OS 216: Hematology Dr.

Edwin Trinidad
Topic Conference 1: Anemias Exam 1

Lecture Outline problem exertional dyspnea, BP, needs further

grade 1-2/6 systolic testing
I. Case Summary
murmur, pale
II. Differential Diagnosis
cojunctiva, pale nail
III. Iron Deficiency Anemia beds
IV. Diagnostic Work-up
V. Management Anemia Fatigue Confirmatory
evaluation needed

Case Summary Type of History of regular Further evaluation

Anemia menorrhagia points needed
EM, a 30 year old female, married, housewife to chronic blood
was brought to the Emergency Room because she Hypoprolifer loss
fainted while attending church services. She gives a ative?
history of occasional dizziness and exertional dyspnea
for the past 3 months. There were no other symptoms. Maturation
Family history is negative for anemia and bleeding disorder?
tendencies. Menstrual and obstetric history: Gravida 2
Para 2. Children’s ages are 3 and 1, all delivered Blood
normally. She had an intrauterine device (IUD) inserted 2 loss/Hemolyt
months after her last delivery. Since then her menses ic?
have become prolonged for 7 days (usual – 3 days) but at
Anemia of Dizziness, No hx of chronic
monthly interval. Her flow is described as profuse,
chronic exertional dyspnea, disease, no signs of
consuming 6 napkins/day, fully soaked with blood for
inflammation pale conjunctiva, acute infection,
the first 4 days of menses.
/infection pale nail beds laboratory
evaluation needed
Physical exam: PR = 80, BP = 110/70, RR = 20,
to differentiate from
Temp = 37°C. Pertinent findings include pale conjuctiva,
iron-deficiency
anicteric sclerae. She has a soft systolic murmur,
anemia
grade 1-2/6 in all valvular areas. No masses were
palpable. Her nail beds are pale. Thalassemia Dizziness, Age of patient
exertional dyspnea, (usually
*pertinent points in Hx and PE are in bold. pale conjunctiva, thalassemia
pale nail beds (s/sx diagnosed at an
Differential Diagnosis
of anemia) early age), no
family history of
In our approach to establishing a diagnosis from
the history and PE, first let us ask: Is the condition of EM thalassemia, no
acute or chronic? hepatosplenomegal
Based on the history, EM already has a 3-month y,
standing history of occasional dizziness and exertional
dyspnea alongside regular menorrhagia. Her PE reveals a Iron- Dizziness, Further evaluation
soft systolic murmur. Both point to a chronic condition. deficiency exertional dyspnea, needed
(Based on History) What chronic conditions anemia profuse menstrual
present with fainting, dizziness, and exertional dyspnea? flow, pale
(Taking into consideration the PE) Which of these
conjunctiva, pale
also present with pallor and a systolic murmur?
nail beds

Differentials Rule in Rule out

Neurocardio Fainting (probably Three-month Working Impression: Iron-Deficiency Anemia (IDA)

genic due to crowded history of secondary to Chronic Blood Loss
syncope environment), pale occasional
conjunctiva, normal dizziness and Iron Deficiency Anemia
PR, normal BP, exertional dyspnea
suggests chronic I. Definition
disease - a condition where there is a decrease in red
blood cells and hemoglobin levels due to lack of iron.
Vertigo Faintness, No findings - occurs when iron stores have already been
dizziness pertaining to lesions used up due to inadequate intake, increased demand,
on visual, impaired absorption or chronic blood loss.
somatosensory or
II. Prevalence
vestibular systems;
Iron deficiency is one of the most common
further evaluation nutritional disorders globally. IDA accounts for 50% of
needed anemias and 841,000 deaths yearly worldwide. Seventy
one percent of mortality can be found in Africa and parts of
Cardiac Fainting, dizziness, Normal PR, normal Asia. North America accounts for only 1.4% of the total

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 OS 216: Hematology Dr. Edwin Trinidad
Topic Conference 1: Anemias Exam 1

mortality and morbidity associated with IDA. It is common reticuloendothelial system) and the body recycles the
in toddlers, adolescent girls and women of childbearing released iron.
age.
The National Nutrition Survey (1998) conducted There is no excretory pathway for iron. The only
by the Food and Nutrition Research Institute, Department mechanisms by which iron is lost from the body are blood
of Science and Technology revealed that the following
loss and the turnover of epidermal cells from the skin and
groups were anemic or suffering from IDA:
gut. The amount of dietary iron required to replace
5-6 out of 10 infants aged 6 months to less ongoing losses averages about 1.0 mg among men and
than 1 year 1.4 mg among women of childbearing age, equivalent to
3 out of 10 children aged 1 to 5 years the amount absorbed in the diet. The following figure
3 out of 10 young children aged 6 to 12 summarizes the process or iron absorption, usage, and
years
storage.
3 out of 10 teenagers aged 13 to 19 years
2-3 out of 10 adults aged 20 to 59
3-4 out of 10 older persons aged 60 years Figure 1.
and over
5 out of 10 pregnant women
4-5 out of 10 lactating women

III. Iron Absorption and Excretion

Iron is crucial for oxygen transport, energy

production and cellular growth and proliferation. Human
body contains around 3.5 g of iron, males having more
stores than females. In the United States, the average iron
intake in adult males is 15 mg/day with 6% absorption; for
the average female, the daily intake is 11 mg/day with
12% absorption. Thus on the average, only 1-2mg of
dietary iron is absorbed per day, which is enough to
replace iron losses from epithelial desquamation. In
pregnancy during the last two trimesters, daily iron
requirements increase to 5-6 mg/day. Iron availability is
affected by the nature of the foodstuff, with heme iron (e.g.
meat) being most readily absorbed.

Iron absorption takes place largely in the luminal

cells of the proximal small intestines (duodenum and
upper jejunum). Absorption is facilitated by the acidic pH of
the stomach, which maintains iron in solution. Transport
across the membrane is accomplished by divalent metal
transporter 1 (DMT1). At the brush border of the luminal
cell, ferrireductase converts ferric iron to ferrous iron,
which is the form used by the body. After absorprtion, iron
can either be used by the body or stored.
Seventy-five percent of iron is used for
hemoglobin production and erythropoiesis. Iron is
transported to the basolateral surface of luminal cells and
are released into the bloodstream as transferrin.
Transferrin is a bilobed glycoprotein with two iron-binding
sites. The iron-transferrin complex circulates in the plasma
until it interacts with specific transferrin receptors on the
surface of marrow erythroid cells (Diferric transferrin has
the highest affinity for the transferrin receptors). Once the
iron-transferrin complex interacts with its receptor, it is
internalized via clarithrin-coated pits and transported to an
acidic endosome, where the iron is released at the low pH.
Within the erythroid cell, iron is used to form hemoglobin.
Iron in excess of the amount needed for hemoglobin
synthesis binds to apoferritin, forming ferritin and is stored.
The mechanism of iron exchange also takes place in other
cells, especially liver parenchymal cells. (see Appendix 1)
Iron is stored in organs like the liver and heart in
the form of ferritin. Ferritin are molecules with a mineral
core containing thousands of iron atoms. The body
produces more ferritin in response to excess dietary
absorption of iron.
Iron is also recycled in the body. In a normal
individual, the average red cell life span is 120 days.
Senescent red cells undergo phagocytosis (through the
January 5, 2009 | Mon
IV. Stages of Iron Deficiency
There are three stages of iron deficiency namely
negative iron balance, iron-deficient erythropoiesis and
iron-deficiency anemia.
Negative iron balance (iron depletion) results
when demands for iron exceed absorption of iron from the
diet. Blood loss, pregnancy, rapid growth spurts in
adolescents, or inadequate iron intake can result to
negative iron balance. The iron deficit is initially
compensated by mobilization of iron stores. During this
stage, these iron stores decrease. As long as there are
adequate stores, serum iron, total iron-binding capacity
(TIBC)---an indirect measure of circulating transferring---
and red cell protoporphyrin (an intermediate in heme
synthesis) levels remain normal. Red cell morphology and
indices are normal during this stage. This stage is
generally asymptomatic and there is no overt effect on
erythropoiesis. It also escapes detection by hemoglobin
or hematocrit.
During iron-deficient erythropoiesis, iron stores
and serum iron decrease. TIBC and red cell
protoporphyrin levels gradually increase. Marrow iron
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 OS 216: Hematology
Topic Conference 1: Anemias
stores are absent and serum ferritin levels are below 15
μg/L. Hemoglobin synthesis is impaired when transferrin
saturation drops to 15-20%.
In iron-deficiency anemia, iron stores are
already inadequate to maintain hemoglobin production.
This stage is reflected by low hemoglobin and hematocrit
levels. Microcytic red cells and hypochromic reticulocytes
begin to appear. Transferrin saturation is now at 10-15%.
When there is moderate anemia (hemoglobin of 10-13
g/dL), the bone marrow remains hypoproliferative. With
severe anemia (hemoglobin of 7-8 g/dL), there is
prominent hypochromia and microcytosis. Target cells
and poikilocytes also appear on the blood smear. The
erythroid marrow also becomes more inefficient. Erythroid
hyperplasia of the marrow, instead of hypoproliferation,
occurs with prolonged IDA.
Figure 2. Comparison the 3 stages of iron
deficiency
IV. Etiology and Pathogenesis of IDA
Iron deficiency anemia (IDA) is the most common
form of anemia. Iron is an essential component of
hemoglobin, the oxygen-carrying pigment in the blood.
Iron is usually obtained from one’s diet and by recycling it
from old red blood cells. Blood cannot carry oxygen
effectively without iron and oxygen is needed for the
normal functioning of every cell in the body.
The causes of IDA are insufficient dietary intake
of iron, poor absorption of iron by the body, blood loss (like
from heavy menstrual bleeding) and need for iron exceeds
the reserves. Furthermore, in men and postmenopausal
women, anemia is usually caused by gastrointestinal
blood loss associated with ulcers, the use of aspirin or
nonsteroidal anti-inflammatory medications (NSAIDS), or
certain types of cancer (esophagus, stomach, colon).
Celiac disease may cause iron deficiency anemia.
January 5, 2009 | Mon
Dr. Edwin Trinidad
Exam 1
Anemia develops slowly after the normal stores
of iron have been depleted in the body and in the bone
marrow. Women of child-bearing age, in general, have
smaller stores of iron than men and have increased loss
through menstruation, placing them at higher risk for
anemia than men. Other high-risk groups include pregnant
or lactating women who have an increased requirement
for iron, infants, children, and adolescents in rapid growth
phases and those with a poor dietary intake of iron.
IDA during infancy
Iron deficiency anemia is a common
nutritional deficiency that affects children, especially
during the first two years of life (around 6-20 months).
There are several factors affecting the development of
IDA in infants, such as sex (more common in males),
rate of weight gain (faster gain associated with IDA),
term, iron stores of the mother, and episodes of intra-
and/or extrauterine bleeding.
After birth, there is decreased red blood cell
(RBC) formation (erythropoiesis) and iron from broken
down RBC is stored. However, when erythropoiesis
resumes (around 5.6-26 months according to some
studies), the stores are not enough, thus leading to a
state of iron deficiency. When iron stores are used up
(exacerbated in cases of decreased iron absorption
and blood loss), IDA (microcytic anemia) ensues.
Normal iron requirements are around 1 mg during
infancy, and factors that affect its absorption and
bioavailability in infants are important causes of iron
deficiency leading to IDA. Diet is one main factor.
Breastfeeding for 6 months usually provide the infant
with enough iron because breast milk contains more
iron and is more bioavailable than the iron found in
the alternative cow’s milk. Also, there is some
association between occult gastrointestinal bleeding
and cow’s milk. Introduction of different
complementary foods affect iron absorption differently
– meat increase iron stores, while drinks such as tea
inhibit iron absorption.
IDA in infants generally results from either
decreased iron absorption or bleeding (blood loss).
Decreased iron absorption occurs in celiac disease,
wherein there is gluten intolerance. There are also
studies associating Helicobacter pylori infection with
reduced iron absorption because the bacteria
compete with the acquisition of iron from food. Blood
loss in infants can be due to a lot of conditions, such
as ulcers, polyps, Meckel’s diverticulum, inflammatory
diseases of the GIT and renal diseases (like
glomerulonephritis/Goodpasture’s syndrome).
Parasitic infections by nematodes like Ascaris,
Trichuris and hookworm are also a source of chronic
blood loss.
IDA during pregnancy
Iron is an important nutrient during
pregnancy. Thus, it is imperative that pregnant women
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 OS 216: Hematology
Topic Conference 1: Anemias
ensure an adequate intake of iron in their diet. Iron is
necessary for the formation of maternal and fetal
hemoglobin, the oxygen-carrying component of blood.
Normally during pregnancy, erythroid hyperplasia of
the marrow occurs, and RBC mass increases.
However, a disproportionate increase in plasma
volume results in hemodilution (hydremia of
pregnancy). Since a woman's blood volume
increases by 25 to 50 percent during pregnancy, and
the baby is manufacturing blood cells too, more iron is
needed to make more hemoglobin for all that
additional blood. The increased need for iron puts the
mother at risk for anemia. Furthermore, during the last
trimester, the baby draws from the mother some of
the iron reserves that it will need during the first four
to six months of life. Thus, it is really essential that the
mother has sufficient iron stores all throughout the
pregnancy. The increased blood volume and iron
stores will also help the mother’s body adjust, to some
degree, to the blood loss that occurs during childbirth.
The causes of IDA during pregnancy may be
poor intake of iron, loss of blood from bleeding
hemorrhoids or gastrointestinal bleeding. Maternal
iron deficiency anemia is associated with an
increased incidence of anemia in the baby during the
first year of life. Pregnant women with iron deficiency
anemia, particularly in the first and second trimesters,
have an increased risk for premature delivery and for
delivering a low-birth weight infant.
IDA during lactation
Studies have shown that anemia is common
among lactating women. Ensuring adequate intake of
all hemopoietic nutrients during lactation is also
critical. The benefits of iron supplementation during
pregnancy to reduce the risk of anemia during
pregnancy and improve iron stores beyond 6 months
postpartum are well established. Although providing
supplements during lactation is not contraindicated,
the efficiency of absorption is much higher during
pregnancy. In contrast to iron, the requirements for
folate and vitamin B12 are increased during lactation.
The iron content of breastmilk is relatively
protected and not influenced by maternal nutritional
status, but depletion of maternal stores can result
among poorly nourished women who are already
anemic prior to lactation. A randomized clinical trial of
pregnant women showed that iron supplementation
during the last trimester of pregnancy did not alter the
concentrations of iron, copper, selenium and zinc in
breast milk. In contrast, there is evidence that the
breast milk level of other hemopoietic nutrients such
as folic acid, vitamin A and vitamin B12 are affected
by maternal status.
* See Appendix 2 for Pathologic Correlation for EM’s
Case
V. Clinical Manifestations
Signs and symptoms of anemia depend on the
severity of the condition. People with mild anemia or
anemia that has come on very slowly may have no
symptoms at all. However, if the anemia is severe, the
symptoms increase and become more serious. Many of
January 5, 2009 | Mon
Dr. Edwin Trinidad
Exam 1
the signs and symptoms of iron-deficiency anemia are true
for all kinds of anemia.
The main manifestations in EM’s case were the
following: fainting, dizziness, exertional dyspnea, pale
conjunctiva, pale nail beds and a soft systolic murmur.
The major symptom of all types of anemia,
including iron-deficiency anemia, is fatigue (feeling tired).
Fatigue is caused by having too few red blood cells to
carry oxygen to the body. This lack of oxygen in the body
can cause people to feel weak or dizzy, have a headache,
or even pass out when changing position (for example,
standing up).
Since the heart must work harder to move the
reduced amount of oxygen, signs and symptoms may
include shortness of breath and chest pain. This can lead
to a fast or irregular heartbeat or a heart murmur.
In anemia, the red blood cells don't have enough
hemoglobin. Common signs of lack of hemoglobin include
pale skin, tongue, gums, and nail beds. Pallor of the skin
may be difficult to appreciate in dark skinned individuals,
therefore scleral or palmar pallor may be more reliable as
a finding.
Other Signs and Symptoms of Anemia
Other signs and symptoms of anemia can include:
Cold hands and feet as well as brittle nails
Swelling or soreness of the tongue and cracks in the sides
of the mouth
An enlarged spleen
Frequent infections
Additional findings include blue sclera, koilonychias,
angular stomatitis, and functional gastrointestinal tract
abnormalities.
Signs and Symptoms of Iron-Deficiency Anemia
Symptoms of iron-deficiency anemia include
unusual cravings for nonfood items such as ice, dirt, paint,
or starch. This craving for nonfood items is called pica.
Another symptom of iron-deficiency anemia is
developing restless legs syndrome (RLS). RLS is a
disorder that causes an uncomfortable feeling in the legs
that can only be relieved by movement. Sleep is difficult
for people with RLS.
Age of onset of anemia is an important clue, as
iron deficiency is uncommon before 4 to 6 months of age
in the absence of prematurity. In infants and young
children, signs and symptoms include a poor appetite,
being irritable, and a slower rate of growth and
development.
Some of the signs and symptoms of iron-
deficiency anemia are related to its causes, such as blood
loss. Blood loss is most often seen with very heavy or long
lasting menstrual bleeding or vaginal bleeding in women
after menopause. Other signs of internal bleeding are
bright red blood in the stool or black, tarry-looking stools.
Diagnostic Work-Up
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I. CBC count
o To establish the presence of anemia
o May also indicate severity of anemia
• In chronic iron deficiency anemia, the cellular
indices show a microcytic and hypochromic
erythropoiesis
 both the mean corpuscular volume
(MCV) and mean corpuscular
hemoglobin concentration (MCHC)
have values below the normal range
(Normal ranges: MCV=83-97 fL;
MCHC=32-36 g/dL
 Platelet count is usually elevated
(>450,000/µL) while WBC count is
within normal ranges (4500-11,000/µL).
 Note: If the CBC count is obtained
succeeding blood loss, values reach
abnormal levels only after most of the
RBCs produced before bleeding are
destroyed at the end of their lifespan
(120 days).
II. Peripheral Blood Smear
o The presence of microcytic and hypochromic
erythrocytes in the examination of a peripheral smear
is indicative of chronic iron deficiency anemia.
Microcytosis is apparent way before MCV values
decrease after an event causing iron deficiency.
Platelet count is often elevated.
o No target cells (rules out thalassemia), anisocytosis
and poikilocytosis not marked
o No intraerythrocytic crystals (rules out Hb C disorders)
III. Serum iron, total iron-binding capacity (TIBC), and
serum ferritin
o Serum iron
• Reflects the amount of circulating iron bound to
transferring
• Normal range: 50–150 mcg/dL
• Clinician must be aware of the diurnal variation
o Total Iron Binding Capacity (TIBC)
• An indirect measure of the circulating
transferrin.
• Normal range: 300–360 mcg/dL
o Transferrin saturation
• serum iron x 100 ÷ TIBC
• Normal range: 25–50%, Iron-deficiency state:
<18%
January 5, 2009 | Mon
Dr. Edwin Trinidad
Exam 1
o Serum Ferritin
• In steady-state conditions, the level of serum
ferritin correlates with with total body iron
stores; therefore it is the most convenient
laboratory parameter that can be used to
estimate iron stores. normal values differ
according to the age and gender of the
individual (Adult males ~ 100 mcg/L, adult
females ~ 30 mcg/L)
• <15 g/L  diagnostic of depleted body iron
stores
A low serum iron and ferritin with an elevated TIBC
are diagnostic of iron deficiency.
Usually, Low serum ferritin  iron deficiency
However, normal serum ferritin can be seen in patients
who are deficient in iron and have coexistent diseases
(hepatitis, anemia of chronic disorders)
May be used in distinguishing iron deficiency anemia from
other microcytic anemias.
IV. Bone Marrow Aspirate/Biopsy
o Can be used to diagnose iron deficiency through the
absence of stainable iron in a bone marrow aspirate
that contains spicules and a simultaneous control
specimen containing stainable iron (no lab tests)
o Largely replaced by the diagnosis of iron deficiency
anemia through the measurement of serum Fe, TIBC
and serum ferritin.
o Diagnostic in identifying/ruling out the sideroblastic
anemias (with ringed sideroblasts in the aspirate
stained with Perls stain)
V. Serum Levels of Transferrin Receptor Protein
o Transferrin receptor protein (TRP or TfR)
• Found most abundantly on the surface of
erythroid cells than on any cell in the body and
released into circulation
• Serum levels reflect total erythroid mass
• Normal values: 4-9 g/L
• Distinguish between iron-deficiency anemia
(elevated TRP) and anemia of chronic disease
(normal TRP)
VI. Other tests
o Test for fecal occult blood
• To rule out the possibility of a GI source of
bleeding (most common cause of iron-
deficiency anemia in adult men and post-
menopausal women)
o Endoscopy
• To rule out GI malignancy
o Tissue lead concentrations
• Chronic lead poisoning may cause mild
microcytosis. Patients with iron deficiency are
at higher risk for lead poisoning due to
increased absorption of lead in this condition.
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 OS 216: Hematology Dr. Edwin Trinidad
Topic Conference 1: Anemias Exam 1

iron, usually due to persistent GI blood

loss
Management • Possibility of anaphylaxis is a concern
• Serious adverse reaction rate to iron
1. Removal of IUD dextran is 0.7%
• Profuse menstrual bleeding is one of the • Newer iron complexes: sodium ferric
possible side effects of IUD’s, especially gluconate (Ferrlecit) and iron sucrose
Copper IUDs (Venofer)  much lower adverse
• IUDs increase the risk of anemia reaction rate
• In this case, the patient is already • Amount of iron needed by individual:
symptomatic, suggesting that the Body weight (kg) x 2.3 x (15-patient’s hemoglobin,
anemia could be severe g/dL) + 500 or 1000 mg (for stores)
• Other contraceptive methods may be
recommended
Appendix 1
2. Red Blood Cell Transfusion
• Patient is already symptomatic – anemia
is probably severe
• Corrects the anemia acutely and
transfused RBCs provide a source of
iron for reutilization
• Stabilizes patient while other options are
reviewed

3. Oral Iron Therapy

• 200-300 mg iron/day, in 3-4 iron tablets
each containing 50-65 mg elemental
iron
• Ideally, should be taken on empty
stomach (food may inhibit iron
absorption)
• Must be sustained for 6-12 months
• Goal: to correct anemia and provide
stores of at least 0.5-1.0 g of iron
• Normal response to therapy: the
reticulocyte count should begin to
increase within 4-7 days after initiation
of therapy and peak at 1 ½ weeks
• Inadequate response may be due to
poor absorption, noncompliance, or a
confounding diagnosis
• To determine iron absorption, do an iron Notes:
tolerance test
o 2 iron tables are given to the
patient on an empty stomach
o Serum iron is measured
serially over subsequent 2 hrs
o Serum iron should increase at
least 100 μg/dL
• If iron deficiency persists despite
adequate treatment, consider parenteral
iron therapy

4. Parenteral Iron Therapy

• Usually given if no response to oral iron
therapy, if iron needs are relatively
acute, or if there is persistent need for

Appendix 2. Pathological Correlation of EM’s Case

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 OS 216: Hematology Dr. Edwin Trinidad
Topic Conference 1: Anemias Exam 1

For EM’s case, the main cause of IDA is blood loss due to prolonged menstruation, a result of irritation to the
intrauterine lining from the inserted IUD. The following figure summarizes the pathogenesis of EM’s condition.

Intrauterine device (IUD) inserted

2 months after her last delivery

Intrauterine lining irritated

Menorrhagia
Menses prolonged for 7 days;
(6 napkins/day) fully soaked decreased hematocrit; increased turbulence
w/ blood for first 4 days decreased blood viscosity

Iron deficiency Soft systolic murmur

(due to unreplaced iron losses
from menstruation)

Decreased hemoglobin production

Decreased O2 transport by RBCs

Inadequate oxygen supply to tissues

Pallor, dizziness, dyspnea

Fainting

Appendix 3.

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