Section Ten
HEMATOLOGY AND ONCOLOGY
CHAPTER 121 
Anemia, Polycythemia, and
White Blood Cell Disorders Timothy G. Janz and Glenn C. Hamilton
ANEMIA
Definition
Anemia is an absolute decrease in the number of circulating red
blood cells (RBCs). The diagnosis is made when laboratory mea-
surements fall below accepted normal values (Table 121-1).
In emergency medicine, anemia is divided into two broad cat-
egories: emergent, having immediate life-threatening complica-
tions; and nonemergent, with less imminent danger to the patient.
Factors other than the absolute number of circulating RBCs may
place the patient in one category or another (e.g., rate of onset and
underlying hemodynamic reserve of the patient). Both groups
necessitate a sound diagnostic approach, but emergent anemia
may require supportive therapy concomitant with or in advance
of the definitive diagnosis. Although patients with nonemergent
anemia are usually referred to a specialist, they are seen in the
hospital often enough to make an understanding of anemia neces-
sary for emergency physicians. The urgency of consultation
depends predominantly on the patient’s hemodynamic tolerance
of the anemia.
Pathophysiology
The major function of the RBC is oxygen transport from the lung
to the tissue and carbon dioxide transport in the reverse direction.
Oxygen transport is influenced by the amount of hemoglobin, its
oxygen affinity, and blood flow. An alteration in any of the major
components usually results in compensatory changes in the other
two. For example, a decrease in hemoglobin from anemia is com-
pensated by both inotropic and chronotropic cardiac changes that
result in increased blood flow and decreased hemoglobin affinity
at the tissue level, thereby allowing more oxygen release. These
compensatory responses may collapse because of disease severity
or underlying pathologic conditions. The result is tissue hypoxia
and eventual cell death.
Anemia often stimulates the compensatory mechanism of
erythropoiesis controlled by the hormone erythropoietin. Eryth-
ropoietin is a glycoprotein produced in the kidney (90%) and
the liver (10%). It regulates the production of RBCs by control-
ling differentiation of the committed erythroid stem cell. It is
stimulated by tissue hypoxia and products of RBC destruction
during hemolysis. Erythropoietin levels are elevated in many types
of anemia.
Bone marrow contains pluripotent stem cells that can differen-
tiate into erythroid, myeloid, megakaryocytic, and lymphoid pro-
genitors. Erythropoietin enhances the growth and differentiation
of erythroid progenitors. When the late normoblast extrudes its
nucleus, it still contains a ribosomal network, which identifies the
1586
Downloaded from ClinicalKey.com at Universitas Tarumanagara September 19, 2016.
For personal use only. No other uses without permission. Copyright ©2016. Elsevier Inc. All rights reserved.
reticulocyte (Fig. 121-1). The reticulocyte retains its ribosomal
network for approximately 4 days, 3 days of which are spent in
bone marrow and 1 day in the peripheral circulation. The RBC
matures as the reticulocyte loses its ribosomal network and circu-
lates for 110 to 120 days. The erythrocyte is then removed by
macrophages that detect senescent signals.
Under steady-state conditions, the rate of RBC production
equals the rate of destruction. RBC mass remains constant because
an equal number of reticulocytes replace the destroyed, senescent
erythrocytes during the same period.
Common sites of blood loss in trauma include the pleural,
peritoneal, pelvic, and retroperitoneal spaces. In nontraumatic
circumstances, especially in patients receiving anticoagulants, the
gastrointestinal tract, retroperitoneal space, uterus, and adnexa
need to be considered.
Causes other than blood loss may be responsible for severe
anemia of rapid onset. Certain rare hemolytic conditions can
cause rapid intravascular destruction of RBCs (Box 121-1). More
common are patients with chronic compensated hemolytic anemia
(e.g., sickle cell disease), who decompensate with an acute-onset
anemia as a result of decreased erythrocyte production triggered
by a viral infection.
Beyond red cell destruction, the status of hemoglobin function
should be considered. Impaired hemoglobin transport of oxygen
is seen in cases of carbon monoxide poisoning. Methemoglobin-
emia from nitrates, cyanhemoglobin from cyanide, and sulfhemo-
globinemia from hydrogen sulfide may severely decrease functional
hemoglobin. These patients often have fatigue, altered mental
status, shortness of breath, and other manifestations of hypoxia
without signs of RBC loss or volume depletion.
Diagnostic Findings in Emergent Anemia
Clinical Features
The most common cause of clinically significant anemia is
blood loss. The clinical manifestation of anemia depends on how
rapidly the hematocrit falls and also on the patient’s ability to
compensate.
Clinical signs and symptoms include tachycardia, decreased
blood pressure, postural hypotension, lightheadedness, increased
heart rate, and increased respiratory rate. Complaints of thirst,
altered mental status, and decreased urine output may also be
present. The patient’s age, concomitant illness, and underlying
hematologic, cerebral, and cardiovascular status tremendously
influence the clinical findings. Children and young adults may
tolerate significant blood loss with unaltered vital signs until a
precipitant hypotensive episode occurs. Pediatric patients may
 Chapter 121 / Anemia, Polycythemia, and White Blood Cell Disorders   1587

History and Physical Examination for Clinically

BOX 121-2 Severe Anemia
History
General
Out-of-hospital status, therapy, response to therapy
Bleeding diathesis
Previous blood transfusion
Underlying diseases, including allergies
Current medications, especially those causing platelet inhibition
Trauma
Nature and time of injury
Blood loss at scene
Nontrauma
Skin: petechiae, ecchymoses
Gastrointestinal: hematemesis, hematochezia, melena, peptic
ulcer
Genitourinary: last menstruation, menorrhagia, metrorrhagia,
Figure 121-1.  Reticulocytes with reticular material after methylene hematuria
blue staining. (From Hoffbrand AV, Pettite JE: Color Atlas of Clinical
Hematology, 3rd ed. London, Mosby, 2000:18.) Physical Examination
Vital Signs Measured Serially
Blood pressure, pulse, respiratory rate, oxygen saturation
Orthostatic blood pressure and pulse (contraindicated with
severe hypotension)
Table 121-1 Hemogram Normal Values Level and content of consciousness
HEMOGLOBIN HEMATOCRIT RED BLOOD CELL Skin
AGE (g/dL) (mL/dL) COUNT (×106) Pallor
3 months 10.4-12.2 30-36 3.4-4.0 Diaphoresis
Jaundice
3-7 years 11.7-13.5 34-40 4.4-5.0 Cyanosis
Adult man 14.0-18.0 40-52 4.4-5.9 Purpura, ecchymoses, petechiae
Evidence of penetrating wounds
Adult woman 12.0-16.0 35-47 3.8-5.2
Cardiovascular
Murmurs, S3, S4
Quality of femoral and carotid pulses
Causes of Rapid Intravascular Red Blood Abdomen
BOX 121-1 Cell Destruction Hepatosplenomegaly
Pain, guarding, rebound on palpation
Mechanical hemolysis associated with disseminated intravascular Rectal and pelvic examination
coagulation Masses
Massive burns Stool hemoglobin testing
Toxins (e.g., some poisonous venoms: brown recluse spider,
cobra)
Infections such as malaria or Clostridium sepsis
Severe glucose-6-phosphate dehydrogenase deficiency with 1. Complete blood count and peripheral smear
exposure to oxidant stress 2. Blood sample for type and crossmatch
ABO incompatibility transfusion reaction 3. Prothrombin time and international normalized ratio
Cold agglutinin hemolysis (e.g., Mycoplasma organisms, 4. Partial thromboplastin time
infectious mononucleosis) 5. Electrolyte levels
Paroxysmal nocturnal hemoglobinuria exacerbated by
6. Glucose level (especially if the patient has altered
transfusion
Immune complex hemolysis (e.g., quinidine) consciousness)
7. Creatinine level
8. Urinalysis for free hemoglobin
9. Clotting and unclotted blood samples for later testing
become markedly tachycardic, physiologically attempting to If possible, a blood sample is obtained for measurement of
maintain cardiac output because their ability to increase stroke hematocrit in the emergency department. Although it may take
volume is limited. Elderly patients commonly have underlying hours before the hematocrit correctly reflects the degree of blood
disease states that compromise their ability to compensate for loss, the initial value is useful in determining a baseline. On occa-
blood loss.1 sion, this value reveals an underlying anemia with the acute blood
Pertinent elements of the history and physical examination of loss superimposed. Depending on severity, a blood sample is sent
patients with acute anemia are listed in Box 121-2. for type and crossmatch. Peripheral smear interpretation is done
on pretreatment blood samples.
Ancillary Evaluation Measurements of coagulation status, electrolytes, glucose, blood
urea nitrogen, and creatinine are useful in the diagnosis of under-
Stabilization of emergent anemia commonly runs parallel to lying disease processes that may relate to the patient’s anemia.
assessment. If the signs and symptoms suggest potential life- Values of folate, vitamin B12, iron, total iron-binding capacity,
threatening conditions, intravenous lines are placed and samples reticulocytes, and direct antiglobulin (Coombs’ test) are altered by
for the following initial laboratory tests are drawn: transfusion. Therefore, pretreatment samples are best saved.

Downloaded from ClinicalKey.com at Universitas Tarumanagara September 19, 2016.

For personal use only. No other uses without permission. Copyright ©2016. Elsevier Inc. All rights reserved.
1588   PART III  ◆  Medicine and Surgery / Section TEN • Hematology and Oncology

BOX 121-3 History and Physical Examination for Nonemergent Anemia

History Physical Examination
Symptoms of Anemia Skin
Chest pain, decreased exercise tolerance, dyspnea Pallor
Weakness, fatigue, dizziness, syncope Purpura, petechiae, angiomas
Ulcerations
Bleeding Diathesis
Bleeding after trauma, injections, tooth extractions Eye
Spontaneous bleeding, such as epistaxis, menorrhagia Conjunctival jaundice, pallor
Spontaneous purpura and petechiae Funduscopic hemorrhage, petechiae
Sites of Blood Loss Oral
Respiratory: epistaxis, hemoptysis Tongue atrophy, papillary soreness
Gastrointestinal: hematemesis, hematochezia, melena
Genitourinary: abnormal menses, pregnancies, hematuria Cardiopulmonary
Skin: petechiae, ecchymoses Heart size, murmurs, extra cardiac sounds
Rales, other signs of pulmonary edema
Intermittent Jaundice, Dark Urine
Abdomen
Dietary History Hepatomegaly, splenomegaly
Vegetarianism Ascites
Poor nutrition Masses
Drug Use and Toxin Exposure, Including Alcohol Lymph Nodes
Racial Background, Family History Neurologic
Altered positions or vibratory sense
Underlying Disease Peripheral neuritis
Uremia, liver disease, hypothyroidism
Chronic disease states such as cancer, rheumatic or renal disease Rectal and Pelvic
Previous surgery
Miscellaneous
Previous treatment of anemia
Weight loss
Back pain

Diagnostic Findings in
Nonemergent Anemia
Clinical Features
Nonemergent anemias are usually seen in ambulatory patients
complaining of fatigue and weakness. Other voiced complaints
include irritability, headache, postural dizziness, angina, decreased
exercise tolerance, shortness of breath, and decreased libido. When
the anemia is of slow onset, the patient may adapt until the hemo-
globin is very low. Alternatively, patients with rapid blood loss may
experience lightheadedness or syncope even when the measured
hemoglobin is not critically low. For patients without evidence of
acute bleeding or emergent condition, elements of history and
physical examination may help identify the cause (Box 121-3).
Most of these patients do not need immediate stabilization and
can be further evaluated as outpatients.

Ancillary Evaluation
The initial laboratory evaluation includes a complete blood count
with leukocyte differential, reticulocyte count, peripheral smear
(Fig. 121-2), and RBC indices, including mean corpuscular volume
(MCV), mean corpuscular hemoglobin (MCH), and mean cor-
puscular hemoglobin concentration (MCHC).
Disposition
Criteria for the admission of patients with nonemergent anemia
are shown in Box 121-4.
Figure 121-2.  Normal smear. (From Hoffbrand AV, Pettite JE: Color
Atlas of Clinical Hematology, 3rd ed. London, Mosby, 2000:22.)
Differential Diagnosis
The differential diagnosis of anemia is facilitated by classification
of the anemia into one of three groups: decreased RBC produc-
tion, increased RBC destruction, and blood loss. A complementary
approach uses RBC morphology and indices. Figure 121-3 pres-
ents an algorithm for the evaluation of anemia.

Downloaded from ClinicalKey.com at Universitas Tarumanagara September 19, 2016.

For personal use only. No other uses without permission. Copyright ©2016. Elsevier Inc. All rights reserved.
 Chapter 121 / Anemia, Polycythemia, and White Blood Cell Disorders   1589

Algorithm for the Evaluation of Anemia

Hgb  12 g/dL

MCV  81 fL MCV 81-100 fL MCV  100 fL

Iron deficiency Acute blood loss B12 deficiency

Thalassemia Chronic disease Folate deficiency
Sideroblastic anemia Chronic renal insufficiency Liver disease
Lead intoxication Hypothyroidism Reticulocytosis
Chronic disease (late) Bone marrow suppression Myelodysplastic syndromes
Hemolysis ETOH abuse
G6PD Drugs (hydroxyurea, AZT,
Aplastic anemia chemotherapeutic agents)

Peripheral blood smear: Peripheral blood smear: Peripheral blood smear:

Microcytic or hypochromic Schistocytes, helmet cells, Large oval-shaped RBCs,
RBCs spherocytes, bite cells Hypersegmented
neutrophils
NO YES NO YES NO YES

Lead intoxication Iron deficiency Acute blood loss Hemolysis Liver disease B12 deficiency
Thalassemia Chronic disease G6PD Reticulocytosis Folate
Sideroblastic Chronic renal (bite cells) Myelodysplastic deficiency
anemia insufficiency syndromes
Chronic disease Hypothyroidism ETOH abuse
(late) Bone marrow LDH, Drugs
suppression Haptoglobin
Aplastic anemia
Hemolysis

Iron, TIBC,
Ferritin Coombs Obtain B12,
Folate levels
NO YES Negative Positive

Thalassemia Iron deficiency Non-autoimmune Autoimmune

Sideroblastic hemolytic hemolytic
anemia anemia anemia
Chronic disease
(late)

Figure 121-3.  Algorithm for the evaluation of anemia. AZT, azathioprine; ETOH, ethanol; fL, femtoliter; G6PD, glucose-6-phosphate
dehydrogenase; Hgb, hemoglobin; LDH, lactate dehydrogenase; MCV, mean corpuscular volume; RBCs, red blood cells; TIBC, total iron-binding
capacity.

securing the diagnosis. The definitive diagnosis is usually made

BOX 121-4 Admission Criteria for Nonemergent Anemia
Developing cardiac symptoms, such as shortness of breath or
chest pain, or neurologic symptoms
Initial unexplained hemoglobin value less than 8-10 g/dL or
hematocrit less than 25-30%
Major difficulty in obtaining outpatient care for patients whose
hemoglobin levels are significantly low or when comorbidity   RBC indices are useful in classifying anemias caused by a pro-
is present
Decreased Red Blood Cell Production
Anemias caused by decreased RBC production have a natural
history of insidious onset and an associated decreased reticulocyte
count. A subclassification by indices of anemias caused by
decreased RBC production is listed in Box 121-5. The RBC indices
and morphology manifested in a peripheral smear are useful in
outside the emergency department and may require bone marrow
examination. The emergency physician rarely initiates replace-
ment therapy, except in circumstances that require transfusion.
Appropriate diagnostic tests may be initiated, but replacement of
iron, vitamin B12, or folate without proof of cause is generally
unnecessary and unwise.
duction deficit. Their calculation and normal ranges are provided
in Table 121-2. MCV is a measure of RBC size; decreases and
increases reflect microcytosis and macrocytosis, respectively.
MCH incorporates both RBC size and hemoglobin concentration.
It is influenced by both and is the least helpful of the indices. The
MCHC index is a measure of the concentration of hemoglobin.
Low values represent hypochromia, whereas high values are noted
only in patients with decreased cell membrane relative to cell
volume, such as in the case of spherocytosis. An additional index
is the RBC distribution width (RDW), which is a measure of the

Downloaded from ClinicalKey.com at Universitas Tarumanagara September 19, 2016.

For personal use only. No other uses without permission. Copyright ©2016. Elsevier Inc. All rights reserved.
1590   PART III  ◆  Medicine and Surgery / Section TEN • Hematology and Oncology
Differential Diagnosis of Anemias Caused and porphyrin (sideroblastic anemia and lead poisoning). Anemia
by Decreased Red Blood Cell Production: of chronic disease, a secondary iron abnormality, rounds out the
BOX 121-5 Subclassification by Red Blood Cell Indices differential diagnosis. Not all microcytic anemias are the result of
iron deficiency, and routine iron therapy for a patient with a low
Hypochromic Microcytic Anemias (Decreased MCV and MCHC is inappropriate.
MCV and Hemoglobin Concentration)
Iron Deficiency Anemia.  Iron deficiency is a frequent cause of
Iron deficiency
Thalassemia chronic anemia seen in the emergency department. It is the most
Sideroblastic anemia or lead poisoning common anemia in women of childbearing age. In older patients,
Chronic disease (e.g., cancer, renal or inflammatory disease); occult blood loss, especially gastrointestinal, may initially appear
normochromic and normocytic indices often found as iron deficiency anemia. Because changes in RBC size and hemo-
globin content occur only after bone marrow and cytochrome iron
Macrocytic (Elevated MCV)
Vitamin B12 deficiency
stores are depleted, a patient may have early symptoms of iron
Folate deficiency deficiency (e.g., fatigue) without manifesting changes in RBC
Liver disease structure.
Hypothyroidism The diagnosis is made by laboratory evaluation of the fasting
level of serum iron, serum ferritin, and total iron-binding capacity.
Normocytic (Normal MCV and Hemoglobin
The laboratory interpretation and pitfalls are outlined in Table
Concentration)
Primary bone marrow involvement: aplastic anemia, myeloid 121-3. A concentrated search for occult blood loss is vital.
metaplasia with myelofibrosis, myelophthisic anemia Therapy consists of oral iron replacement. A cost-effective form
Resulting from underlying disease: hypoendocrine state (thyroid, is ferrous sulfate. The dosage is 300 mg for adults (60 mg of ele-
adrenal, pituitary), uremia, chronic inflammation, liver disease mental iron) or 3 mg/kg/day for children. This medication is gen-
erally well tolerated, although it may cause nausea, vomiting, or
MCV, mean corpuscular volume.
constipation. Patients should be warned that their stools will be
blackened. The patient should also be warned that bleeding from
Calculation of Red Blood Cell Indices the digestive tract can also be manifested as blackened stool. In
Table 121-2 and Normal Values rare patients with poor oral tolerance or absorption, parenteral
iron therapy may be necessary.
INDEX FORMULA FOR CALCULATION NORMAL RANGE The patient may experience a sense of improvement in as few
Mean corpuscular Hematocrit (%) divided by red 81-100 fL as 24 hours. Reticulocytosis appears during a 3- or 4-day period
volume blood cell count (106/µL) in children but may take more than 1 week in adults. The hemo-
Mean corpuscular Hemoglobin (g/dL) divided by 26-34 pg globin concentration rises on a similar schedule. Explanations for
hemoglobin red blood cell count (106/µL) response failures to iron therapy include the following: the patient
Mean corpuscular Hemoglobin (g/dL) divided by 31-36%
is noncompliant with the iron supplementation, the blood loss
hemoglobin hematocrit (%) may exceed the replacement, the diagnosis is incorrect, or the
concentration diagnosis is partially correct with an additional process complicat-
ing the iron deficiency.2
fL, femtoliter. Thalassemia.  Thalassemia is a genetic autosomal defect
reflected by the decreased synthesis of globin chains. The hemo-
globin molecule is present as two paired globin chains. Each type
of hemoglobin is made up of different globins. For example,
normal adult hemoglobin (HbA) is made up of two α chains and
two β chains (α2β2). HbA2 is α2δ2, and fetal hemoglobin (HbF) is
α2γ2. A separate autosomal gene controls each globin chain. Dele-
tions in this globin gene result in an absence or decreased function
of the messenger RNA that codes for the creation of that globin.
The various globins (α, β, δ, and γ) may be affected by a number
of genetic combinations. The decrease in globin production in
thalassemia results in decreased hemoglobin synthesis and inef-
fective erythropoiesis, which is attributable to increased intramar-
row hemolysis with destruction of RBCs before they are released.
Normal erythropoiesis has a 10 to 20% incidence of ineffective
release, with associated intramarrow RBC destruction. This inef-
fective release of erythropoiesis may double or triple in patients
with thalassemia. The cause is believed to be excess chains of the
Figure 121-4.  Iron deficiency anemia with hypochromic, microcytic uninhibited globin precipitating in RBCs.3
cells and poikilocytes (abnormally shaped cells). (From Hoffbrand AV,
Pettite JE: Color Atlas of Clinical Hematology, 3rd ed. London, Mosby,
Although many variations in thalassemia are possible, only
2000:44.) three are commonly considered. Homozygous β-chain thalasse-
mia (thalassemia major) occurs predominantly in Mediterranean
populations. It represents one of the most common single-gene
homogenicity of the RBCs measured. RDW is automatically cal- disorders. The disease is characterized by severe anemia, hepato-
culated as the standard deviation of MCV divided by MCV mul- splenomegaly, jaundice, abnormal development, and premature
tiplied by 100. A normal RDW is 13.5 ± 1.5%. The RDW is usually death. Patients are transfusion dependent and die as a result of
elevated in anemias caused by nutritional deficiencies; however, it iron deposition in tissues, particularly the myocardium, or infec-
is not specific for any abnormality. tion. Treatment is supportive and consists of transfusion and iron
Microcytic Anemias.  Hypochromic microcytic anemias are sub- chelation therapy.4,5
divided into deficiencies of the three building blocks of hemoglo- Heterozygous β-chain thalassemia (thalassemia minor) is man-
bin: iron (iron deficiency anemia; Fig. 121-4), globin (thalassemia), ifested as a mild microcytic hypochromic anemia with target cells

Downloaded from ClinicalKey.com at Universitas Tarumanagara September 19, 2016.

For personal use only. No other uses without permission. Copyright ©2016. Elsevier Inc. All rights reserved.

Table 121-3 Diagnostic Tests for Iron Deficiency Anemia
TEST NORMAL RESULT
Fasting serum iron 60-180 µg/dL
Total iron-binding capacity 250-400 µg/dL
Percentage of saturation (serum iron) 15-45%
of total iron-binding capacity
Serum ferritin 10-10,000 mg/mL
Bone marrow stainable iron Hemosiderin granules in
reticuloendothelial cells
Figure 121-5.  β-Thalassemia with microcytic hemochromic red cells
and target cells. (From Hoffbrand AV, Pettite JE: Color Atlas of Clinical
Hematology, 3rd ed. London, Mosby, 2000:96.)
(erythrocytes with central hyperchromic bull’s-eye surrounded by
pallor) seen on the peripheral smear (Fig. 121-5), an MCV com-
monly more severely lowered than with iron deficiency anemia, a
normal level of serum iron, and an elevated level of HbA2 (α2δ2)
on hemoglobin electrophoresis (2-5%). Usually, no treatment is
necessary.
α-Thalassemia varies in spectrum from an asymptomatic
carrier state to prenatal death. Four gene loci control this range.
In the tolerated forms, it is more commonly seen in Asians and
African Americans. Microcytosis, hypochromia, target cells, and
basophilic stippling are noted on the peripheral smear. The diag-
nosis is made with hemoglobin electrophoresis and genetic testing.
Screening for carriers is performed by measurement of RBC
indices and estimation of the HbA2 concentration. Prenatal diag-
nosis can be made by analysis of fetal blood and, more recently,
by fetal DNA obtained by chorionic villus sampling.
Therapy consists of blood transfusions, which are based on the
clinical severity of the anemia. The goals of transfusion therapy
include correction of anemia, suppression of erythropoiesis, and
inhibition of increased gastrointestinal iron absorption. Iron che-
lation therapy is often required to control excess iron stores. His-
torically, deferoxamine, a subcutaneously administered chelator,
was used; however, it has been replaced at many centers with the
oral chelator deferasirox (Exjade). Deferasirox is renally cleared;
thus dose adjustments may be necessary for chronic renal insuf-
ficiency, and it is contraindicated in end-stage renal disease.6
Bone marrow transplantation from HLA-identical donors has
resulted in disease-free survival in 60 to 90% of recipients, but its
role in thalassemia has yet to be determined. Although much
interest centers on permanent correction of genetic deficits in
thalassemia, gene therapy does not yet exist.7
Sideroblastic Anemia.  Sideroblastic anemia involves a defect
in porphyrin synthesis. The resultant impaired hemoglobin pro-
duction causes excess iron to be deposited in the mitochondria of
the RBC precursor, but some also circulates. The result is increased
Downloaded from ClinicalKey.com at Universitas Tarumanagara September 19, 2016.
For personal use only. No other uses without permission. Copyright ©2016. Elsevier Inc. All rights reserved.
Chapter 121 / Anemia, Polycythemia, and White Blood Cell Disorders   1591
IRON DEFICIENCY LEVEL INTERPRETATION
<60 µg/dL Diurnal variation (draw in morning); increased by
hepatitis, hemochromatosis, hemolytic anemia, and
aplastic anemia; decreased in infection
>400 µg/dL Increased in late pregnancy or hepatitis; decreased
in infection
<15%
<10 mg/mL Reflects iron stores; may increase as an acute-phase
reactant in infection
Absent Standard for assessment of iron stores
serum iron and ferritin levels, with transferrin saturation. The
defective heme synthesis results in ineffective erythropoiesis, mild
to moderate anemia, and a dimorphic peripheral smear with
hypochromic microcytes along with normal and macrocytic cells.
Sideroblastic anemia, although found in a rare sex-linked
hereditary form, is typically a disease of the elderly. Indeed, the
idiopathic form is a common type of refractory anemia in elderly
patients. Pallor and splenomegaly may be noted, and iron staining
of the peripheral smear may demonstrate iron-containing inclu-
sion bodies in RBCs. Some of these patients are deficient in pyri-
doxine (vitamin B6) and respond to treatment with 100 mg of
pyridoxine three times a day. Most remain anemic, but a 1- or
2-month pyridoxine trial is acceptable treatment. These patients
may be susceptible to iron overload, particularly if long-term
transfusion therapy is necessary, but they may respond to iron
chelation therapy. Idiopathic sideroblastic anemia is considered a
preleukemic state, and acute myelogenous leukemia develops in
approximately 5% of these patients.
Secondary causes of sideroblastic anemia include toxins such as
chloramphenicol, isoniazid, and cycloserine as well as diseases
such as hemolytic and megaloblastic anemia, infection, carci-
noma, leukemia, and rheumatoid arthritis. The exact mechanisms
of these causative agents and diseases are unknown. Lead poison-
ing is one reversible cause of sideroblastic anemia. It may be sug-
gested by the appearance of RBC basophilic stippling on the
peripheral smear. Elevated blood lead levels are diagnostic. Alcohol
abuse may also result in disordered heme synthesis, which can be
corrected by alcohol cessation or by parenteral pyridoxal phos-
phate in cases of continued abuse. Oral pyridoxine may be inef-
fective because of impaired conversion to the active form in
alcoholic patients.
Anemia of Chronic Disease.  Anemia of chronic disease is
common and typically normochromic, normocytic. It is charac-
terized by low serum iron levels, low total iron-binding capacity,
and normal or elevated ferritin levels. Bone marrow is normal, but
staining reveals an abnormality in the mobilization of iron from
reticuloendothelial cells. This anemia can be differentiated from
iron deficiency by total iron-binding capacity, serum ferritin level,
bone marrow examination, and nonresponsiveness to a trial of
iron therapy. Because the hematocrit is seldom less than 25 to
30%, therapy is not usually required. A complete search for
occult blood loss is necessary during the evaluation of this
diagnosis because iron deficiency may be superimposed. Dissemi-
nated cancer, chronic inflammation, uremia, and infection are
common causes.8
Macrocytic and Megaloblastic Anemias.  In terms of the potential
for a therapeutic response, the most important cause of macrocy-
tosis is megaloblastic anemia. Megaloblastic anemia is the hema-
tologic manifestation of a total-body alteration in DNA synthesis.
1592   PART III  ◆  Medicine and Surgery / Section TEN • Hematology and Oncology
The defective DNA synthesis is caused by a lack of the coenzyme
forms of vitamin B12 and folic acid. The deficiency appears clini-
cally in tissues with rapid cell turnover, including hematopoietic
cells and those of mucosal surfaces, particularly in the gastroin-
testinal tract. This deficiency is characterized hematopoietically by
ineffective erythropoiesis and pancytopenia. Vitamin B12 and
folate deficiencies have different developmental histories, but the
clinical result may be similar. Differentiation of folate and vitamin
B12 deficiencies usually depends on measured levels in the
laboratory.
Folic acid, absorbed in the duodenum and jejunum, is com-
monly found in green vegetables, cereals, and fruit. It may be
destroyed completely by cooking. The body requires approxi-
mately 100 µg/day and usually stores 6 to 20 mg. Therefore, a 2- to
4-month supply is available before megaloblastic changes occur.
Causes of folate deficiency are listed in Box 121-6. Most patients
with folate deficiency have either an inadequate dietary intake,
such as alcoholic patients, or increased use, as in pregnancy.
Vitamin B12 is found in foods of animal origin only and is not
destroyed by cooking. It is absorbed in the ileum after binding to
intrinsic factor. This glycoprotein factor is secreted by the parietal
cells of the gastric mucosa and allows low levels of B12 to be actively
absorbed. The adult requirement is 1 or 2 µg/day, with a body
store of 5 mg. Therefore, megaloblastic changes may take up to 4
years to develop after cessation of vitamin B12 uptake. The various
causes of vitamin B12 deficiency are listed in Box 121-7. The most
common cause is chronic malabsorption.
BOX 121-6 Causes of Folate Deficiency
Inadequate dietary intake
Poor diet or overcooked or processed food diet
Alcoholism
Inadequate uptake
Malabsorption with sprue and other chronic upper intestinal
tract disorders, drugs such as phenytoin and barbiturates, or
blind loop syndrome
Inadequate use
Metabolic block caused by drugs such as methotrexate or
trimethoprim
Enzymatic deficiency, congenital or acquired
Increased requirement
Pregnancy
Increased RBC turnover: ineffective erythropoiesis, hemolytic
anemia, chronic blood loss
Malignant disease: lymphoproliferative disorders
Increased excretion or destruction or dialysis
BOX 121-7 Causes of Vitamin B12 Deficiency
Inadequate dietary intake
Total vegetarianism: no eggs, milk, or cheese
Chronic alcoholism (rare)
Inadequate absorption
Absent, inadequate, or abnormal intrinsic factor, as seen in
patients with pernicious gastrectomy and anemia. In
anemia, autoimmune antibodies act against gastric parietal
cells and intrinsic factor.
Abnormal ileum, as can occur in sprue and inflammatory
bowel disease
Inadequate use
Enzyme deficiency
Abnormal vitamin B12–binding protein
Increased requirement by increased body metabolism
Increased excretion or destruction
Downloaded from ClinicalKey.com at Universitas Tarumanagara September 19, 2016.
For personal use only. No other uses without permission. Copyright ©2016. Elsevier Inc. All rights reserved.
Megaloblastic anemia that is not responsive to folate or vitamin
B12 is commonly related to antimetabolites used in chemotherapy
or rare inherited disorders of DNA synthesis.
Table 121-4 lists a number of the problems associated with
megaloblastic anemia and their underlying pathologic states. A
unique feature of vitamin B12 deficiency is its neurologic involve-
ment. Patients may have paresthesias in their hands and feet,
decreased proprioception, or decreased vibratory sense. The insid-
iously developing classic neurologic complex includes loss of pro-
prioception; weakness and spasticity of the lower extremities with
altered reflexes; and variable mental changes, such as depression,
paranoid ideation, irritability, and forgetfulness. The last two com-
plaints have also been noted with folic acid deficiency. Vitamin
B12–deficient patients have some of the lowest hemoglobin levels
seen in any disease state.
Macrocytic anemia is suggested when the MCV is greater than
100 fL, but other criteria need to be met for megaloblastosis to be
considered the cause of the macrocytic anemia. On the peripheral
smear, large oval red cells (macro-ovalocytes) and hypersegmented
polymorphonuclear neutrophils are believed to be diagnostic (Fig.
121-6). A bone marrow aspirate may reveal morphologic changes
consistent with megaloblastic erythropoiesis. Other potentially
useful laboratory tests include vitamin B12 and folate levels, red
cell folate, and lactate dehydrogenase (LDH). Laboratory tech-
niques, values, and interpretations are listed in Table 121-5. Once
megaloblastic anemia is diagnosed and folate or vitamin B12 defi-
ciency determined, standard diagnostic regimens are followed to
determine the precise origin of the deficiency.
Because one deficiency may cause gastrointestinal absorption
changes that beget other deficiencies, the emergency physician
may be forced to initiate therapy before the final diagnosis is made.
However, a caution is given to obtain necessary laboratory speci-
mens before this course is pursued. The usual dosage for patients
with megaloblastic anemia secondary to folate deficiency is 1 mg
of oral folic acid per day. Parenteral administration is generally
unnecessary because most cases are due to dietary deficiency. In
contrast, malabsorption is the most common cause of vitamin B12
deficiency, and parenteral therapy is initiated at 100 µg/day intra-
muscularly for the first 7 to 10 days. Thereafter, only monthly
100-µg doses are necessary. The response is often dramatic, with
reticulocyte counts rising up 30 to 50% and normalization of
RBC, white blood cell (WBC), and platelet counts in 6 to 8 weeks.
The use of vitamin B12 or folate supplements in patients with
undiagnosed anemia is to be discouraged. The routine injection
of vitamin B12 in the elderly has decreased but is still a too common
practice.9
Macrocytic anemias unrelated to megaloblastic changes are
seen frequently. Liver disease, often associated with alcoholism, is
Clinicopathologic Correlation of
Table 121-4 Manifestations of Megaloblastic Anemia
CLINICAL FEATURES PATHOLOGIC CONDITION
Lemon yellow skin Combination of pallor with low-grade
icterus from ineffective erythropoiesis
Petechiae, mucosal bleeding Thrombocytopenia
Infection Leukopenia
Fatigue, dyspnea on exertion, Anemia
postural hypotension
Sore mouth or tongue Megaloblastosis of mucosal surfaces
Diarrhea and weight loss Malabsorption from mucosal surface
change
Paresthesias and ataxia Related to myelin abnormality in
vitamin B12 deficiency only
 Chapter 121 / Anemia, Polycythemia, and White Blood Cell Disorders   1593
Table 121-5 Serum Tests for Diagnosis and Differentiation of Megaloblastic Anemia
TEST TECHNIQUE VALUE
Vitamin B12 Microbiologic or Normal: 300-900 µg/L
radioisotope Deficient: <200 µg/L
Folate Microbiologic or Deficient: <3 µg/L
radioisotope
Red cell folate Calculated Normal: 200-700 µg/L
Folate deficiency: <140 µg/L
Lactate dehydrogenase Spectrophotometric Normal: 95-200 IU
Megaloblastic anemia: 4-50 times normal
Figure 121-6.  Megaloblastic anemia with macrocytic red cells and
hypersegmented polymorphonuclear neutrophils. (From Hoffbrand AV,
Pettite JE: Color Atlas of Clinical Hematology, 3rd ed. London, Mosby,
2000:61.)
the most common cause.10 Macrocytic target cells may be seen on
the peripheral smear in conjunction with this disorder. Hypothy-
roidism and hemolysis may also be manifested as macrocytic
anemia. Screening tests to differentiate between megaloblastic
anemia and macrocytic anemia of other causes include a periph-
eral smear for macro-ovalocytes, hypersegmented polymorpho-
nuclear neutrophils, and the LDH level.
Normochromic and Normocytic Anemias.  The origin of normo-
chromic and normocytic anemias secondary to decreased produc-
tion is not as obvious as that of macrocytic and microcytic anemias
because the latter give clues to their origin by alterations in RBC
indices. One hematologic parameter that can aid in the diagnosis
of normocytic anemia associated with hypoproduction is the cor-
rected reticulocyte count. Reticulocytes reflect RBC production in
bone marrow. They are RBCs released from bone marrow every 1
to 3 days and contain residual RNA that can be detected by supra-
vital staining. Reticulocytes have an average MCV of 160 fL and
in sufficient numbers can increase the MCV of the total erythro-
cyte count. The reticulocyte count is expressed as a percentage of
Downloaded from ClinicalKey.com at Universitas Tarumanagara September 19, 2016.
For personal use only. No other uses without permission. Copyright ©2016. Elsevier Inc. All rights reserved.
INTERPRETATION
Although they may overlap clinically, vitamin B12 level is
usually normal in folate deficiency.
Vitamin B12 deficiency may elevate folate levels by blocking
transfer of serum folate to RBCs; hemolysis may elevate
folate levels.
Index of tissue folate is less influenced by diet and is
increased in vitamin B12 deficiency because of block.
Normal in other macrocytic anemias; elevated two to four
times normal in hemolytic anemias; isoenzymes may be
helpful.
Aplastic Anemia Caused by Drugs
Table 121-6 or Chemicals
CAUSE RELATIVE INCIDENCE (%)
Chloramphenicol 61
Phenylbutazone 19
Anticonvulsants 4
Insecticides 4
Solvents 4
Sulfonamides 3
Gold 3
Benzene 2
From Silver BJ, Zuckerman KS: Aplastic anemia: Recent advances in pathogenesis and
treatment. Med Clin North Am 64:607, 1980.
the total RBC population and needs to be related (“corrected”) to
the RBC count of the patient. Thus the corrected reticulocyte
count is equal to the measured percentage of reticulocytes times
the patient’s hematocrit (%) divided by 45% (taken as the normal
hematocrit). The normal range is 1 to 3%.
Normocytic anemia may be classified as being due to primary
bone marrow involvement or a secondary marrow response to
underlying disease.
Aplastic anemia is rare but may have severe manifestations.
It is suspected in anemic patients with normal indices, a low
reticulocyte count, and a history of exposure to certain drugs or
chemicals (Table 121-6). It is related to drug or chemical exposure
in 50% of cases. Viral hepatitis, radiation, and pregnancy have
been associated with aplastic anemia. Another group of patients
is considered to have an “autoimmune” origin.
The aplastic state may extend to all cell lines and results from
destruction by immune-stimulated lymphocytes or failure of the
marrow stem cell. On occasion, only one cell line fails, as in RBC
aplasia. This condition represents injury occurring at a later stage
of cellular differentiation. The precise diagnosis necessitates bone
marrow examination, but the causative factor may be difficult to
determine.
General treatment of aplastic anemia includes removal of sus-
pected marrow toxins from the environment, avoidance of aspirin,
oral hygiene, and suppression of menses. Transfusions are given
in life-threatening circumstances only. Bone marrow or peripheral
blood stem cell transplantation from a histocompatible sibling
can cure the bone marrow failure, with survival rates of 78 to
94% reported.10 However, because just 30% of patients have suit-
ably matched sibling donors, only a small number undergo allo-
geneic transplantation. Immunosuppression with antithymocyte
globulin, antilymphocyte globulin, and other cytotoxic chemo-
therapy is used in the majority of patients who are not stem cell
1594   PART III  ◆  Medicine and Surgery / Section TEN • Hematology and Oncology
Figure 121-7.  Anisocytosis and poikilocytosis. (From Hoffbrand AV,
Pettite JE: Color Atlas of Clinical Hematology, 3rd ed. London, Mosby,
2000:113.)
transplantation candidates. Unrelated donors are preferred to
avoid sensitization of the patient against the non-HLA antigens
that are present in bone marrow from a family donor. The disease
has a wide range of severity, and the overall 5-year survival rate is
30 to 40%. Given supportive therapy, up to 80% of patients with
severe aplastic anemia still die. Bone marrow transplantation
before blood product sensitization has resulted in an 80% 5-year
survival rate. This is usually combined with immunosuppressive
therapy consisting of antilymphocyte globulin. Difficulty is still
encountered in finding the correct immunologic match.11,12
Myelophthisic anemia is bone marrow failure resulting from
replacement by an invading tumor, leukemia, lymphoma, or,
rarely, granuloma. A more basic defect or inhibitor may compli-
cate the problem because the degree of anemia cannot always be
correlated with the extent of bone marrow invasion. Any patient
with oncologic disease may be subject to the development of this
type of anemia. Useful clues are signs of extramedullary hemato-
poiesis, such as hepatosplenomegaly and a leukoerythroblastic
peripheral smear that demonstrates immature WBCs, nucleated
RBCs, and poikilocytosis (teardrop-shaped red cells) (Fig. 121-7).
The final diagnosis is made by bone marrow examination. Therapy
is directed at the underlying disorder.
Myelofibrosis of unknown origin is the usual cause of primary
bone marrow failure associated with extramedullary hematopoi-
esis. This myeloid metaplasia occurs in the liver and spleen and
imparts a blood picture similar to that of myelophthisic anemia.
The diagnosis may be made by bone marrow examination. Treat-
ment is supportive, although splenectomy or the use of alkylating
agents may be necessary to treat complications of extramedullary
blood cell production, such as hepatosplenomegaly.
The hypoplastic anemias of secondary origin are commonly
seen as mild chronic anemias with low reticulocyte counts. They
have a normal MCV and RDW. Their diagnosis is made by exclu-
sion. Anemia of chronic disease may have microcytic or normo-
cytic indices. It is associated with chronic inflammation (e.g.,
Downloaded from ClinicalKey.com at Universitas Tarumanagara September 19, 2016.
For personal use only. No other uses without permission. Copyright ©2016. Elsevier Inc. All rights reserved.
rheumatoid arthritis, chronic infections such as tuberculosis and
osteomyelitis, and malignant disease). Hypoendocrinism caused
by hypothyroidism, hypoadrenalism, or hypopituitarism results in
a hypometabolic state in which the bone marrow responds poorly
to erythropoietin. Erythropoietin levels may be low. The anemia
of chronic renal failure is thought to be caused by a number of
factors including decreased erythropoietin production, hemolysis,
suppression by dialyzable factors, and increased blood loss caused
by platelet abnormalities. If necessary, it may be corrected by
erythropoietin replacement therapy.13
Increased Red Blood Cell Destruction
The hemolytic anemias are defined by a shortened life span of
the erythrocyte. In their acute form, hemolytic anemias can be
devastating and require rapid diagnosis and intervention (see Box
121-1). Fortunately, they are relatively rare in comparison to the
chronic hemolytic conditions. Chronic disorders may be related
to primary blood disorders (e.g., sickle cell anemia) or may be a
result of other disease states (e.g., chronic renal failure). These
disorders may be manifested as acute hemolytic anemia if the
tenuous balance between RBC production and destruction is
upset. If the patient can be demonstrated to have a normal hema-
tocrit and reticulocyte count at the same time, differentiation
between acquired and inherited hemolytic anemia is possible.
Clinical Features.  The clinical signs and symptoms of hemolytic
anemia are, in general, caused by either intravascular or extravas-
cular processes. Although it is not a precise representation of the
underlying pathophysiologic condition, this division assists in the
differential approach in the emergency department.
Intravascular hemolysis is usually associated with an acute
process and has a dramatic appearance. Large numbers of RBCs
may be lysed within the circulation. The pathologic process pri-
marily involves the handling of released hemoglobin and a com-
pensatory response to an acute decrease in oxygen-carrying
capability. Free hemoglobin initially binds to haptoglobin and
hemopexin. This complex is transported to the liver, converted to
bilirubin, conjugated, and excreted. When this binding and trans-
port system is overwhelmed, free hemoglobin may appear in the
blood. Hemoglobin is a large molecule that remains in serum and
may tint it pink.
In contrast, myoglobin is a small molecule that is rapidly cleared
from serum. Examination of spun whole blood demonstrates clear
serum in myoglobinemia, pink serum with free hemoglobin from
intravascular hemolysis, and yellow serum from extravascular
hemolysis with increased bilirubin production. In severe cases, the
last mechanism may also result in free hemoglobin.
The clinical appearance of intravascular hemolysis may vary
from mild chronic anemia, as seen in cases of mechanical hemo-
lysis, to prostration, fever, abdominal and back pain, and mental
changes, as seen with transfusion reactions. Jaundice, brown to red
urine, and oliguria associated with acute renal failure induced by
the hemoglobin complex can also occur.
Extravascular hemolysis is more common and usually better
tolerated. Splenic blood flow slows as RBCs travel in the sinusoids
close to the reticuloendothelial system, which is uniquely designed
for removal of older or damaged cells. Primary splenic overactiv-
ity, antibody-mediated changes, or RBC membrane abnormalities
may cause this normal splenic function to increase to a pathologic
degree. Hemolysis may also occur within the bone marrow. As
stated previously, normal erythropoiesis is ineffective 10 to 20%
of the time. This percentage increases when abnormal RBCs are
produced, as in thalassemia, megaloblastic anemia, or some hemo-
lytic anemias.14
After hemoglobin is disassembled in the reticuloendothelial
cell, globin returns to the amino acid pool, iron is transported by
transferrin to the bone marrow or iron stores, and the pyrrole ring
 Chapter 121 / Anemia, Polycythemia, and White Blood Cell Disorders   1595
is converted to bilirubin. The unconjugated bilirubin circulates to reflects the presence of younger cells associated with reticulocyto-
the liver and is transformed. It is excreted in urine as conjugated sis. The specific diagnosis may be made by a blood smear, as with
bilirubin. The clinical picture of extravascular hemolysis is usually sickled cells or Heinz bodies in glucose-6-phosphate dehydroge-
mild to moderate anemia, mild and intermittent jaundice, and nase (G6PD) deficiency.
enlargement of the spleen. The signs and symptoms vary with the Haptoglobin binds hemoglobin on a molecule-for-molecule
severity and chronicity of the hemolysis. basis. Its absence implies saturation and degradation after binding
Ancillary Evaluation.  Once hemolysis is suspected, the history with hemoglobin and is an early finding in hemolysis. It has a
and laboratory tests have diagnostic precedence over physical normal range of 40 to 180 mg/mL, is decreased in hepatic failure,
examination. Important historical and physical examination and increases as an acute-phase reactant. After haptoglobin is
points are listed in Box 121-8. bound, hemoglobin binds with hemopexin, transferrin, and
Laboratory Assessment.  Important diagnostic tests for hemoly- albumin before circulating in its free form. Plasma free hemoglo-
sis are provided in Box 121-9. bin levels are determined in suspected cases of intravascular
The blood smear is often more diagnostic than bone marrow hemolysis. The result is considered positive if the level is greater
examination. The typical cell seen in intravascular hemolysis is the than 40 to 50 mg/dL. Hemoglobin is excreted by the kidney and
schizocyte (Fig. 121-8). The classic cell of extravascular hemolysis may be found as a smoky red pigment that is orthotoluidine posi-
is the spherocyte (Fig. 121-9). It may be seen in congenital sphe- tive with no associated RBCs. Prussian blue–staining granules of
rocytosis but more commonly indicates splenic activity against an hemosiderin may be found intracellularly in renal tubule cells
antibody-coated RBC membrane. An increase in macrocytes excreted in urine during chronic hemolytic states.
LDH is released when the RBC is broken down peripherally
or in the marrow. It is elevated in hemolytic, thalassemic, sidero-
blastic, and megaloblastic anemia. It may also be seen in cases of
Pertinent Factors in the History and Physical uremia, polycythemia vera, and erythroleukemia. Normal levels of
BOX 121-8 Examination for Hemolytic Anemia LDH range from 95 to 200 IU and may be fractionated.
History In extravascular hemolysis, bilirubin is often delivered to
Alteration of color in urine or feces the liver faster than the conjugating mechanism can handle it.
Association with drugs, cold, sleep Normal total levels are less than 1.5 mg/dL, and the indirect com-
Early or recent-onset anemia history with symptoms ponent amounts to less than 0.5 mg/dL. Conjugated or indirect
Ethnic background bilirubin may rise as high as 4 or 5 mg/dL even with normal liver
Family history of anemia or jaundice function. Higher levels connote some degree of underlying hepatic
Drug or toxic exposure insufficiency.
Disease states associated with hemolysis, such as systemic lupus
The direct antiglobulin (Coombs’) test detects antibody or
erythematosus, renal failure, lymphoma, infectious
mononucleosis, prosthetic heart valve complement on human RBC membranes. It is an essential test in
the evaluation of hemolysis. Approximately 90% of patients with
Physical Examination autoimmune hemolytic anemia have a positive direct Coombs’ test
Jaundice result (warm agglutinin autoimmune hemolytic anemia). The
Hepatosplenomegaly indirect test measures antibody titers in serum (cold agglutinin
Ulcerations, particularly in the lower extremities
Enlarged lymph nodes
autoimmune hemolytic anemia). The key to the direct antiglobu-
lin test is the reagent. It contains an antihuman immunoglobulin
(Ig) G that is produced in rabbits. This antihuman IgG in its
broad-spectrum form reacts with the IgG, IgM, or C3 proteins that
may coat RBCs. The reaction causes an agglutination of RBCs that
BOX 121-9 Diagnostic Tests for Hemolysis is graded 0 to 4. Agglutinating properties depend on the size of
the immunoglobulin. IgM is a large antibody form that can bridge
Peripheral blood smear the distance between cells, cause agglutination, and fix comple-
Corrected reticulocyte index or reticulocyte production index ment. The direct antiglobulin test is limited in diagnosis of IgM-
Haptoglobin levels mediated hemolysis. It is best in determining IgG or complement
Plasma free and urinary hemoglobin on the RBC surface. IgG is not large enough to cause agglutina-
Lactate dehydrogenase level tion, and the antihuman globulin attaches to RBC-bound IgG,
Fractionated bilirubin level
Direct and indirect Coombs’ test
which allows agglutination. C3 is detected in a similar manner.
RBC membrane stability (osmotic fragility) Both represent possible immunologic causes of hemolysis. This
form of hemolysis is usually mediated extravascularly through the

Figure 121-8.  Schizocytes (fragmented cell and nucleated red cells). Figure 121-9.  Spherocytosis. (From Hoffbrand AV, Pettite JE: Color
(From Hoffbrand AV, Pettite JE: Color Atlas of Clinical Hematology, 3rd Atlas of Clinical Hematology, 3rd ed. London, Mosby, 2000:115.)
ed. London, Mosby, 2000:115.)

Downloaded from ClinicalKey.com at Universitas Tarumanagara September 19, 2016.

For personal use only. No other uses without permission. Copyright ©2016. Elsevier Inc. All rights reserved.
1596   PART III  ◆  Medicine and Surgery / Section TEN • Hematology and Oncology
BOX 121-10 Classification of Hemolytic Anemia
Intrinsic
Enzyme defect
Pyruvate kinase deficiency
Glucose-6-phosphate dehydrogenase deficiency
Membrane abnormality
Spherocytosis
Elliptostomatocytosis
Paroxysmal nocturnal hemoglobinuria
Spur cell anemia
Hemoglobin abnormality
Hemoglobinopathies
Thalassemias (anemias)
Unstable hemoglobin
Hemoglobin M
Extrinsic
Immunologic
Alloantibodies
Autoantibodies
Mechanical
Microangiopathic hemolytic anemia
Cardiovascular, such as prosthetic heart valve disease
Environmental
Drugs
Toxins
Infections
Thermal
Abnormal sequestrations, as in hypersplenism
spleen because IgG is a poor initiator of the complement system.
The direct antiglobulin test evaluates the RBC surface for immu-
nologic markers. The indirect test assumes that IgG or C3 is in the
serum and tests for serum antibody activity against RBCs. Positive
test results for immunologic markers do not correlate agglutina-
tion activity with the severity of hemolysis.14
Differential Diagnosis.  Hemolytic anemias may be classified as
congenital or acquired, Coombs’ positive or Coombs’ negative, or
caused by processes intrinsic or extrinsic to the cell membrane.
The last method gives a useful differential classification of hemo-
lysis (Box 121-10).
Intrinsic Enzyme Defects.  Eighty-five percent to 90% of the
membrane-sustaining energy production of the erythrocyte is
through the anaerobic glycolytic pathway. At least eight known
enzyme deficiencies are associated with this pathway. The most
common is pyruvate kinase deficiency, which is manifested with
hemolytic jaundice and is usually diagnosed in infancy.
The remaining 10 to 15% of RBC glycolysis occurs by way of
the hexose monophosphate shunt. This bypass mechanism occurs
in the early stages of the glycolytic pathway and generates reduced
nicotinamide adenine dinucleotide phosphate (NADPH), which
is important in maintaining reduced glutathione. Glutathione is
essential in the protection of hemoglobin from oxidant injury. A
deficiency of the first enzyme in this pathway, G6PD, occurs in
11% of African American men. In this form, the enzyme deterio-
rates with age, and older RBCs are subject to hemolysis by oxidant
stress. G6PD deficiency is sex linked and has a wide range of sever-
ity. The most common form in African Americans is self-limited
because as the bone marrow responds, younger cells with more
normal levels of G6PD predominate and can handle the oxidant
stress. The variants in Sicilians, Greeks, and Arabs can be particu-
larly devastating. The clinical manifestation is usually an acute
hemolytic episode that may be both intravascular and extravascu-
lar in appearance. It occurs 24 to 48 hours after the ingestion of
an oxidant drug (Box 121-11) or after acute infections such as viral
hepatitis. The anemia induced by oxidant drugs is dose related.
Downloaded from ClinicalKey.com at Universitas Tarumanagara September 19, 2016.
For personal use only. No other uses without permission. Copyright ©2016. Elsevier Inc. All rights reserved.
Drugs Associated with Hemolysis
BOX 121-11 in G6PD Deficiency
Analgesics and antipyretics: acetanilid, aspirin, phenacetin
Antimalarials: primaquine, quinacrine, quinine
Nitrofurans
Sulfa drugs: sulfamethoxazole, sulfacetamide, sulfones
Miscellaneous: naphthalene, fava beans, methylene blue,
phenylhydrazine, nalidixic acid
G6PD, glucose-6-phosphate dehydrogenase.
The older cells lyse at certain drug levels. The oxidant creates
forms of activated oxygen, such as peroxide, that either denature
the hemoglobin or destroy cell membranes. The former process
produces Heinz bodies, which are clumps of denatured hemoglo-
bin found in RBCs early during an episode. These cells are removed
by the spleen. The diagnosis is made by enzymatic screening for
G6PD, but this test cannot be performed immediately after the
hemolytic episode. A 3-week delay avoids a false-negative result
caused by a predominance of young cells. Treatment includes
volume and RBC support as necessary. Avoidance of oxidant drugs
is the only prevention.
Intrinsic Membrane Abnormality.  These abnormalities are
manifested in a number of ways. An altered shape is the main
feature of autosomal dominant hereditary spherocytosis or ellip-
tocytosis. The spleen sequesters these abnormal cells. Clinical
sequelae range from compensated asymptomatic anemia to severe
life-threatening acquired aplastic crises. The diagnosis is made by
reviewing the family history, blood smear, and osmotic fragility
testing. Splenectomy is the treatment of choice for patients requir-
ing therapeutic intervention.
Paroxysmal nocturnal hemoglobinemia is a stem cell defect
causing abnormal erythrocyte, neutrophil, and platelet sensitivity
to complement. It is most often seen as chronic hemolysis, hemo-
siderinuria, leukopenia, and thrombocytopenia. The peripheral
smear is normal and the direct Coombs’ test result is negative. Its
major complication is thrombosis, with a predilection for the
hepatic vein. Normal activation of complement with the use of
sucrose or acid hemolysis (the Ham test) is diagnostic. Transfusion
can be a life-threatening hazard in patients with this disease
because RBC lysis is caused by donor complement. Because of this
danger, only washed packed cells should be used.
Intrinsic Hemoglobin Abnormality.  More than 350 types of
abnormal hemoglobin have been documented. Problems that may
be seen include unstable hemoglobins that appear as Heinz body–
positive anemia, M hemoglobins that fix iron in its ferric or met-
hemoglobin state, and hemoglobins with increased oxygen affinity
that result in tissue hypoxia and erythrocytosis.
Sickle Cell Disease.  Sickle cell disease is the most important
hemoglobinopathy with which the emergency physician should be
familiar. In hospitals serving a large African American population,
it is seen on an almost daily basis. Even experienced physicians
may overlook major complications. Clinicians with less experience
may fail to recognize the complexity of the disease and the many
potential complications.15
Pathophysiology.  Sickle cell disease is genetically determined.
An abnormal allele at the gene loci for hemoglobin β chains pro-
duces altered messenger RNA, which in turn results in replace-
ment of glutamic acid by valine at the sixth position from the
N-terminal end of the β chain. On the molecular level, this change
causes an interlocking of the affected chain with adjacent hemo-
globin in the deoxygenated state. This connection causes the for-
mation of bundles of parallel rods called tactoids, polymers that
grow to form a p-crystalline gel, and then a crystal. Gel formation
is facilitated by low pH and reduced by the presence of other
hemoglobins, such as HbF. The result is a sickled cell that is less
 Chapter 121 / Anemia, Polycythemia, and White Blood Cell Disorders   1597
deformable, an increase in the viscosity and sludging tendency of
blood, and the sequestration of RBCs in the spleen and liver. These
changes may occur when smaller amounts of polymer do not
result in a sickled cell and are associated with an RBC membrane
leak. The clinical complex of vaso-occlusive events, chronic hemo-
lysis, thrombosis, and organ injury is derived from this pathologic
process. Patients with sickle cell disease generally fall into two
phenotypic groups: hemolysis phenotype and vaso-occlusion phe-
notype. These groups are not genetically determined, and it is still
unknown why some people fall into one group versus the other.
Patients prone to hemolysis typically do not have pain, stroke, or
acute chest syndrome; instead, they typically have pulmonary
hypertension and leg ulcers. Their hemoglobin tends to be very
low but their LDH is usually high. Patients with the vaso-occlusion
phenotype typically have pain, acute chest syndrome, and stroke;
they have a higher hemoglobin or high WBC level and lower LDH
and indirect bilirubin concentrations.
The globin in hemoglobin is made up of two pairs of identical
polypeptide globin chains. Each person has two non–sex-linked
gene foci for β-globin chains, one from each parent. Normal indi-
viduals express six different types of hemoglobin from varying
globin chain combinations: three embryonic hemoglobins, HbA
(α2β2), HbA2 (α2δ2), and HbF (α2γ2). Embryonic hemoglobins are
expressed only in utero, and after 6 months of age, HbA accounts
for more than 95% of hemoglobin in a normal individual. The
sickle syndromes result from mutations in the β-globin gene.
Instead of HbA (α2β2), an abnormal hemoglobin HbS is produced.
Embryonic and fetal hemoglobins do not contain β-globin; thus
there are no clinical manifestations in early infancy. As their pro-
duction declines, normal HbA (α2β2) cannot be produced, and
symptoms develop.
In sickle cell trait (HbAS), the patient is heterozygous and only
one parent contributes the abnormal S allele. In each cell approxi-
mately 40% of the hemoglobin is HbS. Sickle disease (HbSS) is
homozygous, and more than 85% of the hemoglobin is HbS.
Because a parent may contribute alleles other than S, a wide
number of variants can exist. Two clinically important S variants
are sickle cell–β-thalassemia and sickle cell–hemoglobin C disease.
Therefore, not all hemoglobinopathies that cause sickling are HbS.
In addition, HbSS is not limited to the African American popula-
tion. Up to 10% of patients with various sickling disorders are not
ethnically African American.16,17
The sickle cell trait is found in 8 to 10% of African Americans.
The diagnosis is usually made after sickle cell screening (Sickledex)
and a characteristic result on hemoglobin electrophoresis. Most
individuals with sickle cell trait are asymptomatic but can present
with spontaneous hematuria, renal papillary necrosis, splenic
infarction, venous thromboembolism, traumatic hyphema, exer-
tional rhabdomyolysis, and exertional sudden death.15,18,19 Recent
literature suggests that pregnancy in women with sickle cell trait
is not associated with an increased risk of adverse events.20
In patients with sickle cell trait who have eye trauma, serial
tonometry and observation are indicated to monitor for ocular
complications.
Clinical Features.  Sickle cell disease can be a recurrent, painful,
and frustrating problem for both patients and physicians. A study
suggests that as many as 35% of a sickle cell population are
recurrent emergency department users.21 Sickle cell disease is
characterized by two major clinical features, hemolysis and acute
vaso-occlusive events. The hallmark manifestation of sickle cell
disease and the most common reason for emergency department
visits is the painful vaso-occlusive crisis. Preceding infection, cold
exposure, and stress such as trauma are all potential precipitating
factors. Many episodes are thought to be spontaneous. The painful
crisis is believed to have its origin in tissue ischemia caused by
increased viscosity, sludging, and microvascular obstruction as a
result of irreversibly sickled cells. Sludging and vascular blockage
Downloaded from ClinicalKey.com at Universitas Tarumanagara September 19, 2016.
For personal use only. No other uses without permission. Copyright ©2016. Elsevier Inc. All rights reserved.
cause stasis, deoxygenation, and local acidosis, which promote the
vicious circle of continued sickling. The pain is commonly deep
and aching and is most often found in the abdomen, chest, back,
and extremities. The disease may mimic an acute abdomen (e.g.,
cholecystitis), pulmonary embolus, renal colic, or other painful
problems. A directed history that relates this pain pattern to previ-
ous sickling episodes, a careful repeated physical examination, and
specific organ-related laboratory tests are all the physician has to
differentiate “uncomplicated” crises from a more serious patho-
logic condition. Children may be seen more often with skeletal
crises leading to bone deformities. In these cases, osteomyelitis and
bone infarct needs to be differentiated.22
Neurologic complications can occur and include transient isch-
emic attacks, cerebral infarction, spinal cord infarction, vestibular
hearing problems, and hearing loss.23 Neurologic complications
occur in 25% of patients with sickle cell anemia by the time they
are 45 years old; 13% demonstrate infarction or ischemia in the
absence of symptoms.24 Transcranial Doppler study may be useful
in identifying individuals with sickle cell disease who are at risk
for stroke.25 The use of exchange blood transfusions with the goal
of hemoglobin S less than 30% can reduce the risk of cerebrovas-
cular events by 92%.26 In the setting of an acute stroke, exchange
transfusion is recommended with the goals of hemoglobin S of
less than 30% and a total hemoglobin level limited to 10 g/dL.27,28
Tissue plasminogen activator (tPA) should be considered in adult
sickle cell disease patients with acute nonhemorrhagic strokes. The
use of tPA in this setting is the same as for acute stroke without
sickle cell disease.28
Acute chest syndrome is the most common pulmonary disease
associated with sickle cell disease and one of the most common
causes of death.29 It is a common cause of hospitalization in sickle
cell disease, second only to vaso-occlusive crisis. Patients with
acute chest syndrome have fever, cough, chest pain, dyspnea, and
new infiltrates on the chest radiograph. The pathophysiologic
mechanism of the syndrome is not well understood, but it may be
a specific form of acute lung injury. The injury is postulated to be
related to pulmonary microvascular sludging, infarction of pul-
monary parenchyma, and bone marrow fat embolization from
infarcted bone. Macrovascular pulmonary embolism and infec-
tion may also have a pathogenetic role. Although the causes of
acute chest syndrome are uncertain, approximately 54% of the
cases are associated with infection, including Mycoplasma and
Chlamydia.30 The differential diagnosis includes pneumonia, pul-
monary embolism, congestive heart failure, and adult respiratory
distress syndrome. No definitive diagnostic study is available, and
diagnosis is based on the presence of the clinical features and
exclusion of other pulmonary causes, as mentioned in the differ-
ential diagnosis. Management is primarily supportive and consists
of hydration, analgesia, incentive spirometry, maintenance of
adequate oxygenation and ventilation, and empirical antibiotics.
Approximately 13% of patients will have respiratory failure severe
enough to require mechanical ventilation. Antibiotic choice is
similar to that for pneumonia in other populations. Exchange
blood transfusions, as used in a similar fashion with acute stroke,
are often used and have been associated with better gas exchange
in acute chest syndrome.31,32 However, there are no randomized
controlled studies demonstrating an improvement in outcome
with the transfusions.
Although most of the diagnostic and therapeutic problems of
sickle cell disease are related to vaso-occlusive crises, other serious
complications should be anticipated. Sickle cell disease is a chronic
hemolytic state with reasonably compensated hematocrit values
in the 20 to 30% range and elevated reticulocyte counts. This
compensated balance may be disrupted by a rare iron deficiency
or, more commonly, by folate deficiency. A potentially life-
threatening aplastic crisis may be seen as a result of suppression
of erythropoiesis by an acute postinfectious condition or folate
1598   PART III  ◆  Medicine and Surgery / Section TEN • Hematology and Oncology
Table 121-7 Organ Damage Seen in Sickle Cell Disease
ORGAN OR SYSTEM INJURY
Skin Stasis ulcer
Central nervous system Cerebrovascular accident
Eye Retinal hemorrhage, retinopathy
Cardiac Congestive heart failure
Pulmonary Intrapulmonary shunting, embolism, infarct,
infection
Vascular Occlusive phenomenon at any site
Liver Hepatic infarct, hepatitis resulting from
transfusion, hepatic sequestration,
intrahepatic cholestasis
Gallbladder Increased incidence of bilirubin gallstones
caused by hemolysis
Spleen Acute sequestration
Urinary Hyposthenuria, hematuria
Genital Decreased fertility, impotence, priapism
Skeletal Bone infarcts, osteomyelitis, aseptic necrosis
Placenta Insufficiency with fetal wastage
Leukocytes Relative immunodeficiency
Erythrocytes Chronic hemolysis
deficiency. This aplastic condition is suspected when the hemo-
globin level falls 2 g/dL or more from previous stable levels and
the reticulocyte count remains low (<2%).
Finally, children may have an acute splenic sequestration syn-
drome. This syndrome involves acute splenic enlargement from
increased intrasplenic sickling and obstruction. The child may
demonstrate lassitude and be in shock. Each of these conditions
may result in a rapidly falling RBC count and progressive symp-
toms of anemia. Patients with HbSS are also subject to all other
causes of anemia, such as hemolysis from G6PD deficiency. An
increased susceptibility to infection is well documented
with HbSS.
In infancy, an increased incidence of sudden death may be
related to pneumococcal sepsis and meningitis. A WBC count and
blood cultures should be performed on all febrile children with
sickle cell anemia. HbSS patients who are younger than 2 years
and have associated temperatures of 39.5° C or higher and WBC
counts greater than 20,000/mm3 should be given intravenous anti-
biotics immediately. Adults with fever require careful evaluation
and laboratory assessment, including appropriate cultures. Early
institution of appropriate antibiotics, such as ceftriaxone 1 to 2 g,
adult dose, intravenously or intramuscularly, is necessary in
patients with a discernible source of infection. In children and
adults, infections with Staphylococcus and Pneumococcus species
and Haemophilus influenzae are particularly common.33 An
increased incidence of Salmonella osteomyelitis also occurs.34 The
origin of this related immunologic deficiency is believed to be
multifactorial, involving functional asplenia, poorly migrating
neutrophils, and decreased opsonin production.34
Major, chronic organ damage in patients with sickle cell
anemia is common. A cross section of these problems is listed
in Table 121-7. These associated conditions should be quickly
reviewed every time a patient with sickle cell anemia enters the
emergency department. The leading causes of death in HbSS
patients are cardiopulmonary disease, chronic renal failure, stroke,
and infection.15
Diagnostically, most patients with HbSS seen in the emergency
department are well known with defined pain patterns. Because
Downloaded from ClinicalKey.com at Universitas Tarumanagara September 19, 2016.
For personal use only. No other uses without permission. Copyright ©2016. Elsevier Inc. All rights reserved.
Figure 121-10.  Sickle cells. (From Hoffbrand AV, Pettite JE: Color
Atlas of Clinical Hematology, 3rd ed. London, Mosby, 2000:103.)
of a slow but longer growth period caused by the delayed onset of
puberty, adult patients with HbSS often have a youthful appear-
ance and long, thin extremities. In a patient with suspected sickle
cell disease, inquiry should be made into the family history, previ-
ous pain episodes, and symptoms relative to chronic anemia, sus-
ceptibility to infection, and ischemic organ damage. Table 121-7
suggests an outline to follow for the physical examination.
Most patients, other than those with mild pain crisis, should
have a complete blood count performed, and current blood levels
should be compared with those of previous visits. A reticulocyte
count is recommended whenever the patient’s hemoglobin level
has decreased by 2 g/dL from baseline. In sickle cell disease, the
typical absolute reticulocyte count is three or four times the upper
limit of normal. A reticulocyte count 3% or lower than the patient’s
usual value may suggest an aplastic crisis. A reticulocyte count
greater than 12%, particularly if it is accompanied by numerous
nucleated RBCs, may indicate rapid hemolysis. Other laboratory
tests are selected on the basis of potential organ complications.
Unfortunately, no test is available that detects whether a patient is
in a crisis. Currently, this difficult task is based on clinical grounds.
In new cases, the peripheral smear may show sickled cells (Fig.
121-10), and a sickle cell screening test with Sickledex may help.
Definitive diagnosis of sickle cell disease is aided by hemoglobin
electrophoresis.
Management.  The antisickling agent hydroxyurea reduces the
frequency of painful crises in adults with a history of three or more
crises annually. The beneficial effects of hydroxyurea in sickle cell
disease are assumed to be due to induction of hemoglobin F, but
additional mechanisms may be operative. Hydroxyurea can reduce
the incidence of acute painful crisis as well as increase survival in
sickle cell disease. However, the effects of hydroxyurea can take
weeks to be appreciated, and it is not routinely recommended for
acute episodes.35,36 Other agents, including clotrimazole, magne-
sium, 5-azacitidine, erythropoietin, and butyric acid, may have a
future role in therapy.37,38 Bone marrow transplantation offers the
only current cure for sickle cell disease and is associated with
survival rates greater than 90% and disease-free survival rates of
80 to 90%. However, the role of bone marrow transplantation in
sickle cell disease remains uncertain because of the inability to
predict which patients will benefit, limited patient eligibility as
a result of advanced pulmonary and neurologic vasculopathies,
and concerns related to transplantation mortality and treatment-
induced malignant neoplasms.37,38
 Chapter 121 / Anemia, Polycythemia, and White Blood Cell Disorders   1599
Current therapies, including rest, adequate nutrition, hydration,
oxygenation, analgesia, transfusion, and therapy for infection, are
directed toward symptomatic relief and attempts to stop the cycle
of deoxygenated sickling and intravascular sludging. Most patients
with sickle cell anemia are mildly dehydrated because of difficulty
in concentrating urine. Fluid replacement can be oral or intrave-
nous, and the emergency physician should be aware of the poten-
tial for congestive heart failure in patients past their second decade.
A recommended starting solution is 5% dextrose in half-normal
saline at a rate not to exceed 1.5 times maintenance.15,39 Oxygen
through a nasal cannula at 2 to 4 L/min may help hypoxic patients
and may be given to any patient with HbSS as a low-risk treatment
modality with potential benefit.
Analgesia is a major benefit and essential early therapy for acute
sickle cell crisis. Because a small subgroup of patients repeatedly
and frequently seek care in the emergency department, emergency
department caregivers may become understandably suspicious of
needs and motivations. Care protocols are advised to ensure rapid
appropriate treatment. Many emergency physicians caring for
large populations of sickle cell patients have developed protocols
to establish better physician-patient rapport and to lessen the
chance of narcotic addiction and manipulation. The following is a
protocol for severe pain in adults and children weighing more than
50 kg: patients are evaluated, treated with oxygen and hydration,
and given intravenous morphine sulfate, 5 to 10 mg every 2 to 4
hours, or intravenous hydromorphone, 1.5 mg every 3 to 4 hours.
For children weighing less than 50 kg, intravenous bolus doses of
morphine sulfate, 0.1 to 0.15 mg/kg, can be given every 2 to 4
hours, or intravenous hydromorphone, 0.015 to 0.020 mg/kg, can
be given every 3 to 4 hours.28 At 4 to 6 hours, the patient is allowed
to decide whether inpatient or outpatient therapy is desired. Out-
patient therapy includes 4 to 6 days of an effective oral analgesic.
A 40-mg dose of oral morphine sulfate or equivalent is given 1 or
2 hours before the infusion is stopped. Such a protocol may bring
uniformity to the patient’s expectations for care and the physician’s
decisions about therapy and admission. Its major disadvantage has
been a tendency to treat patients automatically rather than closely
considering the potential acute complications of sickle cell disease.
No standard pain management exists for sickle cell disease. A
variety of analgesics (nonsteroidal anti-inflammatory drugs,
mixed opioid agonist-antagonists, and opiates), dosages, and
timing intervals may be chosen. Because many sickle cell disease
patients can have varying degrees of hepatic or renal dysfunction,
acetaminophen and nonsteroidal anti-inflammatory drugs should
be used with caution.28 Because many patients with acute pain
episodes are undertreated, the most important aspect of pain man-
agement in these patients is a consistent, thorough, and attentive
approach that offers true pain relief.39
Blood transfusion has a well-accepted role in sickle cell anemia.
Selected use can decrease the chronic transfusion problems of
antigen sensitization, iron overload, and hepatitis. Aplastic or
splenic sequestration crises may necessitate transfusion. Serial
hemoglobin values and reticulocyte counts should be obtained
during hospitalization. Whereas the overall goal of simple transfu-
sion therapy for symptomatic anemia is a hemoglobin level no
higher than 10 g/dL, transfusion should not be used to treat
asymptomatic patients, regardless of hemoglobin value.40
Priapism is a painful complication of sickle cell disease and may
lead to impotence. First-line therapy for priapism lasting longer
than 2 hours is aspiration of blood from the corpus cavernosum
and irrigation with an alpha-adrenergic agent (e.g., phenyleph-
rine). Surgical management is reserved for patients who fail to
respond to aspiration and irrigation.41 Aspiration and irrigation
of the corpus cavernosum can be difficult and time-consuming.
This therapy is best reserved for urologic consultation. The use of
exchange transfusions in the treatment of priapism is controver-
sial but appears to have no current role.41
Downloaded from ClinicalKey.com at Universitas Tarumanagara September 19, 2016.
For personal use only. No other uses without permission. Copyright ©2016. Elsevier Inc. All rights reserved.
Exchange transfusions are recommended for patients, particu-
larly children, with cerebrovascular accidents. Acute symptoms
may be reversed and the frequency of recurrence decreased with
a regulated 3- or 4-week transfusion program. The goal is to sup-
press reticulocytosis and to decrease the HbS level to less than
25%. Rarely, transfusions are given for control of bone or visceral
crises. This is not an emergency department procedure and is
considered only after hematologic consultation. Prophylactic
transfusions to dilute HbS levels are also recommended in preg-
nancy and before major surgery.40 As discussed before, for stroke
in children, acute exchange transfusion is the treatment; for adults,
the treatment is tPA.
A number of other therapies are being tested for both prophy-
laxis and crisis management, including supplemental zinc, induced
hyponatremia, gelation inhibitors, membrane-active agents, and
gene manipulation. Poloxamer 188 is an artificial surfactant with
hemorheologic and antithrombotic properties. Although the
mechanism of action of this agent is not fully understood, it
improves microvascular blood flow by reducing blood viscosity
and adhesive frictional forces. In clinical trials of sickle cell patients
with acute painful crisis, poloxamer reduced the total narcotic
requirement, duration of pain, and pain intensity.42
Sickle Cell–β-Thalassemia.  Sickle cell–β-thalassemia disease is
seen most commonly in people of Mediterranean descent. The
severity of the disease is related to the concentration of HbS in
RBCs and the decrease in MCHC. It should be considered in a
patient with a low MCV and a positive response on sickle prepara-
tion. It is generally a milder form than homozygous HbSS but can
be as severe as sickle cell disease. HbSC disease falls between HbSS
and HbS-thalassemia in terms of severity. In addition to many of
the complications of HbSS, HbSC disease has an increased inci-
dence of eye hemorrhage and pregnancy complications and may
cause splenomegaly. The peripheral smear demonstrates a combi-
nation of sickled cells and normocytic target cells.
Extrinsic Alloantibodies.  Alloantibodies are formed in re-
sponse to foreign RBC antigens. In the case of the ABO system,
these antibodies are preformed. The ABO system is one of the
most important RBC wall antigens. ABO incompatibility resulting
in donor cell destruction by the recipient’s alloantibodies can be
a life-threatening reaction. These antibodies are IgM in nature and
can act as a hemolysin, both agglutinating RBCs and fixing com-
plement and consequently causing intravascular hemolysis.
The Rh system is another set of antigens on the RBC. This
system is unique in that individuals do not have antibodies that
correspond to antigens in the Rh system unless they have been
sensitized by previous exposure to antigens that they lack. The
antibodies produced are IgG in nature, and they accelerate extra-
vascular destruction of RBCs by the spleen and liver. Most auto-
immune antibodies are directed toward antigens in the Rh
system.
Extrinsic Autoantibodies.  Evaluation of autoimmune hemoly-
sis is as complex as its origin. The major feature of autoimmune
hemolysis is the production of an IgG or IgM antibody to an
antigen present on the RBC membrane. Why the body responds
in this manner is unknown. IgM antibodies can agglutinate, fix
complement, and act as intravascular hemolysins. IgG antibodies
may fix complement to the cell but do not usually complete the
hemolysis process. These IgG- or C3-labeled cells undergo acceler-
ated extravascular destruction. The direct antiglobulin test is
useful in revealing these labeled cells.43
Autoimmune hemolytic anemias are acquired disorders, with
40 to 50% being idiopathic. The remainder are associated
with a number of diseases (Box 121-12). Classification of autoim-
mune hemolytic anemias is based on the optimal temperature at
which the antibody reacts with the RBC membrane. Therefore,
there are warm-reacting (>37° C) and cold-reacting (<37° C)
antibodies.
1600   PART III  ◆  Medicine and Surgery / Section TEN • Hematology and Oncology
Diseases Associated with Autoimmune
BOX 121-12 Hemolytic Anemia
Neoplasms
Malignant: chronic lymphocytic leukemia, lymphoma, myeloma,
thymoma, chronic myeloid leukemia
Benign: ovarian teratoma, dermoid cyst
Collagen Vascular Disease
Systemic lupus erythematosus
Periarteritis nodosa
Rheumatoid arthritis
Infections
Mycoplasma
Syphilis
Malaria
Bartonella
Virus: mononucleosis, hepatitis, influenza, Coxsackievirus,
cytomegalovirus
Miscellaneous
Thyroid disorders, ulcerative colitis
Drug immune reactions
Warm-reacting antibodies are characterized by a higher inci-
dence in younger patients (30-60 years), predominance in women,
variable complement fixation, and positive direct antiglobulin test
result for IgG. Cold-reacting antibodies, or cold agglutinins, are
seen predominantly in men and older patients (50-80 years)
and with IgM complement fixation. They may also be found in
patients with infectious mononucleosis, Mycoplasma infection,
and lymphoma. Hemolysis may be intravascular and extra­
vascular, and the direct antiglobulin test result is positive for
complement.
Clinically, a patient with immune hemolytic anemia has the
signs and symptoms of anemia and, often, splenomegaly. Sphero-
cytosis and reticulocytosis are noted in the blood smear. The direct
antiglobulin test result is positive in 90% of cases. The strength of
the direct antiglobulin test result does not correlate with the sever-
ity of the hemolysis because the Coombs’ reaction is an antibody
function different from hemolysis or stimulation of reticuloendo-
thelial sequestration. In patients with newly diagnosed, reticulo-
cytopenic or severe hemolytic anemia, the emergency physician
may need to institute transfusion therapy. Compatible blood may
be almost impossible to find because the antibody can react with
almost all donors. The most compatible donor cells in terms of
the ABO and Rh systems should be transfused with the knowledge
that they will be no more compatible than the patient’s own blood
cells. If emergency blood transfusion is required, type-specific or
type O blood (Rh-positive for men; Rh-negative for women of
childbearing age) is indicated as well as prednisone or its equiva-
lent in a dose of 1 mg/kg. Prednisone is believed to produce an
improvement in 60% of patients with warm antibody reactions.
Splenectomy and immunosuppressive therapy are also effective
in treating these reactions. Cold agglutinin hemolytic anemia may
be self-limited, as after infectious mononucleosis. Other forms
respond well to cold avoidance, variably to immunosuppressive
agents, but poorly to steroids and splenectomy. Death commonly
results from uncontrolled hemolysis, the underlying primary dis-
order, and pulmonary embolism.43
Drug-induced hemolytic anemia may be difficult to diagnose.
The emergency physician should know the drugs most often asso-
ciated with this Coombs’-positive phenomenon and realize that
the result of this test is sometimes positive only in the drug’s
presence. Common drugs and mechanisms of action are listed in
Box 121-13.44
Extrinsic Mechanical Causes.  Hemolysis may be caused
by trauma to RBCs. The peripheral smear may demonstrate
Downloaded from ClinicalKey.com at Universitas Tarumanagara September 19, 2016.
For personal use only. No other uses without permission. Copyright ©2016. Elsevier Inc. All rights reserved.
Drugs Associated with Immune
BOX 121-13 Hemolytic Anemia
Hapten type with antibodies to the drug
Complement-fixing antibody: quinidine, quinine, phenacetin,
ethacrynic acid, p-aminosalicylate, sulfa drugs, oral
hypoglycemic agents
Non–complement-fixing antibody: penicillin dosages >20
million units/day
Autoimmune type with antibodies to the RBC membrane:
D-methyldopa, L-dopa, mefenamic acid, chlordiazepoxide
Cephalosporins at dosages >4 g/day may cause hemolysis by
direct membrane injury
schizocytes or fragmented cells, which immediately raise the sus-
picion of traumatic injury (see Fig. 121-8). Microangiopathic
hemolytic anemia, cardiac trauma, and exercise-induced hemo-
globinemia are the most commonly encountered forms of trau-
matic hemolysis.
Microangiopathic hemolytic anemia is a form of microcircula-
tory fragmentation by threads of fibrin deposited in the arterioles.
An underlying disease is inevitably present. It may be found in
renal lesions such as malignant hypertension and preeclampsia,
vasculitis, thrombotic thrombocytopenic purpura, disseminated
intravascular coagulation, and vascular anomalies. The signs and
symptoms are those of intravascular hemolysis. Treatment is
directed at the causative disease.
Cardiac trauma to RBCs results from increased turbulence. It
may be found in patients with prosthetic valves, traumatic arte-
riovenous fistula, aortic stenosis, and other left-sided heart lesions.
Surgical correction may be necessary. Supportive therapy with an
iron supplement is usually required.
March hemoglobinemia is a form of trauma caused by breaking
of intravascular RBCs by repetitive pounding. Soldiers, marathon
runners, and anyone with repetitive striking against a hard surface
may incur this problem. Reassurance and a change in the patient’s
pattern of activity are the recommended therapy.45
Environmental Causes.  Hemolysis may be seen in cases of
severe burns, freshwater drowning, and hyperthermia. Toxic
causes of hemolysis have been documented to be of animal origin,
such as brown recluse spider and some snake bites; vegetable
origin, such as castor beans and certain mushrooms; and mineral
origin, such as copper. Certain infections are associated with
hemolytic states, including malaria, Bartonella infection, and
Clostridium sepsis.
Abnormal Sequestration.  Hypersplenism may be caused
by any disease that enlarges the spleen or stimulates the reticulo-
endothelial system. An unfortunate cycle can be set up in which
the enlarged spleen traps more blood components and grows
larger. It is usually seen as splenomegaly with pancytopenia and
marrow hyperactivity. Chromium-labeled RBCs may demonstrate
increased trapping in the spleen. Therapy for symptomatic or
severe disease is splenectomy. Adults usually tolerate splenectomy
well, but children should be approached conservatively because
the risk of postsplenectomy life-threatening sepsis is increased
significantly.
POLYCYTHEMIA
Definition
Polycythemia is a term commonly used for erythrocytosis (i.e.,
increased number of RBCs). This disorder is seen occasionally in
emergency medicine but rarely in a life-threatening manner that
requires emergency intervention.
 Chapter 121 / Anemia, Polycythemia, and White Blood Cell Disorders   1601
Figure 121-11.  Polycythemia vera. Facial plethora and conjunctival suffusion in a 40-year-old woman (hemoglobin, 19.5 g/dL). (From Hoffbrand
AV, Pettite JE: Color Atlas of Clinical Hematology, 3rd ed. London, Mosby, 2000:248.)
Pathophysiology
Erythropoiesis is controlled by the kidney-produced glycoprotein
hormone erythropoietin. It is activated in the liver and regulates
the committed erythropoietic stem cell. Its major stimulant is
tissue hypoxia. Neoplastic dysfunction of bone marrow may also
result in an elevated absolute RBC count.
The major complication of polycythemia is related to the
increase in blood viscosity associated with increased RBC numbers.
As the hematocrit rises past 60%, viscosity increases in an almost
exponential manner. This condition increases the possibility of
reduced tissue flow, thrombosis, and hemorrhage. This hazard is
usually blunted to a degree by an associated increase in blood
volume and some viscosity-reducing vascular dilation.46
Clinical Features
The history may range from only mild headaches to a full-blown
syndrome of hypervolemia (vertigo, dizziness, blurred vision,
and headache), hyperviscosity (venous thrombosis), and platelet
dysfunction (epistaxis, spontaneous bruising, and gastrointestinal
bleeding).
On physical examination, the skin and mucous membrane
manifestations of the elevated RBC count are often readily
observed. Plethora, engorgement, and venous congestion are com-
monly noted (Fig. 121-11). Other systems to be examined include
the fundus for venous congestion, the abdomen for evidence of
splenomegaly, and the cardiopulmonary system for signs of con-
gestive heart failure. Uterine, central nervous system, renal, and
hepatic tumors should be sought in that these are associated with
secondary polycythemia. An elevated RBC count, usually greater
than the hematocrit, defines the disorder. It results in a low MCV,
usually related to low serum iron and iron stores. Specific labora-
tory testing is discussed in the section on differential diagnosis.
Differential Diagnosis
Polycythemia is classified as apparent, primary, or secondary (Box
121-14). Apparent polycythemia is a decrease in plasma volume
such as found with dehydration. The RBC volume does not exceed
the upper limit of normal. Although it is a questionable diagnostic
entity, “stress” polycythemia is the tendency for an elevated hema-
tocrit and is found in overweight, hypertensive, and overstressed
middle-aged men. Increased cigarette smoking with its associated
increased carboxyhemoglobin level is considered to be partially
responsible. The symptoms are minimal, and treatment is
Downloaded from ClinicalKey.com at Universitas Tarumanagara September 19, 2016.
For personal use only. No other uses without permission. Copyright ©2016. Elsevier Inc. All rights reserved.
Causes of Apparent and Secondary
BOX 121-14 Polycythemia
Appropriately increased erythropoietin caused by tissue hypoxia
Congenital heart disease with a right-to-left shunt
Pulmonary disease (e.g., bronchial-type chronic obstructive
pulmonary disease)
Carboxyhemoglobinemia
High-altitude acclimatization
Decreased tissue oxygen release from hemoglobinopathies
with high oxygen affinity
Inappropriate autonomous erythropoietin production
Renal origin: carcinoma, hydronephrosis, cyst
Other lesions: uterine fibroids, hepatoma of adrenal origin,
cerebellar hemangioma
Congenital overproduction
Pure or essential erythrocytosis
AIDS and zidovudine treatment
confined to moderation, weight loss, and blood pressure control.
The risk of vascular occlusive complications is minimal. The
hematocrit is usually less than 60% and RBC mass measurements
are normal.47
Primary polycythemia vera is a myeloproliferative disorder
found predominantly in middle-aged or older patients. It may
have all the clinical components of polycythemia. Nonspecific
symptoms are reported in up to 30% of patients and include
headache, weakness, dizziness, excessive sweating, and pruritus.
The most serious problems are thrombotic episodes (cerebrovas-
cular accident, myocardial infarction, and deep venous thrombo-
sis), bleeding, and bruising. Primary polycythemia vera is a disease
that involves all cell lines—hematopoietic stem, erythroid, granu-
locytic, and megakaryocytic. Elevated hemoglobin or hematocrit
and RBC mass is present in virtually all patients. However, a plate-
let count above 400,000/µL occurs in 60% and a WBC count above
12,000/µL in 40%. Bone marrow cellularity was increased in 90%
of patients, and storage iron was absent from the marrow in 94%.
The diagnostic criteria used by the Polycythemia Vera Study
Group are listed in Box 121-15.47
Polycythemia vera may be satisfactorily treated by phlebotomy
as necessary. The reduced hematocrit improves some symptoms,
but neither the leukocyte nor the platelet count is decreased.
Maintenance of the hematocrit at less than 55% is recommended
to decrease hypervolemia and hyperviscosity. Complications
necessitating additional therapy include hyperuricemia, refractory
1602   PART III  ◆  Medicine and Surgery / Section TEN • Hematology and Oncology
BOX 121-15 Diagnostic Criteria for Polycythemia Vera*
Category A
Increased RBC mass
In men: hemoglobin >18.5 g/dL
In women: hemoglobin >16.5 g/dL
Normal arterial oxygen saturation (>92%)
Splenomegaly
Category B
Thrombocytosis: platelets >400,000/mm3
Leukocytosis: WBC count >12,000/mm3 (with no fever or
infection)
Leukocyte alkaline phosphatase score >100
Vitamin B12 >900 pg/mL, unbound vitamin B12–binding capacity
<2200 pg/mL
*For polycythemia vera to be diagnosed, either all three criteria in category A or
the first two criteria in category A along with any two criteria in category B needs
to be present.
increased RBC mass, severe pruritus, excessive splenomegaly, and
thrombocytosis. Additional therapy may consist of hydroxyurea,
busulfan, chlorambucil, interferon alfa, anagrelide, or radioactive
phosphorus (32P). Studies suggest no improvement in long-term
survival with the addition of these treatments.48 The natural
history of the disease is that it burns out during a period of 15 to
20 years. However, myelofibrosis with myeloid metaplasia may
develop. In 10% of cases, acute leukemia develops with a rapid
and poorly responsive downhill course. The 15-year survival for
polycythemia vera is 65%.49 The most common causes of death
are thrombosis (29%), hematologic malignant neoplasms (23%),
nonhematologic malignant neoplasms (16%), hemorrhage, and
myelofibrosis with myeloid metaplasia.
Secondary polycythemia is classified first according to the
appropriate erythropoietin response to abnormal tissue oxygen
levels. This group of disorders may be ruled out by normal mea-
sured arterial oxygen saturation. Second, inappropriate autono-
mous erythropoietin production is considered. This condition
can be assessed with an erythropoietin assay. Because of a strong
association with renal pathologic conditions, computed tomogra-
phy should be used to evaluate a patient with a suspected inap-
propriate erythropoietin response. Most patients with secondary
polycythemia have no central nervous system symptoms or sple-
nomegaly. Because erythropoietin stimulates only the red cell
pathway, these patients have normal WBC and platelet counts.
Management
The emergency treatment of any form of symptomatic polycythe-
mia is phlebotomy. Usually, not more than 500 mL of blood is
removed as the volume is replaced with a comparable amount of
saline. No hemodynamic compromise should occur if this proce-
dure is performed slowly. In true emergencies, up to 1 to 1.5 L of
blood may be removed during a 24-hour period. The initial goal
is to lower the hematocrit toward 60%. The final goal is a level less
than 55%. Low-dose aspirin, 80 to 100 mg/day, has been shown
to prevent thrombotic complications in patients with polycythe-
mia vera and can be used in the acute and chronic treatment of
this disorder.50
Disposition
A number of patients with known polycythemia may be managed
by outpatient phlebotomies. Any newly diagnosed or symptomatic
patient should be considered for admission to the hospital for full
evaluation.
Downloaded from ClinicalKey.com at Universitas Tarumanagara September 19, 2016.
For personal use only. No other uses without permission. Copyright ©2016. Elsevier Inc. All rights reserved.
WHITE BLOOD CELL DISORDERS
The WBC count and accompanying differential are the most
common laboratory tests ordered in the emergency department.
It is essential that the basic physiology, pathophysiology, and clini-
cal evaluation of WBCs be understood.
Physiology and Pathophysiology
The series has three morphologically indistinguishable cell types:
B cells (humoral immunity), T cells (cellular immunity), and null
cells. Because lymphocytes can freely leave and return to the cir-
culation, the storage pools are less well defined. Only 5% of the
total lymphocytes in the body are in the circulation. No marginal
pool exists. Leukocytes primarily function extravascularly, and
their function is closely integrated with the other types of white
cells. WBCs reach their site of action through the circulation. The
rate that new cells enter the circulation is usually in equilibrium
with the rate of loss in tissues.
Abnormal cell counts are due to changes in production, the
marginal pool, or the rate of tissue destruction. Just as in anemia
or platelet count abnormalities, the differential diagnosis of
increased (leukocytosis) or decreased (leukopenia) WBC counts
can be organized by processes altering production, destruction,
loss, and sequestration.
The granulocytic and lymphocytic series are the two cell lines
of WBCs. The granulocytic series is primarily involved in phago-
cytic activity. Its origin is the pluripotential stem cells located
in the bone marrow. A subset of these cells differentiates and
matures into the phagocytic cell lines, which include neutrophils,
monocytes, basophils, and eosinophils. Granulocytes are main-
tained in a series of developmental and storage pools. The most
important is the postmitotic storage pool for neutrophils, which
represents 15 to 20 times the circulating population. This pool
contains metamyelocytes, band neutrophils, and mature neutro-
phils (polymorphonuclear neutrophils). The pool can be drawn
on as a ready reserve during rapid consumption of granulocytes.
Circulating neutrophils are subdivided equally into the circulat-
ing neutrophil pool and the marginal pool. The marginal pool
consists of mature cells adherent to the blood vessel walls. These
cells can rapidly enter the circulating pool and cause a substantial
increase, even doubling, of the WBC count. This involvement
does not alter the maturity pattern of the differential count.51
The lymphocytic series matures in lymphoid tissues located in
the bone marrow, thymus, spleen, lymph nodes, and elsewhere.
They are involved in the immune response against foreign
substances.
Normal Values and Influences
One unique problem in WBC disorders is the wide variability in
normal values and the multiple factors influencing them. WBC
counts are generally performed automatically by electrical imped-
ance or optical diffraction techniques. Differential counts are
commonly performed by direct examination of 100 to 500 cells
with the oil immersion lens of the microscope. Automated tech-
niques for all differential counts are becoming more popular,
however. Normal values for the WBC count are listed in Table
121-8. The “normal” count is age dependent until childhood and
may be shifted upward by exercise, gender (women), smoking,
and pregnancy. Decreases in the total WBC count range by 1000
to 1200 cells/mm3 have been noted in the African American
population.51 Laboratory errors may be due to improper sample
preparation, nucleated RBCs, or platelet clumping. The blood
smear differential count may also be influenced by small sample
size, improper cell identification, and age group (children). Dif-
ferential ranges are listed in Table 121-9. One common but easily
 Chapter 121 / Anemia, Polycythemia, and White Blood Cell Disorders   1603
corrected error in laboratory reporting is to give the results in common of the major leukemias (60% acute, 31% chronic lym-
terms of the percentage of cell types. Absolute counts for each phocytic leukemia, and 15% CML), it should be considered in
cell type are more accurate and useful in assessing the risk neutrophilia. Patients with CML are usually older than 40 years
for infection. and have WBC counts greater than 50,000 cells/mm3. The differ-
ential count shows elevated polymorphonuclear neutrophils and
Abnormal Values metamyelocytes. Less often, the basophil and eosinophil counts
are also increased. CML is a stem cell disorder in which the WBC
Because of the wide range of normal values, all abnormal WBC count is elevated and the differential is normal. Mature and inter-
counts should be interpreted in the context of the patient’s condi- mediate granulocytes are overproduced. Platelets may also be
tion. A careful history and physical examination, absolute cell increased, but RBC production is down, thereby resulting in
counts, and review of the peripheral smear differential count are anemia. The patient often complains of fatigue, anorexia, sweat-
the starting points to determine the origins of quantitative WBC ing, and weight loss. Physical findings include pallor, sternal pain
disorders. and tenderness, and splenomegaly (90% of patients; Fig. 121-12).
In the laboratory, decreased leukocyte alkaline phosphatase and
Leukocytosis increased vitamin B12 levels are found, which helps differentiate
CML from other causes of neutrophilia. The Philadelphia chro-
Most cases of leukocytosis are caused by increases in the neutro- mosome (Ph1) is constantly associated with the disease. The
phil or lymphocyte cell lines. Neutrophil leukocytosis (neutro- chronic phase of CML is treated with an alkylating agent (e.g.,
philia) is an absolute neutrophil count greater than 7500 cells/ busulfan) or an antimetabolite (e.g., hydroxyurea). Selected
mm3 and is commonly associated with infection or inflammation patients may benefit from bone marrow transplantation.52
(Box 121-16). Because increased neutrophil destruction is associ-
ated with both of these pathologic processes, bone marrow stores
are drawn on, and the usual ratio of 1 band to 10 neutrophils
increases. This increase is manifested as a “left shift” in the dif-
BOX 121-16  Causes of Leukocytosis
ferential count and represents movement of immature neutrophils Neutrophils (absolute count >7500 cells/mm3)
from the postmitotic pool into the circulation. Inflammation: rheumatoid arthritis, gout
WBC counts can increase without a left shift or an increase in Infection: bacterial most common
band forms by demarginating neutrophils from the vessel walls. It Tissue necrosis: cancer, burns, infarctions
is often seen as a response to stress, exercise, or epinephrine. Severe Metabolic disorders: diabetic ketoacidosis, thyrotoxicosis, uremia
stress can raise the WBC count to 18,000 to 20,000 cells/mm3.51 Rapid RBC turnover: hemorrhage, hemolysis
Myeloproliferative disorders: chronic myeloid leukemia,
polycythemia vera
Chronic Myeloid Leukemia Malignant disease (e.g., gastrointestinal cancers)
Stress: exercise, pain, surgery, hypoxia, seizures, trauma
One of the myeloproliferative causes of neutrophilic leukocytosis Drugs: epinephrine, corticosteroids, lithium, cocaine
is chronic myeloid leukemia (CML). Although it is the least Pregnancy
Heredity or idiopathic disease
Laboratory error: automated counters, platelet clumping,
Normal Ranges for the Blood Leukocyte precipitated cryoglobulin
Table 121-8 Count (cells/mm3) Lymphocytosis (absolute count >9000/mm3,
95% RANGE (AVERAGE ages 1-6 years; >7000/mm3, ages 7-16 years;
AGE AVERAGE VALUE ±2 SD) >4000/mm3, adults)
Viral infection (primary cause): mononucleosis, rubeola, rubella,
1 week 12,200 5,000-21,000
varicella, toxoplasmosis
6 months 11,900 6,000-17,500 Bacterial infection: pertussis, tuberculosis, hepatitis,
cytomegalovirus
12 months 11,400 6,000-17,500
Lymphoproliferative: acute or chronic lymphocytic leukemia
4 years 9,100 5,500-15,500 Immunologic response: immunization, autoimmune diseases,
8 years 8,300 4,500-13,500 graft rejection
Endocrine: hypothyroidism
Adults 7,400 4,500-11,000 Relative lymphocytosis associated with granulocytopenia
Modified from Miale JB: Laboratory Medicine: Hematology, 6th ed. St Louis, Modified from Miale JB: Laboratory Medicine: Hematology, 6th ed. St Louis,
Mosby, 1982. Mosby, 1982.

Table 121-9 Normal Percentage Ranges for the Leukocyte Differential Count in Blood*
AGE SEGMENTED NEUTROPHILS BAND NEUTROPHILS LYMPHOCYTES MONOCYTES EOSINOPHILS BASOPHILS
1 week 34 ± 15 (4100) 11.8 ± 4 (1420) 41 ± 5 (5000) 9.1 (1100) 4.1 (500) 0-4 (50)
6 months 23 ± 10 (2710) 8.8 ± 3 (1000) 61 ± 15 (7300) 4.8 (480) 2.5 (300) 0-4 (50)
12 months 23 ± 10 (2680) 8.1 ± 3 (990) 61 ± 15 (7000) 4.8 (550) 2.6 (300) 0-4 (50)
4 years 34 ± 11 (3040) 8.0 ± 3 (730) 50 ± 15 (4500) 5.0 (450) 2.8 (250) 0-6 (50)
8 years 45 ± 11 (3700) 8.0 ± 3 (660) 39 ± 15 (3300) 4.2 (350) 2.4 (200) 0-6 (50)
Adult 51 ± 15 (3800) 8.0 ± 3 (620) 34 ± 10 (2500) 4.0 (300) 2.7 (200) 0-5 (40)

Modified from Miale JB: Laboratory Medicine: Hematology, 6th ed. St Louis, Mosby, 1982.
*Numbers in parentheses indicate the average number of cells per cubic millimeter.

Downloaded from ClinicalKey.com at Universitas Tarumanagara September 19, 2016.

For personal use only. No other uses without permission. Copyright ©2016. Elsevier Inc. All rights reserved.
1604   PART III  ◆  Medicine and Surgery / Section TEN • Hematology and Oncology
Figure 121-12.  Chronic myeloid leukemia. (From Hoffbrand AV,
Pettite JE: Color Atlas of Clinical Hematology, 3rd ed. London, Mosby,
2000:169.)
The need for urgent therapy in CML is usually related to
hyperuricemia and renal injury or severe anemia and subsequent
angina or heart failure. Rarely, hyperleukocytosis occurs, but the
more mature, “less sticky” cells in CML do not usually cause
problems unless the count exceeds 500,000 cells/mm3. A higher
cell count may cause leukostasis and result in deafness, visual
impairment, pulmonary ventilation-perfusion abnormalities, and
priapism. Treatment involves hydration, leukapheresis, transfu-
sion as necessary, allopurinol to prevent severe hyperuricemia,
and specific chemotherapy (hydroxyurea). Late problems in the
natural history of CML involve progressive loss of cell differentia-
tion and response to therapy. The term blastic crisis represents the
sudden appearance of an acute form of leukemia, which is a rare
substage of the evolving deterioration.52 The condition may occur
in lymphoid or myeloid forms. Blast counts greater than 50,000
cells/mm3 may predispose the patient to the complications of
leukostasis.
Leukemoid Reaction
A leukemoid reaction is a nonleukemic reactive granulocytic leu-
kocytosis that resembles CML but has no associated Ph1 chromo-
some, no absolute increase in basophils and eosinophils, and an
increase in leukocyte alkaline phosphatase. It is difficult to distin-
guish from CML in the emergency department, and both need to
be considered a potential diagnosis in granulocytic leukocytosis.
WBC counts are usually greater than 50,000 cells/mm3. A leuke-
moid reaction may be seen in tuberculosis, Hodgkin’s disease,
sepsis, and metastatic tumor, particularly bronchogenic, gastric,
and renal carcinoma.52
Downloaded from ClinicalKey.com at Universitas Tarumanagara September 19, 2016.
For personal use only. No other uses without permission. Copyright ©2016. Elsevier Inc. All rights reserved.
Lymphocytic Leukocytosis
Lymphocytic leukocytosis (lymphocytosis) is an age-dependent
definition: 9000 cells/mm3, ages 1 to 6 years; 7000 cells/mm3, ages
7 to 16 years; and 4000 cells/mm3, adults. It is seen in a variety of
disorders, primarily infections and lymphoproliferative disease.
In the past, acute and chronic were descriptive terms applied to
lymphocytic neoplasms with respect to survival time of the patient
before present therapy was available. The terms acute and chronic
are currently used to describe the cell maturity, rapidity of onset,
and aggressiveness of therapy.
Chronic Lymphocytic Leukemia.  Chronic lymphocytic leukemia
is primarily a B-cell disorder and is the most common type of
leukemia in the population 50 years or older. Patients initially
complain of fatigue, weight loss, increased susceptibility to infec-
tion, rashes, and easy bruising. The lymph nodes are nontender
and smooth, and they may appear in only one or two areas. Splenic
and hepatic enlargement occurs in more than 50% of patients.
Laboratory support of the diagnosis is an absolute lymphocyte
count greater than 5000 cells/mm3 in adults. Anemia, thrombocy-
topenia, and neutropenia are often found. Autoimmune hemolytic
anemia, a positive direct antiglobulin test result, and other altered
immune system problems are seen. Early therapy may be directed
toward complications of anemia, thrombocytopenia, impaired or
accentuated immune response, or enlarged lymph nodes or spleen.
Leukostasis is seldom seen in chronic lymphocytic leukemia, but
therapy is considered when the total count rises to higher than
200,000/mm3.53
Acute Lymphocytic Leukemia.  Acute lymphocytic leukemia is
most commonly diagnosed in children younger than 10 years. It
is the most frequent malignant neoplasm in children younger than
15 years. The potential for leukostasis increases in acute lympho-
cytic leukemia when the blast count rises above 50,000 cells/mm3.
Oncologic therapy is based on clinical staging and includes che-
motherapy or radiation therapy. Aggressive therapy has improved
childhood survival; current 5-year overall survival rates are esti-
mated at 78 to 85%. This response to treatment has not been
found to the same degree in adults.54,55
Leukopenia
In adults, leukopenia is defined as an absolute blood cell count less
than 4000 cells/mm3. Leukopenia is commonly associated with a
reduction in one cell type, the neutrophil, and this decrease has
the greatest clinical significance. The absolute neutrophil count
is calculated by multiplying the WBC count by the combined
percentage of band and segmented neutrophils. The absolute neu-
trophil count can be classified as mild (1000-1500 cells/mm3),
moderate (500-1000 cells/mm3), or severe (<500 cells/mm3)
according to the risk for infection. The last is a potentially life-
threatening state because the patient is markedly susceptible to
overwhelming infection. The physical signs of infection may be
minimal in severe neutropenia because there are too few cells to
generate a substantial inflammatory or purulent response. Neu-
tropenia may be caused by decreased production, increased
destruction, or movement of circulating neutrophils into marginal
or tissue pools. Until recently, it was most often caused by a
decrease in bone marrow production (Table 121-10). Autoim-
mune neutropenia is also becoming more commonly diagnosed
because it is thought to have a role in acquired immunodeficiency
syndrome.56
A thorough medication history should be taken in all patients
found to have neutropenia. A previous history of neutropenia,
a review of recent infection, and a family history are obtained. The
review of systems focuses on bleeding problems, fatigue, sweats,
weight loss, and autoimmune symptoms. The physical examina-
tion is directed toward sites of infection, lymphadenopathy,
 Chapter 121 / Anemia, Polycythemia, and White Blood Cell Disorders   1605

Linkage of Leukopenia to Phases studies suggest some usefulness in certain clinical situations;
Table 121-10 of Neutrophil Maturation however, the absence of leukocytosis does not exclude the presence
of significant disease. For example, studies evaluating the WBC
MECHANISM EXAMPLE
count for the diagnosis of abdominal pain have found it to be a
Proliferation in Aplastic anemia, leukemia, cancer chemotherapy useful confirming test or helpful in selecting patients for observa-
bone marrow (cyclophosphamide, azathioprine, methotrexate, tion.60 In evaluation of the bacterial infectious potential in febrile
chlorambucil) children, the WBC and differential counts have demonstrated
Drugs: phenothiazines, phenylbutazone,
indomethacin, propylthiouracil, phenytoin, limited usefulness.61 Other biomarkers, such as procalcitonin and
cimetidine, semisynthetic penicillins, sulfonamides C-reactive protein, may have more predictive value.62,63 The test
Infection: viral, tuberculosis, sepsis should be viewed as having limited screening value in the acute
Maturation in Folate or vitamin B12 deficiency, chronic idiopathic
care setting because multiple agents and conditions can increase
bone marrow neutropenia the WBC count.
Starvation Although the WBC count may be nonspecific and nonsensitive,
the differential count may provide helpful information. The abso-
Distribution Hypersplenism: sarcoidosis, portal hypertension,
malaria lute neutrophil count may be more helpful than the total WBC
count in identifying bacterial infection.62,63
Increased use Infection: viral most common (mononucleosis,
rubella, rubeola), Rickettsia organisms,
overwhelming bacterial infection
Autoimmune disease: systemic lupus erythematosus,
AIDS, Felty’s syndrome KEY CONCEPTS
Laboratory error Leukocyte clumping, long delay in performing test ■ Anemia is caused by three basic mechanisms: bleeding,
destruction of red blood cells, and decrease in production of
red blood cells.
■ The use of red blood cell indices and a peripheral blood
smear can help determine the mechanism of anemia.
hepatosplenomegaly, and underlying disease. In patients with ■ One of the most important but often overlooked studies in
severe neutropenia and fever, a full radiologic and direct examina- the evaluation of suspected hemolytic anemia is the
tion of commonly involved areas, such as the chest and urine, peripheral blood smear.
should be performed, and sputum, urine, and blood culture speci- ■ Anemia in the elderly often occurs as an exacerbation of
mens should be obtained. Basic isolation techniques, early admis- preexisting comorbid diseases.
■ Anemia of uncertain etiology should be thoroughly
sion, and consultation with another specialist are recommended.
evaluated. If the patient has no adverse hemodynamic
Specific therapies may be started after cultures and consultation consequences, the evaluation can proceed on an outpatient
are completed. A number of empirical antibiotic regimens are basis.
recommended for febrile patients with neutropenia.57,58 Human ■ Patients with sickle cell disease should be considered to have
granulocyte colony–stimulating factor is often used in the setting an acute pain crisis and treated appropriately until it is
of neutropenia, but it is best done in consultation with a hema- proved otherwise.
tologist.59 Patients with a clear reversible source or without signifi- ■ Acute chest syndrome is one of the most common causes of
cant clinical findings and mild to moderate levels of neutropenia death in sickle cell disease.
may have outpatient follow-up arranged, preferably after discus- ■ Acute transfusion therapy is most useful in sickle cell disease
sion with their physician. associated with acute stroke (in children), acute chest
syndrome, and splenic sequestration.
■ The white blood cell determination in the emergency
RATIONALE FOR SELECTION department has poor sensitivity and specificity for any  
OF WHITE BLOOD CELL AND specific disease.
DIFFERENTIAL COUNTS
The WBC count has not proved to be a highly sensitive or specific The references for this chapter can be found online by
test for the diagnosis of a variety of disease entities. Selected accessing the accompanying Expert Consult website.

Downloaded from ClinicalKey.com at Universitas Tarumanagara September 19, 2016.

For personal use only. No other uses without permission. Copyright ©2016. Elsevier Inc. All rights reserved.
 Chapter 121 / Anemia, Polycythemia, and White Blood Cell Disorders   1605.e1
References
1. Weber P, et al: Anemia in elderly an important diagnostic and
therapeutic problem in geriatric medicine. Adv Gerontol 2009;
22:662-666.
2. Tefferi A: Anemia in adults: A contemporary approach to diagnosis.
Mayo Clin Proc 2003; 78:1274-1280.
3. Olivieri NF: The beta-thalassemias. N Engl J Med 1999; 341:99-109.
4. Borgna-Pignatti C: Modern treatment of thalassemia intermedia. Br J
Haematol 2007; 138:291-299.
5. Rund D, Rachmilewitz E: Beta-thalassemia. N Engl J Med 2005;
353:1135-1139.
6. Galanello R, Campus S, Origa R: Deferasirox: Pharmacokinetics
and clinical experience. Expert Opin Drug Metab Toxicol 2012;
8:123-134.
7. Lucarelli G, Gaziev G: Advances in the allogeneic transplantation for
thalassemia. Blood Rev 2008; 22:53-63.
8. Weiss G, Goodnough LT: Anemia of chronic disease. N Engl J Med 2005;
352:1011.
9. Malouf R, Grimley Evans J: Folic acid with or without vitamin B12 for
the prevention and treatment of healthy elderly and demented people.
Cochrane Database Syst Rev 2008; 4:CD004515.
10. Locatelli F, et al: Cyclosporin A and short-term methotrexate versus
cyclosporin A as graft versus host disease prophylaxis in patients with
severe aplastic anemia given allogeneic bone marrow transplantation
from an HLA-identical sibling: Results of a GITMO/EBMT randomized
trial. Blood 2000; 96:1690-1696.
11. Young NS: Acquired aplastic anemia. Ann Intern Med 2002;
136:534-538.
12. Marsh JC, et al: Guidelines for the diagnosis and management of aplastic
anaemia. Br J Haematol 2009; 147:43-50.
13. Jones M, Ibels L, Schenkel B, Zagari M: Impact of epoetin alfa on
clinical end points in patients with chronic renal failure: A meta-
analysis. Kidney Int 2004; 65:757-765.
14. Packman CH: Hemolytic anemia due to warm autoantibodies. Blood Rev
2008; 22:17-23.
15. Glassberg J: Evidence based management of sickle cell disease in the
emergency department. Emerg Med Pract 2011; 13:1-20.
16. Quinn CT, et al: Prediction of adverse outcomes in children with sickle
cell anemia: A study of the Dallas Newborn Cohort. Blood 2008;
111:544-548.
17. Yanni E, Grusse S, Yang Q, Olney R: Trends in pediatric sickle cell
disease–related mortality in the United States, 1983-2002. J Pediatr 2009;
154:541-545.
18. Tsaras G, Owusu-Ansah A, Boateng FO, Amoateng-Adjepong Y:
Complications associated with sickle cell trait: A brief narrative review.
Am J Med 2009; 122:507-511.
19. Austin H, et al: Sickle cell trait and the risk of venous thromboembolism
among blacks. Blood 2007; 110:908-912.
20. Tita AT, Biggio JR, Chapman V, Neely C, Rouse DJ: Perinatal and
maternal outcomes in women with sickle cell or hemoglobin C trait.
Obstet Gynecol 2007; 110:1113-1119.
21. Aisiku IP, et al: Comparisons of high versus low emergency department
utilizers in sickle cell disease. Ann Emerg Med 2009; 53:587-592.
22. Dampier C, et al: Vaso-occlusion in children with sickle cell disease:
Clinical characteristics and biologic correlates. J Pediatr Hematol Oncol
2004; 26:785-790.
23. Ohene-Frempong K, et al: Cerebrovascular accidents in sickle cell
disease: Rates and risk factors. Blood 1998; 91:288-294.
24. Verduzco LA, Nathan DG: Sickle cell disease and stroke. Blood 2009;
114:5117-5125.
25. Krejza J, et al: Sickle cell disease and transcranial Doppler imaging.
Stroke 2011; 42:81-86.
26. Adams RJ, et al: Prevention of a first stroke by transfusions in children
with sickle cell anemia and abnormal results on transcranial Doppler
ultrasonography. N Engl J Med 1998; 339:5-11.
27. Hulbert ML, et al: Exchange blood transfusion compared with simple
transfusion for first overt stroke is associated with a lower risk of
subsequent stroke: A retrospective cohort study of 137 children with
sickle cell anemia. J Pediatr 2006; 149:710-712.
28. The Management of Sickle Cell Disease. Bethesda, Md: National
Institutes of Health, National Heart, Lung, and Blood Institute, Division
of Blood Diseases and Resources; revised 2004. NIH publication
04-2117.
29. Gladwin MT, Vichinsky E: Pulmonary complications of sickle cell
disease. N Engl J Med 2008; 359:2254-2259.
30. Vichinsky EP, et al: Causes and outcomes of the acute chest syndrome in
sickle cell disease. N Engl J Med 2000; 342:1855-1859.
Downloaded from ClinicalKey.com at Universitas Tarumanagara September 19, 2016.
For personal use only. No other uses without permission. Copyright ©2016. Elsevier Inc. All rights reserved.
31. Turner JM, Kaplan JB, Cohen HW, Billett HH: Exchange versus simple
transfusion for acute chest syndrome in sickle cell anemia adults.
Transfusion 2009; 49:863-868.
32. Alhashimi D, et al: Blood transfusions for treating acute chest syndrome
in people with sickle cell disease. Cochrane Database Syst Rev 2010;
20:CD007843.
33. Battersby AJ, Knox-Macaulay HH, Carrol ED: Susceptibility to invasive
bacterial infections in children with sickle cell disease. Pediatr Blood
Cancer 2010; 55:401-406.
34. Syrogiannopoulos GA, McCracken GH, Nelson JD: Osteoarticular
infections in children with sickle cell disease. Pediatrics 1986;
78:1090-1094.
35. Brawley OW, et al: National Institute of Health consensus development
conference statement: Hydroxyurea treatment for sickle cell disease. Ann
Intern Med 2008; 148:932-937.
36. Steinberg MH, et al: Effect of hydroxyurea on mortality and morbidity
in adult sickle cell anemia: Risks and benefits up to 9 years of treatment.
JAMA 2003; 289:1645-1651.
37. Vichinsky E: New therapies of sickle cell disease. Lancet 2002;
360:629-635.
38. Amrolia PJ, Almeida A, Halsey C, Roberts IA, Davies SC: Therapeutic
challenges in childhood sickle cell disease. Part 1: Current and future
treatment options. Br J Haematol 2003; 120:725-736.
39. Tanabe P, et al: Emergency department management of acute
pain episodes in sickle cell disease. Acad Emerg Med 2007;
14:419-425.
40. Josephson CD, Su L, Hillyer K, Hillyer C: Transfusion in the patient with
sickle cell disease: A critical review of the literature and transfusion
guidelines. Transfus Med Rev 2007; 21:118-133.
41. Montague DK, et al; Members of the Erectile Dysfunction Guideline
Update Panel; American Urological Association: Priapism. Guidelines on
the management of priapism, 2010. Available at www.auanet.org.
42. Gibbs WJ, Hagemenn TM: Purified poloxamer 188 for sickle cell
vaso-occlusive crisis. Ann Pharmacother 2004; 38:320-325.
43. Gehrs BC, Friedberg RC: Autoimmune hemolytic anemia. Am J Hematol
2002; 69:258-263.
44. Arndt P, Garraty G: The changing spectrum of drug-induced immune
hemolytic anemia. Semin Hematol 2005; 42:138-142.
45. Kehat I, Shupak A, Goldenberg I, Shoshani O: Long-term hematological
effects in Special Forces trainees. Mil Med 2003; 168:116-119.
46. Passamonti F, et al: Polycythemia vera in young patients: A study on the
long-term risk of thrombosis, myelofibrosis and leukemia.
Haematologica 2003; 88:13-19.
47. Streiff MB, Smith B, Spivak JL: The diagnosis and management of
polycythemia vera in the era since the Polycythemia Vera Study Group:
A survey of American Society of Hematology members’ practice
patterns. Blood 2002; 99:1144-1148.
48. Spivak JL: Polycythemia vera: Myths, mechanisms, and management.
Blood 2002; 100:4272-4290.
49. Passamonti F, et al: Life expectancy and prognostic factors for survival in
patients with polycythemia vera and essential thrombocythemia. Am J
Med 2004; 117:755-761.
50. Squizzato A, Romualdi E, Middledorp S: Antiplatelet drugs for
polycythaemia vera and essential thrombocythaemia. Cochrane Database
Syst Rev 2008; 2:CD006503.
51. Hillman RS, et al: Normal myelopoiesis. In Hillman RS, et al, eds.
Hematology in Clinical Practice, 5th ed. New York: McGraw-Hill;
2011.
52. Goldman JM, Melo JV: Chronic myeloid leukemia—advances in
biology and new approaches to treatment. N Engl J Med 2003;
349:1451-1456.
53. Kipps TJ: Classification and clinical manifestations of lymphocyte and
plasma cell disorders. In: Kaushansky K, et al, eds. Williams Hematology,
8th ed. New York: McGraw-Hill; 2010.
54. Ribera JM, Oriol A: Acute lymphoblastic leukemia in adolescents
and young adults. Hematol Oncol Clin North Am 2009;
5:1033-1045.
55. Pui CH: Treatment of acute lymphoblastic leukemia. N Engl J Med 2006;
354:166-171.
56. Jacobson MA, Liu RC, Davies D, Cohen PT: Human immunodeficiency
virus–related neutropenia and the risk of hospitalization for bacterial
infection. Arch Intern Med 1997; 157:1825-1831.
57. Viscoli C, Varnier O, Machetti M: Infections in patients with febrile
neutropenia: Epidemiology, microbiology, and risk stratification. Clin
Infect Dis 2005; 40(Suppl 4):S240-S245.
58. Sepkowitz KA: Treatment of patients with hematologic neoplasm,
fever, and neutropenia. Clin Infect Dis 2005; 40(Suppl 4):
S253-S256.
1605.e2   PART III  ◆  Medicine and Surgery / Section TEN • Hematology and Oncology
59. Kuderer NM: Impact of primary prophylaxis with granulocyte
colony–stimulating factor on febrile neutropenia and mortality in adult
cancer patients receiving chemotherapy: A systematic review. J Clin
Oncol 2007; 25:3158-3162.
60. Deibener-Kaminsky J, Lesesve JF, Kaminsky P: Leukocyte differential for
acute abdominal pain in adults. Lab Hematol 2011; 17:1-5.
61. Pucell K, Fergie J: Lack of usefulness of an abnormal white cell count for
predicting a concurrent serious bacterial infection in infants and young
children hospitalized with respiratory syncytial virus lower respiratory
tract infection. Pediatr Infect Dis 2007; 26:311-315.
62. Kuppermann N, Fleisher GR, Jaffe DM: Predictors of occult
pneumococcal bacteremia in young febrile children. Ann Emerg Med
1998; 31:679-687.
63. Seigel TA, et al: Inadequacy of temperature and white blood cell count
in predicting bacteremia in patients with suspected infection. J Emerg
Med 2012; 42:254-259.

Downloaded from ClinicalKey.com at Universitas Tarumanagara September 19, 2016.

For personal use only. No other uses without permission. Copyright ©2016. Elsevier Inc. All rights reserved.