This document provides an overview of thalassemia, including its pathophysiology, clinical signs, workups, management, and prognosis. It describes the different types of alpha and beta thalassemia, their typical clinical and laboratory findings. Investigations including complete blood count, blood film, hemoglobin electrophoresis are discussed. Management involves regular blood transfusions combined with iron chelation therapy to prevent iron overload. Other aspects of care include monitoring of iron levels, possible splenectomy, bone marrow transplantation, diet, and supplements. Prognosis has improved with optimal chelation but remains dependent on treatment compliance.

1. Prepared by: Thong Ching Fung
Supervised by: Dr Chang
THALASSEMIA
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2. CONTENTS
1. PATHOPHYSIOLOGY OF THALASSEMIA
2. CLINICAL SIGNS
3. WORK-UPS
4. MANAGEMENT
5. PROGNOSIS
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3. THALASSEMIA AS AN INHHERITED
HAEMOGLOBINOPATHY
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• a group of hereditary haemolytic diseases caused by faulty haemoglobin synthesis, widespread
in Mediterranean, African, and Asian countries.
• Haemoglobin comprises four globin chains:
• fetal haemoglobin (Hb F) has two α and two gamma chains (α2γ2) and
• adult haemoglobin (Hb A) has two α and two β chains (α2β2).
• Genes in the α-globin and β-globin gene clusters (on chromosomes 16 and 11) control globin-
chain production.
• Due to spontaneous mutation, haemoglobin gene variants are present at low prevalence
(carriers 1–1.5/1000) in all sizeable populations.
• They fall into two broad groups – structural variants that change the amino acid sequence and
produce an unusual haemoglobin, and thalassaemias that lower or abolish production of globin
chain

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7. ALPHA THALLASSEMIA
• Common in Asian population
• Pathology:
• 3 alpha globin genes (coded in chromosome 16)
• Reduced synthesis of alpha globin chains in Human Hb
• Clinical manifestation depends on the number of functional genes
Types Clinical diagnosis Laboratory diagnosis
Alpha-thalassemia trait Normal to mild anaemia
No organomegaly
Hb (>10g/dL)
MCH (<27pg)
Hb analysis (normal)
H inclusion may be present
DNA studies may be necessary
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8. 8

9. BETA-THALASSEMIA
• Commonest in Mediterranean and Middle East population
• Common in Chinese and Malays in Malaysia
Types Clinical Diagnosis Laboratory Diagnosis
Beta thala minor (trait)
-asymptomatic
heterozygous carrier
• Normal to mild anaemia, no orgganomegaly • Hb >10g/dL
• MCH <27pg
• HbF 2.5-5%
• HbA2 4-9% (HbE trait if >20%)
• HbA >90%
Beta Thala intermedia/
HbE Thala
• Milder anaemia >2y/o, not req reg transfusion,
req when fulminant infections, pregnancy,
oxidant drug use
• Thalassemia facies
• Hepatosplenomegaly
• Hb 8-10g/dL
• MCH <27pg
• HbF >10%
• HbA2 4-9% (HbE trait if >10%)
• HbA 5-90%
• HbH disease (presence of H
band)
Beta Thala major
(Cooley’s naemia)
- Homozygous beta thala
• Severe anaemia, usually 4-6 m/o or <2 y/o, req
regular transfusion and iron chelation therapy
• Jaundice
• Thalassemia facies
• Growth failure/mental retardation
• Hb <7g/dL
• MCH <27pg
• HbF >90%
• HbA2 normal or high
• HbA usually absent
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11. POSSIBLE CLINICAL SIGNS
• General inspection
• Bronze skin
• Short stature
• Thalassemia facies
• Pallor (conjunctiva, nailbed, palm)
• Jaundice (scleral, generally jaundice)
• Abdomen
• Desferral scars (pigmented, round, no
lipodystrophy)
• Surgical scars (open, laparascopy)
• Hepatomegaly, with or without
splenomegaly
• Chest
• Displaced apex beat
• Flow murmur
• Signs of CCF
• Others
• Signs of CLD
• Signs of hypothyroidism (dry hair, scaly
hair, hyporeflexia)
• Screen visual acuity
• Tanner staging
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13. • Chipmunk facies (hemolytic facies)
• frontal bossong,
• maxillary hypertrophy,
• depression of nasal bridge,
• mal-occlusion of teeth
• paravetrbral massess
• brood expansion of ribs at
vetebral attachement
• Paraperesis
• pathological fractures
• cortical thinning, crew-cut skull x-
ray, increased porositui of long
bones
• premature fusion of epiphyses (short
stature)
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14. INVESTIGATIONS
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18. 19

19. MANAGEMENT
• Suppress extra-medullary haemopoiesis while minimising complications from transfusion and maintaining normal well-being
• MAINSTAY OF TREATMENT (for transfusion-dependent thalassemia) = REGULAR BLOOD TRANSFUSION + IRON CHELATION
Initiation
(after
completing
blood Ix,
confirmation of
dx)
For beta-thalassemia intermedia
-clinical diagnosis, less severe naemia at
>2 y/o, usual Hb >= 8g/dL
- Follow beta-halassemia major regime if
tx requires
For alpha-thalassemia (HbH disease)
-transfuse only if Hb <7g/dL or
symptomatic
For beta thalassemia major,
-Hb <7g/dL, x2, >2 weeks apart (absence of other factors: infection)
-Hb >7g/dL, beta thalassemia major or severe forms of HbE
thalassemia (impaired growth, para-spinal massess, severe bone
changes, enlarging liver and spleen)
Target Pre-transfusion: 9-10g/dL
Post-transfusion: 13.5-15..5g/dL
Mean Hb 12-12.5g/dL
- Allow for normal physical activity and growth,
- abolishes chronic hypoxaemia,
- reduce compensatory marrow hyperplasia (rreversible facial bone
changes and para-spinal massess)
Interval 4-weekly (rate of Hb decline:
1g/dL/week)
Interval varies (~2-6 weekly)
Volume (Post Hb-Pre Hb) x Wt x 4.5
15-20mls/kg PRBC
Round-up to nearest pint (minimize number of exposure to
immunologically different units of blood product and avoid wastage of
donated blood)
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20. 1) ABOUT TRANSFUSION
In the presence of cardiac failure of HB <5g/dL, use lower volume PRBC (<5ml/kg), slow infusion
rate over >4 hours with IV Frusemide 1mg/kg (20mg max dose)
Use fresh leuco-depleted PRBC of <2 weeks old
- Minimize non-haemolytic febrile reactions and allo-immunization by removing white cells
contaminating PRBC
Complications
Iron deposition Cardiac siderosis (cardiomyopathy), liver (cirrhosis),
pancrease (DM), pit gland (infertility), skin
(hyperpigmentation)
Antibody formation Red cell antibodies, HLAAntibodies, Urticaria or
anaphylactic shock
Infections Hep B &C, HIV, CMV, Syphilis, Malaria
Massive blood Tx Fluid overload, hypothermia, thrombocytopenia, electrolytes
imbalances (hypernatraemia, hyperkalaemia), citrate toxicity
(causing hypocalcaemia), febrile reaction, ARDS
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21. 2) IRON CHELATION THERAPY
• PHYSIOLOGY
• Most adults have ~4g of iron in the body (3g in red blood cell, 1g in liver)
• In early stage, extra iron is stored in liver (max 20g), then once full, will be accumulated in other organs
• GIT absorbs only ~10% in total daily diet,
• There is no natural way to get rid of iron once its in the body, but a small amount excreted every day via skin
and gut
• Normal serum ferritin level= 100-400mcg/L
• AIM: maintain serum ferritin <1000mcg/L
• This is essential to prevent iron overload in transfusion dependent thalassemia
• Compliance to optimal treatment is directly related to superior survival outcome, now possible beyond the 6th
decade
• Currently 3 approved iron chelators are available
• Desferrioxamine (DFO)- subcuutaneous
• Deferipone (DFP)- oral
• Deferasirox (DFX)- oral
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22. NTBI: NON-TRANSFERRIN BOUND IRON
LPI: LABILE PLASMA IRON—CHELATABLE
REVIEW ARTICLE: BIOMEDICAL INTELLIGENCE
ROLE OF LIVER MAGNETIC RESONANCE IMAGING IN HYPERFERRITINAEMIA AND THE DIAGNOSIS OF IRON
OVERLOAD 23

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24. • start iron chelation therapy if serum ferritin >1000 mcg/L, usually 2-3 y/o
• 1st line: monotherapy DFO 20-40mg/kg/day (children dose) up to 50-60mg/kg/day (adult
dose) subcutaneous slow infusion 5 nights per week
• If inadequate chelation, consider
• DFX 20-30mg/kg/day in young children >2 years old
• DFP 75-100mg/kg/day if >6 years old
• In mild iron overload,
• Continue current iron chelator
• Aim for serum ferritin <1000 mcg/L In moderate to severe iron overload
• Check compliance, optimise dose of current drug or monotherapy
• Switch to alternatives: Another monotherapy? DFP-DFO combination? IV DFO?
Degree oof iron overload Mild Moderate Severe
Serum ferritin (mcg/L) <2500 2500-5000 >5000
LIC (mg Fe/g DW) <7 7-15 >15
Cardiac T2 MRI (ms)
For >10y/o
>20 10-20 <10
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25. Desferrioxamine : Desferal* Deferiprone: Ferriprox*/ Kelfer* Deferasirox: Exjade*
• Start when child >2-3 y/o when serum
ferritin reaches 1000 mcg/L
• Usually occurs after 10-20 blood tx
• 250ml prbc/1 unit of blood= 0.2g iron
• Alternative if chelation is
ineffective/inadequae despite
optimal Desferal use, or if Desferal
use is contraindicated
• No formal evaluatiin in children
<10 years old
• Weekly FBC (stop if neutropenic
<1500/mm3)
• Can also be used
for transfusional iron
overload in patients
2 years or older but
expensive
• 20-40mg/kg/day , subcutaneous
continuous infusion using a portable pump
over 8-10 hours daily, 5-7 nights a week
• Severely iron loaded pts require longer or
continuous SC or IV infusion (via
Portacath)
• Vit C augments iron excretion with
Desferal
• 75-100mg/kg/day in 3 divided
doses
• Can be used in combination with
Desferal, lower dose of
50mg/kg/day
• 20-30mg/kg/day in
liquid dispersible
tablet, OD
• Local skin reactions, yersinia infection,
severe allergy, desferal toxicity, ocular
toxicity, auditory toxicity, growth
retardation, skeletal lesions
• GI disturbance, arthritis, rarly
idiopathic agranulocytosis
• Transient skin rash,
GI disturbance,
reversible increase
in serum creatinine
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26. PUBLISHED IN CURRENT OPINION IN HEMATOLOGY 2014
IRON CHELATION: AN UPDATE.
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27. 3) MONITORING OF PATIENTS
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28. 3) MONITORING OF PATIENTS
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29. 4) SPLENECTOMY
• INDICATIONS:
• Blood consumption volume of pure RBC >1.5x normal or >200-220mls/kg/year in those >5
years of age to maintain average haemoglobin levels
• Evidence of hypersplenism
• Massive splenomegaly (risk of splenic rupture)
• PROPHYLAXIS
• Pneumococcal vaccine required in endemic areas
• Revaccination of HiB may be required after 5 years
• Penicilin prophylaxis for life after splenectomy
• Low dose aspirin (75mg daily) if thrombocytosis >800,000mm3 after splenectomy
(platelets in blood usually high after splenectomy)
• Thromboembolic phenomenon is more common in patients with thalassemia intermedia, thus
short-term anti-thrombotic prophylaxis should be considered during risk periods
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30. 5) DIET, SUPPLEMENTS
• Oral folate (min 1mg per day)
• Low dose Vit C (3mg/kg) augments iron excretion for those on Desferral only
• <10 y/o: 50mg daily
• >10 y/o: 100mg daily (only on Desferral days)
• Vit E (reduce platelet hyperactivity and reduce oxidative stress)
• Avoid iron rich food such as red meat and iron fortified cereals or milk
• Tea (may help decrease intestinal iron absorption)
• Dairy products (rich in calcium)
• Calcium and zinc
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31. 6) BONE MARROW TRANSPLANTATION (BMT)
• Potential curative option (when there is HLA-compatible sibling donor)
• Results from matched unrelated donor or unrelated cor 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 or inadequate iron chelation therapy
• Presence of liver fibrosis
• Best results if performed at the earliest age possible in Class 1 patients
• In newly diagnosed transfusion dependent thalassemias, the family should be informed of the
option (and early referral for counselling and HLA typing, subsequently indentifying donor)
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32. THANK YOU
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33. THANK YOU
• References:
• Paediatrics protocol
• Malaysian Transfusion-Dependent Thalassemias
• Clinical Classification, Screening and Diagnosis for Thalassemia
https://www.researchgate.net/publication/323412471_Clinical_Classification_Screening_
and_Diagnosis_for_Thalassemia
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