An Approach to Anemia

Brad Lewis
Director Hematology
San Francisco General Hospital

Blood alone moves the wheels of history.

Benito Mussolini
Blood will tell, but often it tells too much.
Don Marquis
 For the life of the flesh is in
the blood…For every
creature…its blood is its life.
Leviticus
17.11
 Case #1
• 54yo male with anemia
– Visiting from Hawaii
– Presented to the ER weak, febrile
– PMH
• DM with poor control
– Severe diabetic foot ulcers with osteo
• DVT bilat during recent hospitalization
• AIHA w/ 4+ IgG Coombs
– On Prednisone 60mg
– PE
• Sl. Confused w/o focal sx
• Pharynx 1+ thrush
• Cor nl
• Abd soft, no organomegally
• severe foot ulcers
 Lab
• WBC 4.3 w/nl diff
• Hgb 6.7
• Plt 210
• Creat 3.0
• Glu 450

• What next?
 Lab
• Call to Hawaii
– AIHA for 9 months
• Initial HGB 5, nl MCV
• No retic obtained
• Begun on prednisone with initial response
– Hgb 8
– Lost to F/U (??but not to prednisone??)
• What’s going on/What to do?
 Lab
• Hgb 6.7, MCV 100
• Retic Count 0.6
• Smear toxic with ??atypical
granulation, hypersegmented
neutrophils
• ????
 Next step?
BM Biopsy with 75% cellularity
Normal trilineage hematopoiesis

??L shifted erythropoiesis

Hypogranulation??
Binucleate NRBC

Cytogenetics reveal trisomy 8

An Approach to Anemia
Anemia
 An Approach to Anemia
Anemia
Retic Hi Retic Low
 Evaluating Hemolysis
The Bucket with The Hole
 Evaluating Hemolysis
The Bucket with The Hole
 Reticulocytes

Retic #=1/mm
Retic %= 20%

Corr Retic = Retic x hgb/nl hgb

Retic # = 1/mm
Retic % = 30%

RPI = corrected retic. count/Maturation time

(Maturation time = 1 for Hct=45%, 1.5 for 35%, 2 for 25%, and
2.5 for 15%.)
 An Approach to Anemia
Anemia
Retic Hi Retic Low
MCV Lo MCV Nl MCV Hi
 An Approach to Anemia
Anemia
Retic Hi Retic Low
Loss Destruction MCV Lo MCV Nl MCV Hi

Tissue Intrinsic Iron Chronic Disease B12

On Floor Extrinsic (Lead) Renal Folate
Occult Splenic Thal Mixed Liver
Mechanical Frags Mild/Treated ETOH
Recovery Early Thyroid
Transfused Toxic
Endocrine MDS
Intrinsic BM
Dilution
 Initial Diagnostic Tests
• TREAT FIRST?
– Irretrievable data
• Smear, Iron, B12, Hgb Electropheresis
– Hyperviscosity
• Repeat CBC
– Note MCV
• Retic Count
• Smear??
• Chem Panel
• ??Follow your instincts?
 Anemia
Retic Hi Retic Low
Loss Destruction MCV Lo MCV Nl MCV Hi

Tissue Intrinsic
On Floor Hgb’opathy
Occult Enzymopathy
Membrane
HS
PNH
Extrinsic
Splenic
Mechanical
Recovery
An Approach to Anemia
 Anemia
Retic Hi Retic Low
Loss Destruction MCV Lo MCV Nl MCV Hi
Tissue Intrinsic
On Floor Extrinsic
Occult AIHA
Recovery cold
warm
Drug/Toxins
Sepsis
Burns
Splenic/Hepatic
Mechanical
MAHA
UpToDate
 Hemolysis Diagnosis
• Check the RETIC!
• LDH, Haptoglobin, Bili (Wet, Rusty ground)
• Intravascular (massive)
– Plasma Hgb
– Urine Hemosiderin (Hemoglobinuria)
• The Hgb A1C of the hematologist
• Refer if “incongruity”
 Specific Diagnostic Tests-
High Retic
• Smear
• Coombs- Direct and Indirect
– Does NOT diagnose hemolysis
• G6PD ASSAY (and Retic count)
• Hemoglobin Electropheresis???
Microangiopathic Hemolysis
 G6PD
• X-linked, race variable
• Unable to Reduce Glutathione
– Susceptible to oxidant damage
• Drugs
– Sulfa
– Methylene Blue
– Anti-Malarial
– Nitrates
• Infections
• DKA
• Fava Beans
 Case #2

• 32 yo healthy AA male
– 1 week cough, fever
• 2d PTA PMD gives Septra
– Presents to ER w/ increasing fatigue & dyspnea
• WBC 12,000
• Hgb 7
– Retic count 390
– G6PD 11 (nl. 5 – 14)
 G6PD Deficiency
Average G6PD Act.

Time in Circulation
 “Italian” G6PD Deficiency
Average G6PD Act.

Normal

Nl mean

Severe G6PD Def.

Time in Circulation
 “African” G6PD Deficiency
Average G6PD Act.

Time in Circulation
 “African” G6PD Deficiency
hemolysing with oxidant stress
Young Retics with more G6PD

New Average G6PD Activity

Average G6PD Act.

Hemolyzed

Time in Circulation
 Anemia
Retic Hi Retic Low
Loss Destruction MCV Lo MCV Nl MCV Hi
B12
Folate
Hepatic
ETOH
Thyroid
Toxic
AZT
Chemo
Dilantin
MDS
An Approach to Anemia
 Macrocytosis
Normal Hematopoiesis Megaloblastic Hematopoiesis
 Diagnostic Tests-
Low Retic Macrocytic
• Repeat Retic
• Smear (round vs. oval macrocytes,
hypersegmented PMN)
• B12 and Folate (and Iron)
• Cold Agglutinin
• Membrane Lipids
– Hepatic, ETOH, Hypothyroid
• Toxic?
– Chemo, Dilantin
• To BM or not to BM
 Anemia
Retic Hi Retic Low
Loss Destruction MCV Lo MCV Nl MCV Hi

Iron
(Lead)
Thalassemia
Fragmentation
Sideroblastic Anemia
acquired
congenital

An Approach to Anemia
 Diagnostic Tests
Low Retic Microcytic
• Iron/TIBC vs. Ferritin
• Hemoglobin Electropheresis
– GENETIC SCREENING OF FAMILY
– The “Normal” Electropheresis
• Smear?
• Value of MCV and RDW
• Lead?
Inflammation
IL-6 Iron Metabolism
Iron Signal?

Spleen
Hep
c idin
He
pc
id

RBC
in
He

Plasma
pc
idi

Fe-Tf
n

Bone Marrow
Duodenum
Erythropoiesis Signal
(anemia, hypoxia) Tomas Ganz ASH 2006
 Ferroportin
Enterocyte or
Macrophage

fp
Fe
 Ferroportin
Enterocyte or
Macrophage

Lysozome

fp Hepcidin
Fe
 Evaluating Iron
• Ferritin
– Sensitive/specific
• Except increased in inflammation, liver disease, malignancy

• Fe/TIBC (Transferrin)
– Decreased in inflammation, malignancy
• THEREFORE:
• Iron Trial
– Retic Count, Hgb
– Reticulocyte Hgb Concentration?
• Serum (soluble) Transferrin Receptor
– Increased in iron def and hemolysis
• Little change with inflammation
 Treating Iron Deficiency
• Oral Ferrous salts
– All with similar absorption
– Vitamin C?
– QD >>>TID
• Empty stomach
• IV Iron
– Risk of Anaphylaxis with previous
– NOT Faster
– More Certain
• Malabsorption??
• Compliance
 Anemia
Retic Hi Retic Low
Loss Destruction MCV Lo MCV Nl MCV Hi
Early Anything
Mild/Treated
Transfused
Chronic Disease
Renal
Mixed
Endocrine
Intrinsic BM
Myeloma Aplastic
Lymphoma True
Infection Drug
Malignancy Anorexia
Liver Disease with Iron
Deficiency
 Diagnostic Tests
Low Retic Normocytic
• Chem Panel, LDH
• Smear
• Iron, B12 and Folate
• ESR (or a good history?)
• SPEP/Immunofixation
• Time
• To BM or not to BM
 Delayed Transfusion Reaction

• Due to previous Ab, undetectable at time of testing

– Usu. Kidd or Rh
• Hemolysis 2-10 d after Transfusion
– Extravascular (spleen mediated)
– Usu. Clinically mild
• Fever, jaundice
• Spherocytosis
• Positive DAT
• Decreased AA hgb in transfused SSD patients
B12 Deficiency
B12 Hyperseg PMN
 B12 Deficiency
• ??Diagnostic level (<300)
– Role of Methylmalonic acid
• 12% Healthy Elderly Deficient
– ??atrophic gastritis
• Role of Schilling Test today
• Anti-Intrinsic Factor Ab(specific,
?sensitive)
– Anti-Parietal Cell(??sens)
• Diagnostic/therapeutic trial