Anemia, Polycythemia, and White Blood Cell Disorders

Section Ten
HEMATOLOGY AND ONCOLOGY
CHAPTER 121
Anemia, Polycythemia, and

White Blood Cell Disorders Timothy G. Janz and Glenn C. Hamilton
ANEMIA reticulocyte (Fig. 121-1). The reticulocyte retains its ribosomal

Definition network for approximately 4 days, 3 days of which are spent in
bone marrow and 1 day in the peripheral circulation. The RBC
Anemia is an absolute decrease in the number of circulating red matures as the reticulocyte loses its ribosomal network and circu-
blood cells (RBCs). The diagnosis is made when laboratory mea- lates for 110 to 120 days. The erythrocyte is then removed by
surements fall below accepted normal values (Table 121-1). macrophages that detect senescent signals.
In emergency medicine, anemia is divided into two broad cat- Under steady-state conditions, the rate of RBC production
egories: emergent, having immediate life-threatening complica- equals the rate of destruction. RBC mass remains constant because
tions; and nonemergent, with less imminent danger to the patient. an equal number of reticulocytes replace the destroyed, senescent
Factors other than the absolute number of circulating RBCs may erythrocytes during the same period.
place the patient in one category or another (e.g., rate of onset and Common sites of blood loss in trauma include the pleural,
underlying hemodynamic reserve of the patient). Both groups peritoneal, pelvic, and retroperitoneal spaces. In nontraumatic
necessitate a sound diagnostic approach, but emergent anemia circumstances, especially in patients receiving anticoagulants, the
may require supportive therapy concomitant with or in advance gastrointestinal tract, retroperitoneal space, uterus, and adnexa
of the definitive diagnosis. Although patients with nonemergent need to be considered.
anemia are usually referred to a specialist, they are seen in the Causes other than blood loss may be responsible for severe
hospital often enough to make an understanding of anemia neces- anemia of rapid onset. Certain rare hemolytic conditions can
sary for emergency physicians. The urgency of consultation cause rapid intravascular destruction of RBCs (Box 121-1). More
depends predominantly on the patient’s hemodynamic tolerance common are patients with chronic compensated hemolytic anemia
of the anemia. (e.g., sickle cell disease), who decompensate with an acute-onset
anemia as a result of decreased erythrocyte production triggered
Pathophysiology by a viral infection.
Beyond red cell destruction, the status of hemoglobin function
The major function of the RBC is oxygen transport from the lung should be considered. Impaired hemoglobin transport of oxygen
to the tissue and carbon dioxide transport in the reverse direction. is seen in cases of carbon monoxide poisoning. Methemoglobin-
Oxygen transport is influenced by the amount of hemoglobin, its emia from nitrates, cyanhemoglobin from cyanide, and sulfhemo-
oxygen affinity, and blood flow. An alteration in any of the major globinemia from hydrogen sulfide may severely decrease functional
components usually results in compensatory changes in the other hemoglobin. These patients often have fatigue, altered mental
two. For example, a decrease in hemoglobin from anemia is com- status, shortness of breath, and other manifestations of hypoxia
pensated by both inotropic and chronotropic cardiac changes that without signs of RBC loss or volume depletion.
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 Diagnostic Findings in Emergent Anemia
or underlying pathologic conditions. The result is tissue hypoxia Clinical Features
and eventual cell death.
Anemia often stimulates the compensatory mechanism of The most common cause of clinically significant anemia is
erythropoiesis controlled by the hormone erythropoietin. Eryth- blood loss. The clinical manifestation of anemia depends on how
ropoietin is a glycoprotein produced in the kidney (90%) and rapidly the hematocrit falls and also on the patient’s ability to
the liver (10%). It regulates the production of RBCs by control- compensate.
ling differentiation of the committed erythroid stem cell. It is Clinical signs and symptoms include tachycardia, decreased
stimulated by tissue hypoxia and products of RBC destruction blood pressure, postural hypotension, lightheadedness, increased
during hemolysis. Erythropoietin levels are elevated in many types heart rate, and increased respiratory rate. Complaints of thirst,
of anemia. altered mental status, and decreased urine output may also be
Bone marrow contains pluripotent stem cells that can differen- present. The patient’s age, concomitant illness, and underlying
tiate into erythroid, myeloid, megakaryocytic, and lymphoid pro- hematologic, cerebral, and cardiovascular status tremendously
genitors. Erythropoietin enhances the growth and differentiation influence the clinical findings. Children and young adults may
of erythroid progenitors. When the late normoblast extrudes its tolerate significant blood loss with unaltered vital signs until a
nucleus, it still contains a ribosomal network, which identifies the precipitant hypotensive episode occurs. Pediatric patients may
1586
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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.

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

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

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

Table 121-3 Diagnostic Tests for Iron Deficiency Anemia

TEST NORMAL RESULT IRON DEFICIENCY LEVEL INTERPRETATION
Fasting serum iron 60-180 µg/dL <60 µg/dL Diurnal variation (draw in morning); increased by
hepatitis, hemochromatosis, hemolytic anemia, and
aplastic anemia; decreased in infection
Total iron-binding capacity 250-400 µg/dL >400 µg/dL Increased in late pregnancy or hepatitis; decreased
in infection
Percentage of saturation (serum iron) 15-45% <15%
of total iron-binding capacity
Serum ferritin 10-10,000 mg/mL <10 mg/mL Reflects iron stores; may increase as an acute-phase
reactant in infection
Bone marrow stainable iron Hemosiderin granules in Absent Standard for assessment of iron stores
reticuloendothelial cells
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-
Figure 121-5. β-Thalassemia with microcytic hemochromic red cells sion bodies in RBCs. Some of these patients are deficient in pyri-
and target cells. (From Hoffbrand AV, Pettite JE: Color Atlas of Clinical doxine (vitamin B6) and respond to treatment with 100 mg of
Hematology, 3rd ed. London, Mosby, 2000:96.) 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
(erythrocytes with central hyperchromic bull’s-eye surrounded by transfusion therapy is necessary, but they may respond to iron
pallor) seen on the peripheral smear (Fig. 121-5), an MCV com- chelation therapy. Idiopathic sideroblastic anemia is considered a
monly more severely lowered than with iron deficiency anemia, a preleukemic state, and acute myelogenous leukemia develops in
normal level of serum iron, and an elevated level of HbA2 (α2δ2) approximately 5% of these patients.
on hemoglobin electrophoresis (2-5%). Usually, no treatment is Secondary causes of sideroblastic anemia include toxins such as
necessary. chloramphenicol, isoniazid, and cycloserine as well as diseases
α-Thalassemia varies in spectrum from an asymptomatic such as hemolytic and megaloblastic anemia, infection, carci-
carrier state to prenatal death. Four gene loci control this range. noma, leukemia, and rheumatoid arthritis. The exact mechanisms
In the tolerated forms, it is more commonly seen in Asians and of these causative agents and diseases are unknown. Lead poison-
African Americans. Microcytosis, hypochromia, target cells, and ing is one reversible cause of sideroblastic anemia. It may be sug-
basophilic stippling are noted on the peripheral smear. The diag- gested by the appearance of RBC basophilic stippling on the
nosis is made with hemoglobin electrophoresis and genetic testing. peripheral smear. Elevated blood lead levels are diagnostic. Alcohol
Screening for carriers is performed by measurement of RBC abuse may also result in disordered heme synthesis, which can be
indices and estimation of the HbA2 concentration. Prenatal diag- corrected by alcohol cessation or by parenteral pyridoxal phos-
nosis can be made by analysis of fetal blood and, more recently, phate in cases of continued abuse. Oral pyridoxine may be inef-
by fetal DNA obtained by chorionic villus sampling. fective because of impaired conversion to the active form in
Therapy consists of blood transfusions, which are based on the alcoholic patients.
clinical severity of the anemia. The goals of transfusion therapy Anemia of Chronic Disease. Anemia of chronic disease is
include correction of anemia, suppression of erythropoiesis, and common and typically normochromic, normocytic. It is charac-
inhibition of increased gastrointestinal iron absorption. Iron che- terized by low serum iron levels, low total iron-binding capacity,
lation therapy is often required to control excess iron stores. His- and normal or elevated ferritin levels. Bone marrow is normal, but
torically, deferoxamine, a subcutaneously administered chelator, staining reveals an abnormality in the mobilization of iron from
was used; however, it has been replaced at many centers with the reticuloendothelial cells. This anemia can be differentiated from
oral chelator deferasirox (Exjade). Deferasirox is renally cleared; iron deficiency by total iron-binding capacity, serum ferritin level,
thus dose adjustments may be necessary for chronic renal insuf- bone marrow examination, and nonresponsiveness to a trial of
ficiency, and it is contraindicated in end-stage renal disease.6 iron therapy. Because the hematocrit is seldom less than 25 to
Bone marrow transplantation from HLA-identical donors has 30%, therapy is not usually required. A complete search for
resulted in disease-free survival in 60 to 90% of recipients, but its occult blood loss is necessary during the evaluation of this
role in thalassemia has yet to be determined. Although much diagnosis because iron deficiency may be superimposed. Dissemi-
interest centers on permanent correction of genetic deficits in nated cancer, chronic inflammation, uremia, and infection are
thalassemia, gene therapy does not yet exist.7 common causes.8
Sideroblastic Anemia. Sideroblastic anemia involves a defect Macrocytic and Megaloblastic Anemias. In terms of the potential
in porphyrin synthesis. The resultant impaired hemoglobin pro- for a therapeutic response, the most important cause of macrocy-
duction causes excess iron to be deposited in the mitochondria of tosis is megaloblastic anemia. Megaloblastic anemia is the hema-
the RBC precursor, but some also circulates. The result is increased tologic manifestation of a total-body alteration in DNA synthesis.

The defective DNA synthesis is caused by a lack of the coenzyme Megaloblastic anemia that is not responsive to folate or vitamin
forms of vitamin B12 and folic acid. The deficiency appears clini- B12 is commonly related to antimetabolites used in chemotherapy
cally in tissues with rapid cell turnover, including hematopoietic or rare inherited disorders of DNA synthesis.
cells and those of mucosal surfaces, particularly in the gastroin- Table 121-4 lists a number of the problems associated with
testinal tract. This deficiency is characterized hematopoietically by megaloblastic anemia and their underlying pathologic states. A
ineffective erythropoiesis and pancytopenia. Vitamin B12 and unique feature of vitamin B12 deficiency is its neurologic involve-
folate deficiencies have different developmental histories, but the ment. Patients may have paresthesias in their hands and feet,
clinical result may be similar. Differentiation of folate and vitamin decreased proprioception, or decreased vibratory sense. The insid-
B12 deficiencies usually depends on measured levels in the iously developing classic neurologic complex includes loss of pro-
laboratory. prioception; weakness and spasticity of the lower extremities with
Folic acid, absorbed in the duodenum and jejunum, is com- altered reflexes; and variable mental changes, such as depression,
monly found in green vegetables, cereals, and fruit. It may be paranoid ideation, irritability, and forgetfulness. The last two com-
destroyed completely by cooking. The body requires approxi- plaints have also been noted with folic acid deficiency. Vitamin
mately 100 µg/day and usually stores 6 to 20 mg. Therefore, a 2- to B12–deficient patients have some of the lowest hemoglobin levels
4-month supply is available before megaloblastic changes occur. seen in any disease state.
Causes of folate deficiency are listed in Box 121-6. Most patients Macrocytic anemia is suggested when the MCV is greater than
with folate deficiency have either an inadequate dietary intake, 100 fL, but other criteria need to be met for megaloblastosis to be
such as alcoholic patients, or increased use, as in pregnancy. considered the cause of the macrocytic anemia. On the peripheral
Vitamin B12 is found in foods of animal origin only and is not smear, large oval red cells (macro-ovalocytes) and hypersegmented
destroyed by cooking. It is absorbed in the ileum after binding to polymorphonuclear neutrophils are believed to be diagnostic (Fig.
intrinsic factor. This glycoprotein factor is secreted by the parietal 121-6). A bone marrow aspirate may reveal morphologic changes
cells of the gastric mucosa and allows low levels of B12 to be actively consistent with megaloblastic erythropoiesis. Other potentially
absorbed. The adult requirement is 1 or 2 µg/day, with a body useful laboratory tests include vitamin B12 and folate levels, red
store of 5 mg. Therefore, megaloblastic changes may take up to 4 cell folate, and lactate dehydrogenase (LDH). Laboratory tech-
years to develop after cessation of vitamin B12 uptake. The various niques, values, and interpretations are listed in Table 121-5. Once
causes of vitamin B12 deficiency are listed in Box 121-7. The most megaloblastic anemia is diagnosed and folate or vitamin B12 defi-
common cause is chronic malabsorption. 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
BOX 121-6 Causes of Folate Deficiency may be forced to initiate therapy before the final diagnosis is made.
However, a caution is given to obtain necessary laboratory speci-
Inadequate dietary intake mens before this course is pursued. The usual dosage for patients
Poor diet or overcooked or processed food diet with megaloblastic anemia secondary to folate deficiency is 1 mg
Alcoholism of oral folic acid per day. Parenteral administration is generally
Inadequate uptake
Malabsorption with sprue and other chronic upper intestinal
unnecessary because most cases are due to dietary deficiency. In
tract disorders, drugs such as phenytoin and barbiturates, or contrast, malabsorption is the most common cause of vitamin B12
blind loop syndrome deficiency, and parenteral therapy is initiated at 100 µg/day intra-
Inadequate use muscularly for the first 7 to 10 days. Thereafter, only monthly
Metabolic block caused by drugs such as methotrexate or 100-µg doses are necessary. The response is often dramatic, with
trimethoprim reticulocyte counts rising up 30 to 50% and normalization of
Enzymatic deficiency, congenital or acquired RBC, white blood cell (WBC), and platelet counts in 6 to 8 weeks.
Increased requirement The use of vitamin B12 or folate supplements in patients with
Pregnancy undiagnosed anemia is to be discouraged. The routine injection
Increased RBC turnover: ineffective erythropoiesis, hemolytic
of vitamin B12 in the elderly has decreased but is still a too common
anemia, chronic blood loss
Malignant disease: lymphoproliferative disorders practice.9
Increased excretion or destruction or dialysis Macrocytic anemias unrelated to megaloblastic changes are
seen frequently. Liver disease, often associated with alcoholism, is
Clinicopathologic Correlation of
BOX 121-7 Causes of Vitamin B12 Deficiency Table 121-4 Manifestations of Megaloblastic Anemia
Inadequate dietary intake CLINICAL FEATURES PATHOLOGIC CONDITION
Total vegetarianism: no eggs, milk, or cheese
Lemon yellow skin Combination of pallor with low-grade
Chronic alcoholism (rare) icterus from ineffective erythropoiesis
Inadequate absorption
Absent, inadequate, or abnormal intrinsic factor, as seen in Petechiae, mucosal bleeding Thrombocytopenia
patients with pernicious gastrectomy and anemia. In Infection Leukopenia
anemia, autoimmune antibodies act against gastric parietal
cells and intrinsic factor. Fatigue, dyspnea on exertion, Anemia
Abnormal ileum, as can occur in sprue and inflammatory postural hypotension
bowel disease Sore mouth or tongue Megaloblastosis of mucosal surfaces
Inadequate use
Enzyme deficiency Diarrhea and weight loss Malabsorption from mucosal surface
Abnormal vitamin B12–binding protein change
Increased requirement by increased body metabolism Paresthesias and ataxia Related to myelin abnormality in
Increased excretion or destruction vitamin B12 deficiency only

Table 121-5 Serum Tests for Diagnosis and Differentiation of Megaloblastic Anemia
TEST TECHNIQUE VALUE INTERPRETATION
Vitamin B12 Microbiologic or Normal: 300-900 µg/L Although they may overlap clinically, vitamin B12 level is
radioisotope Deficient: <200 µg/L usually normal in folate deficiency.
Folate Microbiologic or Deficient: <3 µg/L Vitamin B12 deficiency may elevate folate levels by blocking
radioisotope transfer of serum folate to RBCs; hemolysis may elevate
folate levels.
Red cell folate Calculated Normal: 200-700 µg/L Index of tissue folate is less influenced by diet and is
Folate deficiency: <140 µg/L increased in vitamin B12 deficiency because of block.
Lactate dehydrogenase Spectrophotometric Normal: 95-200 IU Normal in other macrocytic anemias; elevated two to four
Megaloblastic anemia: 4-50 times normal 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.
Figure 121-6. Megaloblastic anemia with macrocytic red cells and It is suspected in anemic patients with normal indices, a low
hypersegmented polymorphonuclear neutrophils. (From Hoffbrand AV,
Pettite JE: Color Atlas of Clinical Hematology, 3rd ed. London, Mosby, reticulocyte count, and a history of exposure to certain drugs or
2000:61.) 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
the most common cause.10 Macrocytic target cells may be seen on is considered to have an “autoimmune” origin.
the peripheral smear in conjunction with this disorder. Hypothy- The aplastic state may extend to all cell lines and results from
roidism and hemolysis may also be manifested as macrocytic destruction by immune-stimulated lymphocytes or failure of the
anemia. Screening tests to differentiate between megaloblastic marrow stem cell. On occasion, only one cell line fails, as in RBC
anemia and macrocytic anemia of other causes include a periph- aplasia. This condition represents injury occurring at a later stage
eral smear for macro-ovalocytes, hypersegmented polymorpho- of cellular differentiation. The precise diagnosis necessitates bone
nuclear neutrophils, and the LDH level. marrow examination, but the causative factor may be difficult to
Normochromic and Normocytic Anemias. The origin of normo- determine.
chromic and normocytic anemias secondary to decreased produc- General treatment of aplastic anemia includes removal of sus-
tion is not as obvious as that of macrocytic and microcytic anemias pected marrow toxins from the environment, avoidance of aspirin,
because the latter give clues to their origin by alterations in RBC oral hygiene, and suppression of menses. Transfusions are given
indices. One hematologic parameter that can aid in the diagnosis in life-threatening circumstances only. Bone marrow or peripheral
of normocytic anemia associated with hypoproduction is the cor- blood stem cell transplantation from a histocompatible sibling
rected reticulocyte count. Reticulocytes reflect RBC production in can cure the bone marrow failure, with survival rates of 78 to
bone marrow. They are RBCs released from bone marrow every 1 94% reported.10 However, because just 30% of patients have suit-
to 3 days and contain residual RNA that can be detected by supra- ably matched sibling donors, only a small number undergo allo-
vital staining. Reticulocytes have an average MCV of 160 fL and geneic transplantation. Immunosuppression with antithymocyte
in sufficient numbers can increase the MCV of the total erythro- globulin, antilymphocyte globulin, and other cytotoxic chemo-
cyte count. The reticulocyte count is expressed as a percentage of therapy is used in the majority of patients who are not stem cell

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-
Figure 121-7. Anisocytosis and poikilocytosis. (From Hoffbrand AV, cular processes. Although it is not a precise representation of the
Pettite JE: Color Atlas of Clinical Hematology, 3rd ed. London, Mosby, underlying pathophysiologic condition, this division assists in the
2000:113.) differential approach in the emergency department.
Intravascular hemolysis is usually associated with an acute
process and has a dramatic appearance. Large numbers of RBCs
transplantation candidates. Unrelated donors are preferred to may be lysed within the circulation. The pathologic process pri-
avoid sensitization of the patient against the non-HLA antigens marily involves the handling of released hemoglobin and a com-
that are present in bone marrow from a family donor. The disease pensatory response to an acute decrease in oxygen-carrying
has a wide range of severity, and the overall 5-year survival rate is capability. Free hemoglobin initially binds to haptoglobin and
30 to 40%. Given supportive therapy, up to 80% of patients with hemopexin. This complex is transported to the liver, converted to
severe aplastic anemia still die. Bone marrow transplantation bilirubin, conjugated, and excreted. When this binding and trans-
before blood product sensitization has resulted in an 80% 5-year port system is overwhelmed, free hemoglobin may appear in the
survival rate. This is usually combined with immunosuppressive blood. Hemoglobin is a large molecule that remains in serum and
therapy consisting of antilymphocyte globulin. Difficulty is still may tint it pink.
encountered in finding the correct immunologic match.11,12 In contrast, myoglobin is a small molecule that is rapidly cleared
Myelophthisic anemia is bone marrow failure resulting from from serum. Examination of spun whole blood demonstrates clear
replacement by an invading tumor, leukemia, lymphoma, or, serum in myoglobinemia, pink serum with free hemoglobin from
rarely, granuloma. A more basic defect or inhibitor may compli- intravascular hemolysis, and yellow serum from extravascular
cate the problem because the degree of anemia cannot always be hemolysis with increased bilirubin production. In severe cases, the
correlated with the extent of bone marrow invasion. Any patient last mechanism may also result in free hemoglobin.
with oncologic disease may be subject to the development of this The clinical appearance of intravascular hemolysis may vary
type of anemia. Useful clues are signs of extramedullary hemato- from mild chronic anemia, as seen in cases of mechanical hemo-
poiesis, such as hepatosplenomegaly and a leukoerythroblastic lysis, to prostration, fever, abdominal and back pain, and mental
peripheral smear that demonstrates immature WBCs, nucleated changes, as seen with transfusion reactions. Jaundice, brown to red
RBCs, and poikilocytosis (teardrop-shaped red cells) (Fig. 121-7). urine, and oliguria associated with acute renal failure induced by
The final diagnosis is made by bone marrow examination. Therapy the hemoglobin complex can also occur.
is directed at the underlying disorder. Extravascular hemolysis is more common and usually better
Myelofibrosis of unknown origin is the usual cause of primary tolerated. Splenic blood flow slows as RBCs travel in the sinusoids
bone marrow failure associated with extramedullary hematopoi- close to the reticuloendothelial system, which is uniquely designed
esis. This myeloid metaplasia occurs in the liver and spleen and for removal of older or damaged cells. Primary splenic overactiv-
imparts a blood picture similar to that of myelophthisic anemia. ity, antibody-mediated changes, or RBC membrane abnormalities
The diagnosis may be made by bone marrow examination. Treat- may cause this normal splenic function to increase to a pathologic
ment is supportive, although splenectomy or the use of alkylating degree. Hemolysis may also occur within the bone marrow. As
agents may be necessary to treat complications of extramedullary stated previously, normal erythropoiesis is ineffective 10 to 20%
blood cell production, such as hepatosplenomegaly. of the time. This percentage increases when abnormal RBCs are
The hypoplastic anemias of secondary origin are commonly produced, as in thalassemia, megaloblastic anemia, or some hemo-
seen as mild chronic anemias with low reticulocyte counts. They lytic anemias.14
have a normal MCV and RDW. Their diagnosis is made by exclu- After hemoglobin is disassembled in the reticuloendothelial
sion. Anemia of chronic disease may have microcytic or normo- cell, globin returns to the amino acid pool, iron is transported by
cytic indices. It is associated with chronic inflammation (e.g., transferrin to the bone marrow or iron stores, and the pyrrole ring

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.)

Drugs Associated with Hemolysis
BOX 121-10 Classification of Hemolytic Anemia BOX 121-11 in G6PD Deficiency
Intrinsic Analgesics and antipyretics: acetanilid, aspirin, phenacetin
Enzyme defect Antimalarials: primaquine, quinacrine, quinine
Pyruvate kinase deficiency Nitrofurans
Glucose-6-phosphate dehydrogenase deficiency Sulfa drugs: sulfamethoxazole, sulfacetamide, sulfones
Membrane abnormality Miscellaneous: naphthalene, fava beans, methylene blue,
Spherocytosis phenylhydrazine, nalidixic acid
Elliptostomatocytosis
Paroxysmal nocturnal hemoglobinuria G6PD, glucose-6-phosphate dehydrogenase.
Spur cell anemia
Hemoglobin abnormality
Hemoglobinopathies The older cells lyse at certain drug levels. The oxidant creates
Thalassemias (anemias) forms of activated oxygen, such as peroxide, that either denature
Unstable hemoglobin the hemoglobin or destroy cell membranes. The former process
Hemoglobin M
produces Heinz bodies, which are clumps of denatured hemoglo-
Extrinsic bin found in RBCs early during an episode. These cells are removed
Immunologic by the spleen. The diagnosis is made by enzymatic screening for
Alloantibodies G6PD, but this test cannot be performed immediately after the
Autoantibodies hemolytic episode. A 3-week delay avoids a false-negative result
Mechanical
caused by a predominance of young cells. Treatment includes
Microangiopathic hemolytic anemia
Cardiovascular, such as prosthetic heart valve disease volume and RBC support as necessary. Avoidance of oxidant drugs
Environmental is the only prevention.
Drugs Intrinsic Membrane Abnormality. These abnormalities are
Toxins manifested in a number of ways. An altered shape is the main
Infections feature of autosomal dominant hereditary spherocytosis or ellip-
Thermal tocytosis. The spleen sequesters these abnormal cells. Clinical
Abnormal sequestrations, as in hypersplenism 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-
spleen because IgG is a poor initiator of the complement system. ing therapeutic intervention.
The direct antiglobulin test evaluates the RBC surface for immu- Paroxysmal nocturnal hemoglobinemia is a stem cell defect
nologic markers. The indirect test assumes that IgG or C3 is in the causing abnormal erythrocyte, neutrophil, and platelet sensitivity
serum and tests for serum antibody activity against RBCs. Positive to complement. It is most often seen as chronic hemolysis, hemo-
test results for immunologic markers do not correlate agglutina- siderinuria, leukopenia, and thrombocytopenia. The peripheral
tion activity with the severity of hemolysis.14 smear is normal and the direct Coombs’ test result is negative. Its
Differential Diagnosis. Hemolytic anemias may be classified as major complication is thrombosis, with a predilection for the
congenital or acquired, Coombs’ positive or Coombs’ negative, or hepatic vein. Normal activation of complement with the use of
caused by processes intrinsic or extrinsic to the cell membrane. sucrose or acid hemolysis (the Ham test) is diagnostic. Transfusion
The last method gives a useful differential classification of hemo- can be a life-threatening hazard in patients with this disease
lysis (Box 121-10). because RBC lysis is caused by donor complement. Because of this
Intrinsic Enzyme Defects. Eighty-five percent to 90% of the danger, only washed packed cells should be used.
membrane-sustaining energy production of the erythrocyte is Intrinsic Hemoglobin Abnormality. More than 350 types of
through the anaerobic glycolytic pathway. At least eight known abnormal hemoglobin have been documented. Problems that may
enzyme deficiencies are associated with this pathway. The most be seen include unstable hemoglobins that appear as Heinz body–
common is pyruvate kinase deficiency, which is manifested with positive anemia, M hemoglobins that fix iron in its ferric or met-
hemolytic jaundice and is usually diagnosed in infancy. hemoglobin state, and hemoglobins with increased oxygen affinity
The remaining 10 to 15% of RBC glycolysis occurs by way of that result in tissue hypoxia and erythrocytosis.
the hexose monophosphate shunt. This bypass mechanism occurs Sickle Cell Disease. Sickle cell disease is the most important
in the early stages of the glycolytic pathway and generates reduced hemoglobinopathy with which the emergency physician should be
nicotinamide adenine dinucleotide phosphate (NADPH), which familiar. In hospitals serving a large African American population,
is important in maintaining reduced glutathione. Glutathione is it is seen on an almost daily basis. Even experienced physicians
essential in the protection of hemoglobin from oxidant injury. A may overlook major complications. Clinicians with less experience
deficiency of the first enzyme in this pathway, G6PD, occurs in may fail to recognize the complexity of the disease and the many
11% of African American men. In this form, the enzyme deterio- potential complications.15
rates with age, and older RBCs are subject to hemolysis by oxidant Pathophysiology. Sickle cell disease is genetically determined.
stress. G6PD deficiency is sex linked and has a wide range of sever- An abnormal allele at the gene loci for hemoglobin β chains pro-
ity. The most common form in African Americans is self-limited duces altered messenger RNA, which in turn results in replace-
because as the bone marrow responds, younger cells with more ment of glutamic acid by valine at the sixth position from the
normal levels of G6PD predominate and can handle the oxidant N-terminal end of the β chain. On the molecular level, this change
stress. The variants in Sicilians, Greeks, and Arabs can be particu- causes an interlocking of the affected chain with adjacent hemo-
larly devastating. The clinical manifestation is usually an acute globin in the deoxygenated state. This connection causes the for-
hemolytic episode that may be both intravascular and extravascu- mation of bundles of parallel rods called tactoids, polymers that
lar in appearance. It occurs 24 to 48 hours after the ingestion of grow to form a p-crystalline gel, and then a crystal. Gel formation
an oxidant drug (Box 121-11) or after acute infections such as viral is facilitated by low pH and reduced by the presence of other
hepatitis. The anemia induced by oxidant drugs is dose related. hemoglobins, such as HbF. The result is a sickled cell that is less

deformable, an increase in the viscosity and sludging tendency of cause stasis, deoxygenation, and local acidosis, which promote the
blood, and the sequestration of RBCs in the spleen and liver. These vicious circle of continued sickling. The pain is commonly deep
changes may occur when smaller amounts of polymer do not and aching and is most often found in the abdomen, chest, back,
result in a sickled cell and are associated with an RBC membrane and extremities. The disease may mimic an acute abdomen (e.g.,
leak. The clinical complex of vaso-occlusive events, chronic hemo- cholecystitis), pulmonary embolus, renal colic, or other painful
lysis, thrombosis, and organ injury is derived from this pathologic problems. A directed history that relates this pain pattern to previ-
process. Patients with sickle cell disease generally fall into two ous sickling episodes, a careful repeated physical examination, and
phenotypic groups: hemolysis phenotype and vaso-occlusion phe- specific organ-related laboratory tests are all the physician has to
notype. These groups are not genetically determined, and it is still differentiate “uncomplicated” crises from a more serious patho-
unknown why some people fall into one group versus the other. logic condition. Children may be seen more often with skeletal
Patients prone to hemolysis typically do not have pain, stroke, or crises leading to bone deformities. In these cases, osteomyelitis and
acute chest syndrome; instead, they typically have pulmonary bone infarct needs to be differentiated.22
hypertension and leg ulcers. Their hemoglobin tends to be very Neurologic complications can occur and include transient isch-
low but their LDH is usually high. Patients with the vaso-occlusion emic attacks, cerebral infarction, spinal cord infarction, vestibular
phenotype typically have pain, acute chest syndrome, and stroke; hearing problems, and hearing loss.23 Neurologic complications
they have a higher hemoglobin or high WBC level and lower LDH occur in 25% of patients with sickle cell anemia by the time they
and indirect bilirubin concentrations. are 45 years old; 13% demonstrate infarction or ischemia in the
The globin in hemoglobin is made up of two pairs of identical absence of symptoms.24 Transcranial Doppler study may be useful
polypeptide globin chains. Each person has two non–sex-linked in identifying individuals with sickle cell disease who are at risk
gene foci for β-globin chains, one from each parent. Normal indi- for stroke.25 The use of exchange blood transfusions with the goal
viduals express six different types of hemoglobin from varying of hemoglobin S less than 30% can reduce the risk of cerebrovas-
globin chain combinations: three embryonic hemoglobins, HbA cular events by 92%.26 In the setting of an acute stroke, exchange
(α2β2), HbA2 (α2δ2), and HbF (α2γ2). Embryonic hemoglobins are transfusion is recommended with the goals of hemoglobin S of
expressed only in utero, and after 6 months of age, HbA accounts less than 30% and a total hemoglobin level limited to 10 g/dL.27,28
for more than 95% of hemoglobin in a normal individual. The Tissue plasminogen activator (tPA) should be considered in adult
sickle syndromes result from mutations in the β-globin gene. sickle cell disease patients with acute nonhemorrhagic strokes. The
Instead of HbA (α2β2), an abnormal hemoglobin HbS is produced. use of tPA in this setting is the same as for acute stroke without
Embryonic and fetal hemoglobins do not contain β-globin; thus sickle cell disease.28
there are no clinical manifestations in early infancy. As their pro- Acute chest syndrome is the most common pulmonary disease
duction declines, normal HbA (α2β2) cannot be produced, and associated with sickle cell disease and one of the most common
symptoms develop. causes of death.29 It is a common cause of hospitalization in sickle
In sickle cell trait (HbAS), the patient is heterozygous and only cell disease, second only to vaso-occlusive crisis. Patients with
one parent contributes the abnormal S allele. In each cell approxi- acute chest syndrome have fever, cough, chest pain, dyspnea, and
mately 40% of the hemoglobin is HbS. Sickle disease (HbSS) is new infiltrates on the chest radiograph. The pathophysiologic
homozygous, and more than 85% of the hemoglobin is HbS. mechanism of the syndrome is not well understood, but it may be
Because a parent may contribute alleles other than S, a wide a specific form of acute lung injury. The injury is postulated to be
number of variants can exist. Two clinically important S variants related to pulmonary microvascular sludging, infarction of pul-
are sickle cell–β-thalassemia and sickle cell–hemoglobin C disease. monary parenchyma, and bone marrow fat embolization from
Therefore, not all hemoglobinopathies that cause sickling are HbS. infarcted bone. Macrovascular pulmonary embolism and infec-
In addition, HbSS is not limited to the African American population may also have a pathogenetic role. Although the causes of
tion. Up to 10% of patients with various sickling disorders are not acute chest syndrome are uncertain, approximately 54% of the
ethnically African American.16,17 cases are associated with infection, including Mycoplasma and
The sickle cell trait is found in 8 to 10% of African Americans. Chlamydia.30 The differential diagnosis includes pneumonia, pul-
The diagnosis is usually made after sickle cell screening (Sickledex) monary embolism, congestive heart failure, and adult respiratory
and a characteristic result on hemoglobin electrophoresis. Most distress syndrome. No definitive diagnostic study is available, and
individuals with sickle cell trait are asymptomatic but can present diagnosis is based on the presence of the clinical features and
with spontaneous hematuria, renal papillary necrosis, splenic exclusion of other pulmonary causes, as mentioned in the differ-
infarction, venous thromboembolism, traumatic hyphema, exer- ential diagnosis. Management is primarily supportive and consists
tional rhabdomyolysis, and exertional sudden death.15,18,19 Recent of hydration, analgesia, incentive spirometry, maintenance of
literature suggests that pregnancy in women with sickle cell trait adequate oxygenation and ventilation, and empirical antibiotics.
is not associated with an increased risk of adverse events.20 Approximately 13% of patients will have respiratory failure severe
In patients with sickle cell trait who have eye trauma, serial enough to require mechanical ventilation. Antibiotic choice is
tonometry and observation are indicated to monitor for ocular similar to that for pneumonia in other populations. Exchange
complications. blood transfusions, as used in a similar fashion with acute stroke,
Clinical Features. Sickle cell disease can be a recurrent, painful, are often used and have been associated with better gas exchange
and frustrating problem for both patients and physicians. A study in acute chest syndrome.31,32 However, there are no randomized
suggests that as many as 35% of a sickle cell population are controlled studies demonstrating an improvement in outcome
recurrent emergency department users.21 Sickle cell disease is with the transfusions.
characterized by two major clinical features, hemolysis and acute Although most of the diagnostic and therapeutic problems of
vaso-occlusive events. The hallmark manifestation of sickle cell sickle cell disease are related to vaso-occlusive crises, other serious
disease and the most common reason for emergency department complications should be anticipated. Sickle cell disease is a chronic
visits is the painful vaso-occlusive crisis. Preceding infection, cold hemolytic state with reasonably compensated hematocrit values
exposure, and stress such as trauma are all potential precipitating in the 20 to 30% range and elevated reticulocyte counts. This
factors. Many episodes are thought to be spontaneous. The painful compensated balance may be disrupted by a rare iron deficiency
crisis is believed to have its origin in tissue ischemia caused by or, more commonly, by folate deficiency. A potentially life-
increased viscosity, sludging, and microvascular obstruction as a threatening aplastic crisis may be seen as a result of suppression
result of irreversibly sickled cells. Sludging and vascular blockage of erythropoiesis by an acute postinfectious condition or folate

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 Figure 121-10. Sickle cells. (From Hoffbrand AV, Pettite JE: Color
Genital Decreased fertility, impotence, priapism Atlas of Clinical Hematology, 3rd ed. London, Mosby, 2000:103.)
Skeletal Bone infarcts, osteomyelitis, aseptic necrosis
Placenta Insufficiency with fetal wastage
of a slow but longer growth period caused by the delayed onset of
Leukocytes Relative immunodeficiency puberty, adult patients with HbSS often have a youthful appear-
Erythrocytes Chronic hemolysis 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-
deficiency. This aplastic condition is suspected when the hemo- ceptibility to infection, and ischemic organ damage. Table 121-7
globin level falls 2 g/dL or more from previous stable levels and suggests an outline to follow for the physical examination.
the reticulocyte count remains low (<2%). Most patients, other than those with mild pain crisis, should
Finally, children may have an acute splenic sequestration syn- have a complete blood count performed, and current blood levels
drome. This syndrome involves acute splenic enlargement from should be compared with those of previous visits. A reticulocyte
increased intrasplenic sickling and obstruction. The child may count is recommended whenever the patient’s hemoglobin level
demonstrate lassitude and be in shock. Each of these conditions has decreased by 2 g/dL from baseline. In sickle cell disease, the
may result in a rapidly falling RBC count and progressive symp- typical absolute reticulocyte count is three or four times the upper
toms of anemia. Patients with HbSS are also subject to all other limit of normal. A reticulocyte count 3% or lower than the patient’s
causes of anemia, such as hemolysis from G6PD deficiency. An usual value may suggest an aplastic crisis. A reticulocyte count
increased susceptibility to infection is well documented greater than 12%, particularly if it is accompanied by numerous
with HbSS. nucleated RBCs, may indicate rapid hemolysis. Other laboratory
In infancy, an increased incidence of sudden death may be tests are selected on the basis of potential organ complications.
related to pneumococcal sepsis and meningitis. A WBC count and Unfortunately, no test is available that detects whether a patient is
blood cultures should be performed on all febrile children with in a crisis. Currently, this difficult task is based on clinical grounds.
sickle cell anemia. HbSS patients who are younger than 2 years In new cases, the peripheral smear may show sickled cells (Fig.
and have associated temperatures of 39.5° C or higher and WBC 121-10), and a sickle cell screening test with Sickledex may help.
counts greater than 20,000/mm3 should be given intravenous anti- Definitive diagnosis of sickle cell disease is aided by hemoglobin
biotics immediately. Adults with fever require careful evaluation electrophoresis.
and laboratory assessment, including appropriate cultures. Early Management. The antisickling agent hydroxyurea reduces the
institution of appropriate antibiotics, such as ceftriaxone 1 to 2 g, frequency of painful crises in adults with a history of three or more
adult dose, intravenously or intramuscularly, is necessary in crises annually. The beneficial effects of hydroxyurea in sickle cell
patients with a discernible source of infection. In children and disease are assumed to be due to induction of hemoglobin F, but
adults, infections with Staphylococcus and Pneumococcus species additional mechanisms may be operative. Hydroxyurea can reduce
and Haemophilus influenzae are particularly common.33 An the incidence of acute painful crisis as well as increase survival in
increased incidence of Salmonella osteomyelitis also occurs.34 The sickle cell disease. However, the effects of hydroxyurea can take
origin of this related immunologic deficiency is believed to be weeks to be appreciated, and it is not routinely recommended for
multifactorial, involving functional asplenia, poorly migrating acute episodes.35,36 Other agents, including clotrimazole, magne-
neutrophils, and decreased opsonin production.34 sium, 5-azacitidine, erythropoietin, and butyric acid, may have a
Major, chronic organ damage in patients with sickle cell future role in therapy.37,38 Bone marrow transplantation offers the
anemia is common. A cross section of these problems is listed only current cure for sickle cell disease and is associated with
in Table 121-7. These associated conditions should be quickly survival rates greater than 90% and disease-free survival rates of
reviewed every time a patient with sickle cell anemia enters the 80 to 90%. However, the role of bone marrow transplantation in
emergency department. The leading causes of death in HbSS sickle cell disease remains uncertain because of the inability to
patients are cardiopulmonary disease, chronic renal failure, stroke, predict which patients will benefit, limited patient eligibility as
and infection.15 a result of advanced pulmonary and neurologic vasculopathies,
Diagnostically, most patients with HbSS seen in the emergency and concerns related to transplantation mortality and treatment-
department are well known with defined pain patterns. Because induced malignant neoplasms.37,38

Current therapies, including rest, adequate nutrition, hydration, Exchange transfusions are recommended for patients, particu-
oxygenation, analgesia, transfusion, and therapy for infection, are larly children, with cerebrovascular accidents. Acute symptoms
directed toward symptomatic relief and attempts to stop the cycle may be reversed and the frequency of recurrence decreased with
of deoxygenated sickling and intravascular sludging. Most patients a regulated 3- or 4-week transfusion program. The goal is to sup-
with sickle cell anemia are mildly dehydrated because of difficulty press reticulocytosis and to decrease the HbS level to less than
in concentrating urine. Fluid replacement can be oral or intrave- 25%. Rarely, transfusions are given for control of bone or visceral
nous, and the emergency physician should be aware of the poten- crises. This is not an emergency department procedure and is
tial for congestive heart failure in patients past their second decade. considered only after hematologic consultation. Prophylactic
A recommended starting solution is 5% dextrose in half-normal transfusions to dilute HbS levels are also recommended in preg-
saline at a rate not to exceed 1.5 times maintenance.15,39 Oxygen nancy and before major surgery.40 As discussed before, for stroke
through a nasal cannula at 2 to 4 L/min may help hypoxic patients in children, acute exchange transfusion is the treatment; for adults,
and may be given to any patient with HbSS as a low-risk treatment the treatment is tPA.
modality with potential benefit. A number of other therapies are being tested for both prophy-
Analgesia is a major benefit and essential early therapy for acute laxis and crisis management, including supplemental zinc, induced
sickle cell crisis. Because a small subgroup of patients repeatedly hyponatremia, gelation inhibitors, membrane-active agents, and
and frequently seek care in the emergency department, emergency gene manipulation. Poloxamer 188 is an artificial surfactant with
department caregivers may become understandably suspicious of hemorheologic and antithrombotic properties. Although the
needs and motivations. Care protocols are advised to ensure rapid mechanism of action of this agent is not fully understood, it
appropriate treatment. Many emergency physicians caring for improves microvascular blood flow by reducing blood viscosity
large populations of sickle cell patients have developed protocols and adhesive frictional forces. In clinical trials of sickle cell patients
to establish better physician-patient rapport and to lessen the with acute painful crisis, poloxamer reduced the total narcotic
chance of narcotic addiction and manipulation. The following is a requirement, duration of pain, and pain intensity.42
protocol for severe pain in adults and children weighing more than Sickle Cell–β-Thalassemia. Sickle cell–β-thalassemia disease is
50 kg: patients are evaluated, treated with oxygen and hydration, seen most commonly in people of Mediterranean descent. The
and given intravenous morphine sulfate, 5 to 10 mg every 2 to 4 severity of the disease is related to the concentration of HbS in
hours, or intravenous hydromorphone, 1.5 mg every 3 to 4 hours. RBCs and the decrease in MCHC. It should be considered in a
For children weighing less than 50 kg, intravenous bolus doses of patient with a low MCV and a positive response on sickle prepara-
morphine sulfate, 0.1 to 0.15 mg/kg, can be given every 2 to 4 tion. It is generally a milder form than homozygous HbSS but can
hours, or intravenous hydromorphone, 0.015 to 0.020 mg/kg, can be as severe as sickle cell disease. HbSC disease falls between HbSS
be given every 3 to 4 hours.28 At 4 to 6 hours, the patient is allowed and HbS-thalassemia in terms of severity. In addition to many of
to decide whether inpatient or outpatient therapy is desired. Out- the complications of HbSS, HbSC disease has an increased inci-
patient therapy includes 4 to 6 days of an effective oral analgesic. dence of eye hemorrhage and pregnancy complications and may
A 40-mg dose of oral morphine sulfate or equivalent is given 1 or cause splenomegaly. The peripheral smear demonstrates a combi-
2 hours before the infusion is stopped. Such a protocol may bring nation of sickled cells and normocytic target cells.
uniformity to the patient’s expectations for care and the physician’s Extrinsic Alloantibodies. Alloantibodies are formed in re-
decisions about therapy and admission. Its major disadvantage has sponse to foreign RBC antigens. In the case of the ABO system,
been a tendency to treat patients automatically rather than closely these antibodies are preformed. The ABO system is one of the
considering the potential acute complications of sickle cell disease. most important RBC wall antigens. ABO incompatibility resulting
No standard pain management exists for sickle cell disease. A in donor cell destruction by the recipient’s alloantibodies can be
variety of analgesics (nonsteroidal anti-inflammatory drugs, a life-threatening reaction. These antibodies are IgM in nature and
mixed opioid agonist-antagonists, and opiates), dosages, and can act as a hemolysin, both agglutinating RBCs and fixing com-
timing intervals may be chosen. Because many sickle cell disease plement and consequently causing intravascular hemolysis.
patients can have varying degrees of hepatic or renal dysfunction, The Rh system is another set of antigens on the RBC. This
acetaminophen and nonsteroidal anti-inflammatory drugs should system is unique in that individuals do not have antibodies that
be used with caution.28 Because many patients with acute pain correspond to antigens in the Rh system unless they have been
episodes are undertreated, the most important aspect of pain man- sensitized by previous exposure to antigens that they lack. The
agement in these patients is a consistent, thorough, and attentive antibodies produced are IgG in nature, and they accelerate extra-
approach that offers true pain relief.39 vascular destruction of RBCs by the spleen and liver. Most auto-
Blood transfusion has a well-accepted role in sickle cell anemia. immune antibodies are directed toward antigens in the Rh
Selected use can decrease the chronic transfusion problems of system.
antigen sensitization, iron overload, and hepatitis. Aplastic or Extrinsic Autoantibodies. Evaluation of autoimmune hemoly-
splenic sequestration crises may necessitate transfusion. Serial sis is as complex as its origin. The major feature of autoimmune
hemoglobin values and reticulocyte counts should be obtained hemolysis is the production of an IgG or IgM antibody to an
during hospitalization. Whereas the overall goal of simple transfu- antigen present on the RBC membrane. Why the body responds
sion therapy for symptomatic anemia is a hemoglobin level no in this manner is unknown. IgM antibodies can agglutinate, fix
higher than 10 g/dL, transfusion should not be used to treat complement, and act as intravascular hemolysins. IgG antibodies
asymptomatic patients, regardless of hemoglobin value.40 may fix complement to the cell but do not usually complete the
Priapism is a painful complication of sickle cell disease and may hemolysis process. These IgG- or C3-labeled cells undergo acceler-
lead to impotence. First-line therapy for priapism lasting longer ated extravascular destruction. The direct antiglobulin test is
than 2 hours is aspiration of blood from the corpus cavernosum useful in revealing these labeled cells.43
and irrigation with an alpha-adrenergic agent (e.g., phenyleph- Autoimmune hemolytic anemias are acquired disorders, with
rine). Surgical management is reserved for patients who fail to 40 to 50% being idiopathic. The remainder are associated
respond to aspiration and irrigation.41 Aspiration and irrigation with a number of diseases (Box 121-12). Classification of autoim-
of the corpus cavernosum can be difficult and time-consuming. mune hemolytic anemias is based on the optimal temperature at
This therapy is best reserved for urologic consultation. The use of which the antibody reacts with the RBC membrane. Therefore,
exchange transfusions in the treatment of priapism is controver- there are warm-reacting (>37° C) and cold-reacting (<37° C)
sial but appears to have no current role.41 antibodies.

Diseases Associated with Autoimmune Drugs Associated with Immune
BOX 121-12 Hemolytic Anemia BOX 121-13 Hemolytic Anemia
Neoplasms Hapten type with antibodies to the drug
Malignant: chronic lymphocytic leukemia, lymphoma, myeloma, Complement-fixing antibody: quinidine, quinine, phenacetin,
thymoma, chronic myeloid leukemia ethacrynic acid, p-aminosalicylate, sulfa drugs, oral
Benign: ovarian teratoma, dermoid cyst hypoglycemic agents
Non–complement-fixing antibody: penicillin dosages >20
Collagen Vascular Disease million units/day
Systemic lupus erythematosus Autoimmune type with antibodies to the RBC membrane:
Periarteritis nodosa D-methyldopa, L-dopa, mefenamic acid, chlordiazepoxide
Rheumatoid arthritis Cephalosporins at dosages >4 g/day may cause hemolysis by
Infections direct membrane injury
Mycoplasma
Syphilis
Malaria
Bartonella schizocytes or fragmented cells, which immediately raise the sus-
Virus: mononucleosis, hepatitis, influenza, Coxsackievirus,
picion of traumatic injury (see Fig. 121-8). Microangiopathic
cytomegalovirus
hemolytic anemia, cardiac trauma, and exercise-induced hemo-
Miscellaneous globinemia are the most commonly encountered forms of trau-
Thyroid disorders, ulcerative colitis matic hemolysis.
Drug immune reactions 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
Warm-reacting antibodies are characterized by a higher inci- renal lesions such as malignant hypertension and preeclampsia,
dence in younger patients (30-60 years), predominance in women, vasculitis, thrombotic thrombocytopenic purpura, disseminated
variable complement fixation, and positive direct antiglobulin test intravascular coagulation, and vascular anomalies. The signs and
result for IgG. Cold-reacting antibodies, or cold agglutinins, are symptoms are those of intravascular hemolysis. Treatment is
seen predominantly in men and older patients (50-80 years) directed at the causative disease.
and with IgM complement fixation. They may also be found in Cardiac trauma to RBCs results from increased turbulence. It
patients with infectious mononucleosis, Mycoplasma infection, may be found in patients with prosthetic valves, traumatic arte-
and lymphoma. Hemolysis may be intravascular and extra riovenous fistula, aortic stenosis, and other left-sided heart lesions.
vascular, and the direct antiglobulin test result is positive for Surgical correction may be necessary. Supportive therapy with an
complement. iron supplement is usually required.
Clinically, a patient with immune hemolytic anemia has the March hemoglobinemia is a form of trauma caused by breaking
signs and symptoms of anemia and, often, splenomegaly. Sphero- of intravascular RBCs by repetitive pounding. Soldiers, marathon
cytosis and reticulocytosis are noted in the blood smear. The direct runners, and anyone with repetitive striking against a hard surface
antiglobulin test result is positive in 90% of cases. The strength of may incur this problem. Reassurance and a change in the patient’s
the direct antiglobulin test result does not correlate with the sever- pattern of activity are the recommended therapy.45
ity of the hemolysis because the Coombs’ reaction is an antibody Environmental Causes. Hemolysis may be seen in cases of
function different from hemolysis or stimulation of reticuloendo- severe burns, freshwater drowning, and hyperthermia. Toxic
thelial sequestration. In patients with newly diagnosed, reticulo- causes of hemolysis have been documented to be of animal origin,
cytopenic or severe hemolytic anemia, the emergency physician such as brown recluse spider and some snake bites; vegetable
may need to institute transfusion therapy. Compatible blood may origin, such as castor beans and certain mushrooms; and mineral
be almost impossible to find because the antibody can react with origin, such as copper. Certain infections are associated with
almost all donors. The most compatible donor cells in terms of hemolytic states, including malaria, Bartonella infection, and
the ABO and Rh systems should be transfused with the knowledge Clostridium sepsis.
that they will be no more compatible than the patient’s own blood Abnormal Sequestration. Hypersplenism may be caused
cells. If emergency blood transfusion is required, type-specific or by any disease that enlarges the spleen or stimulates the reticulo-
type O blood (Rh-positive for men; Rh-negative for women of endothelial system. An unfortunate cycle can be set up in which
childbearing age) is indicated as well as prednisone or its equiva- the enlarged spleen traps more blood components and grows
lent in a dose of 1 mg/kg. Prednisone is believed to produce an larger. It is usually seen as splenomegaly with pancytopenia and
improvement in 60% of patients with warm antibody reactions. marrow hyperactivity. Chromium-labeled RBCs may demonstrate
Splenectomy and immunosuppressive therapy are also effective increased trapping in the spleen. Therapy for symptomatic or
in treating these reactions. Cold agglutinin hemolytic anemia may severe disease is splenectomy. Adults usually tolerate splenectomy
be self-limited, as after infectious mononucleosis. Other forms well, but children should be approached conservatively because
respond well to cold avoidance, variably to immunosuppressive the risk of postsplenectomy life-threatening sepsis is increased
agents, but poorly to steroids and splenectomy. Death commonly significantly.
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- POLYCYTHEMIA
ciated with this Coombs’-positive phenomenon and realize that Definition
the result of this test is sometimes positive only in the drug’s
presence. Common drugs and mechanisms of action are listed in Polycythemia is a term commonly used for erythrocytosis (i.e.,
Box 121-13.44 increased number of RBCs). This disorder is seen occasionally in
Extrinsic Mechanical Causes. Hemolysis may be caused emergency medicine but rarely in a life-threatening manner that
by trauma to RBCs. The peripheral smear may demonstrate requires emergency intervention.

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 Causes of Apparent and Secondary

BOX 121-14 Polycythemia
Erythropoiesis is controlled by the kidney-produced glycoprotein
hormone erythropoietin. It is activated in the liver and regulates Appropriately increased erythropoietin caused by tissue hypoxia
the committed erythropoietic stem cell. Its major stimulant is Congenital heart disease with a right-to-left shunt
tissue hypoxia. Neoplastic dysfunction of bone marrow may also Pulmonary disease (e.g., bronchial-type chronic obstructive
result in an elevated absolute RBC count. pulmonary disease)
The major complication of polycythemia is related to the Carboxyhemoglobinemia
High-altitude acclimatization
increase in blood viscosity associated with increased RBC numbers. Decreased tissue oxygen release from hemoglobinopathies
As the hematocrit rises past 60%, viscosity increases in an almost with high oxygen affinity
exponential manner. This condition increases the possibility of Inappropriate autonomous erythropoietin production
reduced tissue flow, thrombosis, and hemorrhage. This hazard is Renal origin: carcinoma, hydronephrosis, cyst
usually blunted to a degree by an associated increase in blood Other lesions: uterine fibroids, hepatoma of adrenal origin,
volume and some viscosity-reducing vascular dilation.46 cerebellar hemangioma
Congenital overproduction
Pure or essential erythrocytosis
Clinical Features AIDS and zidovudine treatment
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 confined to moderation, weight loss, and blood pressure control.
bleeding). The risk of vascular occlusive complications is minimal. The
On physical examination, the skin and mucous membrane hematocrit is usually less than 60% and RBC mass measurements
manifestations of the elevated RBC count are often readily are normal.47
observed. Plethora, engorgement, and venous congestion are com- Primary polycythemia vera is a myeloproliferative disorder
monly noted (Fig. 121-11). Other systems to be examined include found predominantly in middle-aged or older patients. It may
the fundus for venous congestion, the abdomen for evidence of have all the clinical components of polycythemia. Nonspecific
splenomegaly, and the cardiopulmonary system for signs of con- symptoms are reported in up to 30% of patients and include
gestive heart failure. Uterine, central nervous system, renal, and headache, weakness, dizziness, excessive sweating, and pruritus.
hepatic tumors should be sought in that these are associated with The most serious problems are thrombotic episodes (cerebrovas-
secondary polycythemia. An elevated RBC count, usually greater cular accident, myocardial infarction, and deep venous thrombo-
than the hematocrit, defines the disorder. It results in a low MCV, sis), bleeding, and bruising. Primary polycythemia vera is a disease
usually related to low serum iron and iron stores. Specific labora- that involves all cell lines—hematopoietic stem, erythroid, granu-
tory testing is discussed in the section on differential diagnosis. locytic, and megakaryocytic. Elevated hemoglobin or hematocrit
and RBC mass is present in virtually all patients. However, a plate-
Differential Diagnosis 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%
Polycythemia is classified as apparent, primary, or secondary (Box of patients, and storage iron was absent from the marrow in 94%.
121-14). Apparent polycythemia is a decrease in plasma volume The diagnostic criteria used by the Polycythemia Vera Study
such as found with dehydration. The RBC volume does not exceed Group are listed in Box 121-15.47
the upper limit of normal. Although it is a questionable diagnostic Polycythemia vera may be satisfactorily treated by phlebotomy
entity, “stress” polycythemia is the tendency for an elevated hema- as necessary. The reduced hematocrit improves some symptoms,
tocrit and is found in overweight, hypertensive, and overstressed but neither the leukocyte nor the platelet count is decreased.
middle-aged men. Increased cigarette smoking with its associated Maintenance of the hematocrit at less than 55% is recommended
increased carboxyhemoglobin level is considered to be partially to decrease hypervolemia and hyperviscosity. Complications
responsible. The symptoms are minimal, and treatment is necessitating additional therapy include hyperuricemia, refractory

WHITE BLOOD CELL DISORDERS

BOX 121-15 Diagnostic Criteria for Polycythemia Vera*
The WBC count and accompanying differential are the most
Category A common laboratory tests ordered in the emergency department.
Increased RBC mass It is essential that the basic physiology, pathophysiology, and clini-
In men: hemoglobin >18.5 g/dL
cal evaluation of WBCs be understood.
In women: hemoglobin >16.5 g/dL
Normal arterial oxygen saturation (>92%)
Splenomegaly Physiology and Pathophysiology
Category B The series has three morphologically indistinguishable cell types:
Thrombocytosis: platelets >400,000/mm3 B cells (humoral immunity), T cells (cellular immunity), and null
Leukocytosis: WBC count >12,000/mm3 (with no fever or
infection)
cells. Because lymphocytes can freely leave and return to the cir-
Leukocyte alkaline phosphatase score >100 culation, the storage pools are less well defined. Only 5% of the
Vitamin B12 >900 pg/mL, unbound vitamin B12–binding capacity total lymphocytes in the body are in the circulation. No marginal
<2200 pg/mL pool exists. Leukocytes primarily function extravascularly, and
their function is closely integrated with the other types of white
*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
cells. WBCs reach their site of action through the circulation. The
to be present. 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
increased RBC mass, severe pruritus, excessive splenomegaly, and or platelet count abnormalities, the differential diagnosis of
thrombocytosis. Additional therapy may consist of hydroxyurea, increased (leukocytosis) or decreased (leukopenia) WBC counts
busulfan, chlorambucil, interferon alfa, anagrelide, or radioactive can be organized by processes altering production, destruction,
phosphorus (32P). Studies suggest no improvement in long-term loss, and sequestration.
survival with the addition of these treatments.48 The natural The granulocytic and lymphocytic series are the two cell lines
history of the disease is that it burns out during a period of 15 to of WBCs. The granulocytic series is primarily involved in phago-
20 years. However, myelofibrosis with myeloid metaplasia may cytic activity. Its origin is the pluripotential stem cells located
develop. In 10% of cases, acute leukemia develops with a rapid in the bone marrow. A subset of these cells differentiates and
and poorly responsive downhill course. The 15-year survival for matures into the phagocytic cell lines, which include neutrophils,
polycythemia vera is 65%.49 The most common causes of death monocytes, basophils, and eosinophils. Granulocytes are main-
are thrombosis (29%), hematologic malignant neoplasms (23%), tained in a series of developmental and storage pools. The most
nonhematologic malignant neoplasms (16%), hemorrhage, and important is the postmitotic storage pool for neutrophils, which
myelofibrosis with myeloid metaplasia. represents 15 to 20 times the circulating population. This pool
Secondary polycythemia is classified first according to the contains metamyelocytes, band neutrophils, and mature neutro-
appropriate erythropoietin response to abnormal tissue oxygen phils (polymorphonuclear neutrophils). The pool can be drawn
levels. This group of disorders may be ruled out by normal mea- on as a ready reserve during rapid consumption of granulocytes.
sured arterial oxygen saturation. Second, inappropriate autono- Circulating neutrophils are subdivided equally into the circulat-
mous erythropoietin production is considered. This condition ing neutrophil pool and the marginal pool. The marginal pool
can be assessed with an erythropoietin assay. Because of a strong consists of mature cells adherent to the blood vessel walls. These
association with renal pathologic conditions, computed tomogra- cells can rapidly enter the circulating pool and cause a substantial
phy should be used to evaluate a patient with a suspected inap- increase, even doubling, of the WBC count. This involvement
propriate erythropoietin response. Most patients with secondary does not alter the maturity pattern of the differential count.51
polycythemia have no central nervous system symptoms or sple- The lymphocytic series matures in lymphoid tissues located in
nomegaly. Because erythropoietin stimulates only the red cell the bone marrow, thymus, spleen, lymph nodes, and elsewhere.
pathway, these patients have normal WBC and platelet counts. They are involved in the immune response against foreign
substances.
Management
Normal Values and Influences
The emergency treatment of any form of symptomatic polycythe-
mia is phlebotomy. Usually, not more than 500 mL of blood is One unique problem in WBC disorders is the wide variability in
removed as the volume is replaced with a comparable amount of normal values and the multiple factors influencing them. WBC
saline. No hemodynamic compromise should occur if this proce- counts are generally performed automatically by electrical imped-
dure is performed slowly. In true emergencies, up to 1 to 1.5 L of ance or optical diffraction techniques. Differential counts are
blood may be removed during a 24-hour period. The initial goal commonly performed by direct examination of 100 to 500 cells
is to lower the hematocrit toward 60%. The final goal is a level less with the oil immersion lens of the microscope. Automated tech-
than 55%. Low-dose aspirin, 80 to 100 mg/day, has been shown niques for all differential counts are becoming more popular,
to prevent thrombotic complications in patients with polycythe- however. Normal values for the WBC count are listed in Table
mia vera and can be used in the acute and chronic treatment of 121-8. The “normal” count is age dependent until childhood and
this disorder.50 may be shifted upward by exercise, gender (women), smoking,
and pregnancy. Decreases in the total WBC count range by 1000
Disposition to 1200 cells/mm3 have been noted in the African American
population.51 Laboratory errors may be due to improper sample
A number of patients with known polycythemia may be managed preparation, nucleated RBCs, or platelet clumping. The blood
by outpatient phlebotomies. Any newly diagnosed or symptomatic smear differential count may also be influenced by small sample
patient should be considered for admission to the hospital for full size, improper cell identification, and age group (children). Dif-
evaluation. ferential ranges are listed in Table 121-9. One common but easily

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.

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
Figure 121-12. Chronic myeloid leukemia. (From Hoffbrand AV, is the most frequent malignant neoplasm in children younger than
Pettite JE: Color Atlas of Clinical Hematology, 3rd ed. London, Mosby, 15 years. The potential for leukostasis increases in acute lympho-
2000:169.) 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
The need for urgent therapy in CML is usually related to found to the same degree in adults.54,55
hyperuricemia and renal injury or severe anemia and subsequent
angina or heart failure. Rarely, hyperleukocytosis occurs, but the Leukopenia
more mature, “less sticky” cells in CML do not usually cause
problems unless the count exceeds 500,000 cells/mm3. A higher In adults, leukopenia is defined as an absolute blood cell count less
cell count may cause leukostasis and result in deafness, visual than 4000 cells/mm3. Leukopenia is commonly associated with a
impairment, pulmonary ventilation-perfusion abnormalities, and reduction in one cell type, the neutrophil, and this decrease has
priapism. Treatment involves hydration, leukapheresis, transfu- the greatest clinical significance. The absolute neutrophil count
sion as necessary, allopurinol to prevent severe hyperuricemia, is calculated by multiplying the WBC count by the combined
and specific chemotherapy (hydroxyurea). Late problems in the percentage of band and segmented neutrophils. The absolute neu-
natural history of CML involve progressive loss of cell differentia- trophil count can be classified as mild (1000-1500 cells/mm3),
tion and response to therapy. The term blastic crisis represents the moderate (500-1000 cells/mm3), or severe (<500 cells/mm3)
sudden appearance of an acute form of leukemia, which is a rare according to the risk for infection. The last is a potentially life-
substage of the evolving deterioration.52 The condition may occur threatening state because the patient is markedly susceptible to
in lymphoid or myeloid forms. Blast counts greater than 50,000 overwhelming infection. The physical signs of infection may be
cells/mm3 may predispose the patient to the complications of minimal in severe neutropenia because there are too few cells to
leukostasis. generate a substantial inflammatory or purulent response. Neu-
tropenia may be caused by decreased production, increased
Leukemoid Reaction destruction, or movement of circulating neutrophils into marginal
or tissue pools. Until recently, it was most often caused by a
A leukemoid reaction is a nonleukemic reactive granulocytic leu- decrease in bone marrow production (Table 121-10). Autoim-
kocytosis that resembles CML but has no associated Ph1 chromo- mune neutropenia is also becoming more commonly diagnosed
some, no absolute increase in basophils and eosinophils, and an because it is thought to have a role in acquired immunodeficiency
increase in leukocyte alkaline phosphatase. It is difficult to distin- syndrome.56
guish from CML in the emergency department, and both need to A thorough medication history should be taken in all patients
be considered a potential diagnosis in granulocytic leukocytosis. found to have neutropenia. A previous history of neutropenia,
WBC counts are usually greater than 50,000 cells/mm3. A leuke- a review of recent infection, and a family history are obtained. The
moid reaction may be seen in tuberculosis, Hodgkin’s disease, review of systems focuses on bleeding problems, fatigue, sweats,
sepsis, and metastatic tumor, particularly bronchogenic, gastric, weight loss, and autoimmune symptoms. The physical examina-
and renal carcinoma.52 tion is directed toward sites of infection, lymphadenopathy,

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.

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1605.e2 PART III ◆ Medicine and Surgery / Section TEN • Hematology and Oncology
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Anemia, Polycythemia, and White Blood Cell Disorders

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Section Ten

HEMATOLOGY AND ONCOLOGY

Anemia, Polycythemia, and

ANEMIA reticulocyte (Fig. 121-1). The reticulocyte retains its ribosomal

History and Physical Examination for Clinically

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BOX 121-3 History and Physical Examination for Nonemergent Anemia

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Algorithm for the Evaluation of Anemia

MCV  81 fL MCV 81-100 fL MCV  100 fL

Iron deficiency Acute blood loss B12 deficiency

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

Thalassemia Iron deficiency Non-autoimmune Autoimmune

securing the diagnosis. The definitive diagnosis is usually made

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Table 121-3 Diagnostic Tests for Iron Deficiency Anemia

serum iron and ferritin levels, with transferrin saturation. The

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Aplastic Anemia Caused by Drugs

the total RBC population and needs to be related (“corrected”) to

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Increased Red Blood Cell Destruction

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Table 121-7 Organ Damage Seen in Sickle Cell Disease

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Pathophysiology Causes of Apparent and Secondary

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WHITE BLOOD CELL DISORDERS

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MCV 81 fL MCV 81-100 fL MCV 100 fL