Thalassemias

Prepared By : Group E , PBL Presented By : ______ ___

Group E, Problem Based Learning

Members Pranodan Poudel Anup Subedi Robin Jung Bhandari Riyaz Shrestha Monica Bohara Sumina Rai Karuna Rayamajhi Puja Pahari

Swati Dhungel Dibasha Adhikari Prabha Bhandari Kipa Shrestha Tutor : Dr. Sajana K.C.

Introduction
Disorder of Hemoglobin. Decreased production of globin chain. In Hemoglobinopathy, globin chains are abnormal.

Definition
Thalassemia is a heterogenous group of disorders characterized by genetically determined reduction in the rate of synthesis of normal globin chains.

Hemoglobin
Fetal Hemoglobin, HbF (2 + 2) Adult Hemoglobin, HbA (2 + 2)

 Thalassemia : Etiopathogenesis
Autosomal recessive disorder. Each chromosome of chromosome number 11 has one allele for the gene to encode beta globin. Point mutation in the beta gene leads to absence or decreased production of beta globin chains.

Etiopathogenesis
- It occurs due to gene mutation. On the basis of occurrence of gene mutations thalassemias are of two types: Thalassemia - absence of globin chains + Thalassemia - decresed production of globin chains

Etiopathogenesis - + Thalassemia
Point mutation in promoter region

REDUCED RNA Polymerase Binding

REDUCED Transcription Rate

+ Thalassemia

Etiopathogenesis - + Thalassemia
Mutation

New sites sensitive to splicing enzymes

Splicing at NORMAL and ABNORMAL junctions

NORMAL as well as ABNORMAL globin chains

+ Thalassemia

Etiopathogenesis 0 Thalassemia
Point Mutation in Exon

Coding of Stop Codon

Premature termination of chains

0 Thalassemia

Etiopathogenesis 0 Thalassemia
Mutation

Alter Normal Splicing Junctions

No Splicing

Abnormal RNA

Unspliced RNA degrades within Nucleus

0 Thalassemia

Mutated genes

Excess chains

Reduced chains synthesis

Decreased HbA

Chains precipitation Anemia Deranged RBC membranes, Apoptosis Decreased O2 Delivery

Increased Erythropoietin

Increased Iron

Peripheral Blood Circulation

Bone Marrow Phagocytosis

Increased Erythropoiesis

Toxicity
Splenic Hemolysis Ineffective Erythropoiesis Bone Marrow Expansion

Hepatosplenomegaly
Fractures and Mongoloid Faces

Types
Thalassemia Minor Thalassemia Major

 Thalassemia Minor
Genotype ( / +) Asymptomatic to Mild Anemia. RBCs are increased in some cases.

 Thalassemia Major
Genotype (0 / 0) or, (+ / +)
globin chains are not produced at all owing to defective genes. Decreased amount of HbA, Major Red cell HbHbF The 4 tetramers are formed. RBC containing these tetramers are destroyed in Bone Marrow (Ineffective Erythropoiesis) or in Spleen. This leads to Anemia. Bone marrow becomes hyperactive to produce more RBCs.

 Thalassemia Major
Hyperactive Bone Marrow

Expansion Thinning of Cortex

Weaker Bones

Pathological Fractures

 Thalassemia Major
Bone Marrow Expands in Marrow cavity of Upper Part of Skull

Rapid Expansion Causes Cracks on Skulls Marrow

HAIR-ON-END Appearance OR, Crew Cut Appearance

 Thalassemia Major
Similar expansions of marrow in facial bones give rise to RODENTS FACE or, CHIPMUNK Appearance.

Hair on end / Crew-Cut Appearance of Skull on Radiography

Rodents Face / Chipmunk Appearance

Clinical Findings
Irritability Pallor Diarrhea Fever Enlarged Abdomen Cardiac failure in 1st decade of life Severe Anemia Growth Retardation Bone Changes Hepatosplenomegaly( due to extramedullary hematopoiesis) Basophilic Stippling

Fig:
Basophilic Stippling and Dacrocyte (Teardrop Cell)

Basophilic stippling /Punctate basophilia refers to an observation found when observing a blood smear in which erythrocytes display small dots at the periphery. These dots are the visualization of ribosomes.

Laboratory Findings
Severe Anemia (2-3 g/dl) Decreased Mean Cell Volume Decreased Mean Cell Hb Concentration

Laboratory Findings
Microcytic Hypochromic Picture Anisopoikilocytosis

Laboratory Findings
Target Cells
Decreased globin chains Decreased Hb

RBC loses its tensile shape Target Cells Formation of blebs in centre of RBC

Hb previously in periphery deposits in blebs too

Bulls Eye Appearance / Target Cells

Fig:
Peripheral smear from a patient with beta-zero thalassemia major showing more marked microcytosis (M) and anisopoikilocytosis (P) than in thalassemia minor. Target cells (T) and hypochromia are prominent.

Laboratory Findings
If Microcytic Hypochromic smear with nucleated RBCs is obtained from a child patients blood sample, the case is always of Thalassaemia.

Alpha Thalassemia
Absence or decreased production of alpha globin chains
Two alpha globin genes on each chromosome 16 The types of alpha thalassemia result from deletion of one or more of these genes

Clinical Syndromes
Silent carrier
Deletion of single -globin gene Not much reduction in -globin chain synthesis Individuals are completely asymptomatic

Clinical Syndromes
-thalassemia trait
Deletion of two -globin genes
Can be from the same chromosome or one from each chromosome

Clinical Syndromes
Hemoglobin H disease
Deletion of 3 -globin genes -globin synthesis markedly reduced Tetramere of beta-globin (4)- Hb H Hb-H very high affinity to O2- tissue hypoxia Hb H prone to oxidation- formation of intracellular inclusions- removed by splenic macrophages

Clinical Syndromes
Hydrops fetalis
Most severe from Deletion of all 4 globin genes In fetus, excess -globin chain form tetramere (Hb Barts)

Hb Barts- very high affinity to O2, delivers almost no O2

Clinical Syndromes
Hydrops fetalis
Severe tissue hypoxia- intrauterine death Fetus- severe pallor, generalized edema, and massive hepatosplenomegaly

Clinical Syndromes

Silent carrier

Alpha thalassemia trait

Hemoglobin H disease

Hydrops fetalis