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Anemias arise from multiple etiologies. A full laboratory evaluation is
necessary to appropriately diagnose and determine the cause of anemia.
Iron deficiency is the most common nutritional deficiency worldwide and
is associated with symptoms of pallor, cardiovascular, respiratory,
cognitive complications, and decreased quality of life.
Oral or parenteral iron is used to treat iron deficiency anemia. The goal
of therapy is an increased hemoglobin of 1 to 2 g/dL within 2 to 4 weeks
Distinguishing between vitamin B12
-deficient and folic acid-deficient
megaloblastic anemia is important to minimize potentially permanent
effects of these deficiencies.
Patients with sickle cell disease should receive appropriate preventive
care, including infection prophylaxis with penicillin and routine
Acute sickle cell crises are an urgent situation and should be managed
with pain control, transfusions, oxygen, or antibiotic therapy as
Anemia of inflammation is associated with the upregulation of
inflammatory cytokines that results in shortened red blood cellsurvival
and decreased production. Treatment focuses on the underlying disease
and the use of erythropoietin (EPO).
Response to EPO depends on the dose and underlying cause of anemia.
Lack of response to treatment with erythropoiesis-stimulating agents
(ESAs) is commonly associated with functional or absolute iron
deficiency. Safety concerns with the use of ESAs have resulted in a
Risk Evaluation and Mitigation Strategy (REMS) program for the use of
Anemia is a reduction in red blood cell (RBC) mass. It is often described as a
decrease in the number of RBCs per microliter (μL) or as a decrease in the
hemoglobin (Hgb) concentration in blood to a level below the normal physiologic
requirement for adequate tissue oxygenation. The term anemia is not a diagnosis, but
rather an objective sign of a disease. Diagnostic terminology for anemia requires the
inclusion of the pathogenesis (e.g., megaloblastic anemia secondary to folate
deficiency, microcytic anemia secondary to iron deficiency) in order to implement
the appropriate specific therapy to correct the anemia.
Anemia is a symptom of many pathologic conditions. It is associated with nutritional
deficiencies, acute and chronic diseases, and may be drug-induced. Anemia is also
caused by decreased RBC production, increased RBC destruction, or increased RBC
loss. When anemia is caused by decreased RBC production, it may be the result of
disturbances in stem cell proliferation or differentiation. Anemias caused by
increased RBC destruction can be secondary to hemolysis, whereas increased RBC
loss may be caused by acute or chronic bleeding. Anemias associated with acute
blood loss, those that are iron-related, and those caused by inflammation constitute
1 Classifications of anemias according to pathophysiologic and
morphologic characteristics are shown in Table 92-1.
Pathophysiologic (Classifies Anemias Based on Pathophysiologic Presentation)
Acute: trauma, ulcer, hemorrhoids
Chronic: ulcer, vaginal bleeding, aspirin ingestion
Inadequate Red Blood Cell Production
Nutritional deficiency: vitamin B12
or bone marrow infiltration (leukemia, lymphoma, myeloma, metastatic solid tumors, myelofibrosis)
Endocrine deficiency: pituitary, adrenal, thyroid, testicular
Chronic disease: renal, liver, infection, granulomatous, collagen vascular
Excessive Red Blood Cell Destruction
Intrinsic factors: hereditary (G6PD), abnormal hemoglobin synthesis
Extrinsic factors: autoimmune reactions, drug reactions, infection (endotoxin)
Morphologic (Classifies Anemias by Red Blood Cell Size [Microcytic, Normocytic, Macrocytic] and
Hemoglobin Content [Hypochromic, Normochromic, Hyperchromic])
Defective maturation with decreased production
Megaloblastic: pernicious (vitamin B12
deficiency), folic acid deficiency
Genetic abnormalities:sickle cell, thalassemia
G6PD, glucose-6-phosphate dehydrogenase.
Normally, RBC mass is maintained by feedback mechanisms that regulate levels of
erythropoietin (EPO), a hormone that stimulates proliferation and differentiation of
erythroid precursors in the bone marrow. Two types of erythroid precursors reside in
the bone marrow: the burst forming unit–erythrocyte cell (BFUe) and colony forming
unit–erythrocyte cell (CFUe). The BFUe is the earliest progenitor, which eventually
develops into a CFUe. The BFUe is moderately sensitive to EPO and is under the
differentiates into erythroblasts and reticulocytes. The kidneys produce 90% of EPO;
liver synthesis accounts for the remainder. Reduced oxygen-carrying capacity is
sensed by renal peritubular cells, which stimulates release of EPO into the
bloodstream. Patients with chronic anemia may have a blunted and inadequate EPO
response for the degree of anemia present.
Signs and symptoms of anemia vary with the degree of RBC reduction as well as
with the time to development. The decreased oxygen-carrying capacity of the reduced
RBC mass results in tissue hypoxia followed by decreased perfusion to nonvital
tissues (e.g., skin, mucous membranes, extremities) in order to sustain tissue
perfusion of vital organs (e.g., brain, heart, kidneys). Slowly developing anemias can
be asymptomatic initially or include symptoms such as slight exertional dyspnea,
increased angina, fatigue, or malaise.
In severe anemia (Hgb <8 g/dL), heart rate and stroke volume often increase in an
attempt to improve oxygen delivery to tissues. These changes in heart rate and stroke
volume can result in systolic murmurs, angina pectoris, high-output heart failure,
pulmonary congestion, ascites, and edema. Thus, anemia is generally not well
tolerated in patients with cardiac disease. Skin and mucous membrane pallor,
jaundice, smooth or beefy tongue, cheilosis, and spoon-shaped nails (koilonychia)
also may be associated with severe anemia of different etiologies.
A thorough history, including a time line of onset of symptoms and current clinical
status, and physical examination are essential because of the complexity of the
pathologic conditions associated with anemia. When evaluating a patient for the
diagnosis of anemia, histories should include: (a) past and current Hgb or hematocrit
(Hct) values; (b) transfusion history; (c) family history, because longstanding
anemias can indicate hereditary disorders; (d) occupational, environmental, and
social histories; and (e) medication history, to eliminate drug reactions or
interactions as the cause of the anemia.
Pallor is most easily observed in the conjunctiva, mucous membranes, nail beds, and
palmar creases of the hand. In addition, postural hypotension and tachycardia can be
seen when hypovolemia (acute blood loss) is the primary cause of anemia. Patients
with vitamin B12 deficiency may exhibit neurologic findings consistent with nerve
fiber demyelination, which may include changes in deep tendon reflexes, ataxia, and
loss of vibration and position sense. Patients with anemia from hemolysis may be
slightly jaundiced from bilirubin release. Manifestations of hemorrhage can include
petechiae, ecchymoses, hematomas, epistaxis, bleeding gums, and blood in the urine
Although anemia may be suspected from the history and physical examination, a full
laboratory evaluation is necessary to confirm the diagnosis, establish severity, and
determine the cause. A list of the routine laboratory evaluations used in the workup
for anemia is found in Table 92-2. The cornerstone of this evaluation is the complete
blood count (CBC). Other evaluations assessing nutritional deficiencies, including
, and folate as well as EPO levels may also provide insight
into the cause of anemia as shown in Table 92-3. Males have higher normal Hgb and
Hct values than do females. The Hgb and Hct are increased in individuals living at
altitudes greater than 4,000 feet in response to the diminished oxygen content of the
Routine Laboratory Evaluation for Anemia Workup
Complete blood count (CBC): Hgb, Hct, RBC count, RBC indices (MCV, MCH, MCHC), WBC count (and
Serum iron, TIBC, serum ferritin, transferrin saturation
Peripheral blood smear examination
Stool examination for occult blood
Bone marrow aspiration and biopsy
aPerformed in patients with abnormal peripheral blood smears.
Hgb, hemoglobin; Hct, hematocrit; RBC, red blood cell; MCV, mean corpuscular volume; MCH, mean
blood cell; LDH, lactate dehydrogenase; TIBC, total iron-binding capacity.
The morphologic appearance of the RBC found in RBC indices included as part of
the CBC, including mean corpuscular volume (MCV), mean cell Hgb (MCH), and
mean cell Hgb concentration (MCHC), provide useful information about the nature of
the anemia. Note: corpuscular and cell may be used interchangeably when referring
to MCV, MCH, etc. Microscopic evaluation of the peripheral blood smear can detect
the presence of macrocytic (large) RBCs, which are associated with vitamin B12 or
folic acid deficiency, or microcytic (small) RBCs, typically associated with iron
deficiency anemia. Acute blood loss generally is associated with normocytic cells.
Supplemental Hematology Values
Erythropoietin (milliunits/mL) 4–26 4–26 4–26
Reticulocyte count (%) 0.5–1.5 0.5–1.5 0.5–1.5
TIBC (mg/dL) 250–400 250–400 250–400
Fe (mg/dL) 50–120 50–160 40–150
Ferritin (ng/mL) 7–140 15–200 12–150
RBC folate (ng/mL) — 140–960 140–960
Fe, iron; RBC, red blood cell; TIBC, total iron-binding capacity.
The history and physical examination and laboratory evaluation typically provide
sufficient information to distinguish among the most common forms of anemia (Fig.
92-1). If not identified after routine evaluation, problems such as autoimmune
disease, collagen vascular disease, chronic infection, or endocrine disorders may be
causing the anemia. When uncertainty exists or an abnormal peripheral blood smear
is noted, a bone marrow aspiration with biopsy is indicated.
Figure 92-1 Laboratory diagnosis of anemia.
There are many causes of anemia. This chapter is limited to the most common
anemias and their medication management. Hemolytic anemias will not be discussed.
Before proceeding, the reader should review the basic hematologic laboratory tests
used to evaluate and monitor anemia (see Chapter 2, Interpretation of Clinical
Iron deficiency is a state of negative iron balance in which the daily iron intake and
stores are unable to meet the RBC and other body tissue needs.
as iron-deficient erythropoiesis, which is a decreased supply of plasma iron to the
marrow for RBC synthesis, which can occur with normal or elevated amounts of
stored iron. The body contains approximately 3 to 4 g of iron, of which 2.5 g is found
4,5 Only a small fraction of iron is found in plasma and most is bound to
transferrin, the transport protein.
Despite the continuing turnover of RBCs, iron stores are well preserved because
the iron is recovered and reused in new erythrocytes. Only about 1 to 2 mg/day of
iron is lost from minor bleeding, urine, sweat, and the sloughing of intestinal mucosal
cells that contain ferritin in men and in nonmenstruating women.
women lose approximately an additional 1 mg of iron per day.
lactation are other common sources of iron loss (see Chapter 49, Obstetric Drug
Individuals with normal iron stores absorb roughly 10% of ingested dietary iron.
The average American diet contains 5 to 15 mg of elemental iron and 1 to 5 mg of
heme iron, resulting in 1 to 2 mg of absorbed iron from the intestines. For
menstruating, pregnant, or lactating women, however, the daily iron intake
requirement may be as high as 20 to 30 mg.
Iron is absorbed from the duodenum and upper jejunum by an active transport
mechanism. Dietary iron exists primarily in the ferric state and is converted to the
more readily absorbed ferrous form in the acidic environment of the stomach. The
ferrous form binds to transferrin for transport to the bone marrow, where it is
incorporated into the Hgb of mature erythrocytes.
Gastrointestinal (GI) absorption of iron is increased as much as three- to fivefold
in iron deficiency states or when erythropoiesis occurs at a more rapid rate.
sources of iron (heme iron) are better absorbed than plant sources (nonheme iron). A
number of issues, including gastrointestinal diseases, surgical bypass, a hypochloric
state, infections, or drug–food complexes, can alter the absorption of iron.
caused by iron deficiency is the most common nutritional deficiency worldwide.
Although iron deficiency anemia has many causes (Table 92-4), blood loss is
considered one of the more common. Common causes of chronic blood loss include
peptic ulcer disease, hemorrhoids, ingestion of GI irritants, menstruation, multiple
pregnancies, and multiple blood donations.
Dietary reference intakes (DRI) for iron are listed in Table 92-5.
amounts of iron required by pregnant or lactating women are difficult to obtain
through diet alone; thus, oral iron supplementation generally is necessary. Although
maternal iron usually provides term infants with sufficient stored iron for the first 6
months, infants 6 months to 3 years of age experience rapid growth and a threefold
increase in blood volume, which can increase the risk of iron deficiency. Premature
infants have reduced iron stores and thus require replacement therapy.
Menstruation, gastrointestinal (e.g., peptic ulcer), trauma, blood donation
Medications, gastrectomy, bariatric surgery, celiac, regional enteritis
Infancy, pregnant/lactating women, adolescence
Insufficient intake, diet (e.g., vegetarian)
Dietary Reference Intake for Iron
Healthy, nonmenstruating adults 8
Term Infants (Birth to 6 months) 0.27
aTwofold higher than those not consuming a vegetarian diet.
QUESTION 1: H.P. is a 31-year-old woman seen in the clinic. Her chief complaints include weakness,
Significant laboratory results include the following:
Total iron-binding capacity (TIBC), 450 g/dL
4+ stool guaiac (normal, negative)
follow-through are planned to evaluate her persistent epigastric pain.
What factors predispose H.P. to iron deficiency anemia?
Several factors predispose H.P. to iron deficiency anemia. Her history of heavy
menstrual bleeding and the 4+ stool guaiac indicate menstrual and GI sources of
blood loss. The GI blood loss may be secondary to H.P.’s chronic use of
nonsteroidal anti-inflammatory drugs, recurrent peptic ulcer disease, or both.
Many women of childbearing age have a borderline iron deficiency that becomes
more evident during pregnancy because of the increased iron requirements.
given birth to two children. Therefore, her iron stores have been repeatedly taxed in
recent years. In addition, absorption of dietary iron may be compromised by her use
of proton pump inhibitors and minocycline (see Case 92-1, Question 6).
Signs, Symptoms, and Laboratory Tests
H.P.’s constitutional symptoms of weakness and dizziness could be a result of her
severe anemia. Generally, until the anemia is severe, such symptoms occur with
equal frequency in the nonanemic population. The most important signs and symptoms
of iron deficiency anemia are related to the cardiovascular system and are a
reflection of the imbalance between the ongoing demands for oxygen against a
H.P.’s increased heart rate, decreased exercise tolerance, and pale appearance are
consistent with tissue anoxia and the cardiovascular response that may be seen in
iron deficiency anemia. H.P.’s iron deficiency has advanced to symptomatic anemia.
In patients who are not yet symptomatic, however, depletion of iron stores can be
detected by measuring ferritin, the iron storage compound. Although ferritin is
primarily an intracellular protein, serum concentrations of ferritin correlate closely
with iron stores with only a few exceptions.
7 Ferritin, an acute-phase reactant, is
generally found in higher levels in patients with inflammatory disorders, infection,
malignancy, liver disease, and chronic renal failure.
3,7 H.P. has a serum ferritin level
of 9 ng/mL; less than 12 ng/mLis consistent with iron deficiency. An increased TIBC
also can reflect depletion of storage iron, but it is less sensitive than serum ferritin.
Thus, in iron deficiency, the serum ferritin concentration is low, whereas the TIBC is
usually high; both of these parameters can be detected before the clinical
manifestations of anemia are apparent. These abnormalities persist and worsen
because anemia develops as illustrated by H.P.’s laboratory values. If the TIBC is
low or normal, rather than high, in association with a low serum ferritin, other causes
of anemia should be considered and evaluated with additional labs and bone marrow
H.P.’s low serum iron, low serum ferritin, and elevated TIBC are typical of the
laboratory findings associated with iron deficiency anemia. Serum transferrin
receptor levels, which reflect the amount of RBC precursors available for active
proliferation, are increased in iron deficiency. After stored iron is depleted, heme
and Hgb synthesis is decreased. In severe iron deficiency, the RBCs become
hypochromic (low MCHC) and microcytic (low MCV).
Usually, the RBC indices do not become abnormal until the Hgb concentration
falls to less than 10 g/dL. H.P.’s corpuscular indices indicate that her anemia is
The reticulocyte count provides an estimate of effective RBC production and is
usually normal or low in iron deficiency anemia. H.P. has a reticulocyte count of
0.2%, which also is compatible with iron deficiency anemia.
In the workup of a microcytic, hypochromic anemia, the stool should be examined
for occult blood. H.P. has a 4+ stool guaiac, which suggests blood loss via the GI
tract. Further diagnostic evaluations (e.g., endoscopy, abdominal X-rays) are
necessary to determine the underlying problem. In summary, H.P.’s signs, symptoms,
and laboratory findings all support the diagnosis of an iron deficiency anemia.
CASE 92-1, QUESTION 3: How should H.P.’s iron deficiency be managed? What dose of iron should be
given to treat H.P.’s iron deficiency anemia?
The primary treatment for H.P. should be directed toward control of the underlying
causes of anemia; GI blood loss, multiple childbirths, heavy menstrual flow,
decreased dietary iron absorption, and perhaps, an inadequate diet. The cause of her
GI blood loss should be corrected, her dietary intake should be analyzed and
modified and supplemental iron should be prescribed to replenish her stores and
The usual adult dose of ferrous sulfate is 325 mg (one tablet) administered 3 times
daily between meals. However, because of limited absorption of iron in the
intestines, repletion with lower doses of iron has been shown to be effective,
potentially minimizing side effects and improving compliance.
lost through bleeding, the required daily dose of elemental iron can be calculated
using a formula that assumes that 0.25 g/dL/day is the maximal rate of Hgb
CASE 92-1, QUESTION 4: What are the differences between iron products? Which is the product of
The ferrous form of iron is absorbed 3 times more readily than the ferric form.
Although ferrous sulfate, ferrous gluconate, and ferrous fumarate are absorbed almost
equally, each contains a different amount of elemental iron that is available for
11 Carbonyl iron, another iron product, is available but its use may be
limited owing to the fact that iron in this form must be solubilized by gastric acid to
be absorbed. Table 92-6 compares the iron content of several oral iron preparations
to assist in making appropriate treatment choices for patients.
Product formulation is of considerable importance in product selection. Sustained
release (SR) and enteric coated preparations may increase GI tolerance or decrease
side effects, increase bioavailability, and also may have additives claimed to
enhance absorption. Because these products can be given once daily, increased
adherence is an additional claim.
Comparisons of Oral Iron Preparations
Ferrous sulfate (time-released) 160 50 32
Note: This is a representative list of example oral iron preparations that may be utilized.
Anecdotal claims that SR iron preparations cause fewer GI side effects have not
been substantiated by controlled studies. These products transport iron past the
duodenum and proximal jejunum, thereby reducing the absorption of iron.
poor absorption and poor hematologic responses might occur with SR formulations,
caution should be used if chosen for initial treatment.
Adjuvants are incorporated into iron preparations in an attempt to enhance
absorption or mitigate side effects. An acidic environment is needed for absorption
in the duodenum and upper jejunum. Ascorbic acid (vitamin C), given in doses up to
1 gram, is able to increase iron absorption by approximately 7%; however, smaller
doses of vitamin C (e.g., 25 mg) do not significantly alter iron absorption.
decrease the side effect of constipation, stool softeners are also sometimes added to
5 The stool softener dose may not be appropriate and additional
doses may need to be taken. In summary, H.P. should take the least expensive iron
preparation containing ferrous sulfate, gluconate, or fumarate.
CASE 92-1, QUESTION 5: What are the goals of iron therapy? How long should H.P. be treated? How
The goals of iron therapy are to normalize the Hgb and Hct concentrations and to
replete iron stores. Initially, if the doses of iron are adequate, the reticulocyte count
will begin to increase by the 3rd to 4th day and peak by the seventh to 10th day of
therapy. By the end of the second week of iron therapy, the reticulocyte count will
fall back to normal. The Hgb response is a convenient index to monitor in outpatients.
Hematologic response is usually seen in 2 to 3 weeks with a 1 to 2 g/dL increase in
Hgb and a 6% increase in the hematocrit. H.P.’s anemia can be expected to resolve
in 1 to 2 months; however, iron therapy should be continued for 3 to 6 months after
the Hgb is normalized to replete iron stores.
7 Therapy duration is related to the
absorption pattern of iron with more iron being absorbed during the first month of
therapy; because iron stores are repleted, less is absorbed.
CASE 92-1, QUESTION 6: What information should be provided to H.P. when dispensing oral iron? What
can be done if she experiences intolerable GI symptoms (e.g., nausea, epigastric pain)?
Iron should be dispensed in a childproof container and H.P. should be counseled
to store it in a safe place, inaccessible to her young children. Accidental ingestion of
oral iron can cause serious consequences in small children
Managing Drug Overdoses and Poisoning). H.P. should be told that oral iron therapy
produces dark stools. She should try to take her iron on an empty stomach because
food, especially dairy products, decreases the absorption by up to 50%.
Gastric side effects, which occur in 5% to 20% of patients, include nausea,
epigastric pain, constipation, abdominal cramps, and diarrhea. Constipation does not
appear to be dose-related but side effects (e.g., nausea and epigastric pain) occur
more frequently because the quantity of soluble elemental iron in contact with the
stomach and duodenum increases.
5 To minimize gastric intolerance, oral iron therapy
can be initiated with a single tablet of ferrous sulfate 325 mg/day and increased by
increments of one tablet per day every 2 to 3 days until the full therapeutic dose of
325 mg 3 times daily can be administered.
H.P. also should be educated about potential drug interactions that can occur with
iron therapy. Currently, she is taking a proton pump inhibitor, which is thought to
inhibit serum iron absorption by increasing the pH of the stomach and decreasing the
solubility of ferrous salts. In addition, antacids can increase stomach pH, and certain
anions (carbonate and hydroxide) also are thought to form insoluble complexes when
combined with iron. Table 92-7 provides additional drug interactions to be
H.P. is also taking minocycline for the treatment of acne. Because the absorptions
of both iron and minocycline are decreased when administered concomitantly, the
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