Thalassemia blood disorder

1. Thalassemia
1

2. Contents
• Introduction
• Types
• Diagnosis
• Complications and management
• Take home message

3. 1. Introduction
THALASSEMIA
1930s: from Greek thalassa ‘sea’
(because the diseases were first
known around the Mediterranean)

4. Thalassaemias are group of the
Haemoglobin disorders
(Hemoglobinopathies)
in which the production of normal
haemoglobin is partly or completely
suppressed as a result of the defective
synthesis of one or more globin chains

5. Thalassemia is inherited
by autosomal
recessive

7. Normal hemoglobin
• Embryonic Hb: 3rd to 10th week of pregnancy
ζ2ε2 (Gower-1), α2ε2(Gower-2), ζ2γ2 ( Portland)
• Fetal Hb α2γ2(HbF)
• Adult Hb
98% HbA α2β2, 2% HbA2 α2δ2

9. Chromosomes 11
Chromosomes 16

10. 2. Types
THALASSEMIA
α
- Silent Carrier
- Trait (Minor)
-Hemoglobin H Disease
(Intermediate)
- Major (Hemoglobin Bart’s)
β
- Trait (Minor)
- Intermedia
- Major (Cooley anemia)

11. Alpha Thalassemia
• Deficient/absent alpha subunits
▫ Excess beta subunits
▫ Excess gamma subunits newborns
• Encoding genes on chromosome 16
• Each cell has 4 copies of the alpha globin gene
▫ Each gene responsible for ¼ production of alpha
globin

12. • Possible mutation states:
▫ Loss of ONE gene  silent carrier
▫ Loss of TWO genes  thalassemia minor (trait)
▫ Loss of THREE genes  Hemoglobin H disease
🞄 Accumulation of beta chains
🞄 Association of beta chains in groups of 4  Hemoglobin H
▫ Loss of FOUR genes  Hemoglobin Barts
🞄 NO alpha chains produced ∴ only gamma chains present
🞄 Association of 4 gamma chains  Hemoglobin Barts
GENE
CHROM
OSOME
CELL
DNA
PROTEIN

13. Beta Thalassemia
• Encoding genes on chromosome 11
• Each cell contains 2 copies of beta globin gene
• Suppression of gene more likely than deletion
▫ β0 refers to the complete absence of production of β -
globin on the affected allele
▫ β+ refers to alleles with some residual production of ‚
β -globin (around 10%)
▫ β++ ;the reduction in β -globin production is very mild

14. β-Thalassaemia
An absence or deficiency of β-chain synthesis of adult HbA
β Chain synthesis
Hb-A α2β2
γ and δ chain

15. • Loss of ONE gene  thalassemia minor (trait)
▫ ↑HbA2
▫ HbA normal
▫ HbF normal
• Loss of BOTH genes
▫ Thalassemia intermedia β+ β+ or β0 β+
▫ Thalassemia major β0β0

16. HbE α2βE
2
• Haemoglobin E disorder is the most common
structural variant resembling thalassemia
disorders
• HbE results from a mutation (GA) at codon 26 of
the ‚ β -globin gene
• HbE/ β thalassemia

17. 3. Diagnosis
• Clinical features
▫ History
▫ Physical examinations
• Lab investigations
• Screening family members

18. Clinical Outcomes of αThalassemia
• Silent carriers
• Asymptomatic
• Alpha Thalassemia minor (trait)
• No anemia
• Microcytosis
• Alpha Thalassemia intermedia (Hemoglobin H)
• Anemia and microcytosis
• Bone deformities
• Splenomegaly

19. • Alpha Thalassemia major
• Hb Bart’s
• Fatal hydrops fetalis

20. Pathophysiology of beta thalassemia

22. Thalassaemia carrier VS iron def anaemia
Hb
Analysis

23. Beta thalassemia
intermedia
“Too haematologically severe to be
called minor, but too mild to be called
major”
Rietti-Greppi-Micheli [1995]

24. Partial or lack of HbA synthesis ↓MCHC &
MCH Hypochromia & microcytosis
Normal
Thalassaemia

25. Inadequate production + ineffective
erythropoiesis + haemolysis Anaemia

26. ↑Haemolysis ↑demands of phagocytic
function  hyperplasia of phagocytes
Hepatosplenomegaly
To compensate anaemia extramedullary
haemopoiesis in liver, spleen & brain
Organomegaly

27. ↑Erythropoiesis marrow expansion & thinning
of cortex of skull bone Thalassaemia facies

28. 5. Complications and management
• Complications of disease
• Complications of treatment

29. Management
Baseline investigations
• Full blood count, Peripheral blood film
•Hb analysis by electrophoresis / High Performance Liquid
Chromatography (HPLC)
• DNA analysis (ideal) – Mutation Studies ( For prenatal
diagnosis) along with screening of family members
• Liver function test.
•Infection screen: HIV, Hepatitis B & C, VDRL screen (before
first transfusion).
• HLA typing (for all patient with unaffected siblings)- For
BMT

30. Transfusion
dependent
thalassemia
Regular maintenance blood
transfusion and iron chelation
therapy is the mainstay of treatment
in this patient

31. βThalassemia major
When to start blood transfusion?
•After completing blood investigations for
confirmation of diagnosis.
•Hb < 7g/dl on 2 occasions > 2 weeks apart (in
absence other factors e.g. infection).
•Hb > 7g/dl in β+-thalassaemia major/severe forms
of HbE-β-thalassaemia if impaired growth, severe
bone changes, enlarging liver and spleen.

32. Transfusion targets?
• Maintain pre transfusion Hb level at 9 -10 g/dl.
• Keep mean post-transfusion Hb at 13.5-15.5g/dl.
• Keep mean Hb 12 - 12.5 g/dl.
•The above targets allow for normal physical activity and
growth, abolishes chronic hypoxaemia, reduce
compensatory marrow hyperplasia which causes
irreversible facial bone changes and para-spinal masses.

33. Transfusion interval?
•Usually 4 weekly interval (usual rate of Hb
decline is at 1g/dl/week).
• Interval varies from individual patients (range: 2
- 6 weekly).
Transfusion volume?
•Volume: 15 - 20mls/kg (maximum) packed red
cells (PRBC).

34. • In the presence of cardiac failure or Hb < 5g/dl,
use lower volume PRBC (< 5ml/kg) at slow
infusion rate over > 4 hours with IV Frusemide 1
mg/kg (20 mg maximum dose).
• It is recommended for patients to use
leucodepleted (pre-storage, post storage or
bedside leucocyte filters) PRBC < 2 weeks old.
• Leucodepletion would minimize non-haemolytic
febrile reactions and alloimmunization by
removing white cells contaminating PRBC.

35. Example
• Beta thalassemia major
• Wt 16 kg
• Hb 4
Calculations:
Total PC: (12-4)(16)(3.5) = 448 cc
1st tx 5cc/kg = (5)(16) =80 cc
2nd tx 10cc/kg= (10)(16) = 160 cc
Balance 384- 80 -160=208 cc
Max possible tx 20cc/kg = 320 cc

36. αThalassemia (HbH disease)
• Transfuse only if Hb persistently < 7g/dl and/or
symptomatic.

37. • Endocrine: growth retardation,
impaired glucose tolerance,
pubertal delay, hypothyroidism,
hypoparathyroidism and diabetes
mellitus.
• Cardiac: arrhythmias, pericarditis,
cardiac failure.
• Hepatic: liver cirrhosis (especially
if with Hepatitis B/C infection).
Problems of Iron overload

38. Iron chelation therapy
• DFO: Desferrioxamine
• DFP: Deferiprone
• DFX: Deferasirox

39. DFO: Deferoxamine
When to start? • Usually when the child is > 2 - 3 years old.
• When serum ferritin reaches 1000 μg/L.
• Usually after 10 – 20 blood transfusions.
Dosage, route • Average daily dose is 20 – 40mg/kg/day.
•By subcutaneous (s.c.) continuous infusion using a
portable pump over 8-10 hours daily, 5 - 7 nights a week.
Complications • Local skin reaction
• Yersinia infection
• Ocular/auditory toxicity
• Skeletal lesion i.e. vertebral growth retardation

40. DFP DFX
• Deferiprone is given orally
@ 75 -100 mg/kg/day in 3
divided doses.
• Can also be used in combination
with deferoxamine with a lower dose
of 50mg/kg/day.
• Risks of GI disturbance, arthritis
and rare occurrence of idiopathic
agranulocytosis.
•Stop if neutropenic
(<1,500/mm³).
• Can also be used for transfusional
iron overload in patients 2 years or
older
• Expensive.
•The dose is 20-30 mg/kg/day in
liquid dispersible tablet, taken once
daily.
•There are risks of transient skin rash,
GI disturbance and a reversible rise in
serum creatinine.

42. Splenectomy
Indications
•Blood consumption volume of pure RBC > 1.5X
normal or >200-220 mls/kg/year in those > 5
years of age to maintain average haemoglobin
levels.
• Evidence of hypersplenism.

43. Note:
•Give pneumococcal and HIB vaccinations 4-6 weeks
prior to splenectomy.
• Meningococcal vaccine required in endemic areas.
• Penicillin prophylaxis for life after splenectomy.
•Low dose aspirin (75 mg daily) if thrombocytosis >
800,000/mm³ after splenectomy.

44. Patient monitoring
Assessment and ix
Blood tx Pre and Post Transfusion – on every visit
HbsAg, anti HCV, Anti HIV - 6 monthly
Growth Wt, Ht , anthropometry – monthly/ every visit
Iron overload Serum ferritin - 3-6 monthly
Pt > 10 y/o:
ECG, ECHO - annually
LIC MRI - 2-5 yearly
Cardiac MRI T2- 2-5
yearly

45. Assessment and ix
Drug toxicity 1) DFO: auditory/ophtalmology annually
2) DFP: CBC - monthly, ALT 3monthly
3) DFX: RFT, LFT, Urine protein – 6 monthly,
auditory/ophtalmology annually
Complications
(especially in
>10 yrs old)
1) Growth failure
DM, hypothyroidism, delayed puberty, bone disorder,
2) Delayed puberty, hypogonadism
Tanner staging LH, FSH, estradiol/testosterone
3)Hypothyroidism : TFT
4) DM: FBS, OGTT
5) Osteoporosis/osteopenia
Serum Ca, PO4, ALP, Xray, DEXA scan

46. Assessment and ix
Complications (cont.) 6) Hypoparathyroidism: PTH
7)Hypoadrenalism
Baseline morning cortisol
ACTH stimulation test

47. Diet and supplements
• Oral folate at minimum 1 mg daily
•Low dose Vitamin C at 3 mg/kg augments iron excretion.
Dose: <10 yrs, 50mg daily; >10yrs, 100mg daily given only if child is
on Deferoxamine therapy)
•Avoid iron rich food such as red meat and iron fortified cereals or
milk.
• Tea may help decrease intestinal iron absorption.
• Dairy products are recommended as they are rich in calcium.
• Vitamin E as antioxidant.
• Calcium and zinc.

48. Bone marrow transplantation
•Potential curative option when there is an HLA-compatible
sibling donor.
•Results from matched unrelated donor or unrelated cord blood
transplant are still inferior with higher morbidity, mortality and
rejection rates.

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