THALASSEMIA

ARBAIN MOHAMED
MAIZATUL AYUNIE BT MEOR AFFINDI
FADHLY SHARIMAN BIN HJ YAHAYA
WELDON LIM
INTRODUCTION
• An autosomal recessive disorder of haemoglobin that results in
haemolytic anaemia.
• 2 alpha globin and 2 beta globin protein chains make up
haemoglobin.
• Thus the pathology in thalassemia is a consequence of an imbalance
in alpha and beta globin chain synthesis.
Thalassemia Genotypes and Syndromes
Alpha thalassemia
• Silent carrier
• 1 gene deletion

• Trait
• 2 gene deletion
• Hb H disease:

 Thal intermedia with 3 genes deletion.

 Hb in the range of 7-11 g/dL
 Intermittent haemolytic episodes esp after infection
or pregnancy
 Splenomegaly
 Hb H on electrophoresis/ H inclusions detected on
blood film
• Hydrops foetalis:

 4 genes deletion
 Incompatible for life
 The type of Hb is Hb Bart (Hb Bart disease)

• Note: No  thalassemia major

•6
  thalassemia

Reduced normal Excess  and 

hemoglobin globin chains
formation
HbH and High o2
Hb Bart’s affinity

Precipitate in Useless
RBCs physiologically

Hemolysis
•7
β thalassemia major
• Cooley's Anemia
• Both genes necessary for beta globin production are
affected
• βchains are not present in fetal hemoglobin.
• Presents at 6 months of age when adult hemoglobin
replaces fetal hemoglobin
• “Ineffective erythropoiesis"
• Classical facial features and skull X-ray findings ("hair on
end" in untreated patients due to excessive extramedullary
hematopoiesis)
• Hepatosplenomegaly
• In untreated patients, death usually occurs by the end of the
first decade of life from anemia and congestive heart failure
Pathogenesis
Clinical features
● Failure to thrive, infections, poor feeding,
pallor
● Progressive hepatosplenomegaly
● Frontal bossing
● Thalassemic facies
● Mild jaundice
● Hemosiderosis Endocrine dysfunction
● Radiology : Hair on end , trabecular pattern
Thalassemia facies
• Frontal bossing
• Maxillary hypertrophy
• Depression of nasal
bridge
• Malocclusion of teeth
Splenomegaly
Malaysian Thalassemia Registry (2009,
August)
• Showed a total of 4,541 registered patients of which 3,310 consist of the
transfusion dependent β Thalassemia major and HbE β Thalassemia
patients. The Thalassemia intermedias accounted for 455 patients while
HbH disease affected 410 individuals and the other subtypes made up the
rest.
• Sabah had the most number of registered patients standing at 1,272 with
the Kadazan-Dusun ethnic group contributing almost half of these affected
individuals.
• While Sarawak however only registered 133 patients with incidentally no
indigenous thalassaemic Ibans.
• The peninsular states showed a distribution pattern that followed the
population density but with a distinct pattern of HbE β Thalassemia being
more pronounced in the northern states bordering Thailand.
CLINICAL DIAGNOSIS
Presentation of β Thalassemia major Presentation of β Thalassemia
at 4 - 6 months or a child younger intermedia is at a later age
than 2 years of age
Anaemia Milder anaemia
Hepatosplenomegaly
Extensive Thalassemia facies
Jaundice
Thalassemia facies Hepatosplenomegaly
Growth failure/retardation
LABORATORY DIAGNOSIS
Screening Tests

Full blood count (FBC)

• Mean corpuscular volume (MCV) & mean corpuscular haemoglobin (MCH)
Red cells are hypochromic (MCH < 27 pg) and microcytic (MCV < 80 fl) in
Thalassemia as well as iron deficiency. (MCH is preferable because it is less
susceptible to storage changes)
• Red Cell Distribution Width (RDW - measure of the degree of variation in red
cell size). Iron deficiency is characterised by an increase in RDW (CV > 14%).
The Thalassemia trait produces a uniform microcytic red cell population
without a concomitant increase in RDW. RDW is increased in Thalassemia
intermedia and Thalassemia major
Diagnostic Tests

High performance liquid chromatography (HPLC)

-HPLC provides precise quantification of HbA2 and HbF, and
presumptive identification and quantification of variant haemoglobins
• In most cases of heterozygosity for β0 or severe β+ Thalassemia, the
HbA2 is 4 - 9%. In mild β+ Thalassemia it is usually 3.6 - 4.2%.
Other useful haematological tests
• Peripheral blood film (PBF)
• Haemoglobin electrophoresis
• H-inclusion test
• Kleihauer test
• Sickle solubility test
Haemoglobin electrophoresis
Laboratory Findings
• β Thalassemia Major
• Anaemia is severe (7 g/dL and below)
• Haematocrit low
• RBC low
• MCV low (50 - 60 fl)
• MCH low (12 - 18 pg)
• MCHC reduced
• The predominant Hb subtype seen is HbF ( > 90%). This will be significantly
elevated in nearly every case of severe β Thalassemia. The complete absence
of HbA indicates homozygous β0 Thalassemia, while the diagnosis of β+
Thalassemia is suggested by the finding of small amounts of HbA.
PBF: Marked anisocytosis,
poikilocytosis (including fragments
and tear-drop poikilocytes), Basophilic stippling Poikilocyte Target cell
hypochromia and microcytosis.
Basophilic stippling,
Pappenheimer bodies and target
cells. Circulating nucleated red
cells showing defective
haemoglobinisation and
dyserythropoietic features are
present.

The total white cell count and the neutrophil

count are increased.
If hypersplenism develops, there is leucopaenia,
neutropaenia and thrombocytopaenia
• Thalassemia Intermedia
• Anaemia is moderate (8 - 10 g/dL)
• Hb subtypes seen are HbF, HbA and HbA2
• If the HbA2 level is above 10%, this suggests the presence of HbE
• If the predominant Hb consists of HbF and HbE, this corresponds to the
diagnosis of HbE-β Thalassemia
• In β+ Thalassemia intermedia, there is raised HbF
 Hypochromia Microcyte

PBF: A milder
Thalassemia picture
DNA tests
• DNA tests are required in:
1. Inability to confirm a haemoglobinopathy by haematological tests
2. Genetic counselling and prenatal diagnosis
Genetic counselling
• Genetic counselling is the process in which patients or relatives at risk of a
disorder that may be hereditary are advised of the consequences of the
disorder, the probability of developing or transmitting it, and of the ways in
which this may be prevented/ avoided or ameliorated.
• Genetic counselling is essential to protect the autonomy of an individual or
couple and to fulfil their rights to maximum information about the disorder
and to help them to understand and to choose among the options
available.
When to provide the genetic counselling?
• before carrier screening is conducted
• once a diagnosis is made and further visits may have to be arranged
• The topics of discussion should include;
• Information about Thalassemia
• Treatment options
• The risk of having the condition and inheritance
• The purpose, nature and consequences of the genetic testing
• The risks involved in the procedure
• The limitations of testing
• Alternatives the counselee should consider
• Practical information on what will happen next
• The potential harm of testing
• The risks to family members
• The option of prenatal diagnosis and other choices
• Information on the available support groups
Cascade screening
• A genetic-screening strategy that targets relatives of carriers/affected
individuals of genetic disorders through the testing of their
phenotypes or genotypes
• Preventing Thalassemia births is based on identifying individuals at
risk, providing adequate information on risk and possibilities to
reduce that risk
• Screening family members (siblings, parents, aunts, uncles and
cousins) of an index case (Thalassemia major or carriers) should be
performed
Management of Thalassemia

• Regular maintenance blood transfusion and iron chelation

therapy is the mainstay of treatment in transfusion
dependent thalassemia patients
Blood transfusion
• To suppress extramedullary hematopoeisis and maintain normal
physical growth and well being

• Type of blood products:

1. Fresh packed cells
2. Leukocyte Reduced Red Cells - effective in reducing transfusion
reactions; the better the filter, the greater the reduction in
transfusion reactions
• When?
–Hb < 7g/dl on 2 occasions > 2 weeks apart OR Hb > 7g/dl in β+-
Thalassemia major/severe forms of HbE-β-Thalassemia if impaired
growth, para-spinal masses, severe bone changes, enlarging liver and
spleen

• Pre-Transfusion Investigations
1. Phenotyping for ABO, Rh, Kell, Kidd, Duffy and MNSs
2. Viral screening- Hepatitis B surface antigen (HBsAg), Hepatitis C
antibody (Anti HCV) and HIV antibody (Anti HIV)
• Transfusion targets
-Pre transfustion Hb level 9-10 g/dL (hypertransfusion 10-12 g/dL,
supertransfusion >12 g/dL)
Keeping pre-transfusion Hb to 9-10 g/dL may be sufficient to provide suppression of erythropoiesis and
allow a reduction in blood consumption, compared to classical hyper or super-transfusion (Cazzola et al.,
1995)
-Mean post transfusion Hb 13.5-15.5g/dL (half to one hour post transfusion)
-Mean Hb 12-12.5 g/dL

• Transfusion volume

(14g/dL – Actual Hb) X Body weight/kg X 3.5

-15 - 20mls/kg (maximum) packed red cells
-In the presence of cardiac failure or Hb < 5g/dL, use lower volume
packed red cell (<5ml/kg) at slow infusion rate over > 4 hours with IV
Frusemide 1 mg/kg (20 mg maximum dose)

• Transfusion intervals
-Usually 4 weekly interval (usual rate of Hb decline is at 1g/dL/week)
-Interval varies from individual patients (range: 2 - 6 weekly)
• Monitoring of patient during blood transfusion
-For suspected acute transfusion reaction, the blood transfusion must
be STOPPED immediately and resuscitation measures taken and
appropriate investigations carried out simultaneously to determine the
cause
-Acute transfusion reactions present as adverse signs or symptoms
during or within 24 hours of a blood transfusion
-Fever, chills, pruritus, or urticarial. More severe: SOB, red urine
Causes of transfusion reaction:
1. Acute hemolytic reactions (ABO incompatibility)
2. Febrile nonhemolytic reactions – leukocytes, platelets, plasma
3. Allergic reactions
4. Anaphylactic reactions – commonly in recipients with IgA deficiency
5. Circulatory (volume) overload – pulmonary edema
6. Bacterial contamination (sepsis)
Complications of chronic iron overload
• Hepatic: Liver cirrhosis (especially if with Hepatitis B/C infection)
A local study at Hospital University Kebangsaan Malaysia showed a
seroprevalence rate of 22.4% and 1.2% for Hepatitis C and Hepatitis B
respectively in Thalsassemia patients being treated (Jamal et al., 1998)

• Cardiac: Arrhythmias, pericarditis, cardiac failure

• Endocrine: Growth retardation, impaired glucose tolerance, pubertal

delay, hypothyroidism, hypoparathyroidism and diabetes mellitus
Infection
• Common infections occurring in Thalassaemic patients are:
1. Hepatitis C
2. Hepatitis B
In patients found to be HBsAg positive, the following tests should be done: LFT, HBeAg, anti-HBe
and HBV-DNA.
3. HIV
Transfusion acquired HIV infection - rare
HIV serology should be carried out six monthly in these patients
• Liaison with microbiologist for urgent confirmation of preliminary
positive ‘anti-HIV Antibody’ test is required
• Confirmed HIV positive cases should be referred urgently to Infectious
Disease Physician for counselling and management
• Blood bank needs to be contacted for donor tracing
Cardiac complication
• Major cause of mortality (71%) and morbidity in patients with
transfusion dependent Thalassemia
• Patients with serum ferritin > 2,500 µg/L have a higher risk of
developing cardiac complications and death
• Onset of cardiac iron overload can be as early as 10 years old
although the risk is usually higher in the late teens and twenties
• Ssx: Usually asymptomatic until late stage, can present as heart
failure, arrhythmias, and sudden death; reversible with intensive
chelation therapy
Ix: ECG, ECHO, HOLTER, CXR
MRI T2*
• Currently the best available method for early detection of cardiac
siderosis
• Should be done from age 10 onwards where possible and should be
repeated every 2 years if normal, yearly if the value is between 10 -
20 ms and 6 monthly if it is <10 ms
• T2* level < 20 ms indicates presence of cardiac iron overload
• T2* level < 10 ms indicates severe cardiac iron overload. Of patients with
heart failure, 89% have T2* < 10 ms
Endocrine complications
1. Growth failure
• Attributed to hypothyroidism, delayed sexual maturation, diabetes
mellitus, zinc deficiency, low haemoglobin levels, bone disorders, DFO
toxicity, IGF-1 deficiency and growth hormone deficiency (GHD)
• Definition: Height less than 3rd percentile for age and gender, 10 cm
or more below mid-parental height (MPH), slow growth rate observed
over a period of 6 months to 1 year
• Plot percentile height/weight 3 monthly
• After confirming GHD and correcting other factors, consider GH
therapy
2. Delayed Puberty and Hypogonadism
• Associated with failure of adequate bone mineralisation and achievement of peak
bone mass in Thalassemia patients
• Delayed puberty  the complete lack of pubertal development in girls by the age of
13 years and in boys by the age of 14 years
• Hypogonadism  absence of testicular enlargement (< 4 mls) in boys, absence of
breast development (thelarche) by the age of 16 years in girls
• Tanner staging should be determined every six months from the age of 10 years
onwards
• Ethinyl oestradiol had been used in girls and testosterone depot in boys for induction
of puberty
3. Hypothyroidism
• Majority – primary thyroid dysfunction
• There is a strong association between high iron overload and
decreased thyroid function
• No obvious clinical signs and symptoms of hypothyroidism
• Ix: Free T4 and TSH and bone age
• Tx: Full L-thyroxine replacement dose is 100 µg/m2/day. Subsequent
dosage should be titrated according to thyroid function
4. Diabetes Mellitus
• Believed to be due to damage of pancreatic β cells caused by iron overload.
There is reduced insulin secretion in normoglycaemic β Thalassemia major
patients
• Risk factors: Poor compliance with DFO treatment, delayed age at start of
chelation therapy, liver cirrhosis or severe fibrosis, and hepatitis C infection,
positive family history
• Dx: Modified GTT from 10 years onwards (7/11 mmol/L)
• Early and adequate use of iron chelation can prevent DM and major
endocrinopathies
• Insulin treatment is normally required in DM but metabolic control may be
difficult to achieve
5. Osteoporosis/Osteopaenia
• Low bone mass is present in a significant proportion of children with transfusion
dependent Thalassemia
• Bone Mineral Density (BMD) of Thalassemia children normal until 10-12 years,
then deviates
• Bone changes related to DFO toxicity should be suspected and investigated in
children with bone or joint pain. Also vit D, zinc deficiency
• Osteopaenia  mild decrease in bone mineral content, 1.1 to 2.4 SD below the
mean for age and sex
• Osteoporosis  a decrease in bone mineral content, 2.5 SD or more below the
mean for age and sex, and resulting in weak bones and pathological fractures
• Ix: X-ray of affected joints, ANF, Rheumatoid factor, ESR
• Adequate vitamin D and calcium intake according to recommended dietary
allowances (RDA) should be ensured in all Thalassemia patients
6. Hypoparathyroidism
• Majority of Thalassemia patients have no clinical symptoms of
hypocalcaemia
• Annual screening is suggested from age of 10 years onwards
• Ix: Serum Ca, Mg, PO4, ALP. In patients with low serum calcium and
high phosphate level, proceed with serum parathyroid level
• Tx: Calcitriol 0.25 - 1.0 µg once to twice daily. Calcium supplements
may be offered to patients with poor dietary intake. Phosphate
binders in patients with persistently high PO4
7. Hypoadrenalism
• Annual estimation of basal cortisol level in patients who are more
than 10 years old especially those with wasting
• Patients usually asymptomatic
• Ix: Baseline cortisol (morning) with higher cutoff point > 400 nmol/L.
If abnormal, ACTH stimulation test should be done. A peak cortisol
level of < 500 nmol/L with stimulation is abnormal
• Tx: Hydrocortisone in stressful conditions
Monitoring of Thalassemia patients

• Check liver and spleen in cm every visit

• 3 monthly – Plot percentile height and weight
• 6 monthly (June and December) – FBP, LFT, HIV, HBsAg and Ab,
T4+TSH, RBS, Ferritin, Calcium, PO4

Endocrinology (Teenager) – FSH, LH, Gonodotrophine, fasting growth

hormone assay, modified GTT
Iron chelation therapy
• Prevents iron overload in transfusion dependent Thalassemia,
minimizing tissue and organ damage
• 3 approved iron chelators:
Desferrioxamine (DFO) Desferal®
Deferiprone (DFP) Ferriprox®/Kelfer®
Oral iron chelators
Deferasirox (DFX) Exjade®
• Desferrioxamine (Desferal®)
1. Average daily dose is 20 – 40mg/kg/day, slow subcutaneous
infusion over at least 8 hours per night for 5 nights per week
2. Vitamin C augments iron excretion with Desferal®
3. Complications due to inadequately diluted Desferal® or infection

!Toxicity: if using high doses > 50mg/kg/day in the presence of low

serum ferritin in children can lead to ocular, auditory toxicity and
skeletal lesions i.e. pseudo rickets, metaphyseal changes, vertebral
growth retardation
• Deferiprone / L1 (Ferriprox®/Kelfer®)
1. Alternative if iron chelation is ineffective or inadequate despite
optimal Desferal® use
2. Oral Deferiprone 75 – 100 mg/kg/day in 3 divided doses
3. 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
Weekly full blood count monitoring is recommended. Stop if
neutropenic (<1,500/mm³)
• Deferasirox (Exjade®)
1. Oral DFX 20-30 mg/kg/day, OD
2. Expensive
Bone marrow transplatation
• From human leucocyte antigen (HLA) identical/compatible family or
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, inadequate iron
chelation and presence of liver fibrosis.
• Best results if performed at the earliest age possible in Class 1
patients
Risk factors:
1. Hepatomegaly > 2cm
2. Inadequate iron chelation
3. Presence of liver fibrosis
Splenectomy
• Some patients with hypersplenism might still require splenectomy to
reduce transfusion requirements
• Reduces blood consumption significantly, up to 30 - 50% and is long lasting
• When to consider:
1. Increased transfusion requirements which is 1.5 times than usual or
exceeding 200 - 250 ml/kg/yr of pure red blood cells
2. Evidence of hypersplenism as documented by splenomegaly with
persistent leucopaenia or thrombocytopaenia
3. Massive splenomegaly causing discomfort and risk of infarct or rupture
from trauma
Complications of splenectomy:
1. Sepsis
- Streptococcus pneumoniae accounts for 50 - 90% of infections in asplenic
patients, other infective organisms include Haemophilus, Neisseria and
other encapsulated gram negative organisms
- Prevention with immunoprophylaxis Pneumococcal and HIB 4-6 weeks
prior, Meningococcal vaccination and oral penicillin prophylaxis for life
2. Thromboembolism
3. Thrombocytosis
- Low dose aspirin (75 mg daily) if thrombocytosis > 800,000/mm³ after
splenectomy
References
1. Management of Thalassemia, Health Technology Assessment Unit,
Medical Development Division, Ministry Of Health Malaysia
Moh/Pak/77.03 (Tr), 2017
2. Paediatric Protocols for Malaysian Hospitals 3rd Edition, Ministry of
Health Malaysia, 2012
3. Management of Transfusion Dependent Thalassemia, Clinical
Practice Guidelines, Ministry of Health Malaysia, Nov 2009
4. Thalassemia Protocol, Paediatric Clinic, Paediatric Department
Hospital Tengku Ampuan Rahimah Klang.