A Practical

Approach to Anemia
How to efficiently and accurately
work up an anemic patient ?

What is Anaemia ?
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 !! Well make it
Its very common and imp. in our practice
Drug Rx. depends on the cause
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Definition of Anaemia
Decrease in the number 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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Erythron

Erythron is the machinery of RBC production

EPO, IL, Growth factors, Cytokines stimulate it
Hypoxia is strong stimulus for the Erythron
Its functioning is influenced by
1. Normal renal production of EPO
2. A functioning Erythroid marrow
3. An adequate supply of substrates for Hb production

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The RBC Lineage

Let us meet the Grand Parents !

Haemopoesis in Bone Marrow

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Pro Erythroblast

Large purple nucleus

Thin rim of cytoplasm
Basophilic in stain
Cell > 35

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Early Normoblast

Large purple nucleus

Denser nucleus
Thin rim of cytoplasm
Basophilic in stain
Cell > 25

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Intermediate Normoblast

Medium sized nucleus

Reticulated nucleus
More cytoplasm
Neutral in stain
Cell > 20

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Late Normoblast

Small dense nucleus

Darkly staining
Increased cytoplasm
Pink in stain
Cell > 15

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Reticulocyte

No definite nucleus
Reticulum of RNA
Deep blue staining
Light blue cytoplasm
Cell size about 10

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Normal Red Cells

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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 - capill. 2
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 increased in Anaemia
Large white areas are marrow fat
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Normal BM High Power

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Hemoglobin (Hb)

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First Question
The onset of Anaemia
Acute versus chronic
Clues
Hemodynamic stability
Previous CBC
Overt blood loss
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Types of Anaemia

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Screening Tests Anaemia

Clinical Signs and symptoms of Anaemia
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

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 Basic Measures

Measurement

Normal

Range

A. RBC count

5 million

4 to 6

B. Hemoglobin

15 g%

12 to 17

C. Hematocrit

45

38 to 50

A x 3 = B x 3 = C - This is the rule of thumb

Check whether this holds good in given results
If not -indicates micro or macrocytosis or hypochro.
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The Three Derived Indicies

Measurement

Normal

Range

A. RBC count

5 million

B. Hemoglobin

15 g%

12 to 17

C. Hematocrit

45

38 to 50

MCV
MCH
MCHC
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C A x 10
B A x 10
B C x 100

4 to 6

=
=
=

90 fl
30 pg
33%

Causes of Anaemia
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 Anaemias

Nuclear
breakdown

Failure of cell
maturation

Cytoplasmic
breakdown

Folate or B12 deficiency

Haem defect

Globin defect

Defective DNA synthesis

Fe

Sickle cell A

Megaloblastic Anaemia
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Phorph

IDA, SA

Thalassemia

Anaemia First 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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Reticulocytes

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Supravital

Leishmans

Reticulocyte Production Index

For example the RPI is calculated as follows
Reticulocyte count
9%
Hb content
7.5 g%
1. Correction for Anaemia
= 9 x (7.5 15) = 9 x 0.5 = 4.5 %
2. Correction for increased life span
4.5 2 = 2.25 %
3. Thus, the RPI is 2.25
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Anaemia
Hb% < 12, Hct < 38%

Hypoproliferative

Hemolytic

RPI < 2

RPI > 2

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Normal CBC

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Workup Second Test

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 anaemia (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 volume (rather) is measured by
The Mean Cell Volume or MCV and RDW

MCV

Microcytic

Normocytic

Macrocytic

< 80 fl

80 -100 fl

> 100 fl

< 6.5

6.5 - 9

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>9

Anaemia Workup - MCV

MCV

Microcytic

Normocytic

Macrocytic

Iron Deficiency IDA

Chronic disease

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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Anaemia Workup 3rd Test

Red cell Distribution Width RDW
RDW
< is1313
RDW
Mean
MCV90
90 fl
fl

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Red cell Distribution Width - RDW

MCV

Microcytic

Normocytic

Macrocytic

Left

Mean 90

Right

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Anaemia Workup - 4th Test

Peripheral Smear Study

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 intra RBC there any hemo-parasites ?
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 Anaemia

Serum Ferritin
< 33 pmol / l

> 270pmol / l

33-270 pmol / l
TIBC
N or

HIGH

BM Fe

Iron Deficiency Anaemia IDA

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+
Not IDA, Other Mi A

IDA Special Tests

Iron related tests

Normal

IDA

Serum Ferritin (pmo/L)

33-270

< 33

TIBC (g/dL)

300-340

> 400

Serum Iron (g/dL)

50-150

< 30

Saturation %

30-50

< 10

++

Absent

Bone marrow Iron

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IDA Summary
MicrocyticMCV < 80 fl, RBC < 6
RDW

Widened and shift to left

Hypochromic
RPI

MCH < 27 pg, MCHC < 30%

<2

Retic. count

May be > 2 %

Serum ferritin

Very low < 30 (p mols/L)

TIBC

Increased > 400 (g/dL)

Serum Iron

Very low < 30 (g/dL)

BM Fe Stain

Absent Fe

Response to Fe Rx.

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Excellent

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 Anaemias
MCV < 80 fl

Serum Iron

TIBC

BM Perls stain

++

++++

Hemoglobinopathy

Lead poisoning

++
++

++++

Iron Def. Anemia

Chronic Infection
Thalassemia

Sideroblastic
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Ringed Sideroblasts in BM
Prussian Blue Stain

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Macrocytic Anaemias
A. Megaloblastic Macrocytic B12 and Folate
B. Non Megaloblastic Macrocytic Anaemias
1. Liver disease/alcohol
2. Hemoglobinopathies
3. Metabolic disorders, Hypothyroidism
4. Myelodystrophy, BM infiltration
5. Accelerated Erythropoesis - destruction
6. Drugs (cytotoxics, immunosuppressants, 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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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 Anaemia

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HSN - MBA

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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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Pernicious Anaemia - Tongue

Bald, smooth, lemon

yellowish red tongue

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Normocytic Anaemias
1.
2.
3.
4.
5.
6.
7.
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Chronic disease
Early IDA
Hemoglobinopathies
Primary marrow disorders
Combined deficiencies
Increased destruction
Anaemia of investigations -ICU

Anaemia of Chronic Disease

Thyroid diseases
Malignancy
Collagen Vascular Disease
Rheumatoid Arthritis
SLE
Polymyositis
Polyarteritis Nodosa
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IBD
Ulcerative Colitis
Crohns Disease
Chronic Infections
HIV, Osteomyelitis
Tuberculosis
Renal Failure

Dimorphic Anaemia
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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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 Anaemia

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Autosplenectomy - SS
Normal spleen is 8 to 12 cm

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Hemolytic Anaemia
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.
3.
4.
5.
6.
7.
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Reticulocyte count
Combined with serial Hb
Serum LDH
Serum bilirubin
Haptoglobin
Urine hemosiderin
Hemoglobinuria

Findings in Hemolytic Anaemia

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.
2.
3.
4.
5.
6.
7.
8.

Hemoglobin electrophoresis
Hemoglobin A2 (eta-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 Anaemia

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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 Anaemia

1. Chloramphenicol
2. Neomercazole
3. Sulfonamides
4. Analgin
5. Phenytoin
6. Butazolidin group
7. Anti Ca drugs
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Howell-Jolly Bodies
Absence of Splenic function; Nuclear chromatin in RBC

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Anaemia Diagnosis
-Algorithm
Anaemia 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 Anaemia

Macrocytic hypo/normo

Coombs DAT, IDAT

Iron Def. Anaemia

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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Anaemia - Summary

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 anaemia
If hypo proliferative Microcytic or Macrocytic? (MCV, RDW)
If microcytic IDA or others Spl. Iron tests, BM Iron
If macrocytic Megaloblastic (B12, FA) or Normoblastic BM
If normocytic Anaemia of chr. Disease Liver, MRD, 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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Thank You ALL

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