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 Exam
Family history Mouth
Timing of symptoms Sternal tenderness
Medications Lymph nodes
Occupation/Hobbies Cardiac murmurs
Diet Liver/Spleen size
Mouth problems Skin exam
GI symptoms Pelvic/rectal
Bruising/bleeding
GU symptoms

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

Maturation Mature RBC

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
23 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
RI 5.8%
1 RI = 1.6
45 2 days
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 90 110 130
MCV
 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
 Microcytosis,
Normal rbc
hypochromia
Normal Macrocytic/megaloblastic
Spur cell anemia Microangiopathic
(liver disease) hemolytic anemia
Hereditary spherocytosis
Rouleaux (myeloma, Waldenstroms)
Neutrophil hyposegmentation Leukoerythroblastic
(myelodysplastic syndrome) (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 Thal
inflammation
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 36%
B12/folate 21%
Medications 11%
Reticulocytosis 7%
Liver disease 6%
MDS 5%
Hypothyroidism 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 DEFICIENCY
Methymalonate B-12
Homocysteine B-12 or folate
 Megaloblastic Anemia -
Drugs
Folate antagonists
methotrexate
Nitrous oxide
trimethoprim Arsenic
Most cancer Chlordane
chemotherapy Anticonvulsants
Anti-retroviral Dilantin
agents Valproate
zidovudine
Lamotrigine
delavirdine
lamivudine
zalcitabine
 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
Serum EPO

Upper
Lower
100

10

1
10 20 30 40 50 60 70
Hematocrit
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, 52, 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

Rule out treatable

Evaluate for hemolysis
nutritional deficiency,
and bleeding
endocrinopathy, etc

Epo level
Low-EPO High-EPO

Continue EPO Trial of EPO Consider BMBx

Response No
response