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Robb Friedman, MD
Modified by Sean Hesselbacher,
MD, Eyal Oren, MD, David
Antonetti, MD and Cathy Okuliar,

What is Anemia?

Reduction below normal in the mass
of red blood cells in the circulation
Hemoglobin concentration,
hematocrit, RBC count
Men: HGB < 14 or HCT < 41%
Women: HGB < 12.0 or HCT < 36%

Anemia and Volume Status


Therefore dependent upon plasma volume
Acute bleeds not reflected for 24-36 hrs
Due to volume deficit being slowly repaired via
movement of fluid from extravascular space to

Anemic patients who are dehydrated will

not appear anemic
Pregnant women expand RBCs 25% but
plasma volume increases 50%, producing
physiologic anemia

Anemia: Special Cases

People who live at high altitude have greater
RBC volume
Smokers have increased HCT impairs the
ability of the RBCs to deliver O2

African-American HGBs are 0.5 to 1.0g/dL

lower than Caucasians
Athletes (increased plasma volume, Fe
deficiency, hemolysis, polycythemia, use
of performance enhancing agents)

Anemia and the Elderly


studies show that the elderly

do not have a lower normal range
Anemia, while common in the
elderly, is still abnormal
HGB < 13 in males and < 12 in
females associated with an increased
relative risk of mortality (1.6 and 2.3

Anemia: History

Is the patient bleeding?

Menstrual history, if applicable (include older women)
Prior intestinal surgery?
Hx of hemorrhoids, hematochezia, or melena?

Past medical history of anemia? Family history?

Alcohol, nutritional questions
Liver, renal diseases
Environmental/work toxins (ie lead)

Symptoms of Anemia

O2 delivery
Hypovolemia if acute loss
Exertional dyspnea, fatigue,
palpitations, lightheadedness
Severe: heart failure, angina
Pica craving for clay or paper
Pagophagia craving for ice

Signs of Anemia

Tachycardia, tachypnea, orthostasis

Koilonychia or Spoon nails
Splenomegaly, lymphadenopathy
Petechiae, ecchymoses
Atrophy of tongue papillae
Heme + stool

The Four Causes of Anemia


red blood cell

Increased red blood cell
Red blood cell loss
Red blood cell sequestration
* Underlying disorder is abnormal production vs.
premature loss

Decreased RBC production


of iron, B12, folate

Marrow is dysfunctional from
myelodysplasia, tumor infiltration,
aplastic anemia, etc.
Bone marrow is suppressed by
chemotherapy or radiation
Low levels of erythropoeitin, thyroid
hormone, or androgens

Increased RBC destruction


live about 100 days

Acquired: autoimmune hemolytic
anemia, TTP-HUS, DIC, malaria
Inherited: spherocytosis, sickle cell,

RBC Loss

vs occult
Iatrogenic: venesection e.g. daily
CBC, surgical, hemodialysis

Approach to Anemia
Reticulocyte count

RI > 2%

RI < 2%


Increased destruction or loss


MCV < 80

MCV 81 99

MCV > 100


Further work up
Based on history,
Physical, other

Approach to Anemia

Convenient to separate
into three classes based
on the size of the RBC
Microcytosis: < 80 fL
Normocytosis: 80-100 fL
Macrocytosis: >100 fL
CBC, reticulocyte count,
Fe, Ferritin, TIBC, folate,


Nucleated RBCs form in marrow where

they mature for 3 days and then spend 1
day in circulation (before maturing to RBC)
Given avg life span of RBC of 100 days, 1%
of RBCs are destroyed each day
Retics form 1% of circulating RBCs qd
Nl RBC count is 5 million/uL so marrow
makes 50,000 reticulocytes/uL blood qd
With epo, can increase to 250,000 retics/uL
blood qd (given nl marrow and replete iron,
folate, b12)

Reticulocyte Count

Assess adequacy of bone marrow response to anemia

Must adjust for the degree of anemia, use
Reticulocyte Production Index
RI = (measured retic) x (Hct/45) / (Correction Factor)
CF: Hct 41-50 (1); 30-40 (1.5); 20-29 (2); 10-19 (2.5)
Reflects increased circulating time for retics as Epo pushes
them out of the marrow earlier

RI < 1.0 is abnormally low and indicates inadequate

marrow response

Microcytic Anemia

Iron Deficiency
Anemia of chronic

Iron Deficiency Anemia

The definitive test is serum
Low serum ferritin (<12
ug/L)is diagnostic of iron
Although ferritin is an acute
phase reactant, it will still be
low in iron deficiency
Also, high TIBC

Fe saturation = Fe/TIBC <

10% in Fe deficiency
If ferritin is indeterminate

Low serum Fe is not in itself

diagnostic, neither is marrow
Anisocytosis (heterogeneous
in shape) and poikilocytosis
(abnormal shape)
Reactive thrombocytosis

Iron deficiency


production of either globin or -globin chains

Abnormal hemoglobin
Polychromasia (dark staining retics),
target cells, basophilic stippling
Normal/increased RBC mass
Mentzer index: MCV/RBC ct < 13

Alpha-Thalassemia: 4 genes
1/4: silent carrier
2/4: Alpha-Thalassemia trait,
microcytosis and mild anemia
3/4: excess Beta-chains form
tetramers, results in severe anemia
and microcytosis
4/4: hydrops fetalis
Most common in SE Asian populations

Basophilic stippling


1/2 mutation: Beta-Thal trait, increased
Hgb A2, rarely anemic, mild
2/2 mutation: Beta-Thalassemia
disease, Hgb F, microcytosis, anemia
Usually found in people of African or
Mediterranean descent but has worldwide distribution

Beta - Thalassemia

Sideroblastic Anemia
Failure of synthesis of
porphyrin ring
Acquired (INH, EtOH,
B6 deficiency, Lead)
Smear: sideroblasts
and basophilic stippling

Macrocytic Anemia
Drug Induced (hydroxyurea, AZT,
MTX, chemotherapy, anticonvulsants)
B12 / folate deficiency
Myelodysplastic syndrome
Liver disease
Alcohol abuse

Folate and B12

Serum folate usually sufficient, but if folate

level is normal but folate deficiency is
suspected, check serum homocysteine
(elevated because of impaired folate
dependent conversion of homocysteine to
methionine) or RBC-folate.
B12 can be spuriously low a more sensitive
and specific test is serum methylmalonic acid
level, will be increased if B12 is low.
Classically check Schilling Test for B12
deficiency (parietal cell antibody or Intrinsic
Factor antibody)

B12 and Folate Deficiency

Myelodysplastic Syndrome

Primary bone
marrow disorder,
often found in
abnormality the
bilobed nucleus

Normocytic Anemia

and complicated group of

Hemolytic anemias
Anemia of chronic disease
Bone marrow disorder
Nutritional (early Fe, B12, folate
Renal insufficiency

Nutritional Anemias

deficiency and B12/folate

deficiency can present with
normocytic anemia esp. if both
deficiencies are concurrent.
Check iron studies and B12, folate

Anemia of Renal
Unremarkable peripheral blood smear
Inappropriately normal erythropoietin
Anemia usually severe and symptomatic
when Cr > 3.0
Mild to moderate anemia found in Cr 1.53.0
Tx: Epogen or similar, Fe (oral, IV) if iron
stores are found to be low

Hemolytic Anemias

Evaluation of Hemolysis

LDH: increases
Indirect bilirubin increases
(increased Hgb catabolism)
Haptoglobin decreases
Reticulocyte count increases
Urine hemosiderin test =
present in intravascular,
absent in extravascular
Coombs test:

(+) = autoimmune
hemolytic anemia
(-) consider PNH (abnormal
GPI protein, send flow for
CD55 and CD59)

Hemolytic Anemia: Intrinsic

Spherocytosis, Sickle Cell

More hemolytic anemias

Anemia of Chronic Disease

Thought to be a cytokine mediated process

which inhibits red blood cell production or
interferes with action of erythropoietin
Therefore, the disease needs to be inflammatory

Decreased iron utilization/mobilization

Seen with rheumatologic diseases, chronic
infections, malignancy
Indices: Low Fe, Low TIBC, Nl/increased
May be seen in conjunction with Fe-deficiency

Anemia due to Primary Bone

Marrow Disorder

Bone marrow
infiltration: nucleated
red blood cells found in
Might see rouleaux
formation in multiple
WBC, plts often
Bone marrow biopsy

Anemia: Treatments


CAD: Hgb > 10

All pts: Hgb > 7.0


Erythropoietin analogs
B12, folate

What in the world is a HowellJolly Body?

Acanthocytes vs

Acanthocytes: spur cells found in liver disease

Echinocytes: burr cells found in renal disease

Helmet vs. Teardrop Cells

Anemia: Summary


Determine if ACUTE or CHRONIC

MKSAP Questions

An 80-year-old man who had a hemicolectomy for colon

cancer is evaluated because of a 4-month history of
diarrhea, anorexia, and fatigue. He had a remote history of
On physical examination, he is cachectic and mildly
confused. His pulse rate is 70/min, and blood pressure is
140/85 mm Hg. His tongue is smooth. The abdomen is soft;
there are no palpable masses or hepatosplenomegaly. A
stool specimen is negative for occult blood. Neurologic
examination shows loss of position sense in the feet. He has
a wide-based gait. The Romberg test is positive. His
hemoglobin is 9.4 g/dL, reticulocyte count is 2.5%, mean
corpuscular volume is 125 fL, and serum lactate
dehydrogenase is 400 U/L.
Which of the following is the most likely cause for his
( A ) Alcoholic cerebellar degeneration
( B ) Vitamin B12 deficiency
( C ) Brain metastases
( D ) Folate deficiency
( E ) Liver metastases

Critique (Correct Answer = B)

The patient most likely has vitamin B12 deficiency, based on the degree of macrocytosis and
neurologic findings. An elevated serum lactate dehydrogenase level, due to intramarrow cell death
from ineffective erythropoiesis, is consistent with this diagnosis.
Severe macrocytosis (mean corpuscular volume > 120 fL) is often associated with vitamin B12
deficiency or folate deficiency (megaloblastic anemia), usually seen in conjunction with oval
macrocytes. The presence of frequent hypersegmented neutrophils (> 5 segments) is strongly
suggestive of vitamin B12 or folate deficiency.
Bone marrow morphology in patients with vitamin B12 or folate deficiency is referred to as
megaloblastic and is characterized by the presence of large cells with immature nuclear chromatin
but maturing erythrocyte cytoplasm (nuclear-cytoplasmic dissociation). Anemia accompanies this
process; hence the term ineffective erythropoiesis. The intramarrow death of megaloblastic cells
causes the serum lactate dehydrogenase level to rise. If a patient has a low serum vitamin B12 or
folate level, a bone marrow examination is probably unnecessary. However, the physician should
determine the cause of the deficiency. If a patient has a normal serum vitamin B12 or folate level, a
bone marrow examination is frequently helpful to exclude myelodysplastic syndromes or other
infiltrative marrow disorders.
Folate deficiency can induce megaloblastosis within weeks to months, whereas vitamin B12 deficiency
requires years to cause megaloblastosis since stores of vitamin B12 persist for years in the liver and
other tissues. In patients with vitamin B12 or folate deficiency, parenteral or oral repletion of vitamin
B12 or folate reverses some morphologic abnormalities within hours. Serum folate levels fluctuate
quickly with changes in dietary consumption. Low erythrocyte folate levels often reflect prior
nutritional depletion. In patients who are hospitalized and are begun on regular diets, the erythrocyte
folate test may provide a better assessment of tissue folate levels than determination of the serum
folate level. The erythrocyte folate test often requires a special laboratory, and results often are not
quickly available.
In patients with megaloblastic anemias, erythrocyte production is diminished and a corrected
reticulocyte count is inappropriately low for the degree of anemia. This patient had a corrected
reticulocyte count of 1% (inappropriately low for a hemoglobin level of 9.4 g/dL).
In addition to changes in the blood, the epithelial cells in patients with megaloblastic anemias may
become atrophic and cause a smooth tongue and cheilosis. Posterior column dysfunction, particularly
in patients with vitamin B12 deficiency, may lead to changes in vibratory or position sense, causing
ataxia. Signs of dementia may appear. However, neurologic dysfunction is very uncommon in adults
with folate deficiency.
Alcoholic cerebellar degeneration results in ataxia but not position loss. Although liver metastases are
possible in a patient with a history of colon cancer, their presence would not account for the
neurological findings in this patient. Brain metastases would most likely produce focal neurological
findings and also would not account for the blood findings.

A 26-year-old man is evaluated because of progressive

fatigue, dyspnea on exertion, and orthostatic dizziness for
the past 2 to 3 weeks. He takes no medications. Physical
examination is normal except for pallor.
Laboratory Studies: Hematocrit 13%Leukocyte count
8300/L; normal differential. Reticulocyte count: 0, Platelet
count 320,000/L. A routine biochemical profile, including
liver function tests, is normal. A chest radiograph shows
normal lung fields and a widened mediastinum, suggestive
of an anterior mediastinal mass. Bone marrow biopsy shows
absent erythrocyte precursors, normal megakaryocytes,
and normal leukocyte numbers and maturation.
Which of the following is the most likely cause of the
mediastinal mass and anemia?
( A ) Hodgkins disease
( B ) Non-Hodgkins lymphoma
( C ) Thyroid carcinoma
( D ) Thymoma
( E ) Germ cell carcinoma

Critique (Correct Answer = D)

Each of the listed neoplasms may present as an anterior

mediastinal mass and may be associated with anemia of
chronic disease. However, pure red cell aplasia (which this
patient has) is often associated with a benign or invasive
thymoma. Approximately 5% to 15% of thymomas occur
in patients with pure red cell aplasia. Other thymomaassociated autoimmune disorders include myasthenia
gravis, systemic lupus erythematosus, thrombocytopenia,
and, rarely, malabsorption states. A careful search by CT
or MRI is always warranted in patients with newly
diagnosed or relapsing red cell aplasia or myasthenia.
The other listed entities are also included in the
differential diagnosis for an anterior mediastinal mass.
Germ cell tumors have not been associated with pure red
cell aplasia, and Hodgkins disease, non-Hodgkins
lymphoma, and thyroid carcinoma are rarely associated
with this disorder. Chronic lymphocytic leukemia is also
commonly associated with red cell aplasia and may
present with variable degrees of lymphadenopathy but not
with an isolated anterior mediastinal mass, as in the
patient discussed here.

A 36-year-old black man with known sickle cell anemia is

evaluated because of a 2-week history of fever, a macular
rash on his trunk, and arthralgias. Subsequently, he
developed weakness and dyspnea on exertion. Several of
his children had febrile illnesses with associated rashes and
fatigue over the past month. These illnesses resolved
spontaneously without sequelae.
On physical examination, his temperature is 38.8 C (101.8
F), pulse rate is 100/min, and blood pressure is 160/70 mm
Hg. A maculopapular, truncal rash is noted. There is
conjunctival pallor. The remainder of his examination is
Laboratory StudiesHemoglobin 5.2 g/dLLeukocyte count
5000/LReticulocyte count 0%Platelet count
130,000/LSerum lactate dehydrogenase 622 U/LWhich of
the following is the most likely diagnosis?
( A ) Paroxysmal nocturnal hemoglobinuria
( B ) Parvovirus infection
( C ) Glucose-6-phosphate dehydrogenase deficiency
( D ) Aplastic anemia

Critique (Correct Answer = B)

Patients with hemolytic disorders may occasionally present with reticulocytopenia and an
aplastic crisis. This patient has sickle cell anemia with parvovirus infection, which is causing
an aplastic crisis. Parvovirus may infect patients with hemolytic anemias (for example, patients
with hereditary spherocytosis, sickle cell disease, or thalassemia). In children with sickle cell
anemia, over 80% of aplastic crises may be attributed to parvovirus infections. In adults, the
usual presenting features are rash, arthritis, and anemia. The slapped cheek syndrome is
rarely a presenting feature. There is usually a complete suppression of erythropoiesis to a
reticulocyte level of 0%. The bone marrow shows giant dysplastic (megaloblastoid)
erythroblasts, occasionally with viral inclusions. The diagnosis is usually made by
demonstrating IgM antibodies to the virus. IgG antibodies appear later during the course of the
infection and persist. Parvovirus in the blood may be detected by the polymerase chain
reaction, which is the definitive diagnostic method. Occasionally, other blood components such
as leukocytes and platelets are affected and result in mild to moderate pancytopenia.
The diagnosis of paroxysmal nocturnal hemoglobinuria (PNH) should be considered in patients
with bone marrow failure or aplasia, unusual location of thromboses, and unexplained
hemolysis. The anemia may be severe, and patients with PNH typically have reticulocytopenia.
There is no characteristic finding on bone marrow examination, although the bone marrow of
patients with PNH may demonstrate myelodysplastic changes. The diagnosis is based on
demonstration of exquisite sensitivity to complement-mediated lysis by the sucrose lysis test or
the acidified serum lysis test (Hams test).
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is another cause of hemolysis that
occasionally is associated with reticulocytopenia. In patients with G6PD deficiency, erythrocytes
are subject to oxidative stresses. Hemoglobin becomes oxidized and precipitates within the
erythrocytes, which then undergo destruction by the reticuloendothelial system. G6PD
deficiency is an autosomal recessive disorder that predominantly affects males. After a
hemolytic episode, qualitative assays may be normal because only erythrocytes that are
resistant to G6PD remain. The African variant of G6PD is associated with a mild form of
hemolysis, whereas the Mediterranean variant is usually severe. Causes include infectious
stresses, drugs such as quinidine and sulfonamides, or, in the Mediterranean variant, favism
(consumption of fava beans). Therapy requires avoiding certain medications and supportive
care in crisis situations.
In contrast to this patients presentation, patients with aplastic anemia have pancytopenia with
severe anemia, reticulocytopenia, thrombocytopenia, and granulocytopenia. In patients with
severe aplastic anemia, the bone marrow examination shows less than 5% cellularity with only
residual lymphocytes and plasma cells. The abnormal cells described above that are
attributable to parvovirus infection are not seen.

A 36-year-old man is evaluated because of fatigue. He has had

two episodes of acute gouty arthritis over the past 6 months. He
has a 10-year history of significant alcohol use, but he quit
drinking 4 months ago. He works in a factory making battery
products. A complete blood count obtained prior to elective hernia
repair surgery 4 years ago was normal. He takes no medications.
On physical examination, his temperature is 37.3 C (99.1 F),
pulse is 60/min, and blood pressure is 135/70 mm Hg. His skin is
normal. There is slight scleral icterus. There is a blue line at the
edge of his gums.
The remainder of the examination is normal. Stool specimens are
negative for blood on three occasions.
Laboratory StudiesHemoglobin 7.5 g/dLMean corpuscular
volume 71 flLeukocyte count 9400/LReticulocyte count
5.3%Platelet count 435,000/LSerum lactate dehydrogenase 553
U/LSerum uric acid 11 mg/dLA peripheral blood smear is shown.
Which of the following diagnostic studies is most useful for
determining the cause of this patients anemia?
( A ) Serum iron, total iron-binding capacity, and ferritin levels
( B ) Serum lead levels
( C ) Direct and indirect antiglobulin tests
( D ) Hemoglobin A2 quantitation
( E ) Serum ethanol and folic acid levels

Critique (Correct Answer = B)

The patient has chronic lead intoxication that can be confirmed by measuring serum
lead levels. He has a hypochromic, microcytic anemia with coarse basophilic stippling
and reticulocytosis. He also has evidence of hemolytic anemia with increased serum
lactate dehydrogenase and indirect bilirubin levels. His physical examination is
remarkable for gingival lead lines. Bone marrow examination shows erythroid
hyperplasia and ringed sideroblasts. The anemia of lead poisoning fits this
description. Sideroblastic anemia with hypochromic indices is typical. Hemolysis is
common, and basophilic stippling, blue staining polyribosomal aggregates with
mitochondrial fragments in the erythrocytes, is frequently seen. Lead inhibits
pyrimidine 5-nucleotidase which normally clears ribosomal fragments. Occupational
exposures to lead are relatively uncommon today. However, workers who produce
batteries or are exposed to paint, particularly those who remove leaded paint from
old buildings, are at greatest risk if they are not protected from inhalation of paint
particles during the sanding process. Other manifestations of lead toxicity in adults
include peripheral neuropathy, abdominal colic, and saturnine gout (effects of lead on
renal tubules that prevent the excretion of uric acid). Chelation therapy is indicated
for patients with serum lead levels exceeding 70 g/dL and should be continued until
lead levels fall below 40 g/dL. Agents such as EDTA or dimercaprol may also be
This patient is unlikely to have iron deficiency since his reticulocytes are increased. In
addition, basophilic stippling usually is not seen in patients with iron deficiency.
Thalassemia is associated with a microcytic anemia, reticulocytosis, and basophilic
stippling. However, a normal complete blood count 4 years ago rules out this
possibility. Therefore, quantitative studies to measure hemoglobin A2 are not
Autoimmune hemolytic anemia should be excluded by performing a direct
antiglobulin test in any patient who has evidence of hemolysis on a peripheral blood
smear. However, the lead lines on this patients gingivae are classic for lead
poisoning, and autoimmune hemolytic anemia therefore is less likely.
Alcoholism may cause a transient sideroblastic anemia, which resolves with cessation
of alcohol intake. Folic acid deficiency may complicate alcoholism but usually
presents with macrocytosis.

A 22-year-old man is evaluated in the intensive care unit

because of bleeding immediately after scoliosis surgery.
During surgery, 12 units of packed red blood cells and 12
units of fresh frozen plasma were transfused. There is no
history of a bleeding disorder or of drug administration that
could affect platelet function.
On physical examination, the patient is afebrile. His pulse
rate is 100/min, and blood pressure is 110/72 mm Hg.
Petechiae are present on his arms, and blood is oozing from
the drains.
Laboratory StudiesHemoglobin 9.0 g/dLPlatelet count
43,000/LProthrombin time 12 sActivated partial
thromboplastin time 32 sPlasma fibrinogen 400 g/dLdDimers NegativeWhich of the following is the most
likely cause of the thrombocytopenia and bleeding?
( A ) Dilutional thrombocytopenia
( B ) Incompatible blood transfusion
( C ) Posttransfusion purpura
( D ) Septic transfusion reaction

Critique (Correct Answer = A)

Approximately a 50% reduction in the platelet count occurs when

transfusions of 1.5 to 2 times the blood volume are given over 4 to 8
hours. Blood stored for more that 2 to 3 days has essentially no
platelets, which explains the thrombocytopenia. Fresh frozen plasma
contains all of the clotting proteins in normal concentrations. This
patient received one unit of fresh frozen plasma for each unit of
transfused red blood cells, which resulted in no measurable
alteration in the prothrombin time or activated partial
thromboplastin time. Incompatible red blood cell transfusions can
lead to the development of disseminated intravascular coagulation,
which is characterized by thrombocytopenia. The other hallmarks of
disseminated intravascular coagulation are absent in this patient,
namely, he has a normal fibrinogen, prothrombin time, activated
partial thromboplastin time, and negative d-dimers. Posttransfusion
purpura is characterized by profound thrombocytopenia that
develops 5 to 7 days after a transfusion. It occurs in patients who
are negative for the PLA-1 human platelet antigen and have been
transfused or pregnant in the past. Posttransfusion purpura almost
always occurs in women.
Septic transfusion reactions can be associated with
thrombocytopenia when either bacteremia or endotoxemia causes
disseminated intravascular coagulation. This patient has no
indication of either sepsis or disseminated intravascular coagulation.