EVALUATION OF THE
ANEMIC PATIENT
Is the patient really anemic?
• Hemoglobin declines with advanced age
• African heritage - 0.5 g/dl lower hgb
• Hematocrit lower by a mean of 4 points in
recumbent vs standing position
• Edematous pts have 12% drop in Hct/Hgb
after one hour of recumbence
Blood 2004;104:2263-2268
• Data from the Third National Health and Nutrition
Examination Survey (1988-1994)
• Prevalence of anemia rises rapidly after age 50,
prevalence 20% over age 85
• 11% of men, 10.2% of women over 65 anemic
• 1/3 due to nutritional deficiency, 1/3 to chronic
inflammation or renal disease, 1/3 unexplained
• Most cases mild; only 2.8% of women and 1.6% of
men had Hgb < 11 g
 Unexplained mild “anemia” in elderly people may
simply be an effect of aging in some cases
Clinical Clues
• History
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–
–
–
–
–
–
Family history
Timing of symptoms
Medications
Occupation/Hobbies
Diet
Mouth problems
GI symptoms
Bruising/bleeding
GU symptoms
• Exam
–
–
–
–
–
–
–
Mouth
Sternal tenderness
Lymph nodes
Cardiac murmurs
Liver/Spleen size
Skin exam
Pelvic/rectal
• Always consider/rule out blood loss!
Look hardest for readily treatable
causes of anemia
• Nutritional deficiency (iron, B-12, folate)
• Endocrinopathy (esp thyroid)
• Low-EPO state (more common than you
think)
• GI blood loss
• Most treatable causes of anemia can be
diagnosed without marrow biopsy
Confirm laboratory data
• CBC performed by machine, including
differential
• Quality of “flagging” abnormal values
varies
• All “flagged” results should be reviewed
when diagnosis is not known.
• Blood smear from abnormal CBC should
be reviewed by a human
KINETICS OF ERYTHROPOIESIS
Hyporegenerative (marrow not working well)
Hyperregenerative (marrow working)
Calculating the reticulocyte index will
usually tell you which category your
patient is in
Reticulocytes
• “Reticulin” - insoluble
ribosomal RNA
• Present after extrusion
of nucleus until
degradation of rRNA.
• Retics normally spend
3.5 days in marrow, 1
day in blood
• Normal 28 -115
thousand per microliter
Reticulocytes demonstrated by
Crystal Violet stain of blood smear
(most labs now use flourescent
dye and automated cell counter)
Measuring Reticulocytes
Mature RBC
Maturation
High fluorescence
Low fluorescence
* False positive - Howell-Jolly, Heinz, & Pappenheimer bodies ,
Malaria, Babesia, porphyria
Reticulocyte Response
• Reticulocyte count = % retics
• Reticulocyte Index correlates best with RBC
production
– Correct for low RBC count (absolute retic count)
– Correct for immature retics if present (factor of 2)
• “Normal” RI = 1 but should go up in anemia if
marrow function normal
– Normal or low RI in anemia implies
hyporegenerative state
– Very high RI (>4) suggests hemolysis
– Misleading results possible if not in steady state
Retic Index
Hct
1
RI  Retic % 

45 Maturation Time
When Hct 25 or less, use 1/2 for maturation time term
Retic Index
Response
<2
Inappropriate
2–3
Not sure
>3
Appropriate
Example
• 75 yo with osteomyelitis
– receiving extended antibiotic therapy
– poor appetite, weight loss
– Labs:
• Hct 25, WBC 12.0, Platelets 545, MCV 92,
• Retic 5.8% (normal 0.5 to 2.2%)
25
1
RI  5.8% 
45 2 days
RI = 1.6
too low
Hyporegenerative anemia
Retic index not appropriately increased
• Nutritional deficiency (iron, B-12, folate)
• Marrow dyscrasia (leukemia,
myelodysplasia, aplastic anemia etc)
• Thalassemia
• Low EPO state (renal disease,
inflammation, endocrinopathy, ? old
age)
Hyperregenerative anemia
Retic index increased
• Hemolysis
• Blood loss
Retic count increase generally less striking
than in hemolysis
Interpreting the MCV
• The MCV reflects the average size of
RBC
 Macrocytic (MCV >95)
 Microcytic (MCV <82)
 Normocytic
Pernicious anemia
Aplastic anemia
Myelodysplasia
Hemolysis
Normal
inflammation
Thal trait
Iron deficiency
50
70
90
MCV
110
130
BLOOD SMEAR
• RBC size, shape
• Polychromasia (young retics)
• RBC inclusions (nucleated rbc,
Howell-Jolly bodies, etc)
• Rouleaux
• Abnormal/immature leukocytes
• Platelet number/morphology
Normal
Polychromasia
Normal rbc
Microcytosis,
hypochromia
Normal
Macrocytic/megaloblastic
Spur cell anemia
(liver disease)
Microangiopathic
hemolytic anemia
Hereditary spherocytosis
Rouleaux (myeloma, Waldenstroms)
Neutrophil hyposegmentation
(myelodysplastic syndrome)
Leukoerythroblastic
(marrow infiltration)
DIFFERENTIAL DIAGNOSIS
GUIDED BY RETIC INDEX, MCV
• Hyporegenerative
 Microcytic
 Macrocytic
 Normocytic
• Hyperregenerative
Microcytic,
hyporegenerative anemia
Microcytosis implies defective
hemoglobin production
•
•
•
•
Iron deficiency (R/O GI bleeding!)
Thalassemia
Inflammation
Sideroblastic anemia (myelodysplasia,
lead poisoning etc)
Laboratory assessment of
microcytic anemia
Test
Fe Defic
Anemia of
inflammation
Thal
Ferritin
Low*
NL/high
NL
Serum Fe
Low
Low
NL
TIBC
High
NL/low*
NL
% Sat
Low
Low
NL
Retic
index
NL/low
NL/low
NL/high
*best discriminators of Fe defic vs anemia of inflammation
TESTS OF IRON STATUS
Practical aspects
• Low serum ferritin almost always indicates iron
deficiency
• Low serum iron and high TIBC almost always indicate
iron deficiency
• Ferritin > 100 rarely found in iron deficiency
– Exception - liver inflammation/necrosis
• Normal serum iron rarely found in iron deficiency
– Exception - iron deficiency recently treated with oral
iron
• When TIBC is low or normal, low serum iron not a
reliable indicator of iron deficiency!
• Iron deficiency may be hard to diagnose via blood tests
in setting of inflammation (eg, low iron, low TIBC,
intermediate ferritin level)
– Therapeutic trial of iron +/- EPO a reasonable alternative to
marrow biopsy
Macrocytic,
hyporegenerative anemia
Megaloblastic:
B12/folate deficiency
Myelodysplastic syndrome
Drug-induced
Non-megaloblastic:
Liver disease
Alcohol
Hypothyroidism
Reticulocytosis
Macrocytic Anemia - Causes
Alcohol
B12/folate
Medications
Reticulocytosis
Liver disease
MDS
Hypothyroidism
36%
21%
11%
7%
6%
5%
2%
Colon-Othero; Med Clin North Am: 581, 1992
B-12/Folate deficiency
• Therapeutic trial reasonable if blood level
of vitamin borderline
• In equivocal cases consider confirmatory
tests:
TEST
Methymalonate
DEFICIENCY
B-12
Homocysteine
B-12 or folate
Megaloblastic Anemia Drugs
• Folate antagonists
 methotrexate
 trimethoprim
• Most cancer
chemotherapy
• Anti-retroviral
agents




zidovudine
delavirdine
lamivudine
zalcitabine
•
•
•
•
Nitrous oxide
Arsenic
Chlordane
Anticonvulsants
 Dilantin
 Valproate
 Lamotrigine
Normocytic,
hyporegenerative anemia
Marrow disorders
Aplastic anemia
Pure red cell aplasia
Inherited anemia (Diamond-Blackfan)
Myelophthisic state
Myelodysplasia
Leukemia and other heme malignancy
Low EPO state
Uremia, inflammation, endocrinopathy, HIV
infection, etc
Relatively common in elderly
Expected EPO Levels in
Uncomplicated Anemia
100000
10000
1000
Upper
Lower
100
10
1
10
20
Hematocrit→
30
40
50
60
70
Anemia of Renal Insufficiency
• Due to low EPO, shortened RBC survival,
and altered iron kinetics.
• Anemia begins to develop when CrCl is
below 40ml/min/1.73M2
• Common problem in elderly, can be
improved with EPO, often given with po or
iv iron
• Example: 70yo woman, 5’2”, 110 lbs, Cr 1.6
CrCl = 22ml/min/1.73M2
ANEMIA WITH IMPAIRED ERYTHROPOIETIN
RESPONSE IN DIABETIC PATIENTS
Arch Intern Med. 2005;165:466-469
• Subjects: 722 patients with diabetes mellitus
• Measurements/data collection: Clinical data, lab
measurements including CBC, iron studies, EPO
• Findings: 23.3% of patients were anemic. 77.4%
of these had inappropriately low (ie, normal) EPO
levels
• EPO levels inappropriately low in 69% of anemic
diabetic patients with apparently normal renal
function. Most of these patients had albuminuria
and only mild anemia.
• CONCLUSIONS: Diabetic renal disease can cause
mild anemia in the absence of renal impairment.
Most diabetics with anemia could benefit from
EPO treatment
ERYTHROPOIETIN AND AGING
In 143 initially healthy subjects followed for 8-30 years, serum
erythropoietin levels rose steadily with age, while hemoglobin levels
remained constant or declined slightly.
This suggests that older individuals are more dependent on EPO to
maintain the Hgb, and are at greater risk for anemia if there is even
slight impairment in EPO production.
Ershler et al, J Am Geriatr Soc 2005;53:1360
Hyperregenerative anemia
Blood loss
Hemolysis
Immune
Mechanical/microangiopathic
Hereditary (hemoglobinopathy, membrane defect,
enzyme deficiency)
Acquired membrane defect (PNH, spur
cells)
Infection (malaria, Clostridia, babesiosis)
Hemolytic anemia –
laboratory evaluation
• Blood smear (fragments, spherocytes,
sickle cells, malaria, etc)
• Nonspecific indicators of hemolysis: LDH,
bilirubin
• Direct Coombs test
 Warm antibody = IgG  C3
 Cold antibody = C3 only (cold agglutinin)
• Indicators of intravascular hemolysis:
haptoglobin, urine hemosiderin, plasma or
urine hemoglobin
• Other: Hgb electrophoresis, rbc enzyme
levels, G6PD, osmotic fragility, PNH
testing etc
INDICATIONS FOR BONE
MARROW BIOPSY
• Retic index not appropriately increased
• No evidence of iron/B-12/folate deficiency,
renal failure, endocrinopathy,
inflammation or other low EPO state
• Poor response to EPO, iron or vitamin
replacement
• WBC/plts/diff abnormal, monoclonal
gammopathy, or other peripheral blood
evidence of marrow disorder
 Would you treat leukemia/MDS or other
neoplastic disorder if you found it?
ALGORITHM FOR EVALUATION OF ANEMIA
ANEMIC PATIENT
Retic index
Hyper-regenerative
Hypo-regenerative
Evaluate for hemolysis
and bleeding
Rule out treatable
nutritional deficiency,
endocrinopathy, etc
Epo level
Continue EPO
Response
Low-EPO
High-EPO
Trial of EPO
Consider BMBx