Anaemia Comprehensive by Dr Sarma

A Practical Approach to Anemia

How to efficiently and accurately work up an anemic patient ?

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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 !! We’ll 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

Let us meet the Grand Parents !

The RBC Lineage

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Haemopoesis in Bone Marrow

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Pro Erythroblast

Large purple nucleus

Thin rim of cytoplasm

Basophilic in stain

Cell > 35 µ

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Early Normoblast

Large purple nucleus

Denser nucleus

Thin rim of cytoplasm

Basophilic in stain

Cell > 25 µ

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Intermediate Normoblast

Medium sized nucleus

Reticulated nucleus

More cytoplasm

Neutral in stain

Cell > 20 µ

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Late Normoblast

Small dense nucleus

Darkly staining

Increased cytoplasm

Pink in stain

Cell > 15 µ

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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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Normal Red Cells

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Normal Red Cells

No nucleus, Enzyme packetsBiconcave discs – Haem + GlCenter 1/3 pallorPink cytoplasm (Hb filled)

Cell size 7 - 8 µ - capill. 2 µEM pathway, HMPNegative charge – no phagoNa less, K more inside100-120 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

• 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

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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 4 to 6

B. Hemoglobin 15 g% 12 to 17

C. Hematocrit 45 38 to 50

MCV C ÷ A x 10 = 90 flMCH B ÷ A x 10 = 30 pgMCHC B ÷ C x 100 = 33%

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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

Megaloblastic Anaemia

Defective DNA synthesis

Folate or B12 deficiency Haem defect Globin defect

Thalassemia

Sickle cell AFe Phorph

IDA, SA

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Anaemia – First Test

RETICULOCYTE COUNT %

NormalLess than

2%

• ‘RBC to be’ or Apprentice RBC

• Fragments of nuclear material

• RNA strands which stain blue

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Reticulocytes

Leishman’sSupravital

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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

Hypoproliferative Hemolytic

RPI < 2 RPI > 2

Hb% < 12, Hct < 38%

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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

Microcytic

< 80 fl

MCV

Normocytic Macrocytic

80 -100 fl > 100 fl

< 6.5 µ 6.5 - 9 µ > 9 µ

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Anaemia Workup - MCV

Microcytic

MCV

Normocytic Macrocytic

Iron Deficiency IDA

Chronic Infections

Thalassemias

Hemoglobinopathies

Sideroblastic Anemia

Chronic disease

Early IDA

Hemoglobinopathies

Primary marrow disorders

Combined deficiencies

Increased destruction

Megaloblastic anemias

Liver disease/alcohol

Hemoglobinopathies

Metabolic disorders

Marrow disorders

Increased destruction

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Anaemia Workup – 3rd TestRed cell Distribution Width – RDW

RDW < 13

Mean 90 fl

RDW is 13

MCV 90 fl

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Red cell Distribution Width - RDW

Microcytic

Left

MCV

Normocytic Macrocytic

Mean 90 Right

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Anaemia Workup - 4th TestPeripheral 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 > 270pmol / l

Not IDA, Other Mi A

TIBC

HIGH N or ↓

BM Fe +-

Iron Deficiency Anaemia IDA

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IDA – Special Tests

Iron related tests Normal IDA

Serum Ferritin (pmo/L) 33-270 < 33

TIBC (µg/dL) 300-340 > 400

Serum Iron (µg/dL) 50-150 < 30

Saturation % 30-50 < 10

Bone marrow Iron ++ Absent

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IDA Summary

• Microcytic MCV < 80 fl, RBC < 6 µ

• RDW Widened and shift to left

• Hypochromic MCH < 27 pg, MCHC < 30%

• RPI < 2

• Retic. count May be > 2 %

• Serum ferritin Very low < 30 (p mols/L)

• TIBC Increased > 400 (µg/dL)

• Serum Iron Very low < 30 (µg/dL)

• BM Fe Stain Absent Fe

• 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 Anaemias

MCV < 80 fl Serum Iron TIBC BM Perls stain

Iron Def. Anemia ↓↓ ↑↑ 0

Chronic Infection ↓↓ ↓↓ + +Thalassemia ↑↑ N + + + +

Hemoglobinopathy N N + +Lead poisoning N N + +Sideroblastic ↑↑ N + + + +

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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. Chronic disease

2. Early IDA

3. Hemoglobinopathies

4. Primary marrow disorders

5. Combined deficiencies

6. Increased destruction

7. Anaemia of investigations -ICU

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Anaemia of Chronic Disease

• Thyroid diseases• Malignancy• Collagen Vascular Disease

– Rheumatoid Arthritis– SLE– Polymyositis– Polyarteritis Nodosa

• IBD

– Ulcerative Colitis

– Crohn’s 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 – AnisocytosisDifferent sizes of RBC

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PoikilocytosisDifferent 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. Reticulocyte count 2. Combined with serial Hb3. Serum LDH4. Serum bilirubin5. Haptoglobin6. Urine hemosiderin7. Hemoglobinuria

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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. Hemoglobin electrophoresis

2. Hemoglobin A2 (βeta-Thalassemia trait)3. RBC enzymes (G6PD, PK, etc)4. Direct & indirect antiglobulin tests (immune)5. Cold agglutinins6. Osmotic fragility (spherocytosis)7. Acid hemolysis test (PNH)8. 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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StomatocytesSlit like central pallor in RBC

1. Liver Disease

2. Acute Alcoholism

3. H Stomatocyosis

4. Malignancies

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EchinocytesEvenly distributed spicules > 10

1. Uremia

2. Peptic ulcer

3. Gastric Ca

4. PK-D

Called Burr Cells

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Acanthocytes5-8 spikes of varying length, irregular intervals

Called Spur Cells, Occur in A H A

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Shistocytes

1. MAHA

2. Prosthetic valves

3. Uremia

4. Malignant HT

Fragmented, Helmet or triangle shaped RBC

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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 Suspected

Thorough Clin, Bleed Hb%, RCC, Hct Decreased

RPI, Retic count <2 RPI, Retic count >2

Hemolytic Anaemia

Coombs DAT, IDAT

Hb electrophoresis

Osmotic fragility

MCV, MCH, MCHC, PSE

Microcytic hypochromic Macrocytic hypo/normo

Megaloblastic NormoblasticIron Def. Anaemia

Ferritin, TIBC, BM Fe

Thalassemia, Hb pathy

Sederoblastic Anaem.

Chr. Infection, Lead

Folate defici.

B12 def., PA

Ca, Leukemia, Ulcer

Identify the cause

ALD, CLD, Drug

Chr. Renal dis.

Hypothyroid

BM infiltration

Acid hemolysis

Cold agglutinins

Coagulopathy, DIC

Anaemia Diagnosis -Algorithm

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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