Anaemia and Thalassaemia

8/3/2019 Anaemia and Thalassaemia

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Anaemia and

Thalassaemia

Luke Woon Sy-Cherng


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Introduction

Haematopoiesis is the production anddevelopment of blood cells

Occurs in 3 stages:

Mesoblastic

Hepatic

myeloid

From pluripotent stem cells to progenitorcells of different cell lines


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Introduction

Erythropoiesis: regulated by erythropoietin(EPO)

Haemoglobin (Hb): tetramer (2 pairs ofpolypeptide 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)


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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.

Downloaded from: StudentConsult (on 4 March 2009 10:57 AM)

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Introduction


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Introduction

Fetal Hb has higher affinity than adult Hb

Fetal Hb is gradually replaced by adult Hb duringthe 1st yr of life

Proportion of Hb:

BirthHbF 70 80%, HbA 25

30%, HbA2

1 3%

Adults HbA 97%, HbA2 2%


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Introduction

Lifespan of neonatal RBC is 60 90 d

Hb is high at birth (14 21.5 g/dl), becomethe lowest at 2 mo (10 g/dl)

Average blood volume 80 ml/kg


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Anaemia

Anaemia: Hb level below the normal range

Common features of anaemia:

Pallor Weakness, palpitations

Tachypnoea, tachycardia

Congestive heart failure

Neonate < 14 g/dl

1 12 mo < 10 g/dl

1 12 yr < 11 g/dl


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Anaemia

Anaemia results from:

Impaired production:

Ineffective erythropoiesis

Red cell aplasia

Haemolysis

Blood loss


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Anaemia

Ineffective erythropoiesis:

Deficiency:

iron deficiency

folic acid deficiency

vitamin B12 deficiency

Anaemia of chronic disease (ACD)

Anaemia of renal disease


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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


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Investigations:

Hypochromic, microcytic anaemia

Poikylocytosis, anisocytosis Low serum ferritin & high total iron binding

capacity (TIBC)

Elevated transferrin receptor (TfR) DD: - & -Thalassaemia trait, ACD


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


2005 Elsevier



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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, stopblood loss etc

Packed cell transfusion: very severeanaemia only


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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)


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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


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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


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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


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Anaemia of Chronic Disease

Associated with infection, inflammation ortissue breakdown (e.g. bronchiectasis, SLE)

Blunted response to EPO and decreasediron availability

Manisfestations: anaemia with underlyingdisease

Investigations:

Normocytic normochromic anaemia

Low serum iron, normal TIBC


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Anaemia of Chronic Disease

Elevated serum ferritin

Normal TfR

Treatment:

Underlying disease

Recombinant human EPO


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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


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Red Cell Aplasia

Pure red cell aplasia

Diamond-Blackfan anaemia (DBA)

Transient erythroblastopenia of childhood

(TEC)

Red cell aplasia associated with chronichaemolysis

Aplastic anaemia (pancytopenia) Inherited aplastic anaemia

Acquired aplastic anaemia


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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


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Transient Erythroblastopenia of

Childhood

Triggered by viral infections

Recover within 1 2 mo

Severe anaemia may need transfusionsRed Cell Aplasia associated with

Chronic Haemolysis

Caused by parvovirus B19 infection

Aplastic crisis in patients with haemolysis

Transfusion may be needed


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Aplastic Anaemia

Pancytopenia with hypocellularity of thebone marrow

Presented with anaemia, infection and

bleeding Divided into:

Inherited: Fanconi anaemia, Schwachman-

Diamond syndrome, etc Acquired: viral infections (e.g. hepatitis),drugs (e.g. chloramphenicol), chemicals (e.g.benzene), radiation, infiltration


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


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Aplastic Anaemia


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Haemolytic Anaemia

Reduced red cell lifespan due to increaseddestruction

Presented with anaemia, jaundice andhepatosplenomegaly

Investigation:

reticulocyte count/polychromasia

unconjugated bilirubin and urobilinogen

Abnormal red cells on blood film


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Haemolytic Anaemia

Inherited Membrane defects: hereditary spherocytosis,

hereditary elliptocytosis Metabolic defects: G6PD deficiency, pyruvate

kinase deficiency Haemoglobinopathies: thalassaemia, sickle

cell diseaseAcquired

Immune: haemolytic disease of the newborn,autoimmune haemolytic anaemia

Non-immune: malaria, DIC, hypersplenism


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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


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Investigations:

Blood film: spherocytes

Osmotic fragility test: positive

Coombs test: negative

Treatment:

Folic acid supplementation

Splenectomy


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Figure 5. Spherocytes (arrowed). This blood film also shows reticulocytes, polychromasias and anucleated 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 pentosephosphate pathway

Needed for the reduction of oxidizedglutathione, which is responsible for theprotection against oxidative stress

Deficiency intravascular haemolysis


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G6PD Deficiency

Presented with:

Neonatal jaundice

Acute haemolysis, precipitated by: Infections

Drugs (e.g. antimalarials, sulphonamides)

Naphthalene

Fava beans

Anaemia, jaundice, haemoglobinuria


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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: avoidprecipitating factors


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


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G6PD Deficiency


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Thalassaemia

Genetic disorder of globin chain ( or )production, leading to ineffectiveerythropoiesis and haemolysis

Common along the Thalassaemia Belt,including Southeast Asia

Divided into:

-Thalassaemia

-Thalassaemia


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Figure 7. Major haemoglobin abnormalities: geographical distribution.Downloaded from: StudentConsult (on 4 March 2009 11:05 AM) 2005 Elsevier

Thalassaemia


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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


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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, maxillaryhyperplasia)


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


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Thalassaemia Major


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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


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


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Thalassaemia Major


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Figure 10. Patterns of haemoglobin electrophoresis.


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Thalassaemia Major


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Thalassaemia Major

Transfusion haemosiderosis

Iron overload cause by repeatedtransfusions

Cardiomyopathy, hepatic cirrhosis,diabetes mellitus, delayed growth & sexualmaturation, bronze pigmentation of skin

Iron status monitoring: serum ferritin,hepatic iron


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Thalassaemia Major

Transfusion haemosiderosis

Prevention:

Iron-chelating agents

Desferrioxamine (Desferal), SC over 8 12hr, 5 7 d per week (SE: nerve deafness,cataracts, retinal damage)

Ascorbic acid 100 250 mg/d Low iron diet, tea drinking


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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


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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 & hereditarypersistence of fetal haemoglobin

Extramedullary erythropoiesis may occur


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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 microcyticanaemia

Hb E/-thalassaemia thalassaemiamajor


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-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 bloodpicture


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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

-Thalassaemia


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Sickle Cell Disease

Sickle cell Hb (Hb S): point mutation(22

6gluval)

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 vascularobstruction


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


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Sickle Cell Disease


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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


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Sickle Cell Anaemia

Prophylaxis: immunizations, penicillin,avoidance of vaso-occlusive crisis

Treatment:

Acute crisis: analgesics, hydration,oxygen, antibiotics, exchange transfusion

Chronic problems: hydroxyurea, bonemarrow transplant

Haemol tic Disease of the


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Haemolytic Disease of the

Newborn

Due to feto-maternal incompatibility of redcell antigens:

ABO incompatibility

RhD incompatibility

Sensitization antibody production

Haemolytic anaemia of the newborn

Coombs test: positive

Management: neonatal jaundice

Autoimmune Haemolytic


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Autoimmune Haemolytic

Anaemia

Increased red cell destruction due to redcell autoantibodies

Idiopathic or secondary (autoimmune

disorders, malignancies, infections) Divided into:

Warm AIHA (37C, IgG)

Cold AIHA (


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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


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Thank You


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Classification of anaemia. MCV, mean corpuscular volume.


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Antiglobulin (Coombs') tests. The anti-human globulin forms bridges between the sensitized cellscausing visible agglutination. The direct test detects patients' cells sensitized in vivo. The indirect

Anaemia and Thalassaemia

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