A Practical
Approach to Anemia
How to efficiently and accurately
work up an anemic patient ?
Dr.R.V.S.N.Sarma., M.D., M.Sc., (Canada)
Consultant Physician & Chest Specialist
Visit us at : www.drsarma.in
What is Anemia ?
Important to remember
• Anemia is a clinical sign of disease
• It is not a single disease by itself
• Need to look for the underlying cause !
• Will we ignore a fever with out investigation ?
• Its diagnosis is not that simple !! We’ll make it
• Its very common and imp. in our practice
• Drug Rx. depends on the cause
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Definition of Anemia
• Decrease in the quantum of circulating red
blood cell mass and there by ↓ O2 carrying
capacity
• Most common hematological disorder by far
• Almost always a secondary disorder
• As such, critical for all practitioners to know
how to evaluate / determine its cause / treat
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Normal Red Cells
No nucleus, enzyme packets
Biconcave discs – Haem + Gl
Center 1/3 pallor
Pink cytoplasm (Hb filled)
Cell size 7- 8 µ - capill. 2 µ
EM pathway, HMP
Negative charge – no phago
Na less, K more inside
100-120 days life span
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The Factory – Bone Marrow
Sternum, pelvis, vertebrae, long
bones, skull bones, Tibia (paed)
From stem cells (pleuripotent)
75% of marrow for WBC
25% of BM for Red cells
Erythrod / Granulocyte Ratio 1:3
E:G ratio increases in Anemia
Large white areas are marrow fat
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Hemoglobin (Hb)
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1
• History and Clinical Examination
• Thorough exam for any bleeding -
2
• Hb%, then RCC and Hematocrit
• Derive MCV, MCH, MCHC
3
• Reticulocyte count –
• Reticulocyte Production Index (RPI)
4
• Microcytosis, Macrocytosis, Hypochromia
• Red cell distribution width (RDW)
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5
• Peripheral Smear Examination
• Microcytic hypochromic Anemias
6
• Serum Ferritin, TIBC, Bone Marrow Fe
• IDA, Other Microcytic Anemias
7
• Macrocytic Megaloblastic – B12 & Folate
• Macrocytic Normoblastic – Non MBA
8
• Normocytic Normochromic – Chr Disease
• Hemolytic Anemia – Further work up
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First Question
• The onset of Anemia
• Acute versus chronic
• Clues
– Hemodynamic stability
– Previous CBC
– Overt blood loss
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Screening Tests – Anemia
• Clinical Signs and symptoms of Anemia
• Look for bleeding – all possible sites
• Look for the causes for anemia
• Routine Hemoglobin examination
• Cut off marks for Hb –
– US < 13.5 g
WHO < 12.5 g
– India (ICMR)
Less than 12 g%
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Clinical Signs to be looked for
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Skin / mucosal pallor,
Skin dryness, palmar creases
Bald tongue, Glossitis
Mouth ulcers, Rectal exam
Jaundice, Purpura
Lymph adenopathy
Hepato-splenomegaly
Breathlessness
Tachycardia, CHF
Bleeding, Occult Blood
PCV or Hematocrit
• 57% Plasma
• 1% Buffy coat – WBC
• 42% Hct (PCV)
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The Three Primary Measures
Measurement
Normal
A. RBC count (RCC) 5 million
B. Hemoglobin
15 g%
C. Hematocrit (PCV) 45
Range
4 to 5.7
12 to 17
38 to 50
A x 3 = B x 3 = C - This is the rule of thumb
Check whether this holds good in a given result
If not -indicates micro or macrocytosis or hypochro.
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The Three Derived Indicies
Measurement
Normal
Range
A. RCC
5 million
B. Hemoglobin
15 g%
12 to 17
C. Hematocrit
45 %
38 to 50
MCV
C ÷ A x 10
MCH
B ÷ A x 10
MCHC (%) B ÷ C x 100
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4 to 5.7
=
=
=
90 fl
30 pg
33%
Types of Anemia
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A
• Hemopoetic
B
• Hemolytic
C
• Hemorrhagic
Causes of Anemia
1. Decreased production of Red Cells
- Hypo proliferative, marrow failure
2. Increased destruction of Red Cells
- Hemolysis (decreased survival of RBC)
3. Loss of Red Cells due to bleeding
- Acute / chronic blood loss (hemorrhagic)
M = P x S ( L)
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Hypoproliferative Anemias
Nuclear
breakdown
Failure of cell
maturation
Cytoplasmic
breakdown
Folate or B12 deficiency
Haem defect
Globin defect
Defective DNA synthesis
Fe
Sickle cell A
Megaloblastic Anemia
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Phorph
IDA, SA
Thalassemia
Anemia – Second Test
RETICULOCYTE COUNT %
• ‘RBC to be’ or Apprentice RBC
• Fragments of nuclear material
• RNA strands which stain blue
Normal
Less than 2%
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Reticulocyte
No definite nucleus
Reticulum of RNA
Deep blue staining
Light blue cytoplasm
Cell size about 10 µ
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Reticulocytes
Supravital
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Leishman’s
Reticulocyte Production Index
For example, the RPI is calculated as follows
Reticulocyte count
9%
Hb content
7.5 g%
1. Correction for Anemia
= 9 x (7.5 ÷ 15) = 9 x 0.5 = 4.5 %
2. Correction for life span
4.5 ÷ 2 = 2.25 %
3. Thus, the RPI is 2.25
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Anemia
Hb% < 12, Hct < 38%
Hypoproliferative
Hemolytic
RPI < 2
RPI > 2
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Workup – Third Test
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The next step is ‘What is the size of RBC’ ?
MCV indicates the Red cell volume (size)
Both the MCH & MCHC tell Hb content of RBC
If the RPI is 2 or less
We are dealing with either
– Hypoproliferative Anemia (lack of raw material)
– Maturation defect with less production
– Bone marrow suppression (primary/ secondary)
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Red Cell Size
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Mean Cell Volume (MCV)
• RBC size is measured indirectly by
• The Mean Cell Volume (MCV) and RDW
MCV
Microcytic
Normocytic
Macrocytic
< 80 fl
80 -100 fl
> 100 fl
< 6.5 µ
6.5 - 9 µ
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>9µ
Anemia Workup - MCV
MCV
Microcytic
Normocytic
Macrocytic
Iron Deficiency (IDA)
Chronic diseases, CKD
Megaloblastic anemias
Chronic Infections
Early IDA
Liver disease/alcohol
Thalassemias
Hemoglobinopathies
Hemoglobinopathies
Hemoglobinopathies
Primary marrow disorders Metabolic disorders
Sideroblastic Anemia
Combined deficiencies
Marrow disorders
Increased destruction
Increased destruction
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Anemia Workup – 4th Test
Red cell Distribution Width – RDW
RDW
< 13
RDW is 13
Mean
MCV90
90 fl
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Red cell Distribution Width - RDW
MCV
Microcytic
Normocytic
Macrocytic
Left
Mean 90
Right
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Anemia Workup - 5th Test
Peripheral Smear Study
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Are all RBC of the same size ?
Are all RBC of the same normal discoid shape ?
How is the colour (Hb content) saturation ?
Are all the RBC of same colour/ multi coloured ?
Are there any RBC inclusions ?
Are there any hemo-parasites in the RBC ?
Are leucocytes normal in number and D.C ?
Is platelet distribution adequate ?
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IDA -CBC
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Severe Hypochromia
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Microcytic Hypochromic - IDA
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Microcytic Hypochromic Anemia
Serum Ferritin
< 33 pmol / l
> 270pmol / l
33-270 pmol / l
TIBC (300-340)
N or ↓
HIGH
-
BM Fe
Iron Deficiency Anemia IDA
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+
Not IDA, Other Mi A
IDA Summary
• Microcytic
MCV < 80 fl, RBC < 6 µ
• RDW
Widened and shifted to left
• Hypochromic
MCH < 27 pg, MCHC < 30%
• RPI
<2
• Retic. count
May be > 2 %
• Serum ferritin
Very low < 33 (p mols/L)
• TIBC
Increased > 340 (µg/dL)
• BM Iron stain
Iron is Absent
• Response to Fe Rx.
Excellent
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IDA- Some Nuggets
• Look for occult blood loss – 2 days non veg. free
• Pica and Pagophagia – Ice sucking
• Absorption of Haem Iron > Fe ++ > Fe+++
• Food, Phytates, Ca, Phosphate, antacids ↓absorption
• Ascorbic acid ↑absorption
• Oral iron Rx. always is the best, ? Carbonyl Fe
• FeSO4 is the best. Reserve parenteral Rx.
• Packed cell transfusion in emergency
• Continue Fe Rx at least 2 months after normal Hb
• 1 gram ↑in Hb every week can be expected
• Always supplement protein for the Globin component
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Microcytic Anemias
MCV < 80 fl
Serum Ferritin TIBC BM Perls stain
↓↓
↓↓
↑↑
↑↑
↓↓
++
N
++++
Hemoglobinopathy
N
N
Lead poisoning
N
N
++
++
↑↑
N
++++
Iron Def. Anemia
Chronic Infection
Thalassemia
Sideroblastic
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0
Ringed Sideroblasts in BM
Prussian Blue Stain
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Macrocytic Anemias
A. Megaloblastic Macrocytic – B12 and Folate↓
B. Non Megaloblastic Macrocytic Anemias
1. Liver disease/alcohol
2. Hemoglobinopathies
3. Metabolic disorders, Hypothyroidism
4. Myelodystrophy, BM infiltration
5. Accelerated Erythropoesis -↑destruction
6. Drugs (cytotoxics, immuno suppressants,
AZT, anticonvulsants)
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Anemia - Macrocytic (MCV > 100)
Premature gray hair – consider MBA
Macrocytic anemias may be asymptomatic until
the Hb is as low as 6 grams
MCV 100-110 fl
must look for other causes of macrocytosis
MCV > 110 fl
almost always folate or B12 deficiency
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Macrocytosis of Alcoholism
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25-96% of alcoholics
MCV elevation usually slight (100-110 fl)
Minimal or no anemia
Macrocytes round (not oval)
Neutrophil hyper segmentation absent
Folate stores normal
Smoking increases the Red Cell Mass
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Megaloblastic Hematopoiesis
Marrow failure due to
• Disrupted DNA synth. & ineffective erythropoesis
• Giant precursors (Megaloblasts)
• Nuclear : Cytoplasmic dyssynchrony in marrow
• Neutrophil hyper segmentation & macro ovalocytes
• Anemia (and often leukopenia & thrombocytopenia)
• Almost always due to B12 or folate deficiency
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MBA
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Macrocytosis -MBA
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Anisocytosis - Macrocytic Anemia
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HSN - MBA
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Basophilic Stippling - MBA
BS occurs in Lead poisoning also
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Megalocyte in PS
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MBA - BM
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MBA - BM
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Megaloblast – FA deficiency
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Pernicious Anemia - Tongue
Bald, smooth, lemon
yellowish red tongue
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Normocytic Anemias
1.
2.
3.
4.
5.
6.
7.
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Chronic diseases, CKD
Early IDA
Hemoglobinopathies
Primary marrow disorders
Combined deficiencies
Increased destruction
Anemia of investigations -ICU
Anemia of Chronic Disease
• Thyroid diseases
• Malignancy
• Collagen Vascular Disease
– Rheumatoid Arthritis
– SLE
– Polymyositis
– Polyarteritis Nodosa
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• IBD
– Ulcerative Colitis
– Crohn’s Disease
• Chronic Infections
– HIV, Osteomyelitis
– Tuberculosis
• CKD, Renal Failure
‘Dimorphic’ Anemia
• Folate & Fe deficiency (pregnancy, alcoholism)
• B12 & Fe deficiency (PA with atrophic gastritis)
• Thalassemia minor & B12 or folate deficiency
• Fe deficiency & hemolysis (prosthetic valve)
• Folate deficiency & hemolysis (Hb SS disease)
• Peripheral smear exam is critical to assess these
• RDW is increased very much
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Algorithm for Diagnosis of Anemia
Anemia Suspected
Thorough Clin, Bleed
Hb%, RCC, Hct Decreased
Ca, Leukemia, Ulcer
Identify the cause
Microcytic hypochromic
RPI, Retic count <2
RPI, Retic count >2
MCV, MCH, MCHC, PSE
Hemolytic Anemia
Macrocytic hypo/normo
Coombs DAT, IDAT
Iron Def. Anemia
Megaloblastic
Normoblastic
Hb electrophoresis
Ferritin, TIBC, BM Fe
Folate defici.
ALD, CLD, Drug
Osmotic fragility
Thalassemia, Hb pathy
B12 def., PA
Chr. Renal dis.
Acid hemolysis
Sederoblastic Anaem.
Hypothyroid
Cold agglutinins
Chr. Infection, Lead
BM infiltration
Coagulopathy, DIC
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In order to make a differential diagnosis
LET US LOOK AT SOME
REPORTS OF PATIENTS
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Test Done
Value
Remarks
RBC
3.96 million/c mm
Decreased
Hb%
9.7 g%
Decreased
Hematocrit
23.9 %
Decreasd
MCV
60.4 fl
Microcytosis
MCH
24.6 pg/l
Hypochromia
MCHC
40.5 %
Not relevant
RC and RPI
4 %, 1.29
Not Hemolytic
Peripheral Smear
Microcytic hypochromic
DD of Microcytic
Serum Ferritin
46 pmol/l
Boarderline
TIBC
390 µg/dl
Elevated
BM
Iron stain
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Absent
Clinches IDA
Test Done
Value
Remarks
RBC
3.86 million/c mm
Decreased
Hb%
10.4 g%
Decreased
Hematocrit
26.9 %
Decreasd
MCV
69.7 fl
Microcytosis
MCH
25.8 pg/l
Hypochromia
MCHC
38.66 %
Not relevant
RC and RPI
5 %, 1.73
Not Hemolytic
Peripheral Smear
Microcytic hypochromic
DD of Microcytic
Serum Ferritin
320 pmol/l
High
TIBC
300 µg/dl
Normal
BM
Iron stain
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Ringed sideroblasts
Clinches SBA
Test Done
Value
Remarks
RBC
2.69 million/c mm
Decreased
Hb%
10.6 g%
Decreased
Hematocrit
31.6 %
Decreasd
MCV
117.5 fl
Macrocytosis (Severe)
MCH
39.4 pg/l
Hyperchromia
MCHC
33.5 %
Normal
RC and RPI
5 %, 1.76
Not Hemolytic
Peripheral Smear
Macrocytic Hyperchromic
DD of Macrocytic
Serum Ferritin
240 pmol/l
Normal (Not required)
TIBC
338 µg/dl
Normal (Not required)
BM
Exam
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Megaloblastic BM
Clinches MBA (F, B12)
Test Done
Value
Remarks
RBC
3.09 million/c mm
Decreased
Hb%
10.6 g%
Decreased
Hematocrit
31.6 %
Decreasd
MCV
102.3 fl
Macrocytosis (Moderate)
MCH
34.3 pg/l
Hyperchromia
MCHC
33.5 %
Normal
RC and RPI
3 %, 1.06
Not Hemolytic
Peripheral Smear
Macrocytic Hyperchromic DD of Macrocytic
Serum Ferritin
240 pmol/l
Normal (Not required)
TIBC
338 µg/dl
Normal (Not required)
BM
Exam
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Normoblastic BM
Clinches MCA (Chr D)
Test Done
Value
Remarks
RBC
3.10 million/c mm
Decreased
Hb%
9.3 g%
Decreased
Hematocrit
27.9 %
Decreasd
MCV
90 fl
Normocytosis
MCH
30.0 pg/l
Normochromia
MCHC
33.3 %
Normal
RC and RPI
1.5 %, 0.47
Not Hemolytic
Peripheral Smear
Normocytic Normochromic DD of Normocytic A
Serum Ferritin
240 pmol/l
Normal (Not required)
TIBC
338 µg/dl
Normal (Not required)
BM
Exam
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Normoblastic BM
CLD, ALD, CKD, Drugs
Test Done
Value
Remarks
RBC
3.81 million/c mm
Decreased
Hb%
11.1 g%
Decreased
Hematocrit
33.3 %
Decreasd
MCV
87.4 fl
Normocytosis
MCH
29.2 pg/l
Normochromia
MCHC
33.33 %
Normal
RC and RPI
10 %, 3.70
Hemolytic
Peripheral Smear
Piokilo, Aniso, target cells
DD of Hemolytic Anemia
Serum Ferritin
240 pmol/l
Normal (Not required)
TIBC
338 µg/dl
Normal (Not required)
BM
Exam
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E : G Ratio is 2 : 1
Hypercellular marrow
Anemia - Summary
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If Hb% is low – Do not start on Iron straight away
Ask for RCC, Hematocrit – Derive MCV, MCH, MCHC
Order for Reticulocyte count – Is RPI < 2 % or > 2%
Thoroughly look for blood loss – acute / chronic / occult
Is it hypo-proliferative or hemolytic or hemorrhagic Anemia
If hypo proliferative – Microcytic or Macrocytic? (MCV, RDW)
If microcytic – IDA or others – Sr Ferritin TIBC, BM Iron
If macrocytic – Megaloblastic (B12, FA) or Normoblastic BM
If normocytic – Anemia of chr. Disease – Liver, CKD, Ca
Peripheral smear study for RBC size, shape, colouration etc.
If retic. count is ↑- HA work up; Hb EP, spl. tests
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RBC Size – Anisocytosis
Different sizes of RBC
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Poikilocytosis
Different Shapes of RBC
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Polychromasia - Spherocytosis
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Target Cells
1. Liver Disease
2. Thalassemia
3. Hb D Disease
4. Post splenectomy
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Tear Drop Cells
1. Myelofibosis
2. Infiltration of BM
3. Tumours of BM
4. Thalassemia
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Hair on end - Thalassemia Major
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Drepanocytes - SS
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Sickle Cell Anemia
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Autosplenectomy - SS
Normal spleen is 8 to 12 cm
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Hemolytic Anemia
Anemia of increased RBC destruction
– Normochromic, normocytic anemia
– Shortened RBC survival
– Reticulocytosis – due to ↑ RBC destruction
Will not be symptomatic until the RBC life span is
reduced to 20 days – BM compensates 6 times
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Tests Used to Diagnose Hemolysis
1.
2.
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4.
5.
6.
7.
8.
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Reticulocyte count
Combined with serial Hb
Hemoglobin electrophotesis
Serum LDH
Serum bilirubin
Haptoglobin
Urine hemosiderin
Hemoglobinuria
Findings in Hemolytic Anemia
Reticulocyte count and RPI
Increased
Serum Unconjugated Bilirubin
Increased
Serum LDH 1: LDH 2
Increased
Serum Haptoglobin
Decreased
Urine Hemoglobin
Present
Urine Hemosiderin
Present
Urine Urobilinogen
Increased
Cr 51 labeled RBC life span
Decreased
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Tests to define
the cause of hemolysis
1.
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7.
8.
Hemoglobin electrophoresis
Hemoglobin A2 (βeta-Thalassemia trait)
RBC enzymes (G6PD, PK, etc)
Direct & indirect antiglobulin tests (immune)
Cold agglutinins
Osmotic fragility (spherocytosis)
Acid hemolysis test (PNH)
Clotting profile (DIC)
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MAHA
Micro Angiopathic Hemolytic Anemia
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MAHA
Micro Angiopathic Hemolytic Anemia
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Hyperactive BM – Skull
Hemolytic Anemia
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Spherocytosis
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Spherocytosis
Hereditary Spherocytosis
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Spherocytosis
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Elliptocytes
Hereditary Elliptocytosis, B12 or Folate↓
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Stomatocytes
Slit like central pallor in RBC
1. Liver Disease
2. Acute Alcoholism
3. H Stomatocyosis
4. Malignancies
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Echinocytes
Evenly distributed spicules > 10
1. Uremia
2. Peptic ulcer
3. Gastric Ca
4. PK-D
Called Burr Cells
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Acanthocytes
5-8 spikes of varying length, irregular intervals
Called Spur Cells, Occur in A H A
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Shistocytes
Fragmented, Helmet or triangle shaped RBC
1. MAHA
2. Prosthetic valves
3. Uremia
4. Malignant HT
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Leukoplakia - Aplastic Anemia
1. Chloramphenicol
2. Neomercazole
3. Sulfonamides
4. Analgin
5. Phenytoin
6. Butazolidin group
7. Anti Ca drugs
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Normal BM High Power
E:G=1:3
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Shift in E : G Ratio
E:G=2:1
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BM - Aplastic Anemia
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Myelofibrosis
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Post transfusion - CBC
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Howell-Jolly Bodies
Absence of Splenic function; Nuclear chromatin in RBC
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Pelger-Huet Anomaly
• Inherited condition
• PMN - Spectacles
• Heterozygous
• Homozygous fatal
• Neutrophil Bands ↑
• Normal WCC
• No e/o infection
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Thank You ALL
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