Approach to Anemia

Maen Hussein, MD, and Rami Y. Haddad, MD, FACP

Anemia is one of the most common blood diseases. The number of visits
to physician offices, hospital outpatient and emergency departments with
anemia as primary diagnosis was 5.5 million in the year 2005-2006.1
Nineteen percent of nursing home residents are diagnosed with anemia.2
The World Health Organization criteria for anemia is a Hb ⬍13 in men
and ⬍12 in women within the context of international nutrition studies, so
they are not the gold standard for the diagnosis of anemia.3,4 There are
many other definitions of anemia with the Hb levels being ⬍13-14 for
men and 12-13 for women. Those ranges may not apply in special
populations (athletes, high altitude, elderly, patients with chronic disease,
smokers).5
There are 2 approaches to help identify the causes of anemia.6,7 The first
approach is a kinetic approach, which addresses the mechanisms of
anemia; it is divided into 3 categories.
1. Decreased RBC production; this could be secondary to lack of
nutrients such as iron, folate, or B12; this could be because of
malabsorption or blood loss. Gastric bypass surgery can result in
malabsorption of iron and B12, leading to such anemia.8 Other causes
of decreased production include bone morrow disorders or suppression
and low levels of erythropoietin, thyroid hormone, or androgens.
Anemia of chronic disease or inflammation because of decreased use
of iron and a relative decrease in erythropoietin level and RBC
lifespan. This can also be seen in acute illnesses.
2. Increased destruction such as in hemolytic anaemia, which could be
inherited (sickle cell, thalassemia, spherocytosis) or acquired (autoim-
mune anemia, thrombotic thrombocytopenic purpura, malaria, and
hemolytic uremic syndrome).9
3. Blood loss whether through the gastrointestinal (GI) tract or from
surgery or injury. Bleeding in the retroperitonium or in the thigh can
be significant with a less obvious clinical picture; this is more common

Adapted from Nathan DG, Oski FA. Hematology of Infancy and Childhood, 4th ed. Philadelphia, PA:
WB Saunders, 1993. p. 352.
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 in patients on anticoagulation. This may require computed tomography
scans to diagnose.10
The second approach is a morphologic approach: this divides anemias
into 3 main categories.
1. Macrocytic anemia—Macrocytic anemias are characterized by an
MCV above 100 femtoliters. An increased MCV is a normal charac-
teristic of reticulocytes but also can be secondary to abnormal nucleic
acid metabolism of erythroid precursors (eg, folate or cobalamin
deficiency and drugs interfering with nucleic acid such as hydroxyurea
and human immunodeficiency virus medications), or abnormal RBC
maturation (eg, myelodysplastic syndrome, acute leukemia, large
granular lymphocytic leukemia). Other common causes include alco-
hol abuse, liver disease, and hypothyroidism.6,9
2. Microcytic anemia—Microcytic anemias are characterized by the
presence of “small” RBCs (ie, MCV below 80 femtoliters). Microcy-
tosis is usually accompanied by a decreased Hb content within the
RBC, with parallel reductions in MCV and MCH, producing a
hypochromic (low MCH) as well as a microcytic (low MCV) ane-
mia.9,13 The 3 most common causes of microcytosis in clinical
practice are iron deficiency, alpha- or beta-thalassemia minor, and
(less often) anemia of chronic disease (anemia of chronic inflamma-
tion). With iron-deficiency anemia, the serum ferritin is low, and the
RBC count is low. In thalassemia, the serum ferritin could be elevated
and the RBC count is usually normal. Those diseases can be diagnosed
by demonstrating increased levels of Hb A2. Hb electrophoresis may
help.9,13
3. Normocytic anemia, where the mean RBC volume is normal (MCV
between 80 and 100 femtoliters). This can be seen in blood loss and
anemia of chronic disease.11,12,13

Patient Evaluation
To evaluate a patient with anemia, a detailed history and physical
examination can help reach a diagnosis. This is of course complemented
by laboratory investigations.
History
Anemia can present with symptoms that are nonspecific, such as fatigue
and shortness of breath, although those symptoms can indicate the acuity
and severity of anemia. A patient with a Hb of 6 mg/dL but who does not
450 DM, August 2010
complain of fatigue could indicate that this is a chronic process, while a
patient with severe fatigue with Hb of 10 mg/dL may indicate an acute
drop in Hb, which could be related to blood loss or hemolysis. Those
symptoms can vary from mild fatigue and shortness of breath on exertion
to severe fatigue with dyspnea at rest. Patients with severe anemia can
even be lethargic and may present with syncope.
One of the most common etiologies is blood loss through the GI tract so
it is important to ask about GI symptoms, change in bowel habits, blood
with stool or melena (black tarry stools, which is a sign of upper GI
bleeding). Symptoms of reflux or peptic ulcer disease can result in chronic
blood loss from the GI tract.
Gynecologic history in females is also important, as females lose blood
through menstruation and it is important to estimate the amount of blood
loss through asking about the length of the period in days, and the amount
of pads or tampons used with the degree of saturation.
Ice craving is a symptom of iron deficiency that is common in females
and it can be used to assess the response to therapy because it disappears
after treatment.
Symptoms of chronic disease involving the kidney or the heart and a
history of liver disease can help establish the etiology of anemia of
chronic disease. A history of previous blood transfusions is also important
because it indicates a previous history of anemia.
A family history is important to rule out hereditary causes of anemia.
Certain anemias are also more common in different ethnicities such as
sickle cell disease, thalassemias, and other hemolytic anemias.
Medication history is important, as well as the use of nonsteroidal
anti-inflammatory medicines and exposure to chemotherapy agents that
can cause anemia. Medication history also can help identify the patient’s
other illnesses.
Social history including illicit drug use, smoking, and alcohol can relate
to certain types or risk factors for anemia such as liver disease,
malignancy or risk of HIV.6,7

Physical Examination
The physical examination of a patient with anemia can uncover clues to
the etiology of the condition. The appearance of the patient with certain
physical features (short stature and skeletal abnormalities) is associated
with certain syndromes such as Fanconi syndrome.14
Careful examination of the hair is important, iron deficiency can cause
thinning and loss of hair. Hypothyroidism is associated with loss of the
DM, August 2010 451
lateral aspects of the eyebrows. Brittle hair can be associated with
significant copper deficiency in malnourished patients.14 Pallor is a sign
of anemia, which can be seen in the face, palms, and nail beds or
conjunctiva. Jaundice can indicate hemolysis or liver disease.7,14 Vitiligo
can be part of autoimmune complex that includes cobalamin deficiency
(pernicious anemia).
Telangiectasias in the mouth or around the ears raise then possibility of
gastrointestinal bleeding from similar lesions in the gut.
Spooning of the finger nails (koilonychias) occurs with long standing
cases of iron deficiency. Splinter hemorrhage in the nail beds raise the
possibility of anemia secondary to bacterial endocarditis.
Angular stomatits and glossitis (which is characterized by smooth, shiny
tongue) can result form deficiency of iron or cobalamin.14
Chronic severe anemias can cause cardiomegaly with a third heart
sound present.14
Abdominal examination can reveal splenomegaly, which occurs in
many types of anemia. The quality of the spleen can help in differenti-
ating certain types of anemia with soft spleen being typical of hemolytic
anemia. An enlarged firm spleen can develop with infiltrative process
such as myelofibrosis. Liver exam is also important with enlarged liver
indicating hepatitis or tumors in the liver and shrunken liver being
associated with liver cirrhosis.
Rectal exam is also important where the presence of occult or non
occult blood can be secondary to colorectal cancers. Also the presence of
hemorrhoids can explain anemia. Neurologic abnormalities can be asso-
ciated with cobalamin deficiency.6,14
Laboratory Evaluation
Initial testing of a patient with anemia should include a complete blood
count with peripheral smear; this should include a white blood cell count
with a differential, platelet count, and reticulocyte count. The complete
blood count includes RBC indexes that are mean corpuscular volume with
a normal range from 80 to 100 fl that might be the most important index
because it can distinguish different types of anemia, with a low value
(microcytosis) suggestive of iron deficiency, thalassemia, and occasion-
ally anemia of chronic disease. A high MCV is seen in B12 and folic acid
deficiency. It also can be seen in liver disease and in myeolodysplastic
syndrome. A very high value can be attributed to the presence of cold
agglutinin, which causes the RBC to go through the counting apparatus in
doublets or triplets. Warming the specimen to body temperature before a
repeat count should return the MCV to normal. A normal RBC count with
452 DM, August 2010
low MCV and Hb can indicate hemoglobinopathies (ie, thalassemia)
rather than iron-deficiency anemia.
Mean corpuscular Hb ranges from 27.5 to 33.2 picograms of Hb per
RBC and low values are seen in iron-deficiency anemia and thalassemia.
Mean corpuscular Hb concentration has normal values between 31 and
35. Low values can occur in the same conditions, causing low MCV and
MCH, but high values occur in the presence of acquired or congenital
spherocytosis or congenital hemolytic anemia (sickle cell disease, hemo-
globin C).14
The reticulocyte count, as either a percentage of all RBCs, the absolute
reticulocyte count, or the corrected absolute reticulocyte count, helps
differentiate different types of anemia. High reticulocyte count indicates
active bone morrow trying to compensate for blood loss or hemolysis,
while a stable anemia with low reticulocyte count indicates a decreased
production of RBC. If low reticulocyte count is accompanied by pancy-
topenia, it suggests aplastic anemia. With normal white blood cells and
platelet count, it reflects pure red cell aplasia.7
White blood cells are also important and help distinguish different
etiologies, with high count and anemia indicating infection or hemato-
logic malignancy. Low count could indicate bone marrow suppression.
White blood cells differential helps define the etiology of anemia; for
example, high neutrophil count indicates infection; monocytosis can
suggest MDS; eosinophils can be associated with certain infections; and
low lymphocytes can be caused by human immunodeficiency virus,
which also causes anemia. Neutropenia can be associated with chemo-
therapy.6
The morphology of white blood cells such as hypersegmented neuto-
phils (defined as the presence of ⬎5% of neutrophils with 5 or more lobes
and/or the presence of 1 or more neutrophil with 6 or more lobes) along
with macrocytosis can be seen in B12 or folate deficiency, resulting in
impaired DNA synthesis.6,7,13,14
Platelet count is also important with a high platelet count commonly
seen with iron deficiency but it can also indicate malignancy or infection.
Low platelet count can be part of bone marrow suppression, or intravas-
cular hemolysis, such as in thrombotic thrombocytopenic purpura, or
because of chemotherapy.
Peripheral smear evaluation helps in looking for the morphology of the
RBC; schistocytes and helmet cells can be associated with intravascular
hemolysis. Sickling of the RBC can result in sickle cell disease.
Teardrops in RBCs can be associated with myelofibrosis. Nucleated red
blood cells and immature white blood cells can be a result of bone
DM, August 2010 453
morrow replacement (leukoerythroblastic picture). Burr cells can be seen
in liver disease.
Serial Hb is helpful in distinguishing bone marrow suppression (gradual
fall) and blood loss or destruction (fast drop); in blood loss or destruction,
the drop will be higher than 1% of Hb per day than we see with bone
morrow suppression where the reticulocyte count is zero.
Iron studies are also important if iron deficiency is suspected. Those
include iron levels, iron saturation, total iron binding capacity, and ferritin
(which is an indicator of iron storage). Low values of iron, total iron
binding capacity, and iron saturation with elevated ferritin are signs of
anemia of chronic disease.
If hemolysis is suspected, then LDH and bilirubin with the reticulocyte
count may help. Low haptoglobin level in the absence of liver disease
indicates hemolysis.
Erythropoietin level is also important to help diagnose anemia of
chronic disease, especially anemia of kidney disease. The level of
erythropoietin should be adjusted to the level of anemia, with a lower
level of Hb as the level of erythropoietin rises.15
Bone morrow biopsy may help in certain conditions, mainly if there are
other cytopenia, to diagnose diseases affecting the bone morrow such as
MDS or an infiltrative process. Iron stores can be assessed too. Increased
erythropoiesis can result in erythroid hyperplasia and megaloblastic
features can be seen in folate and B12 deficiency. Increased iron-laden
precursors indicate sideroblastic anemia.7,14

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