thalassemia

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 Mediterranean)

3

Thalassaemias are group of the

haemoglobindisorders 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

6

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

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 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

2. Types

14

TH

AL

AS

SE

MIA α

- Silent Carrier

- Trait (Minor)

- Hemoglobin H Disease (Intermediate)

- Major (Hemoglobin Bart’s)

- Hemoglobin Constant Spring

β- Trait (Minor)

- Intermedia

- Major (Cooley anemia)

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

• 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

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 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

β-ThalassaemiaAn 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 intermedia β+ β+ or β0 β+

▫ Thalassemia major β0β0

20

HbE α2βE2

• 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

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

• Microcytosis

• Alpha Thalassemia intermedia (Hemoglobin H)• Anemia and microcytosis

• Bone deformities

• Splenomegaly

• Hemoglobin Constant Spring• Similar to HbH but no microcytosis

• Anemia

• Growth delay

• Alpha Thalassemia major• Hb Bart’s

• Fatal hydrops fetalis

25

Pathophysiology of beta thalassemia

27

Beta thalassemia intermedia

“Too haematologically severe to be called minor, but too mild to be called

major”

Rietti-Greppi-Micheli [1995]

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 extramedullary

haemopoiesis in liver, spleen & brain

Organomegaly

↑Erythropoiesis marrow expansion & thinning

of cortex of skull bone Thalassaemia facies

32

Algorithm for screening of thalassaemia in

Malaysia

FBP, HbAnalysis

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

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

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 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

Transfusion dependent thalassemia

Regular maintenance blood transfusion and iron chelation therapy is the mainstay of treatment in this patient

40

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

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

Transfusion interval?

• Usually 4 weekly interval (usual rate of Hbdecline 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

• 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

Example

• Beta thalassemia major• Wt 16 kg• Hb 4

Calculations:Total PC: (12-4)(16)(3.5) = 448 cc1st tx 5cc/kg = (5)(16) =80 cc2nd tx 10cc/kg= (10)(16) = 160 ccBalance 384- 80 -160=208 ccMax possible tx 20cc/kg = 320 cc

46

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 (Exjade®)

48

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

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 combinationwith 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 transfusionaliron 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

12.5mg: Rm40/pill

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).

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 age to maintain average haemoglobin levels.

• Evidence of hypersplenism.

55

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/kg3600cc/16kg=225cc/kg/yr

• Annual pure red cells requirement/kg(225)(0.55)=123.75cc/kg/yr

57

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

Hemophilus influenzaStreptococcus 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 Serum ferritin 3 monthly

Pt > 10 y/o:ECG, ECHO annuallyLIC MRI 1-2 yearlyCardiac MRI T2 1-2 yearly

60

Assessment and ix

Drug toxicity 1) DFO: auditory/ophtalmology annually 2) DFP: FBC weekly, ALT 3monthly3) DFX: RFT, LFT, Urine protein monthly,

auditory/ophtalmology annually

Complications (especially in >10 yrs old)

1) Growth failureDM, hypothyroidism, delayed puberty, bone disorder,

2) Delayed puberty, hypogonadismTanner staging 6 monthly LH, FSH, estradiol/testosterone

3)Hypothyroidism : TFT

4) DM: FBS, OGTT

5) Osteoporosis/osteopeniaSerum Ca, PO4, ALP, Xray, DEXA scan

61

Assessment and ix

Complications (cont.) 6) Hypoparathyroidism: PTH

7) HypoadrenalismBaseline morning cortisolACTH stimulation test

62

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 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

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

68

Algorithm for management of transfusion dependent

thalassemia - cpg

5. Take home messages

• What is thalassemia?

• Genetic transmission and variations

• Family screening

• Patient education and compliance

• Complications

69

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

thalassemia

Health & Medicine