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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
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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
1. 2. 3. 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 Normal renal production of EPO A functioning Erythroid marrow 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 India
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WHO < 12.5 g Less than 12 g%

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 A. RBC count B. Hemoglobin Normal 5 million 15 g% Range 4 to 6 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 A. RBC count B. Hemoglobin Normal 5 million 15 g% Range 4 to 6 12 to 17

C. Hematocrit
MCV MCH MCHC
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45
C A x 10 B A x 10 B C x 100 = = =

38 to 50
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
Failure of cell maturation

Nuclear breakdown

Cytoplasmic breakdown Globin defect

Folate or B12 deficiency Defective DNA synthesis Megaloblastic Anaemia


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Haem defect Fe Phorph

Sickle cell A
Thalassemia

IDA, SA

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

Supravital
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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
RPI < 2

Hemolytic
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
< 6.5
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80 -100 fl
6.5 - 9

> 100 fl
>9

Anaemia Workup - MCV


MCV

Microcytic
Iron Deficiency IDA
Chronic Infections Thalassemias

Normocytic
Chronic disease
Early IDA Hemoglobinopathies Combined deficiencies Increased destruction

Macrocytic
Megaloblastic anemias
Liver disease/alcohol Hemoglobinopathies Marrow disorders Increased destruction

Hemoglobinopathies
Sideroblastic Anemia
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Primary marrow disorders Metabolic disorders

Anaemia Workup 3rd Test Red cell Distribution Width RDW


RDW < is 13 13 RDW Mean 90 fl MCV 90

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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 33-270 pmol / l TIBC HIGH N or > 270pmol / l

BM Fe

+
Not IDA, Other Mi A

Iron Deficiency Anaemia IDA


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IDA Special Tests

Iron related tests Serum Ferritin (pmo/L) TIBC (g/dL) Serum Iron (g/dL) Saturation % Bone marrow Iron
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Normal 33-270 300-340 50-150 30-50 ++

IDA < 33 > 400 < 30 < 10 Absent

IDA Summary
Microcytic MCV < 80 fl, RBC < 6

RDW
Hypochromic RPI

Widened and shift to left


MCH < 27 pg, MCHC < 30% <2

Retic. count
Serum ferritin TIBC Serum Iron BM Fe Stain
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May be > 2 %
Very low < 30 (p mols/L) Increased > 400 (g/dL) Very low < 30 (g/dL) Absent Fe Excellent

Response to Fe Rx.

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 www.drsarma.in

Microcytic Anaemias
MCV < 80 fl Iron Def. Anemia Chronic Infection Thalassemia Hemoglobinopathy Lead poisoning Serum Iron TIBC BM Perls stain 0


N N


N N N

++
++++

++ ++
++++

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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Macrocytosis of Alcoholism
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 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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MBA - BM

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MBA - BM

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Megaloblast FA deficiency

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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

IBD Ulcerative Colitis Crohns Disease Chronic Infections HIV, Osteomyelitis Tuberculosis Renal Failure

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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 Serum Unconjugated Bilirubin Serum LDH 1: LDH 2 Serum Haptoglobin Urine Hemoglobin Urine Hemosiderin Increased Increased Increased Decreased Present Present

Urine Urobilinogen
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Increased
Decreased

Cr 51 labeled RBC life span

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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MAHA
Micro Angiopathic Hemolytic Anaemia

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Hyperactive BM Skull 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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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 Anaemia

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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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Anaemia Diagnosis -Algorithm


Anaemia Suspected

Thorough Clin, Bleed


Ca, Leukemia, Ulcer Identify the cause

Hb%, RCC, Hct Decreased RPI, Retic count <2 MCV, MCH, MCHC, PSE RPI, Retic count >2 Hemolytic Anaemia Coombs DAT, IDAT Hb electrophoresis Osmotic fragility

Microcytic hypochromic Iron Def. Anaemia Ferritin, TIBC, BM Fe Thalassemia, Hb pathy Sederoblastic Anaem. Chr. Infection, Lead

Macrocytic hypo/normo Megaloblastic Folate defici. B12 def., PA Normoblastic ALD, CLD, Drug Chr. Renal dis. Hypothyroid BM infiltration

Acid hemolysis
Cold agglutinins 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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