Anaemia and Thalassaemia

Luke Woon Sy-Cherng

Introduction
Haematopoiesis is the production and development of blood cells Occurs in 3 stages:
Mesoblastic Hepatic myeloid

From pluripotent stem cells to progenitor cells of different cell lines

Introduction
Erythropoiesis: regulated by erythropoietin (EPO) Haemoglobin (Hb): tetramer (2 pairs of polypeptide chains) + heme group Embyronic Hb: Hb Gower 1, Hb Gower 2, Hb Portland Fetal Hb: Hb F (22) Adult Hb: Hb A (22), Hb A2 (22)

Introduction

Figure 1. Model of the haemoglobin molecule showing (pink) and (blue) chains. 2,3-BPG (bisphosphoglycerate) binds in the centre of the molecule and stabilizes the deoxygenated form by cross-linking the chains. M, methyl; P, propionic acid; V, vinyl.
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Introduction
Fetal Hb has higher affinity than adult Hb Fetal Hb is gradually replaced by adult Hb during the 1st yr of life Proportion of Hb: Birth Adults HbF 70 80%, HbA 25 30%, HbA2 1 3% HbA 97%, HbA2 2%

Introduction
Lifespan of neonatal RBC is 60 90 d Hb is high at birth (14 21.5 g/dl), become the lowest at 2 mo (10 g/dl) Average blood volume 80 ml/kg

Anaemia
Anaemia: Hb level below the normal range

Neonate
1 12 mo 1 12 yr

< 14 g/dl
< 10 g/dl < 11 g/dl

Common features of anaemia:

Pallor Weakness, palpitations Tachypnoea, tachycardia Congestive heart failure

Anaemia
Anaemia results from: Impaired production:
Ineffective erythropoiesis Red cell aplasia

Haemolysis Blood loss

Anaemia
Ineffective erythropoiesis: Deficiency:
iron deficiency folic acid deficiency vitamin B12 deficiency

Anaemia of chronic disease (ACD) Anaemia of renal disease

Iron Deficiency Anaemia

Caused by:
Inadequate intake (> 6 mo, excessive cow milk intake) Malabsorption Blood loss (e.g. hookworm infestation)

Manifestations :
Hb < 6 7 g/dl Pallor, tiredness Pica Intellectual impairment

Iron Deficiency Anaemia

Investigations:
Hypochromic, microcytic anaemia Poikylocytosis, anisocytosis Low serum ferritin & high total iron binding capacity (TIBC) Elevated transferrin receptor (TfR)

DD: - & -Thalassaemia trait, ACD

Iron Deficiency Anaemia

Figure 2. Hypochromic microcytic cells (arrow) on a blood film. Poikilocytosis and anisocytosis are seen.

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Iron Deficiency Anaemia

Treatment: Oral ferrous salts:
E.g. FeSO4 (20% elemental iron) 4 6 mg/kg/d elemental iron Hb 1 g/dl per wk, continue for 3 mo

Underlying cause: dietary advice, stop blood loss etc Packed cell transfusion: very severe anaemia only

Folic Acid Deficiency

Caused by:
Inadequate intake (e.g. haemolysis) Decreased absorption (e.g. chronic diarrhoea) Metabolic abnormalities

Manifestations:
Anaemia, irritability Associated features (e.g. malnutrition)

Folic Acid Deficiency

Investigation:
Macrocytic anaemia Low reticulocyte count Neutrophil: hypersegmented nuclei Low serum folic acid Bone marrow: megaloblast

DD: vitamin B12 deficiency Treatment:

Folic acid 0.5 1 mg/d Transfusion: very severe case

Folic Acid Deficiency

Figure 3. Macrocytes and a hypersegmented neutrophil (arrowed) on a peripheral blood film.

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Vitamin B12 Deficiency

Caused by:
Inadequate intake (rare) Lack of intrinsic factor (IF): pernicious anaemia Impaired absorption (e.g. regional enteritis) Transcobalamin II deficiency (rare)

Manifestations:
Anaemia, glossitis Neurologic symptoms: parasthesiae, seizures, developmental delay

Vitamin B12 Deficiency

Investigations:
Macrocytic anaemia Hypersegmented neutrophil Bilirubin may be raised Low serum vitamin B12 Bone marrow: megaloblast

Schilling test: radioactive vitamin B12 IF Treatment:

Parenteral vitamin B12

Anaemia of Chronic Disease

Associated with infection, inflammation or tissue breakdown (e.g. bronchiectasis, SLE) Blunted response to EPO and decreased iron availability Manisfestations: anaemia with underlying disease Investigations:
Normocytic normochromic anaemia Low serum iron, normal TIBC

Anaemia of Chronic Disease

Elevated serum ferritin Normal TfR

Treatment:
Underlying disease Recombinant human EPO

Anaemia of Renal Disease

Due to:
Reduced EPO production Bone marrow suppression Reduced lifespan of RBC Haematinic deficiency Increased blood loss

Normocytic normochromic anaemia Laboratory evidence of renal failure Treatment: recombinant human EPO

Red Cell Aplasia

Pure red cell aplasia
Diamond-Blackfan anaemia (DBA) Transient erythroblastopenia of childhood (TEC) Red cell aplasia associated with chronic haemolysis

Aplastic anaemia (pancytopenia)

Inherited aplastic anaemia Acquired aplastic anaemia

Diamond-Blackfan Anaemia
Congenital hypoplastic anaemia Gene mutation increased apoptosis Majority are sporadic cases Usually presented with profound anaemia at 2 6 mo Congenital anomalies e.g. short stature, abnormal thumbs Treatment: oral steroids or transfusions

Transient Erythroblastopenia of Childhood

Triggered by viral infections Recover within 1 2 mo Severe anaemia may need transfusions

Red Cell Aplasia associated with Chronic Haemolysis

Caused by parvovirus B19 infection Aplastic crisis in patients with haemolysis Transfusion may be needed

Aplastic Anaemia
Pancytopenia with hypocellularity of the bone marrow Presented with anaemia, infection and bleeding Divided into:
Inherited: Fanconi anaemia, SchwachmanDiamond syndrome, etc Acquired: viral infections (e.g. hepatitis), drugs (e.g. chloramphenicol), chemicals (e.g. benzene), radiation, infiltration

Aplastic Anaemia

Figure 4. Bone marrow trephine biopsies in low-power view. Hypocellularity in aplastic anaemia.

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Haemolytic Anaemia
Reduced red cell lifespan due to increased destruction Presented with anaemia, jaundice and hepatosplenomegaly Investigation:
reticulocyte count/polychromasia unconjugated bilirubin and urobilinogen Abnormal red cells on blood film

Haemolytic Anaemia
Inherited Membrane defects: hereditary spherocytosis, hereditary elliptocytosis Metabolic defects: G6PD deficiency, pyruvate kinase deficiency Haemoglobinopathies: thalassaemia, sickle cell disease Acquired Immune: haemolytic disease of the newborn, autoimmune haemolytic anaemia Non-immune: malaria, DIC, hypersplenism

Hereditary Spherocytosis
Autosomal dominant, 25% sporadic Abnormalities of structural proteins (e.g. spectrin, ankyrin) spheroidal shape destruction in spleen Presented with:
Neonatal jaundice Anaemia Splenomegaly Aplastic crisis gallstones

Hereditary Spherocytosis
Investigations:
Blood film: spherocytes Osmotic fragility test: positive Coombs test: negative

Treatment:
Folic acid supplementation Splenectomy

Hereditary Spherocytosis

Figure 5. Spherocytes (arrowed). This blood film also shows reticulocytes, polychromasias and a nucleated erythroblast.
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G6PD Deficiency
The commonest red cell enzymopathy Prevalent in Southeast Asia X-linked recessive enzyme deficiency Glucose-6-phosphate dehydrogenase (G6PD) is an enzyme in the pentose phosphate pathway Needed for the reduction of oxidized glutathione, which is responsible for the protection against oxidative stress Deficiency intravascular haemolysis

G6PD Deficiency
Presented with: Neonatal jaundice Acute haemolysis, precipitated by:
Infections Drugs (e.g. antimalarials, sulphonamides) Naphthalene Fava beans

Anaemia, jaundice, haemoglobinuria

G6PD Deficiency
Investigation:
Blood film: blister cells, Heinz bodies Reduced G6PD activity

Treatment:
Underlying cause (e.g. withdraw offending drug) Blood transfusions Adequate hydration

Prevention of haemolysis: avoid precipitating factors

G6PD Deficiency

Figure 6. 'Blister' cells (arrowed) in G6PD deficiency.

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Thalassaemia
Genetic disorder of globin chain ( or ) production, leading to ineffective erythropoiesis and haemolysis Common along the Thalassaemia Belt, including Southeast Asia Divided into:
-Thalassaemia -Thalassaemia

Thalassaemia

Figure 7. Major haemoglobin abnormalities: geographical distribution.

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-Thalassaemia
chain production: reduced (+) or none (0) Increased HbA2 and HbF Excessive chains precipitation ineffective erythropoiesis and haemolysis Clinically divided into:
Thalassaemia major (Cooleys anaemia) Thalassaemia intermedia Thalassaemia minor/trait

Thalassaemia Major
Homozygous -thalassaemia (0/0, +/+) Presented with:
Failure to thrive, recurrent infections Severe anaemia from 3 6 mo Extramedullary erythropoiesis: hepatosplenomegaly, thalassaemic facies ( frontal bossing, flat nasal bridge, maxillary hyperplasia)

Thalassaemia Major

Figure 8. A child with thalassaemia, showing the typical facial features.

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Thalassaemia Major
Investigation:
Severe microcytic hypochromic anaemia Blood film: deformed red cells Skull X-ray: bone marrow hyperplasia

Diagnosis confirmed by Hb electrophoresis Treatment:

Monthly transfusion (keep Hb 10 g/dl) Folic acid supplementation Splenectomy Bone marrow transplantation Genetic counseling

Thalassaemia Major

Figure 9. Skull x-ray of a child with thalassaemia, showing the hair on end appearance.

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Thalassaemia Major

Figure 10. Patterns of haemoglobin electrophoresis.

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Thalassaemia Major
Transfusion haemosiderosis Iron overload cause by repeated transfusions Cardiomyopathy, hepatic cirrhosis, diabetes mellitus, delayed growth & sexual maturation, bronze pigmentation of skin Iron status monitoring: serum ferritin, hepatic iron

Thalassaemia Major
Transfusion haemosiderosis Prevention:
Iron-chelating agents Desferrioxamine (Desferal), SC over 8 12 hr, 5 7 d per week (SE: nerve deafness, cataracts, retinal damage) Ascorbic acid 100 250 mg/d Low iron diet, tea drinking

Thalassaemia Minor
Heterozygous -thalassaemia/carrier state (0/, +/) No or mild anaemia Microcytic hypochromic red cells, increased red cell count DD: iron deficiency anaemia Normal iron stores Diagnosis: Hb electrophoresis

Thalassaemia Intermedia
Moderate anaemia (Hb 7 10 g/dl) Do not require regular transfusions Combinations of -thalassaemia mutations (0/+, 0/variant, etc), -thalassaemia & thalassaemia, -thalassaemia & hereditary persistence of fetal haemoglobin Extramedullary erythropoiesis may occur

Haemoglobin E
Hb E (2226glulys) is the most common Hb variant in Southeast Asia Heterozygous Hb E: asymptomatic, microcytic red cells Homozygous Hb E: mild microcytic anaemia Hb E/-thalassaemia thalassaemia major

-Thalassaemia
4 genes for -chains Caused by gene deletions:
4-gene deletion: no -chain, only Hb Barts (4) hydrops fetalis 3-gene deletion: Moderate anaemia and splenomegaly, Hb Barts and Hb H (4) present Hb H disease 2-gene deletion: -thalassaemia trait, microcytosis mild anaemia, Hb H present 1-gene deletion: silent trait, normal blood picture

-Thalassaemia
Mostly found in Southeast Asia Diagnosis confirmed by DNA analysis: globin gene deletion Treatment:
Folic supplementation Splenectomy Hb H disease: intermittent transfusion Hydrops fetalis: chronic transfusion/bone marrow transplant

Sickle Cell Disease

Sickle cell Hb (Hb S): point mutation (226gluval) Homozygous (Hb SS): sickle cell anaemia Heterozygous (Hb AS): sickle cell trait Combined heterozygocity (Hb SC): intermediate symptoms Mainly among Africans Deoxygenated Hb S polymerization sickling haemolysis and vascular obstruction

Sickle Cell Disease

Figure 11. Sickle cells (arrowed) and target cells.

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Sickle Cell Anaemia

Vaso-occlusive crisis
Precipitated by infections, hypoxia, cold, dehydration, acidosis Dactylitis (hand-foot syndrome), stroke

Acute anaemia
Splenic sequestration Aplastic crisis haemolysis

Splenomegaly, priapism, infections Long-term problems: retarded growth, leg ulcers, cardiomegaly, etc

Sickle Cell Anaemia

Prophylaxis: immunizations, penicillin, avoidance of vaso-occlusive crisis Treatment: Acute crisis: analgesics, hydration, oxygen, antibiotics, exchange transfusion Chronic problems: hydroxyurea, bone marrow transplant

Haemolytic Disease of the Newborn

Due to feto-maternal incompatibility of red cell antigens:
ABO incompatibility RhD incompatibility

Sensitization antibody production Haemolytic anaemia of the newborn Coombs test: positive Management: neonatal jaundice

Autoimmune Haemolytic Anaemia

Increased red cell destruction due to red cell autoantibodies Idiopathic or secondary (autoimmune disorders, malignancies, infections) Divided into:
Warm AIHA (37C, IgG) Cold AIHA (<37C, IgM)

Positive Coombs test Treatment: steroids, splenectomy

Anaemia due to Blood Loss

In newborn:
Feto-maternal bleeding Twin-twin transfusion Perinatal blood loss e.g. placental abruption

Gastrointestinal bleeding
E.g. Meckels diverticulum

Inherited bleeding disorders

E.g. von Willebrands disease

Thank You

Classification of anaemia. MCV, mean corpuscular volume.

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Antiglobulin (Coombs') tests. The anti-human globulin forms bridges between the sensitized cells causing visible agglutination. The direct test detects patients' cells sensitized in vivo. The indirect test detects normal cells sensitized in vitro. HDN, haemolytic disease of newborn.
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