CHAPTER 158 ApproAchtotheAnemiAs

1059

158
APPROACH TO THE ANEMIAS
H. FRANKLIN BUNN

Anemia is defined as a significant reduction in the mass of circulating red

blood cells. As a result, the oxygen binding capacity of the blood is dimin-
ished. Because blood volume is normally maintained at a nearly constant
level, anemic patients have a decrease in the concentration of red cells or
hemoglobin in peripheral blood. As shown in Table 158-1, hemoglobin and
hematocrit levels vary with the age of the individual and, in adults, with
gender. The values in women of childbearing age are 10% lower than those
in men. At altitude, higher values are found, roughly in proportion to the
elevation above sea level. Anemic patients values are more than 1 standard
deviation below the mean values for their gender. However, because of the
wide range in normal hemoglobin and hematocrit levels, it is often difficult
to document mild anemia. Anemia affects one fourth of the worlds popula-
tion, with a higher prevalence in low socioeconomic groups.1
Sometimes the diagnosis of anemia is confounded by a concomitant
change in the plasma volume. For example, if a patient with a low red cell
mass sustains a loss of plasma volume from dehydration, diarrhea, vomiting,
or severe burns, the blood hemoglobin and hematocrit levels will be increased
and may even be in the normal range. Another important example, discussed
in detail later in this chapter, is acute hemorrhage, in which the loss of both
red blood cells and plasma results in a false elevation of hemoglobin and
hematocrit. In contrast, hemoglobin and hematocrit values may be falsely low
in patients with an expanded plasma volume, such as in pregnancy or conges-
tive heart failure.
1060 CHAPTER 158 ApproAchtotheAnemiAs

PATHOBIOLOGY Blood Flow

Impact of Anemia on Oxygen Transport Anemia has a marked impact on blood flow, the left-hand variable in the Fick
In any organ or region of the body, the transport of oxygen is a product of equation. In all anemic individuals, there is enhanced flow to vital organs,
three independent variables expressed in the Fick equation (Fig. 158-1). The including the heart, brain, liver, and kidneys, at the expense of nonvital
middle variablethe oxygen carrying capacity of the bloodis, by defini- organs. Anemic patients are pale because blood is diverted away from the skin
tion, low in anemic patients. The two other variables in the Fick equation and mucous membranes to preserve oxygen supply to the critical organs.
undergo compensatory changes that, as explained later, greatly enhance Resting cardiac output is normal in patients with mild or moderate anemia,
oxygen transport.2 but with exercise, it increases more than that of a normal individual. In severe
anemia, resting cardiac output is increased, putting patients at risk for devel-
oping high-output cardiac failure, particularly those with coronary artery
insufficiency or other types of preexisting cardiac disease.
TABLE 158-1 NORMALVALUESFORREDBLOODCELL
MEASUREMENTS Oxygen Binding to Hemoglobin
NORMALRANGE The variable on the right side of the Fick equation is the difference in frac-
MEASUREMENT UNIT (APPROXIMATE)* tional oxygenation between the arterial and venous blood. This difference in
Hemoglobin g/dL Males: 13.5-17.5 oxygen saturation is determined by the hemoglobin oxygen-binding curve. A
Females: 12-16 comparison between a normal individual and an anemic patient is shown in
Figure 158-2. As shown in part A, the curve is shifted to the right in an anemic
Hematocrit % Males: 40-52
Females: 36-48 patient. At any given oxygen tension (Po2), the oxygen saturation of hemo-
globin is lower. Thus, red cells of anemic patients have decreased oxygen
Red blood cell (RBC) count 106/L of blood Males: 4.5-6.0 affinity. This change is due entirely to elevated levels of red cell
Females: 4.0-5.4
2,3-diphosphoglycerate (2,3-DPG) in red cells. This glycolytic intermediate
Mean cell volume (MCV) fL 81-99 is the principal determinant of oxygen affinity in human red cells. The Po2 in
Mean cell hemoglobin (MCH) pg 30-34 arterial blood is normally approximately 95 mm Hg, resulting in nearly 100%
Mean cell hemoglobin concentration g/dL 30-36 oxygen saturation. During the transit of red cells from an artery through its
(MCHC) capillary bed to its vein, oxygen is released to respiring cells. In normal indi-
RBC size distribution width viduals, at a normal venous Po2 of about 40 mm Hg, the oxygen saturation
RDW-CV % 12-15 is approximately 80%. Thus, as shown in Figure 158-2A, 20% of the oxygen
RDW-SD fL 37-47 in the blood is unloaded. In contrast, in patients with anemia and elevated
Reticulocyte count (absolute No./L of blood 20,000-100,000 red cell 2,3-DPG levels, the lower oxygen affinity of their red cells enables a
number) much higher fraction of the oxygen (as much as 35%) to be unloaded. In
Reticulocyte percentage % of RBCs 0.5-1.5
Figure 158-2B, the oxygen-binding curves are depicted with the volume frac-
tion of oxygen plotted on the y-axis. One gram of hemoglobin binds up to
*Actual normal ranges for many of these values may vary slightly, depending on factors such as the
location and type of laboratory instruments used, altitude above sea level, and patient age.
1.34 mL of oxygen under standard conditions of temperature and pressure.

Depending on analyzer instrument used, the RDW (red cell distribution width) can be reported as Thus, in a normal individual having a hemoglobin of 15 g/dL, the oxygen-
coefficient of variation (CV) and/or standard deviation (SD), RDW-CV and/or RDW-SD, carrying capacity of the blood is 15 1.34, or 20 mL O2/dL. As mentioned
respectively. earlier, 20% of this oxygen will be unloaded, that is, 4 mL O2/100 mL blood
during arterial-venous transit. In contrast, an anemic patient with a hemoglo-
bin of 7.5 g/dL has an oxygen-binding capacity that is half normal, or
O2 Delivery = Blood Flow Hb Concentration (Asat Vsat) 10 mL O2/dL. If this patient had red cells with normal oxygen affinity, 20%,
or only 2 mL of oxygen, would be unloaded per 100 mL of blood. However,
because the patients red cells have a lower affinity for oxygen, 3.5 mL is
Cardiac output Plasma RBC 2,3-DPG unloaded, nearly as much as normal. Thus, the decrease in oxygen affinity is
In anemia:
Altered flow distribution Erythropoietin RBC O2 affinity an important mechanism by which anemic patients compensate for the
deficit in red cell mass.
FIGURE 158-1. The Fick equation expresses the three independent variables that
determinethetransportofoxygentoagivenorganortissue.theimpactofanemia
on each of these variables is shown beneath the equation. Asat = oxygen saturation Methemoglobinemia
of arterial blood (oxyhemoglobin/oxyhemoglobin + deoxyhemoglobin); 2,3-DpG = In order for hemoglobin to reversibly bind oxygen, the iron atom in the heme
2,3-diphosphoglycerate(2,3-bisphosphoglycerate);hb=hemoglobin;rBc=redblood must be in the reduced (Fe2+) valence state. As red cells circulate, the heme
cell;Vsat=oxygensaturationofvenousblood. iron slowly auto-oxidizes to Fe3+, forming methemoglobin, which is incapable

100 20
20%
4 mL
O2 Content (volume %)

35%
% O2 Saturation

50 10
3.5 mL

Normal individual Normal individual

Anemic patient Anemic patient
DPG DPG

0 20 40 60 80 100 0 20 40 60 80 100
A PO2 B P O2

FIGURE 158-2. Oxygen-bindingcurvesforhemoglobinofanormalindividualandapatientwithanemia.A,conventionalplotofpercentofoxygen(o2)saturationversusoxygen

tension(po2).B,they-axisshowsthevolumeofoxygeninmillilitersper100mLofblood.DpG=diphosphoglycerate.
 CHAPTER 158 ApproAchtotheAnemiAs

1061
of binding oxygen. Normal red cells are endowed with a very efficient enzy- 10,000
matic pathway composed of cytochrome b5, cytochrome b5 reductase, and
NADH that rapidly reduces the iron in methemoglobin back to its functional
Fe2+ form. Thus, normal red cells contain less than 0.5% methemoglobin.
However, either an inherited deficiency in cytochrome b5 reductase or expo- 1,000

Ot
sure to an oxidant drug or toxin can result in methemoglobinemia.3 Labora-

he
tory samples of blood containing methemoglobin are dark brown, whereas

ra
Epo (mU/mL)

ne
patients with greater than 10% methemoglobinemia have cyanosis, a blue

mi
discoloration of the skin indistinguishable from that commonly seen in 100

as
patients having normal hemoglobin but low oxygen saturation owing to pul-
monary or cardiac disease. In many hospitals and large clinical laboratories,
the instrument that measures oxygen saturation in blood samples also pro- Uremia
vides an accurate determination of methemoglobin. 10 Normal
Patients with congenital methemoglobinemia inherit an autosomal reces-
sive deficiency in cytochrome b5 reductase. Heterozygote relatives have
low or undetectable methemoglobin levels, whereas affected individuals
(homozygotes and compound heterozygotes) generally have 10 to 35% met- 1
hemoglobin. These individuals are usually asymptomatic because the methe- 0 20 40 60
moglobin is distributed primarily in the older population of red cells. Hematocrit
Nevertheless, many affected individuals have cosmetic concerns. Treatment
with oral ascorbic acid or riboflavin is effective in lowering the level of met- FIGURE 158-3. Plasmaerythropoietin(Epo)levelsinpatientswithdifferentdegrees
ofanemia.thesubsetofanemiapatientswithchronicrenaldisease(labeledUremia)
hemoglobin below the threshold of detectable cyanosis. havemuchlowerplasmaerythropoietinlevelsthanthosewithothertypesofanemia.
A variety of drugs can cause methemoglobinemia, including acetamino- Valuesfornormalindividualsarealsoshown.
phen (Tylenol), dapsone, nitroprusside, amyl nitrate, procaine congeners
used for local anesthesia4, and recreational drugs (volatile nitrites called
poppers and cocaine). It is not clear why only a very small fraction of those
using these drugs develop this complication, but some affected individuals
have been shown to be heterozygous for cytochrome b5 reductase deficiency.
When these drugs are taken in prescribed doses, methemoglobinemia seldom
reaches levels high enough to cause clinical concern.
In contrast, individuals exposed to industrial toxins such as nitrite, nitrate,
or aniline may develop life-threatening levels of methemoglobin. The thresh-
old at which symptoms occur is highly variable. Acute induction of 20%
methemoglobin may cause fatigue; at 30%, individuals often develop tachy-
cardia. When methemoglobin exceeds 50%, patients experience weakness,
breathlessness, and confusion. At 70 to 80%, coma and death may occur. The
toxicity of methemoglobinemia is not just because of the inability of oxidized
hemes to bind oxygen; the remaining functional (Fe2+) hemes in the hemo-
globin tetramer have increased oxygen affinity and therefore, as suggested in
Figure 158-2, are much less effective in releasing oxygen to tissues. Patients
with toxic methemoglobinemia can be effectively treated with intravenous
infusion of methylene blue (1 to 2 mg/kg).

Regulation of Erythropoiesis by Erythropoietin

Anemia also affects the middle component of the Fick equation (see Fig.
158-1). As mentioned earlier, hemoglobin levels are, by definition, low in
anemic patients. The resultant decrease in the oxygen-carrying capacity of the
blood causes cellular hypoxia. In all cells of the body, a molecular sensor
detects even modest degrees of low oxygen tension and induces a hypoxia-
inducible transcription factor called HIF. HIF upregulates expression of the
hormone erythropoietin in the kidney and, to a lesser extent, in the liver.
Erythropoietin (Chapter 156) binds to a specific receptor abundantly
expressed on erythroid progenitor cells in the bone marrow and salvages
these cells from apoptosis, thereby enhancing red blood cell production.
Normal individuals maintain nearly constant levels of circulating red cells by
finely tuned regulation of erythropoietin production. In anemic patients, the
hypoxic signal in the kidneys and, to a lesser extent, in the liver results in a
robust induction of erythropoietin expression. As the hematocrit falls, the
plasma erythropoietin level rises markedly; in severely anemic patients, it
may be 1000-fold higher than normal (Fig. 158-3). In patients with anemia
due to impaired red cell production, the erythroid progenitors are unrespon-
sive to such high levels of plasma erythropoietin. In contrast, in patients
whose anemia is due to hemolysis or blood loss, elevated erythropoietin
levels maximize red cell production.
CLINICAL MANIFESTATIONS
Figure 158-4 is a 17th-century painting of a pale young woman clutching her
chest, apparently complaining of palpitations. Her physician is feeling her
pulse, documenting her rapid, forceful heartbeat. These signs and symptoms,
common in patients with very low hemoglobin levels, can be readily explained
by the cardiovascular adjustments discussed in the preceding section. These
clinical findings pertain to anemia per se, irrespective of cause, and are
FIGURE 158-4. The Sick Lady, a 17th-century painting attributed to Caspar
Netscher,fromtheRoyalCollection,BuckinghamPalace.
dependent on its severity and chronicity. The history and physical examina-
tion may reveal additional findings peculiar to specific causes of anemia or to
other comorbid conditions. The degree to which symptoms occur in an
anemic patient depends on several contributing factors. If the anemia has
developed rapidly, there may not have been adequate time for compensatory
adjustments to take place, and the patient may have more marked symptoms
than if an anemia of equivalent severity had developed insidiously. Further-
more, the patients complaints may depend on the presence of local vascular
disease. For example, symptoms owing to ischemia in patients with angina
pectoris, intermittent claudication, or transient cerebral episodes may be trig-
gered by the development of anemia.
Symptoms
Many individuals with mild anemia have no complaints and are unaware that
they have tired blood. Others may complain of fatigue as well as dyspnea
and palpitations, particularly following exercise. Patients with severe anemia
are often symptomatic at rest and are unable to tolerate significant exertion.
If the hemoglobin concentration falls below 7.5 g/dL, resting cardiac output
is likely to rise, with an increase in both stroke volume and heart rate. The
patient may be aware of this hyperdynamic state and complain of a rapid,
1062 CHAPTER 158 ApproAchtotheAnemiAs
pounding sensation in the precordium. Patients with compromised myocar-
dial reserve may develop complaints due to cardiac failure.
The symptoms of severe anemia often extend beyond the cardiac or circu-
latory system. Patients sometimes experience dizziness and headache and,
less often, syncope, tinnitus, or vertigo. Many are irritable and have difficulty
sleeping or concentrating. Because blood flow is shunted away from the skin,
patients may complain of increased sensitivity to cold. In like manner, gastro-
intestinal symptoms such as indigestion, anorexia, or even nausea are attrib-
utable to the shunting of blood away from the splanchnic bed. Females
commonly develop abnormal menstruation, either amenorrhea or increased
bleeding. Males may experience impotence or loss of libido.
Physical Findings
Pallor is the most commonly encountered physical finding in patients with
anemia. As mentioned earlier, this sign is due to the shunting of blood away
from the skin and other peripheral tissues, permitting enhanced blood flow
to vital organs. The usefulness of pallor as a physical finding is limited by other
factors that affect the appearance of the skin. Blood flow to the skin may
undergo wide fluctuations. Moreover, the skins thickness and texture vary
widely among individuals. Those with a fair complexion may appear pale
even though they are not anemic, whereas pallor is difficult to detect in deeply
pigmented individuals. The amount of melanin in the epidermis is an impor-
tant determinant of skin color. Pallor may be difficult to detect in patients
who have increased melanin pigmentation due to Addison disease or hemo-
chromatosis. Nevertheless, even in blacks, the presence of anemia may be
suspected by the color of the palms or of noncutaneous tissues such as oral
mucous membranes, nail beds, and palpebral conjunctivas. When the creases
of the palm are as pale as the surrounding skin, the patient usually has a
hemoglobin of less than 7 g/dL.
In addition to tachycardia, wide pulse pressure, and hyperdynamic precor-
dium, a systolic ejection murmur is often heard over the precordium, particu-
larly at the pulmonic area. In addition, a venous hum may be detected over
the neck vessels. These findings disappear when the anemia is corrected.
DIAGNOSIS
Laboratory Evaluation of the Patient with Anemia
In the clinical assessment of the anemic patient, it is important to proceed in
a systematic way so that the diagnosis can be established with a minimum of
laboratory tests and procedures. A thorough history and careful physical
examination are critical in the initial evaluation of the anemic patient. For
example, a family history that reveals a dominant inheritance pattern would
reinforce the tentative diagnosis of hereditary spherocytosis. The presence of
fever, a new heart murmur, and splenomegaly is an anemic patient suggests
subacute bacterial endocarditis.
In evaluating the anemic patient, the clinician must first ask whether the
anemia is caused by decreased production of red cells or by loss of blood cells
as a result of hemorrhage or hemolysis (Table 158-2). Blood loss may be
either the sole cause of the anemia or a significant contributor. Therefore,
examination of the stool for occult blood is an indispensable part of the evalu-
ation of all anemic patients.
The laboratory work-up of anemia includes a complete blood count, red
cell indices, reticulocyte count, and microscopic examination of the blood
smear. In addition, in many cases a bone marrow examination is a critical
component of the initial laboratory assessment.
TABLE 158-2 INITIALASSESSMENTOFANEMIA
Decreased red cell production
Usually acquired
Onset is insidious
Reticulocyte count is inappropriately low
Red cell indices (MCV, MCHC) are informative
Bone marrow examination is often required for diagnosis
Increased red cell destruction (hemolysis)
Often inherited
Onset may be abrupt or insidious
Reticulocyte count is increased
Red cell morphology on peripheral blood smear is usually informative
Bone marrow examination is usually not indicated
Blood lossmust be ruled out in any patient with anemia
MCHC = mean cell hemoglobin concentration; MCV = mean cell volume.
Complete Blood Count
Most hospitals and clinical laboratories use equipment that provides high-
throughput analyses of red cell, platelet, and white cell counts and white cell
differential, along with measurements of cell size. The mean red cell volume
(MCV) is normally 81 to 99 f L. These instruments also provide accurate
determinations of hemoglobin concentration. The hematocrit, or fraction of
packed red cells over total blood volume, is determined indirectly from the
red cell count and the MCV. The mean concentration of hemoglobin within
the red cell population (MCHC) is the quotient of hemoglobin divided by
hematocrit. The MCV is particularly useful in classifying the anemias caused
by decreased red cell production. Microcytic anemias have low MCV values
and often low MCHC. Microscopic examination reveals small and often pale
red cells. The MCV in the macrocytic anemias is increased, and large, oval
cells (macro-ovalocytes) are seen. In contrast to the anemias of underproduc-
tion, the hemolytic anemias are either normocytic or slightly macrocytic
owing to the preponderance of young red cells that are relatively large. Severe
forms of thalassemia (Chapter 162) are an exception; there, microcytic red
cells may be accompanied by brisk hemolysis.
Reticulocyte Count
This simple and cost-effective test is extremely useful for distinguishing
anemias secondary to decreased red cell production from those caused by
hemolysis. With the application of an appropriate supravital stain, the 1- to
2-day-old red cells in the peripheral blood reveal a network of purple
strands, which are aggregates of ribosomes. The reticulocyte count in normal
individuals is about 1%, consistent with a red cell lifespan of approximately
120 days. An elevated reticulocyte count reflects the release of an increased
number of young cells from the bone marrow. The rate of red cell produc-
tion can be assessed more quantitatively by determining the absolute reticu-
locyte count, the product of the percentage of reticulocytes and the red cell
count. Thus, normal blood contains about 50,000 reticulocytes/mm3. In
interpreting this test, one should consider the distribution of reticulocytes
between the bone marrow and the peripheral blood. When erythropoiesis
is robust, marrow reticulocytes enter the circulation prematurely. These
shift reticulocytes appear larger than average on a routine (Wright-stained)
blood smear and have a lavender hue, called polychromatophilia. Because
the circulation of shift reticulocytes in the peripheral blood is prolonged,
the reticulocyte count should be divided by two. This correction should
always be made if normoblasts are encountered in the peripheral blood
because this finding indicates the premature release of newborn red cells
into the circulation.
A failure to produce red cells is reflected in an inappropriately low reticu-
locyte count. In contrast, a significant elevation of reticulocytes is suggestive
of hemolysis. Exceptions include the following:
The brisk reticulocyte response seen in patients with hemorrhage
Reticulocytosis encountered in patients recovering from impaired eryth-
ropoiesis (e.g., an individual with pernicious anemia who received an injec-
tion of cobalamin 1 week earlier)
Mild to moderate elevations in reticulocytes (3 to 7%) encountered in
myelophthisic anemia (Chapter 157), in which the orderly release of cells
is affected by alterations of the marrow stroma owing to tumor, fibrosis, or
granuloma
These exceptions are generally appreciated in the initial evaluation of the
patient.
A number of ancillary laboratory tests described later under Hemolytic
Anemias are useful in determining both the cause and extent of hemolysis.
Examination of the Blood Smear
In the evaluation of any patient with unexplained anemia, the physician
should take the time to examine a well-stained peripheral blood film (Chapter
157). Many subtleties escape the attention of the technologist, whose primary
aim is to confirm or refine the white cell differential count provided by auto-
mated cell counters. The clinician approaches the specimen with a prepared
mind and can scrutinize it for specific abnormalities. Examination of the
blood film can confirm the size and color of red cells estimated by red blood
cell indices. In contrast to the mean statistical values provided by automated
cell counters, microscopic examination can reveal variations in red cell size
(anisocytosis) or shape (poikilocytosis), abnormalities that are helpful in
diagnosing specific anemias. Examination of the blood smear is particularly
important in a patient with hemolysis. Many types of hemolytic anemia have
characteristic abnormalities in red cell morphology. The presence of
 CHAPTER 158 ApproAchtotheAnemiAs
abnormal white cells may be the first clue to a lymphoproliferative or primary
bone marrow disorder.
Bone Marrow Examination
A microscopic examination of the bone marrow (aspirate with or without a
core biopsy) is often useful and may be critical in the work-up of any unex-
plained anemia. Study of the bone marrow is informative in the diagnosis of
anemias of underproduction, particularly those accompanied by abnormali-
ties in white cells and/or platelets, suggesting disordered hematopoiesis. The
more severe the anemia, the more likely it is that the procedure will be infor-
mative. An assessment of the quantity and quality of red cell precursors may
identify a defect in cell production due to either hypoplasia or ineffective
erythropoiesis. A marrow biopsy is required for estimating overall cellularity.
The ratio of myeloid (M) to erythroid (E) precursors is normally about 2 : 1,
but it may be artifactually increased by the inclusion of circulating leukocytes.
The ratio is increased in patients with infection, a leukemoid reaction, or
neoplastic proliferation of myeloid cells. Rarely, a high M/E ratio is due to
selective aplasia of the red cell precursors. A decreased M/E ratio indicates
erythroid hyperplasia. Erythroid maturation is normal in hemolysis and hem-
orrhage, but it is disordered when erythropoiesis is ineffective, such as in
megaloblastic and sideroblastic anemias and in -thalassemia major or inter-
media. The bone marrow examination is also important in demonstrating the
presence of cellular infiltrates such as those found in leukemia, lymphoma,
or multiple myeloma. The demonstration of tumor, fibrosis, or granuloma
usually requires a bone marrow biopsy, which provides information not avail-
able from bone marrow aspiration. A portion of the marrow specimen should
be stained with Prussian blue. In addition to providing an assessment of iron
stores, this iron stain is required for the identification of erythroid
sideroblasts.
ANEMIA DUE TO BLOOD LOSS
The clinical presentation of anemia resulting from blood loss varies consider-
ably, depending on the site, severity, and rapidity of the hemorrhage. At
opposite extremes are acute fulminant bleeding producing hypovolemic
shock and chronic occult blood loss leading to iron deficiency anemia.
Acute Blood Loss
Patients who have had a sudden hemorrhage present with clinical findings
secondary to hypovolemia and hypoxia. Symptoms and signs depend on the
severity of the process. The patient may experience weakness, fatigue, light-
headedness, or stupor and may appear pale, diaphoretic, and irritable. The
vital signs reflect cardiovascular compensation for the acute blood loss. The
degree of hypotension and tachycardia depends on the extent of the hemor-
rhage. Elicitation of postural signs is useful in the initial evaluation of a patient
with acute blood loss. When a patient is lifted from a supine to a sitting posi-
tion, an increase in the pulse of 25% or more or a fall in the systolic blood
pressure of 20 mm Hg or more signifies significant hypovolemia (blood loss
>1000 mL). Acute blood loss in excess of 1500 mL usually leads to cardio-
vascular collapse.
Following acute hemorrhage, the red cell mass and plasma volume are
contracted in parallel; accordingly, there is often not a significant decrease in
the hemoglobin or hematocrit level initially. This stress induces a moderate
leukocytosis and a shift to the left in the white cell differential count. In
both acute and chronic blood loss, the platelet count is often increased, par-
ticularly if the patient is already iron deficient. During the first few days after
acute blood loss, there is usually an increase in reticulocytes. Severe hypoxia
may trigger the release of nucleated red cells from the bone marrow into the
peripheral blood. Because young red cells are larger than old ones, the MCV
generally rises slightly. If significant blood loss continues, reticulocytosis will
persist until iron stores have been exhausted. Internal bleeding is often
accompanied by an increase in unconjugated bilirubin, reflecting an increase
in the catabolism of heme from extravasated red cells. Patients with acute
gastrointestinal blood loss sometimes have an elevation of blood urea nitro-
gen owing to impaired renal blood flow and perhaps to the absorption of
digested blood protein.
These patients must be assessed promptly, and treatment must be initiated
without delay. Patients with severe acute blood loss require transfusion of
packed red cells, with central monitoring of the appropriate amount of
volume replacement. The site or sites of bleeding should be emergently iden-
tified and controlled. In addition, an emergency coagulation profile should
be obtained. The approach to the patient with shock is discussed in detail in
Chapter 106.
1063
Chronic Blood Loss
Chronic blood loss is usually due to lesions in the gastrointestinal tract
or the uterus. Testing of stool specimens for occult blood is an essential but
frequently overlooked part of the evaluation of anemia. It is sometimes neces-
sary to examine serial specimens over a prolonged period because gastroin-
testinal bleeding may be intermittent. The hematologic manifestations of
chronic blood loss are those of iron deficiency anemia, discussed in detail in
Chapter 159.
ANEMIAS DUE TO DECREASED RED CELL
PRODUCTION
As shown in Table 158-3, anemias caused by the underproduction of red cells
can be conveniently classified according to red cell size: microcytic, macro-
cytic, and normocytic.
Microcytic Anemias
The presence of small red cells (MCV <77 f L) indicates a defect in the pro-
duction of hemoglobin.5 As shown in Figure 158-5, hemoglobin is composed
of globin subunits into which heme is inserted. Heme is produced by the
insertion of an iron atom into porphyrin (protoporphyrin IX). A defect in
any of these three key components can cause microcytic anemia. Most indi-
viduals with microcytosis have either iron deficiency anemia (Chapter 159)
or thalassemia (Chapter 162). A congenital or, more often, acquired impair-
ment in porphyrin synthesis can lead to a buildup of excess iron in erythroid
cells, resulting in the morphologic entity of ringed sideroblasts, which are
identified in red cell precursors in the bone marrow (Chapter 159). Most
patients with acquired sideroblastic anemia actually have a normal or some-
what elevated MCV but a broad distribution of red cell size, including a
population of microcytes (because of this ambiguity, sideroblastic anemia
appears in parentheses in Table 158-3). Iron deficiency anemia, the thalas-
semias, and sideroblastic anemia all involve some degree of ineffective
erythropoiesis.
The anemias of chronic inflammation and malignancy, described in detail
later, may be slightly microcytic owing to a defect in the availability of iron.
However, these disorders are more often normocytic. Measurement of serum
TABLE 158-3 ANEMIASDUETODECREASEDREDCELL
PRODUCTION
Heme Fe Iron deficiency
anemia
Fe
Porphyrin
Hemoglobin Sideroblastic
anemias
Fe
Thalassemias
Globin
FIGURE 158-5. Components of hemoglobin that are deficient in the microcytic
anemias.
1064 CHAPTER 158 ApproAchtotheAnemiAs

Unsaturated
Total iron- transferrin
binding
capacity Serum iron bound
to transferrin
500 10,000

400
1000
g/mL

ng/mL
300
100

200
10
100

0 1

n
er n
fic Iron

na te

fic Iron

er n
ad
y

ad
e
al

di er
io

io
nc

nc

nc
ov Iro

ov Iro
as
eg a
m

lo

lo
at

at

v
pr L
ie

ie

se
Li
or

m
N

m
de

de
fla

fla
In

In
A Serum iron and iron-binding capacity B Serum ferritin
FIGURE 158-6. A,Serumironandtransferrinsaturationindifferent conditions.B,Serumferritinin differentconditions.notethat they-axis in panel Bis on alogscale.the
normalrange(10to200ng/mL)isshownbythebeigeshadedarea.

iron and iron-binding capacity (Fig. 158-6A) and serum ferritin (Fig. 158-
6B) particularly useful in distinguishing between iron deficiency and the
anemia of chronic inflammation.
Macrocytic Anemias
A modest increase in red cell size is encountered in a variety of conditions,
including liver disease, hypothyroidism, acute blood loss, hemolytic anemia,
aplastic anemia, and alcoholism. Macrocytosis is so commonly seen in alco-
holism that the MCV has been used as a clinical screen for abstinence from
alcohol. Even in nonalcoholics, alcohol use can elevate the MCV. The mac-
rocytes in liver disease and hypothyroidism may be related to an increased
deposition of lipid in the red cell membrane. If the MCV exceeds approxi-
mately 105 f L, the patient is likely to be deficient in either cobalamin (vitamin
B12) or folic acid. The bone marrow reveals megaloblastic morphology,
reflecting impaired replication of DNA. Because nuclear maturation lags
behind cytoplasmic development, large red cells tend to be produced in the
bone marrow. Megaloblastic anemias are discussed in detail in Chapter 164.
Like the microcytic anemias, these disorders are maturation defects associ-
ated with ineffective erythropoiesis.
Normocytic Anemias
The normocytic anemias of underproduction are a diverse group of disor-
ders. They can be conveniently divided into two categories: those due to
intrinsic pathology within the bone marrow, and those secondary to some
other underlying disease.
PRIMARY BONE MARROW DISORDERS
The primary disorders of the bone marrow, such as the leukemias (Chapters
183 and 184), myelodysplasia (Chapter 182), aplastic anemia (Chapter 165),
and myelophthisis, are best approached by microscopic examination of a
marrow aspirate and biopsy. This group of anemias is often accompanied by
leukopenia and thrombocytopenia. A lesser degree of pancytopenia can also
occur in hypersplenism and in the megaloblastic anemias.
ANEMIAS OF CHRONIC DISEASE
Among the most common anemias and the ones most prevalent in patients
hospitalized on a medical service are those secondary to an underlying
chronic disease. The diagnosis is usually quite straightforward. However, in
some patients the predisposing illness may not be apparent. Thus, the pres-
ence of an unexplained normocytic anemia should prompt the search for the
disorders listed in Table 158-4. Even if the presence of an underlying illness
is established, the physician should investigate whether other factors such as
blood loss or a nutritional deficiency are also contributing to the patients
TABLE 158-4 ANEMIASSECONDARYTOCHRONICDISEASE
Inflammation
Chronic infections
Cancer
Connective tissue disorders
Renal insufficiency
Endocrine disorders
Hypothyroidism
Hypoadrenalism
Hypopituitarism
Hypogonadismmales
Liver disease
Aging
anemia. Generally, the anemias due to chronic inflammation, an endocri-
nopathy, or liver disease are of only moderate severity. In contrast, the anemia
of uremia is often severe.
ANEMIA OF CHRONIC INFLAMMATION
If a systemic inflammatory disorder persists for more than a few weeks, it is
nearly always accompanied by anemia. As shown in Table 158-4, the most
common causes of chronic inflammation are infection, tumor, or a connec-
tive tissue disorder. Many chronic infections can be responsible, including
tuberculosis, lung abscess, subacute bacterial endocarditis, pyelonephritis,
and osteomyelitis. The pathogenesis is more complex in some types of
chronic infections. For example, in AIDS (Chapter 393), the human immu-
nodeficiency virus can directly attack hematopoietic cells and suppress eryth-
ropoiesis. In malaria and babesiosis, the parasite enters circulating red cells
and triggers their destruction.
There is considerable variability in tumors ability to evoke an inflamma-
tory response. Many tumors express inflammatory cytokines as part of their
profile of abnormal gene expression. In some cases, impaired supply of
oxygen or nutrients to the interior of the tumor mass can lead to necrosis and
an inflammatory response. Red cell production may be further compromised
by encroachment of the bone marrow with leukemia, lymphoma, or meta-
static tumor.
Anemia is also a feature of a broad range of inflammatory conditions that
are not associated with either infection or cancer. In some of these disorders,
the autoimmune attack on the patients cells and tissues is met with a robust
inflammatory response. Rheumatoid arthritis (Chapter 264) is the most
commonly encountered connective tissue disorder and gives rise to the pro-
totypical anemia of chronic inflammation. Even more intense inflammation
 CHAPTER 158 ApproAchtotheAnemiAs
and, accordingly, more severe anemia are seen in polymyalgia rheumatica and
temporal arteritis (Chapter 271). In patients with systemic lupus erythema-
tosus (Chapter 266), the anemia of chronic inflammation is often com-
pounded by either immune hemolysis (Chapter 160) or renal insufficiency
(discussed later).
PATHOBIOLOGY
Recently, the mechanism underlying the anemia of chronic inflammation has
been elucidated by the discovery that plasma hepcidin levels are markedly
increased as a result of induction by inflammatory cytokines. As shown in
Figure 158-7, hepcidin blocks both iron absorption from the gut and the exit
of iron from macrophages, thus explaining both reduced levels of serum iron
and increased iron stores.
DIAGNOSIS
The anemia of chronic inflammation is associated with disordered iron
homeostasis. Increased storage of iron in macrophages within the bone
marrow, liver, and spleen results in elevated levels of serum ferritin (Fig. 158-
6B). However, because of a block in the transfer of this excess iron into the
plasma, serum iron is low (see Fig. 158-6A). The level of total transferrin in
Normal
Enterocyte Macrophage
Food iron
Fe
Fe
Ferroportin
Ferroportin
A Fe-Tf Plasma Fe ~100 g/dL Fe-Tf
Inflammation
Enterocyte Macrophage
Food iron
Fe
Fe
Ferroportin
Ferroportin
Hepcidin
Hepcidin
B Plasma Fe ~25 g/dL
FIGURE 158-7. Pathogenesis of the block in iron availability in the anemia of
chronic inflammation.the primary sources of iron in the plasma are from the break-
down of senescent red blood cells (rBcs) within macrophages and from duodenal
absorption.A,inthepresenceofphysiologicallylowlevels of hepcidinintheplasma,
thereisefficientreleaseofironfromtheduodenalenterocyteandfrommacrophages
throughferroportin.B,inpatientswithinflammation,theinductionofplasmahepcidin
by interleukin-6 and other cytokines results in the inactivation of ferroportin and the
lossofiron egressfromtheduodenalenterocyteandfromthemacrophage.
1065
the serum is also low for unclear reasons. With the recent development of a
reliable assay for hepcidin, elevated serum levels of this master regulator of
iron homeostasis should become useful in the diagnosis of the anemia of
chronic inflammation. Because of the impairment in iron availability, eryth-
ropoiesis is somewhat iron deficient. The amount of cytoplasmic iron is
decreased in erythroid precursors in the bone marrow, and the red cells that
enter the circulation are slightly microcytic. This suppression of red cell pro-
duction is earmarked by a low reticulocyte index. Because this block in iron
utilization is subtle, the degree of anemia is seldom severe in patients with
inflammatory disorders. If the hemoglobin is less than 8 g/dL, it is necessary
to look for additional contributors such as hemolysis or bleeding.
TREATMENT
Becausetheanemiaofchronicinflammationisnotsevere,patientsseldom
require red cell transfusions. Some patients may benefit from recombinant
erythropoietintherapy.However,theanemiaisnotfullycorrectedunlessthe
underlyingdiseaseiseffectivelytreated.
ANEMIA OF RENAL INSUFFICIENCY
A normocytic anemia almost always accompanies uremia (Chapter 130).
Although the hemoglobin level is highly variable, the severity of the anemia
is roughly proportional to the degree of impaired renal function. The cause
of the kidney failure usually has little bearing on the extent of anemia.
RBC However, for any level of serum creatinine, patients with polycystic disease
tend to be less anemic than those with other types of renal disease. In contrast
to the anemias associated with other chronic disorders, the anemia of uremia
can be very severe, with hemoglobin levels as low as 4 g/dL.
Examination of the bone marrow seldom reveals any abnormalities. Red
cell morphology is usually normal. In a minority of patients, the peripheral
blood smear reveals so-called burr cells characterized by an evenly scalloped
border. Neither the degree of anemia nor the red blood cell lifespan is influ-
enced by the presence of burr cells. In most patients, the corrected reticulo-
cyte count is low, and the red blood cell survival is only modestly decreased.
Thus, the low red blood cell mass is due to decreased red blood cell
production.
PATHOBIOLOGY
The primary basis for the anemia is the diseased kidneys inability to secrete
adequate amounts of erythropoietin. Plasma erythropoietin levels are lower
than those of nonuremic patients with a comparable degree of anemia (see
Fig. 158-3). Erythropoiesis is further impaired but not abolished in patients
who have undergone bilateral nephrectomy. In addition, red blood cell pro-
duction may be suppressed by the accumulation of substances that are nor-
mally cleared by the kidneys.
Other factors may aggravate the anemia of renal disease. Uremic patients
have a propensity to hemorrhage, owing to a qualitative defect in platelet
RBC
function. As in other patients, chronic gastrointestinal blood loss leads to iron
deficiency. Folic acid deficiency may also occur, owing to the poor nutrition
of many patients or to the loss of this vitamin during dialysis. Patients whose
renal failure is due to thrombotic thrombocytopenic purpura or hemolytic-
uremic syndrome (Chapter 172) have a severe form of microangiopathic
hemolytic anemia, with characteristic abnormalities of red blood cell mor-
phology (Chapter 157).
TREATMENT
Treatment of the anemia of uremia first focuses on reversing the renal
failure. A prompt and dramatic correction of the anemia follows successful
renal transplantation. Occasionally, polycythemia may be encountered after
renalengraftmentandmaybeaharbingerofimpendingrejection.
Inpatientswhoarenotcandidatesforrenaltransplantation,thetreatment
ofanemiaofuremiahasbeenrevolutionizedbytheadministrationofrecom-
binant human erythropoietin (rHuEPO). The rapid and complete responses
thatoccurunderscoretheimportanceoferythropoietininthepathogenesis
of anemia. Figure 158-8 shows the hematologic response of oneof the first
patientstreatedwithrHuEPO. WithinafewdaysofinitiatingrHuEPOtherapy,
thehematocritapproachednormal,necessitatingareductionindose.Before
rHuEPOtreatment,thispatientwasoverloadedwithiron,asdocumentedby
increasedserumferritinandnearlyfullsaturationofserumtransferrin.Asthe
 1066 CHAPTER 158 ApproAchtotheAnemiAs
45
Hematocrit
35
25
15
Transfusions: 200 mL RBCs
rHuEPO 150 units/kg 3 /wk
Reticulocytes, corrected (%)
6.0
Serum Fe 229 99
TIBC 227 201
% sat. 100 49
4.5 Ferritin 5738 4067
2.0
0 the cytoplasm of red and white blood cell precursors. In addition, ringed
12 8 4 0 +4 +8 + 12
Weeks
FIGURE 158-8. Responseofauremicpatienttorecombinanthumanerythropoietin
(rHuEPO) therapy. Before therapy, the patient was severely anemic and transfusion
dependent.treatmentwithrhueporesultedinareticulocytosis,followedby aprogres-
sive increase in hemoglobin. the dose of rhuepo had to be lowered to prevent the
hemoglobinfromrisingtoohigh.Beforerhuepotherapy,thepatientwasseverelyiron
overloaded.themarkedincreaseinredcellmassfollowingtherapywasaccompanied
byasignificantreductioninironstores.rBc=redbloodcell;tiBc=totaliron-binding
capacity.(FromeschbachJW,egrieJc,Downingmr,etal.correctionoftheanemiaof
end-stagerenaldiseasewithrecombinanthumanerythropoietin:resultsofacombined
phaseiandiiclinicaltrial.N Engl J Med.1987;316:73-78.)
redcellmassincreasedrapidlyfollowingtreatment,the robustutilization of
ironstoresresultedinadeclineinserumferritinandtransferrinsaturation.In
contrasttothispatientwithironoverload,manyuremicpatientsondialysis
therapy have normal or low iron stores before rHuEPO therapy and need
the concomitant administration of iron to maximize the erythropoietic
response. (See ErythropoietinTherapy in section on Approach to the Treat-
mentofAnemia.)
ANEMIA OF ENDOCRINE HYPOFUNCTION
The in vitro proliferation of erythroid cells is stimulated by a number of
hormones, including thyroxine, glucocorticoids, testosterone, and growth
hormone. Therefore, it is not surprising that a mild to moderate normocytic
anemia generally accompanies endocrine deficiency states, including hypo-
thyroidism, Addison disease, hypogonadism, and panhypopituitarism.
In the anemia of hypothyroidism, erythropoiesis is suppressed, and the red
blood cell lifespan is normal. A minority of patients have macrocytic red
blood cells, sometimes owing to cobalamin deficiency. Patients with hypo-
thyroidism have an increased incidence of pernicious anemia. Some patients,
particularly females with menorrhagia, develop iron deficiency and a micro-
cytic anemia. The anemia of hypothyroidism may be masked because of a
reduction in plasma volume. Because the signs and symptoms of hypothy-
roidism are sometimes elusive (Chapter 226), this diagnosis should be con-
sidered in any patient with unexplained anemia.
The anemia of adrenal insufficiency, including Addison disease, may also
be masked by a decrease in plasma volume. Untreated patients have an
average hemoglobin level of about 13 g/dL. Upon hormone replacement, the
plasma volume is rapidly reconstituted, and the hemoglobin level falls to 80%
of its pretreatment value. With continued therapy, the red blood cell mass
returns to normal.
Testosterone influences erythropoiesis in a physiologic manner. In males,
the mean hemoglobin level increases from 13 to 15 g/dL during the transi-
tion from puberty to adulthood. Eunuchoid males usually have a mild anemia
(hemoglobin 13 g/dL). Pituitary dysfunction or ablation is also associated
with a mild anemia.
The anemias secondary to endocrine failure are all readily corrected when
adequate hormone replacement is given.
ANEMIA OF CHRONIC LIVER DISEASE
Chronic liver disease, regardless of cause (Chapter 146), is usually accompa-
nied by mild or moderate anemia that is normocytic or slightly macrocytic.
An increased plasma volume may artificially lower the hematocrit, making
the anemia seem worse than it is. Red cell morphology is normal, except for
the presence of target cells (see Fig. 157-6) and occasional stomatocytes that
have a slitlike rather than a circular area of central pallor. These morphologic
features reflect an increased red cell membrane surface area due to increased
deposits of cholesterol and phospholipid. The bone marrow is usually normal.
Erythropoiesis fails to compensate for a modest shortening of the red cell
lifespan. The mechanism underlying the anemia of chronic liver disease is not
understood. The anemia is usually corrected if the patient regains normal
hepatic function.
In patients with alcoholic liver disease (Chapters 152 and 153), the situa-
tion is much more complex. Many factors can contribute to the development
of anemia. Alcohol in high doses suppresses not only erythropoiesis but also
neutrophil and platelet production. In alcoholics who continue to drink up
to the time of clinical evaluation, the bone marrow often reveals vacuoles in
+ 16
sideroblasts may be observed, especially if there is concurrent malnutrition.
Folic acid deficiency is common in alcoholics because of both a suboptimal
diet and an impairment of folate utilization. Moreover, the anemia in alcohol-
ics is often compounded by gastrointestinal hemorrhage as a result of gastric
erosions, duodenal ulcers, or esophageal varices. The risk for blood loss is
further increased by the presence of thrombocytopenia and/or deficiencies
in soluble clotting factors. Although alcoholics usually have increased iron
stores, they may become iron deficient after prolonged gastrointestinal bleed-
ing. Rarely, patients with alcoholic cirrhosis develop a severe hemolytic
anemia accompanied by the appearance of rigid blood cells with irregular
borders called acanthocytes or spur cells.
ANEMIA OF THE ELDERLY
As individuals age there is a slight and gradual fall in hemoglobin and hema-
tocrit levels. Elderly individuals whose values fall below 2 standard deviations
of normal have significantly enhanced morbidity and mortality. As people
age, there is also an increased incidence of cancer, myelodysplasia, renal insuf-
ficiency, and chronic inflammatory disorders, all of which can suppress red
cell production. Because of the high likelihood of comorbid conditions
among the elderly,6 it is not possible to affirm with any certainty whether
aging per se is a cause of anemia. Nevertheless, a fall in hemoglobin in any
patient, old or young, should prompt an investigation into the possible pres-
ence of one of these underlying disorders. Further studies will be needed to
elucidate the molecular pathogenesis of anemia of elderly people, as well as
to determine the appropriate hemoglobin concentrations for older adults in
light of age, gender, race, and comorbidities.
HEMOLYTIC ANEMIAS
With the exception of sickle cell disease (Chapter 163), hemolytic anemias
are encountered much less frequently than those caused by decreased red cell
production. Although they are a diverse group, the hemolytic anemias share
a number of clinical and laboratory features. Patients with moderate or severe
hemolysis may have icterus owing to an elevation in nonconjugated (indi-
rect) bilirubin. In addition, individuals with various types of hemolytic
anemia often have splenomegaly, signifying the primary site of enhanced red
cell destruction.
PATHOBIOLOGY
The presence of hemolysis is established by the laboratory tests outlined in
Table 158-5. Further evaluation is required to establish the specific diagnosis.
The clinician saves both time and money by using the available tests in a
rational and orderly manner. Diagnosis of hemolytic anemias is greatly facili-
tated by the use of a logical and pathophysiologically based classification
scheme. Table 158-6 groups these disorders going from the outside of the red
cell into the cytoplasm, as well as by whether the defect is inherited or
acquired. Hemolytic anemias due to environmental factors such as immune
destruction or traumatic rupture (Chapter 160) are acquired. Abnormalities
of red cell membrane proteins can also cause hemolysis. Mutations in
 CHAPTER 158 ApproAchtotheAnemiAs
TABLE 158-5 LABORATORYFEATURESCOMMONTO
HEMOLYTICANEMIAS
TABLE 158-6 CLASSIFICATIONOFTHEHEMOLYTIC
ANEMIAS*
*A more detailed differential diagnosis of the hemolytic anemias is presented in Table 160-1 in
Chapter 160.
G6PD = glucose-6-phosphate dehydrogenase; HUS = hemolytic-uremic syndrome; TTP =
thrombotic thrombocytopenic purpura.
proteins of the red cell cytoskeleton may cause hemolysis of varying severity.
The most commonly encountered is hereditary spherocytosis (Chapter 161).
Acquired red cell membrane defects are rare. Paroxysmal nocturnal hemoglo-
binuria is discussed in Chapter 160, and spur cell anemia was mentioned
earlier in the section on anemias secondary to chronic liver disease. The
proteins in the cytosol of the red cell include hemoglobin and enzymes.
Mutations in these proteins can result in inherited hemolytic anemias. Sickle
cell disease (Chapter 163) and the thalassemias (Chapter 162) are the most
commonly encountered hemoglobinopathies. Homozygous SS disease and
the compound heterozygous states SC disease and S/-thalassemia are pure
hemolytic anemias. In contrast, anemia in the clinically significant forms of
-thalassemia is primarily due to ineffective erythropoiesis. By far the most
common red cell enzyme defect is glucose-6-phosphate dehydrogenase defi-
ciency (Chapter 161).
DIAGNOSIS
A number of laboratory tests are used to establish the presence of accelerated
breakdown of red cells (see Table 158-5). As mentioned in the section Labo-
ratory Evaluation of the Patient with Anemia, the reticulocyte count is the
simplest and most cost-effective way to distinguish between hemolytic
anemias and those due to decreased red cell production. In this test, a super-
vital stain or a probe for RNA reveals strands of polyribosomes that are
present for only 24 to 48 hours after red cells exit the bone marrow. On a
routine Wright or Romanowsky stain, these cells often appear relatively large,
with a blue-gray hue (so-called polychromasia). The reticulocyte count is
nearly always elevated in patients with hemolysis (unless there is concomitant
marrow suppression, such as by folic acid or iron deficiency). This test is a
reliable index of red cell production. Thus, in patients with hemolytic anemia,
the bone marrow nearly always exhibits erythroid hyperplasia. Because this
result is predictable, a bone marrow examination is seldom helpful in patients
with hemolytic anemia, unless there is suspicion that the hemolysis is due to
an underlying lymphoma.
A number of serum and urine tests are available to confirm the presence
of hemolysis and assess its magnitude. As mentioned earlier, serum noncon-
1067
jugated bilirubin is elevated in proportion to the severity of the hemolysis.
Lactate dehydrogenase (LDH) isoforms type 1 through 3 are released from
red cells during hemolysis, resulting in increased serum LDH. Most kinds of
hemolytic anemia are extravascular, with red cell destruction mediated by
macrophages in the spleen, liver, and bone marrow. In these patients, a rela-
tively small amount of hemoglobin is released from engulfed red cells into
the plasma, where it binds specifically to haptoglobin. The hemoglobin-
haptoglobin complex is rapidly cleared from the circulation. Measurement of
serum haptoglobin is a useful test of hemolysis. Most patients with clinically
significant hemolysis have very low or absent levels. Less often, patients have
intravascular hemolysis with much higher levels of free hemoglobin in the
plasma, sufficient to traverse renal glomeruli and exceed the tubular reabsorp-
tion capacity. These patients have red or brown urine that, after centrifuga-
tion, tests positive with a dipstick that detects heme protein. Hemoglobinuria
can be readily distinguished from myoglobinuria. In the former, both the
plasma and the urine are pigmented. In the latter, the plasma remains color-
less because the smaller myoglobin molecule rapidly traverses the glomeruli.
Hemoglobinuria is often transient. For a week or so after the episode has
abated, the urine sediment will contain hemosiderin, which can be readily
detected with the Prussian blue iron stain.
After these general laboratory tests confirm the presence of hemolysis, an
array of specific tests is available to establish the specific cause (Chapters 160
through 163).
APPROACH TO THE TREATMENT OF ANEMIA
As in other disorders, the effective treatment of anemia is based on a thor-
ough diagnostic evaluation. Hematinics such as iron, cobalamin, or folic acid
should not be administered unless a specific deficiency has been demon-
strated or is anticipated. Although indiscriminate treatment with cobalamin
is not harmful per se, it lulls both the patient and the physician into a false
sense of security in the absence of a firm diagnosis. In contrast, the inappro-
priate use of iron preparations over a prolonged period can be directly
harmful, leading to a state of iron overload in some incorrectly diagnosed
patients.
Many kinds of anemias can be corrected if a precipitating cause can be
uncovered and reversed. If a drug or toxin is responsible, its withdrawal may
allow full recovery. Correction of anemia secondary to a chronic disease
usually depends on whether the underlying condition can be reversed. One
of the most dramatic dividends of successful renal transplantation is the rapid
correction of the anemia of uremia.
Erythropoietin Therapy
The administration of erythropoiesis-stimulating agents (ESA) (epoetin alfa
and darbepoetin alfa) is remarkably effective in certain circumstances. In
addition to those with the anemia of chronic renal failure, selected patients
with other types of anemia may benefit from ESAs. Treatment can lower
transfusion requirements in patients with cancer or HIV infection in whom
anemia has been aggravated by chemotherapy. In comparison with patients
with renal failure, higher doses are required for those with cancer or AIDS to
achieve the same increase in red cell mass. Treatment with ESAs has also been
effective in some patients with primary bone marrow disorders, particularly
myelodysplasia (Chapter 182). Transfusion requirements in surgical patients,
both perioperatively and postoperatively, may be reduced by prior short-term
administration of ESAs. Treatment may also benefit rare patients who are
unable to receive blood transfusions because of either antigen incompatibil-
ity or religious convictions.
A note of caution has emerged from a number of large studies suggesting
that high doses of ESAs that drive the hemoglobin level above 12 g/dL are
associated with a slight but significant increase in the risk for thrombosis
and cardiovascular mortality. Systematic reviews and meta-analyses of treat-
ment with ESAs in patients with chronic kidney disease that target higher
hemoglobin levels increase the risk for vascular access thrombosis and car-
diovascular complications (Chapters 130 and 131),A1A2 and likewise for
,
thromboembolic events in patients with cancer. A3
Primary bone marrow disorders pose a formidable therapeutic challenge.
Aplastic anemia (Chapter 165) can be cured by both immunosuppressive
therapy and stem cell transplantation. Long-lasting remissions can be
achieved in an increasing fraction of patients with acute leukemias by chemo-
therapy, often coupled with stem cell transplantation (Chapter 178). Other
primary bone marrow disorders that are unresponsive to these interventions
are treated with supportive measures such as transfusions of red cells and
platelets.
Red Cell Transfusion
The decision whether to transfuse an anemic patient is often challenging. The
risks and complications of the administration of blood products are discussed
in Chapter 177. Patients with chronic or long-standing anemia are able to
compensate in several ways, discussed earlier in this chapter. A considerable
reduction in red cell mass can be surprisingly well tolerated, especially if the
patient is young or sedentary. Transfusion is seldom indicated in a patient
with chronic anemia whose hemoglobin is 9 g/dL or greater. Those who are
expected to respond to the administration of a specific agent such as iron,
folic acid, or vitamin B12 can usually be spared transfusions.
Current evidence does not support the benefit of liberal transfusions in
patients with asymptomatic anemia and heart disease. Indeed the American
College of Physicians Guidelines on Treatment for Anemia in Patients with
Heart Disease warns against both red cell transfusion and the use of ESAs in
patients with cardiovascular disease who have mild to moderate anemia.7
However, if the anemia is severe and accompanied by myocardial or cerebral
ischemia or by congestive heart failure, prompt but slow administration of
packed red cells is indicated. Whole blood should be given only if the patient
is hypovolemic.

Splenectomy
Splenectomy is indicated in the treatment of certain hemolytic anemias. The
efficacy of splenectomy correlates with the degree to which the abnormal or
defective red cells are destroyed or sequestered in the spleen. Splenectomy is
curative in nearly all patients with hereditary spherocytosis (Chapter 161).
The operation may be also beneficial in selected patients with immunohemo-
lytic anemia, congestive splenomegaly, spur cell anemia, and certain hemo-
globinopathies and enzymopathies. The operative morbidity and mortality
from elective splenectomy are very low. The procedure can often be done by
laparoscopy. Occasional patients develop postoperative left subphrenic
abscess. Following splenectomy, young children are at risk for developing
overwhelming septicemia. This complication can be partially prevented by
vaccination against pneumococcus and meningococcus. Post-splenectomy
sepsis occurs rarely in adults. The risk for sepsis can be circumvented by
partial splenectomy. Thrombocytosis generally develops promptly following
splenectomy. However, in most cases it is transient. In patients with contin-
ued hemolysis or with a myeloproliferative disorder (Chapter 166), the
thrombocytosis usually persists and may occasionally be associated with
thromboembolic complications.

Grade A References

A1. Vinhas J, Barreto C, Assuncao J, et al. Treatment of anaemia with erythropoiesis-stimulating agents
in patients with chronic kidney disease does not lower mortality and may increase cardiovascular
risk: a meta-analysis. Nephron Clin Pract. 2012;121:c95-c101.
A2. Palmer SC, Navaneethan SD, Craig JC, et al. Meta-analysis: erythropoiesis-stimulating agents in
patients with chronic kidney disease. Ann Intern Med. 2010;153:23-33.
A3. Tonia T, Mettler A, Robert N, et al. Erythropoietin or darbepoetin for patients with cancer. Cochrane
Database Syst Rev. 2012;12:CD003407.

GENERALREFERENCES
For the General References and other additional features, please visit Expert Consult
at https://expertconsult.inkling.com.
 CHAPTER 158 ApproAchtotheAnemiAs
GENERALREFERENCES
1. Balarajan Y, Ramakrishnan U, Ozaltin E, et al. Anaemia in low-income and middle-income countries.
Lancet. 2011;378:2123-2135.
2. Bunn HF, Aster JA. Pathophysiology of Blood Disorders. New York: McGraw Hill; 2010.
3. Skold A, Cosco DL, Klein R. Methemoglobinemia: pathogenesis, diagnosis, and management. South
Med J. 2011;104:757-761.
4. Chowdhary S, Bukoye B, Bhansali AM, et al. Risk of topical anesthetic-induced methemoglobinemia:
a 10-year retrospective case-control study. JAMA Intern Med. 2013;173:771-776.
1068.e1
5. DeLoughery TG. Microcytic anemia. N Engl J Med. 2014;371:1324-1331.
6. Price EA, Mehra R, Holmes TH, et al. Anemia in older persons: etiology and evaluation. Blood Cells
Mol Dis. 2011;46:159-165.
7. Qaseem A, Humphrey LL, Fitterman N, et al. Treatment of anemia in patients with heart disease:
a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2013;159:
770-779.
1068.e2 CHAPTER 158 ApproAchtotheAnemiAs
REVIEW QUESTIONS
1. Which of the following laboratory tests would be least informative for
establishing the presence of ineffective erythropoiesis in a patient with
anemia?
A. Serum lactate dehydrogenase (LDH)
B. Serum bilirubin
C. Reticulocyte count
D. Serum erythropoietin level
E. Bone marrow examination
Answer: D In patients with ineffective erythropoiesis, there is erythroid
hyperplasia in the bone marrow. Therefore, the bone marrow examination
(answer E) is informative. Moreover, these patients have markedly enhanced
destruction of these erythroid precursors and, as a direct consequence, eleva-
tions of serum (nonconjugated) bilirubin (answer B) and LDH (answer A).
Unlike patients with hemolytic anemia, the reticulocyte count (answer C) is
low in ineffective erythropoiesis. In contrast to these informative tests, serum
erythropoietin (answer D) is not helpful because it will be elevated in nearly
all patients with anemia irrespective of pathogenesis.
2. What physiologic mechanism determines the regulation of erythropoietin
levels in the plasma?
A. Sensing of arterial oxygen tension in the carotid body
B. Sensing of intracellular oxygen tension in the carotid body
C. Sensing of arterial oxygen tension in the kidney
D. Sensing of intracellular oxygen tension in the kidney
E. Sensing of blood viscosity in the kidney
Answer: C The kidney is the primary site of erythropoietin production in
humans and other mammals. The transcriptional regulation of the erythro-
poietin gene depends on the sensing of oxygen tension within a subset of
renal interstitial cells at the boundary of the cortex and medulla. Note that
sensing of arterial oxygen tension in the kidney (answer D) would not benefit
the patient with anemia because arterial Po2 would likely be normal. The
sensing of oxygen tension in the carotid body (answers A and B) regulates
the rate of respiration. Regulation of the red cell mass by sensing blood vis-
cosity would be maladaptive (answer E).
3. Which of the following causes of anemia is best explained by inadequate
production of erythropoietin?
A. Uremia
B. Chronic liver disease
C. Iron deficiency
D. Renal cell carcinoma
E. Aplastic anemia
Answer: A In most patients with chronic renal failure (answer A), there is
damage to cells at the medullary-cortical boundary that produce erythropoi-
etin. Therefore, serum erythropoietin levels in these patients are inappropri-
ately low. The liver (answer B) produces much less erythropoietin than the
kidney, and therefore liver disease does not significantly affect erythropoietin
production. Renal cell carcinoma (answer D) sometimes causes elevated
levels of serum erythropoietin but never decreased levels. Serum erythropoi-
etin is markedly elevated in patients with aplastic anemia.
4. Which of the following best characterizes the impact of hepcidin on iron
homeostasis?
A. Decreased release of iron from the duodenal enterocyte and decreased
release of iron from the macrophage
B. Increased release of iron from the duodenal enterocyte and decreased
release of iron from the macrophage
C. Decreased release of iron from the duodenal enterocyte and increased
uptake of iron into the bone marrow
D. Increased release of iron from the duodenal enterocyte and decreased
uptake of iron into the bone marrow
E. Increased release of iron from the duodenal enterocyte and increased
uptake of iron into the bone marrow
Answer: A Hepcidin binds to and inactivates ferroportin, the transmem-
brane protein responsible for the export of iron from mucosal epithelial cells
in the duodenum as well as macrophages in the bone marrow and liver. As a
result, there is impairment of iron absorption from the gut and release of iron
from macrophages.
5. What is the most effective way a patient compensates for anemia due to
impaired red cell production?
A. Increased heart rate and stroke volume
B. Increased red cell oxygen affinity
C. Decreased red cell oxygen affinity
D. Decreased peripheral vascular resistance
E. Increased production of erythropoietin
Answer: C By far the most effective way in which the anemic patient com-
pensates for a reduction in red cell mass and oxygen carrying capacity is by
elevation of red cell 2,3-DPG, which shifts the oxygen binding curve to the
right and lowers oxygen affinity, thereby enhancing oxygen unloading to
tissues. Erythropoietin production (answer E) is markedly enhanced in
nearly all patients with moderate or severe anemia (except those with
chronic renal failure), but the high levels of plasma erythropoietin are inef-
fective in boosting hemoglobin levels in those with impairment of red cell
production. Increased resting heart rate and stroke volume (answer A) occur
only in patients with severe anemia, and neither these cardiac changes nor
decreased peripheral vascular resistance (answer D) are efficient modes of
compensation.