vascular injury, as in
thrombotic thrombocytopenic purpura, or from thrombocyto-
sis in the myeloproliferative disorders.
Laboratory Evaluation
The following basic tests are widely used to diagnose hema-
tologic disorders.
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HEMATOLOGY:I Approach to Hematologic Disorders–6
 a b
Posterior
Iliac Crest
Subcutaneous
Biopsy Fat
Needle Cortical
Bone
Skin
Dimple Marrow
Figure 4 Bone marrow aspirate and biopsy procedure. (a) The posterior iliac crest is the usual site for sampling; (b) the needle is
placed through the skin to the marrow space; (c) the marrow sample is aspirated; and (d) the biopsy sample is carefully removed.
complete blood cell counts
CBCs are routinely performed in most laboratories through
the use of an electronic particle counter, which determines the
total white blood cell and platelet counts and calculates the
hematocrit and hemoglobin levels from the erythrocyte count
and the dimensions of the red cells. Abnormalities in the CBC
are described in other Hematology subsections [see also the Nor-
mal Laboratory Values section].
peripheral blood smears
Peripheral blood smears usually stain with Wright stain.
When examined by light microscopy, they reveal the size and
shape of blood cells, which allows an estimate to be made of the
amount of hemoglobin in erythrocytes. Differential leukocyte
counts, enumerating the number of neutrophils, monocytes,
lymphocytes, eosinophils, and basophils, are made by manual-
ly counting cells on the blood smears or by using an automated
cell counter [see the Normal Laboratory Values section]. The
morphology of the leukocytes often provides a clue for the diag-
nosis of leukemia and for recognizing some disorders of leuko-
cytes that lead to susceptibility to infections [see 5:VII Nonmalig-
nant Disorders of Leukocytes].
reticulocyte counts
Reticulocyte counts are useful for evaluating the marrow re-
sponse to anemia [see the Normal Laboratory Values section].
Normally, during their first 24 to 36 hours in the circulation,
young red cells contain residual ribosomal RNA, which precip-
itates with certain dyes such as methylene blue. An increase in
the proportion or absolute number of reticulocytes occurs a few
days after significant blood loss or in response to red blood cell
destruction in hemolytic anemias. Low reticulocyte counts in
chronic anemia suggest either an endogenous erythropoietin
deficiency or a marrow abnormality.
bone marrow examination
Hematopoietic cells of the bone marrow can be removed by
aspiration or by needle biopsy. In adults, the best site is the pos-
terior iliac crest, with the patient in a prone position [see Figure
4]. Under special circumstances and in children, other sites can
be used, such as the anterior iliac crest, the sternum, or the long
bones. With local anesthesia and sterile technique, the patient
experiences only transient pain. Bleeding or infection at the in-
© 2003 WebMD Inc. All rights reserved.
June 2003 Update
c d
Needle
Obturator
jection site is quite uncommon. The aspirate yields cells for
morphologic examination, and differential counts reveal the ra-
tio of myeloid cells to erythroid cells (M:E ratio) [see the Normal
Laboratory Values section]. A biopsy reveals the cellularity of
the marrow at the site sampled. Biopsies are particularly useful
for examination of the marrow for infiltrative cells (e.g., in lym-
phomas or carcinomas involving the marrow) and for diagnos-
ing leukemia, characterized by the marrow’s being so densely
packed with cells that none of the bone marrow can be aspirat-
ed. Biopsies take longer for interpretation because they must be
decalcified and stained before examination.
Imaging Studies
Radionuclide scanning (e.g., using technetium-99m) reveals
the extent of the hematopoietic tissue in the marrow because
the phagocytic cells of the marrow take up the radiolabeled
particles. Marrow scanning is sometimes used to determine the
extensiveness of the hematopoietic tissue; more often, it is use-
ful in determining whether there are localized areas of in-
creased uptake resulting from infection or a malignancy that
has metastasized to the marrow. Computed tomography and
ultrasonography are useful in determining the size of lymph
nodes and the spleen, but they are not particularly useful for
marrow examination. The marrow is seen well with magnetic
resonance imaging. This technique is principally used to look
for infiltrative processes in the marrow space, such as those that
occur in malignancies and infections.
The author is a consultant for, receives research support from, and is a member
of the speakers’ bureau of Amgen, Inc.
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Acknowledgment
Figures 1 through 4 Seward Hung.
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