A Practical Approach to Anemia

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 :

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

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

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 Normal renal production of EPO A functioning Erythroid marrow An adequate supply of substrates for Hb production

Let us meet the Grand Parents !
The RBC Lineage Let us meet the Grand Parents !

Haemopoesis in Bone Marrow

Pro Erythroblast Large purple nucleus Thin rim of cytoplasm
Basophilic in stain Cell > 35 µ

Early Normoblast Large purple nucleus Denser nucleus
Thin rim of cytoplasm Basophilic in stain Cell > 25 µ

Intermediate Normoblast
Medium sized nucleus Reticulated nucleus More cytoplasm Neutral in stain Cell > 20 µ

Late Normoblast Small dense nucleus Darkly staining
Increased cytoplasm Pink in stain Cell > 15 µ

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

Normal Red Cells

Normal Red Cells No nucleus, Enzyme packets
Biconcave discs – Haem + Gl Center 1/3 pallor Pink cytoplasm (Hb filled) Cell size µ - capill. 2 µ EM pathway, HMP Negative charge – no phago Na less, K more inside days life span

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

Normal BM High Power

Hemoglobin (Hb)

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

Types of Anaemia

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%

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

PCV or Hematocrit 57% Plasma 1% Buffy coat – WBC 42% Hct (PCV)

The Three Basic Measures
Measurement Normal Range RBC count million to 6 Hemoglobin 15 g% 12 to 17 Hematocrit 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.

The Three Derived Indicies
Measurement Normal Range RBC count million to 6 Hemoglobin 15 g% 12 to 17 Hematocrit to 50 MCV C ÷ A x 10 = 90 fl MCH B ÷ A x 10 = 30 pg MCHC B ÷ C x 100 = 33%

Causes of Anaemia Decreased production of Red Cells
- Hypo proliferative, marrow failure Increased destruction of Red Cells - Hemolysis (decreased survival of RBC) Loss of Red Cells due to bleeding - Acute / chronic blood loss (hemorrhagic) M = P x S ( L)

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 A Fe Phorph 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%

Reticulocytes Supravital Leishman’s

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

Anaemia Hypoproliferative Hemolytic Hb% < 12, Hct < 38%
RPI < 2 RPI > 2

Normal CBC

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)

Red Cell Size

Mean Cell Volume (MCV) Microcytic < 80 fl Normocytic Macrocytic
RBC volume (rather) is measured by The Mean Cell Volume or MCV and RDW Microcytic < 80 fl MCV Normocytic Macrocytic fl > 100 fl < 6.5 µ µ > 9 µ

Anaemia Workup - MCV Microcytic Normocytic Macrocytic MCV
Iron Deficiency IDA Chronic Infections Thalassemias Hemoglobinopathies Sideroblastic Anemia Chronic disease Early IDA Primary marrow disorders Combined deficiencies Increased destruction Megaloblastic anemias Liver disease/alcohol Metabolic disorders Marrow disorders

Anaemia Workup – 3rd Test Red cell Distribution Width – RDW
Mean 90 fl RDW is 13 MCV 90 fl

Red cell Distribution Width - RDW
MCV Microcytic Normocytic Macrocytic Left Mean 90 Right

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 ?

IDA -CBC

Severe Hypochromia

Microcytic Hypochromic - IDA

Microcytic Hypochromic Anaemia
Serum Ferritin < 33 pmol / l pmol / l > 270pmol / l Not IDA, Other Mi A TIBC HIGH N or ↓ BM Fe + - Iron Deficiency Anaemia IDA

IDA – Special Tests Iron related tests Normal IDA
Serum Ferritin (pmo/L) 33-270 < 33 TIBC (µg/dL) > 400 Serum Iron (µg/dL) 50-150 < 30 Saturation % 30-50 < 10 Bone marrow Iron ++ Absent

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

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

Microcytic Anaemias ↓↓ ↑↑ + + N + + + + MCV < 80 fl Serum Iron TIBC
BM Perls stain Iron Def. Anemia ↓↓ ↑↑ Chronic Infection + + Thalassemia N Hemoglobinopathy Lead poisoning Sideroblastic

Ringed Sideroblasts in BM
Prussian Blue Stain

Macrocytic Anaemias A. Megaloblastic Macrocytic – B12 and Folate↓
B. Non Megaloblastic Macrocytic Anaemias Liver disease/alcohol Hemoglobinopathies Metabolic disorders, Hypothyroidism Myelodystrophy, BM infiltration Accelerated Erythropoesis - ↑destruction Drugs (cytotoxics, immunosuppressants, AZT, anticonvulsants)

Anemia - Macrocytic (MCV > 100)
Premature gray hair – consider MBA Macrocytic anemias may be asymptomatic until the Hb is as low as 6 grams MCV fl must look for other causes of macrocytosis MCV > 110 fl almost always folate or B12 deficiency

Macrocytosis of Alcoholism
25-96% of alcoholics MCV elevation usually slight ( fl) Minimal or no anemia Macrocytes round (not oval) Neutrophil hyper segmentation absent Folate stores normal Smoking increases the Red Cell Mass

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

Macrocytosis -MBA

Anisocytosis - Macrocytic Anaemia

HSN - MBA

Basophilic Stippling - MBA
BS occurs in Lead poisoning also

Megalocyte in PS

MBA - BM

Megaloblast – FA deficiency

Pernicious Anaemia - Tongue
Bald, smooth, lemon yellowish red tongue

Normocytic Anaemias 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 – Crohn’s 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

RBC Size – Anisocytosis Different sizes of RBC

Poikilocytosis Different Shapes of RBC

Polychromasia - Spherocytosis

Target Cells Liver Disease Thalassemia Hb D Disease Post splenectomy

Tear Drop Cells Myelofibosis Infiltration of BM Tumours of BM
Thalassemia

Hair on end - Thalassemia Major

Drepanocytes - SS

Sickle Cell Anaemia

Autosplenectomy - SS Normal spleen is 8 to 12 cm

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

Tests Used to Diagnose Hemolysis
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 Serum LDH 1: LDH 2 Serum Haptoglobin Decreased Urine Hemoglobin Present Urine Hemosiderin Urine Urobilinogen Cr 51 labeled RBC life span

Tests to define the cause of hemolysis
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)

Micro Angiopathic Hemolytic Anaemia
MAHA Micro Angiopathic Hemolytic Anaemia

Hyperactive BM – Skull Hemolytic Anaemia

Spherocytosis

Hereditary Spherocytosis

Spherocytosis

Hereditary Elliptocytosis, B12 or Folate↓
Elliptocytes Hereditary Elliptocytosis, B12 or Folate↓

Stomatocytes Slit like central pallor in RBC
Liver Disease Acute Alcoholism H Stomatocyosis Malignancies

Echinocytes Evenly distributed spicules > 10
Uremia Peptic ulcer Gastric Ca PK-D Called Burr Cells

Acanthocytes 5-8 spikes of varying length, irregular intervals
Called Spur Cells, Occur in A H A

Fragmented, Helmet or triangle shaped RBC
Shistocytes Fragmented, Helmet or triangle shaped RBC MAHA Prosthetic valves Uremia Malignant HT

Leukoplakia - Aplastic Anaemia
Chloramphenicol Neomercazole Sulfonamides Analgin Phenytoin Butazolidin group Anti Ca drugs

Normal BM High Power E : G = 1 : 3

Shift in E : G Ratio E : G = 2 : 1

BM - Aplastic Anaemia

Myelofibrosis

Post transfusion - CBC

Howell-Jolly Bodies Absence of Splenic function; Nuclear chromatin in RBC

Pelger-Huet Anomaly Inherited condition PMN - Spectacles Heterozygous
Homozygous fatal Neutrophil Bands ↑ Normal WCC No e/o infection

Microcytic hypochromic Macrocytic hypo/normo
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 Normoblastic Iron 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

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

Thank You ALL

A Practical Approach to Anemia

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