Thalasaemia is a disorder of hemoglobin synthesis. Autosomal recessive.

1. THALASSAEMIA
Dr.K.M Parakrama
Registrar WD 15A2

2. INTRODUCTION
• Also known as Cooley's anaemia.
• Monogenic Disorder-Autosomal Recessive
• Common disorder in “Thalassaemia Belt” –from Mediterranean
region via sub Saharan Africa and middle east to south and south east
Asia.
• Sri lanka has high prevalence
• Highest in north western and north central provinces.
• Sri Lanka commonly has β thalasaemia.

3. MOLECULAR BASIS
• Mutation in human globin genes encoding α and β globin polypeptide
chains
• Reduced or absent α chain production or defective β chain
production
• Categorized as β0 -, β+ - and β++-thalassemia alleles according to the
degree of reduction of the βglobin chain
• s β++-thalassemia results in only subtle effects

4. • Point mutation at codon 26 of the βglobin gene results in a structurally
abnormal haemoglobin E (α2β E 2)
• Produces the phenotype of β-thalassemia
• HbE /βthalassaemia accounts for nearly half of the patients with β-
thalassaemia worldwide
• Occurs by Inheritance of a βthalassaemia allele from one parent and the
HbE allele from the other parent

5. CLINICAL CLASSIFICATION
• Thalassemia exhibits a remarkable clinical heterogeneity
• Individuals having a heterozygous mutation in β-globin gene (β-
thalassemia trait) are asymptomatic
• Homozygotes are known as transfusion dependent thalassaemia
• A substantial proportion of patients have an intermediate clinical
phenotype
• previously referred to as β-thalassemia intermedia

6. CLINIC FEATURES
• Most Patients Are Diagnosed Before Two Years Of Age
• Pallor
• Irritability
• Poor Weight Gain
• Abdominal Distension
• Hepatosplenomegaly.

8. • Ix
• FBC-
• Low haemoglobin (Hb)
• Low mean corpuscular volume
• Low mean corpuscular haemoglobin.
• Blood Picture-
• Microcytes, poikilocytes,
• Hypochromia, anisocytosis, and nucleated red cells

9. Beta Thal Major

10. Beta Thalasaemia
Trait

11. • β0/β0 thalassemia-
• HbF 95–98%
• HbA2 2–5%
• No HbA
• β0/β+- or β+/β+-thalassemia-
• HbA 10–30%
• HbF 70–90%
• HbA2 2–5%

12. • HbE/β-thalassaemia-
• HbE 30%-70%
• Remainder HbF

13. MANAGMENT
• Management options
• Blood transfusion
• Iron chelation,
• Splenectomy
• Haematopoietic stem cell transplantation.

14. • Mainstay of thalassaemia management is blood transfusion
• Aims to,
• Promote normal growth and physical activity
• Adequately suppress bone marrow activity
• Minimizing transfusion related iron accumulation
• Categorisation requires frequent revisiting
• Patients can move from TDT to NTDT and vice-versa

15. • TDT require regular transfusions
• 2-5 weekly
• Maintain a target pre-transfusion Hb level of 9–10.5g/dl
• currently accepted protocol is to achieve a post transfusion Hb level of
14g/dl
• Transfusing leucodepleted (reduced to <1 x 106 leucocytes per unit) packed
RBC
• Blood should be <2 weeks old

16. • Volume (ml) of blood to be transfused = (14g/dl –pre-transfusion Hb) x
weight (kg) x 3 / haematocrit of transfused blood

17. • Indications to transfuse in NTDT,
• Growth Failure,
• Reduced Exercise Tolerance,
• Poor Quality Of Life
• Rapidly Enlarging Spleen (>3cm/Year)

18. IRON OVERLOAD
• A unit of transfused packed RBC contains approximately 200–250 mg
of iron
• Increased intestinal absorption of iron due to suppression of hepcidin
secretion from the liver by increased red cell turnover

19. • Indications for Iron Chelation-
• TDT, serum ferritin above 1000μg/l
• Serum ferritin >2500μg/l is associated with increased risk of cardiac and
endocrine disease
• NTDT, serum ferritin >800μg/l
• (MRI) to noninvasively assess liver and myocardial iron concentration

20. IRON CHELATION
• Three iron chelators are currently available
• Desferrioxamine,
• Deferasirox
• Deferiprone

22. • Deferasirox as first line iron chelator in children >2 years
• Desferrioxamine is used as first line in children <2 years,
• In Contraindications for deferasirox ,
• Emergency treatment for acute cardiac failure due to cardiomyopathy
• Deferiprone has a higher chelating ability of myocardial iron
• Not recommended as monotherapy.
• Combination of deferasirox and desferrioxamine is used when a single
chelator is unable to control iron overload

23. • Combination of desferrioxamine and deferiprone is used when cardiac iron
chelation becomes a priority
• Splenectomy-
• Not routinely done
• Increased risk of post-splenectomy sepsis,
• Venous thrombosis,
• Pulmonary hypertension, leg
• Ulcers
• Silent strokes

24. • Indications-
• Hypersplenism
• Clinically symptomatic splenomegaly
• Patients with very high transfusion requirements (annual transfusion
requirement rises above 200-250ml/kg/year)

27. HAEMOPOIETIC STEM CELL TRANSPLANTATION
• Only available cure for thalassaemia
• Overall survival of 90% and disease free survival of over 80%,
• With HLA-matched sibling donors
• Only 10% of thalassaemia patients have HLA-matched sibling donors
• HLA matched-unrelated donors or umbilical cord blood as the HSC
source

28. • Overall survival rates 60%-65%
• Mortality related to transplant conditioning, graft-versus-host disease and
graft failure
• Routinely indicated only in patients who are transfusion dependent and
have well-matched sibling donors
• Best if performed before 14-years of age
• Before iron-related complications have developed

29. • Emerging therapies-
• Induction of γ-globin with an aim to increase fetal haemoglobin
production
• Hydroxyurea-increase fetal haemoglobin to prevent sickling crisis in sickle
cell disease
• Not shown to reduce the need for blood transfusion in thalassaemia
• Improving ineffective erythropoiesis- ruxolitinib (JAK2 inhibitor) or
luspatercept (activin type IIB receptor ligand trap)
• Pharmacological down regulation of α-globin to improve globin chain
balance
• Gene therapy

30. • Harvesting of HSCs from patients with thalassaemia
• Insertion of normal β-globin gene
• Transplanting the HSC with normal β-globin gene back
• Poor efficacy in bone marrow harvesting, gene transfer and normal gene
expression
• Oncogenic potential of the procedure
• Genome editing-
• Programmable nucleases
• Edit in a pre-determined target site in the human genome
• Upregulate γ-globin or downregulate α-globin