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Thalassemia
By: Dr Ismah
1
Contents
• Introduction
• Types
• Diagnosis
• Complications and management
• Take home message
2
1. Introduction
THALASSEMIA
1930s: from Greek thalassa ‘sea’
(because the diseases were first
known around the Mediterrane...
4
Thalassaemias are group of the
haemoglobin
disordersin which the
production of normal haemoglobin is
partly or completely ...
Thalassemia is inherited
by autosomal
recessive
6
7
8
Normal hemoglobin
• Embryonic Hb: 3rd to 10th week of pregnancy
ζ2ε2, α2ε2, ζ2γ2 tetramers
• Fetal Hb α2γ2
• Adult Hb
98% ...
10
11
Chromosomes 11
Chromosomes 16
Epidemiology
12
5 in every 100 people are thalassaemia carriers
• β-Thalassaemia major is an inherited blood
disorder presenting with anaemia at 4 – 6
months of age.
• The carrier rates ...
2. Types
14
THALASSEMIA
α
- Silent Carrier
- Trait (Minor)
- Hemoglobin H Disease
(Intermediate)
- Major (Hemoglobin Bart’...
Alpha Thalassemia
• Deficient/absent alpha subunits
▫ Excess beta subunits
▫ Excess gamma subunits newborns
• Encoding gen...
• Possible mutation states:
▫ Loss of ONE gene  silent carrier
▫ Loss of TWO genes  thalassemia minor (trait)
▫ Loss of ...
17
β/γ β/γ
β/γ
β/γ
Beta Thalassemia
• Encoding genes on chromosome 11
• Each cell contains 2 copies of beta globin gene
• Suppression of gene...
β-Thalassaemia
An absence or deficiency of β-chain synthesis of adult HbA
β Chain synthesis
Hb-A α2β2
γ and δ chain
• Loss of ONE gene  thalassemia minor (trait)
▫ ↑HbA2
▫ HbA normal
▫ HbF normal
• Loss of BOTH genes
▫ Thalassemia interm...
HbE α2βE
2
• Haemoglobin E disorder is the most common
structural variant resembling thalassemia
disorders
• HbE results f...
3. Diagnosis
• Clinical features
▫ History
▫ Physical examinations
• Lab investigations
• Screening family members
22
Clinical Outcomes of α Thalassemia
• Silent carriers
• Asymptomatic
• Alpha Thalassemia minor (trait)
• No anemia
• Microc...
• Hemoglobin Constant Spring
• Similar to HbH but no microcytosis
• Anemia
• Growth delay
• Alpha Thalassemia major
• Hb B...
25
Pathophysiology of beta thalassemia
26
27
Beta thalassemia
intermedia
“Too haematologically severe to be
called minor, but too mild to be called
major”
Rietti-Gr...
Partial or lack of HbA synthesis ↓MCHC &
MCH Hypochromia & microcytosis
Normal
Thalassaemia
Inadequate production + ineffective
erythropoiesis + haemolysis Anaemia
↑Haemolysis ↑demands of phagocytic
function  hyperplasia of phagocytes
Hepatosplenomegaly
To compensate anaemia extrame...
↑Erythropoiesis marrow expansion & thinning
of cortex of skull bone Thalassaemia facies
32
Algorithm for screening of thalassaemia in
Malaysia
FBP, Hb
Analysis
33
34
The red blood cells here are normal, happy RBC's. They have a zone of central
pallor about 1/3 the size of the RBC. The...
35
The RBC's here appear smaller than normal and have an increased zone of central
pallor. This is indicative of a hypochr...
36
Schistocytes
37
basophilic stippling
5. Complications and management
• Complications of disease
• Complications of treatment
38
Management
Baseline investigations
• Full blood count, Peripheral blood film
• Hb analysis by electrophoresis / High Perfo...
Transfusion dependent
thalassemia
Regular maintenance blood
transfusion and iron chelation
therapy is the mainstay of trea...
β Thalassemia major
When to start blood transfusion?
• After completing blood investigations for
confirmation of diagnosis...
Transfusion targets?
• Maintain pre transfusion Hb level at 9 -10 g/dl.
• Keep mean post-transfusion Hb at 13.5-15.5g/dl.
...
43
Transfusion interval?
• Usually 4 weekly interval (usual rate of Hb
decline is at 1g/dl/week).
• Interval varies from indi...
• In the presence of cardiac failure or Hb < 5g/dl,
use lower volume PRBC (< 5ml/kg) at slow
infusion rate over > 4 hours ...
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...
α Thalassemia (HbH disease)
• Transfuse only if Hb persistently < 7g/dl and/or
symptomatic.
47
Iron chelation therapy
• DFO: Desferrioxamine (Desferal®)
• DFP: Deferiprone (Ferriprox®/Kelfer®)
• DFX: Deferasirox (Exja...
DFO: Desferrioxamine (Desferal®)
When to start? • Usually when the child is > 2 - 3 years old.
• When serum ferritin reach...
DFP DFX
• An alternative if iron chelation is
ineffective or inadequate despite
optimal Desferal® use, or if
Desferal® use...
51
12.5mg:
Rm40/pill
52
• Endocrine: growth retardation,
impaired glucose tolerance,
pubertal delay, hypothyroidism,
hypoparathyroidism and dia...
53
54
Algorithm to start iron chelation therapy - CPG
Splenectomy
Indications
• Blood consumption volume of pure RBC > 1.5X
normal or >200-220 mls/kg/year in those > 5
years of...
56
Example of calculation
(volume pure RBC/kg/yr)
▫ Wt 16 kg
▫ Average HCT of pack RBC given 50-55% (0.55)
• Total PC transfu...
Note:
• Give pneumococcal and HIB vaccinations 4-6 weeks
prior to splenectomy.
• Meningococcal vaccine required in endemic...
59
Hemophilus influenza
Streptococcus pneumoniae
Neisseria meningitidis
Patient monitoring
Assessment and ix
Blood tx HbsAg, anti HCV, Anti HIV 6 monthly
Growth Wt, Ht 3-6 monthly
Iron overload ...
Assessment and ix
Drug toxicity 1) DFO: auditory/ophtalmology annually
2) DFP: FBC weekly, ALT 3monthly
3) DFX: RFT, LFT, ...
Assessment and ix
Complications (cont.) 6) Hypoparathyroidism: PTH
7) Hypoadrenalism
Baseline morning cortisol
ACTH stimul...
63
Management of complications cont.
64
Diet and supplements
• Oral folate at minimum 1 mg daily
• Low dose Vitamin C at 3 mg/kg augments iron excretion for those...
Bone marrow transplantation
• Potential curative option when there is an HLA-compatible
sibling donor.
• Results from matc...
67
68
Algorithm for management
of transfusion dependent
thalassemia - cpg
5. Take home messages
• What is thalassemia?
• Genetic transmission and variations
• Family screening
• Patient education ...
References:
1. Pediatric Protocol 3rd ed
2. Illustrated Textbook of Pediatrics of 3rd ed
3. Nelson Essential of Pediatrics...
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Thalassemia

  1. 1. Thalassemia By: Dr Ismah 1
  2. 2. Contents • Introduction • Types • Diagnosis • Complications and management • Take home message 2
  3. 3. 1. Introduction THALASSEMIA 1930s: from Greek thalassa ‘sea’ (because the diseases were first known around the Mediterranean) 3
  4. 4. 4
  5. 5. Thalassaemias are group of the haemoglobin disordersin 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
  6. 6. Thalassemia is inherited by autosomal recessive 6
  7. 7. 7
  8. 8. 8
  9. 9. Normal hemoglobin • Embryonic Hb: 3rd to 10th week of pregnancy ζ2ε2, α2ε2, ζ2γ2 tetramers • Fetal Hb α2γ2 • Adult Hb 98% HbA α2β2, 2% HbA2 α2δ2 9
  10. 10. 10
  11. 11. 11 Chromosomes 11 Chromosomes 16
  12. 12. Epidemiology 12 5 in every 100 people are thalassaemia carriers
  13. 13. • β-Thalassaemia major is an inherited blood disorder presenting with anaemia at 4 – 6 months of age. • The carrier rates of α-thalassaemia and Haemoglobin E (HbE) are 1.8-7.5% and 5-46% respectively • Interaction between a β-thalassaemia carrier with a HbE carrier may result in the birth of a patient with HbE/β-thalassaemia or thalassaemia intermedia with variable clinical severity 13
  14. 14. 2. Types 14 THALASSEMIA α - Silent Carrier - Trait (Minor) - Hemoglobin H Disease (Intermediate) - Major (Hemoglobin Bart’s) - Hemoglobin Constant Spring β - Trait (Minor) - Intermedia - Major (Cooley anemia)
  15. 15. 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
  16. 16. • 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 ▫ Hb constant spring similar to HbH but no microcytosis ▫ 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
  17. 17. 17 β/γ β/γ β/γ β/γ
  18. 18. 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
  19. 19. β-Thalassaemia An absence or deficiency of β-chain synthesis of adult HbA β Chain synthesis Hb-A α2β2 γ and δ chain
  20. 20. • 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 20
  21. 21. 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 21
  22. 22. 3. Diagnosis • Clinical features ▫ History ▫ Physical examinations • Lab investigations • Screening family members 22
  23. 23. Clinical Outcomes of α Thalassemia • Silent carriers • Asymptomatic • Alpha Thalassemia minor (trait) • No anemia • Microcytosis • Alpha Thalassemia intermedia (Hemoglobin H) • Anemia and microcytosis • Bone deformities • Splenomegaly
  24. 24. • Hemoglobin Constant Spring • Similar to HbH but no microcytosis • Anemia • Growth delay • Alpha Thalassemia major • Hb Bart’s • Fatal hydrops fetalis
  25. 25. 25 Pathophysiology of beta thalassemia
  26. 26. 26
  27. 27. 27 Beta thalassemia intermedia “Too haematologically severe to be called minor, but too mild to be called major” Rietti-Greppi-Micheli [1995]
  28. 28. Partial or lack of HbA synthesis ↓MCHC & MCH Hypochromia & microcytosis Normal Thalassaemia
  29. 29. Inadequate production + ineffective erythropoiesis + haemolysis Anaemia
  30. 30. ↑Haemolysis ↑demands of phagocytic function  hyperplasia of phagocytes Hepatosplenomegaly To compensate anaemia extramedullary haemopoiesis in liver, spleen & brain Organomegaly
  31. 31. ↑Erythropoiesis marrow expansion & thinning of cortex of skull bone Thalassaemia facies
  32. 32. 32 Algorithm for screening of thalassaemia in Malaysia FBP, Hb Analysis
  33. 33. 33
  34. 34. 34 The red blood cells here are normal, happy RBC's. They have a zone of central pallor about 1/3 the size of the RBC. The RBC's demonstrate minimal variation in size (anisocytosis) and shape (poikilocytosis). A few small fuzzy blue platelets are seen. In the center of the field are a band neutrophil on the left and asegmented neutrophil on the right.
  35. 35. 35 The RBC's here appear smaller than normal and have an increased zone of central pallor. This is indicative of a hypochromic (less hemoglobin in each RBC) and microcytic (smaller size of each RBC) anemia. There is also increased anisocytosis (variation in RBC size) and poikilocytosis (variation in RBC shape).
  36. 36. 36 Schistocytes
  37. 37. 37 basophilic stippling
  38. 38. 5. Complications and management • Complications of disease • Complications of treatment 38
  39. 39. Management Baseline investigations • Full blood count, Peripheral blood film • Hb analysis by electrophoresis / High Performance Liquid Chromatography (HPLC) • Serum ferritin. • Red cell phenotyping (ideal) before first transfusion. • DNA analysis (ideal) • Liver function test. • Infection screen: HIV, Hepatitis B & C, VDRL screen (before first transfusion). • HLA typing (for all patient with unaffected siblings) 39
  40. 40. Transfusion dependent thalassemia Regular maintenance blood transfusion and iron chelation therapy is the mainstay of treatment in this patient 40
  41. 41. β Thalassemia 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. 41
  42. 42. 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. 42
  43. 43. 43
  44. 44. 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). 44
  45. 45. • 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. 45
  46. 46. 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 46
  47. 47. α Thalassemia (HbH disease) • Transfuse only if Hb persistently < 7g/dl and/or symptomatic. 47
  48. 48. Iron chelation therapy • DFO: Desferrioxamine (Desferal®) • DFP: Deferiprone (Ferriprox®/Kelfer®) • DFX: Deferasirox (Exjade®) 48
  49. 49. DFO: Desferrioxamine (Desferal®) 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 49
  50. 50. DFP DFX • An alternative if iron chelation is ineffective or inadequate despite optimal Desferal® use, or if Desferal® use is contraindicated. • Deferiprone is given 75 – 100 mg/kg/day in 3 divided doses. • Can also be used in combination with Desferal®, using 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. 50
  51. 51. 51 12.5mg: Rm40/pill
  52. 52. 52 • 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).
  53. 53. 53
  54. 54. 54 Algorithm to start iron chelation therapy - CPG
  55. 55. 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. 55
  56. 56. 56
  57. 57. Example of calculation (volume pure RBC/kg/yr) ▫ Wt 16 kg ▫ Average HCT of pack RBC given 50-55% (0.55) • Total PC transfused in a yr (300cc)(12)=3600cc • Annual blood requirement/kg 3600cc/16kg=225cc/kg/yr • Annual pure red cells requirement/kg (225)(0.55)=123.75cc/kg/yr 57
  58. 58. 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. 58
  59. 59. 59 Hemophilus influenza Streptococcus pneumoniae Neisseria meningitidis
  60. 60. Patient monitoring Assessment and ix Blood tx HbsAg, anti HCV, Anti HIV 6 monthly Growth Wt, Ht 3-6 monthly Iron overload Serum ferritin 3 monthly Pt > 10 y/o: ECG, ECHO annually LIC MRI 1-2 yearly Cardiac MRI T2 1-2 yearly 60
  61. 61. Assessment and ix Drug toxicity 1) DFO: auditory/ophtalmology annually 2) DFP: FBC weekly, ALT 3monthly 3) DFX: RFT, LFT, Urine protein 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 6 monthly LH, FSH, estradiol/testosterone 3)Hypothyroidism : TFT 4) DM: FBS, OGTT 5) Osteoporosis/osteopenia Serum Ca, PO4, ALP, Xray, DEXA scan 61
  62. 62. Assessment and ix Complications (cont.) 6) Hypoparathyroidism: PTH 7) Hypoadrenalism Baseline morning cortisol ACTH stimulation test 62
  63. 63. 63
  64. 64. Management of complications cont. 64
  65. 65. Diet and supplements • Oral folate at minimum 1 mg daily • Low dose Vitamin C at 3 mg/kg augments iron excretion for those on Desferral only. Dose: <10 yrs, 50mg daily; >10yrs, 100mg daily given only on desferral days • 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. 65
  66. 66. 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. • Classification of patients into Pesaro risk groups based on the presence of 3 risk factors: hepatomegaly > 2cm, irregular iron chelation and presence of liver fibrosis. • Best results if performed at the earliest age possible in Class 1 patients. 66
  67. 67. 67
  68. 68. 68 Algorithm for management of transfusion dependent thalassemia - cpg
  69. 69. 5. Take home messages • What is thalassemia? • Genetic transmission and variations • Family screening • Patient education and compliance • Complications 69
  70. 70. References: 1. Pediatric Protocol 3rd ed 2. Illustrated Textbook of Pediatrics of 3rd ed 3. Nelson Essential of Pediatrics 6th ed 4. Malaysian CPG Management of Transfusion Dependent Thalassemia November 2009 5. Guidelines for the Clinical Management of Thalassemia 2nd Revised ed by Thalassemia International Federation 2008 6. www.mytalasemia.net.my 7. Molecular basis of thalassemia by Chris Chan, Louis Chiu, Lok Tin Liu and Janet Lui 8. http://library.med.utah.edu/WebPath 9. CDC 70
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