Thalassaemia

1. Clinical Overview

Summary

Thalassaemia is a group of inherited haemoglobinopathies characterised by reduced or absent synthesis of globin chains (alpha or beta) of the haemoglobin molecule, resulting in an imbalance in the alpha/beta-globin chain ratio. [1] This imbalance leads to ineffective erythropoiesis (destruction of erythroid precursors in the bone marrow before they mature), chronic haemolytic anaemia, and varying degrees of clinical severity ranging from asymptomatic carriers to severe transfusion-dependent disease. [1,2]

Thalassaemia represents one of the most common monogenic disorders worldwide, with an estimated 270 million carriers globally and approximately 60,000-70,000 births with severe thalassaemia annually. [3] The condition is particularly prevalent in populations from the Mediterranean basin, Middle East, South Asia, Southeast Asia, and sub-Saharan Africa, where it provides a selective advantage against malaria. [1,3]

The two principal types are beta-thalassaemia (reduced beta-globin chain production due to mutations in the HBB gene on chromosome 11) and alpha-thalassaemia (reduced alpha-globin chain production due to deletions or mutations in the HBA1 and HBA2 genes on chromosome 16). [1,4] Clinical phenotypes are classified based on severity: thalassaemia trait (minor) is an asymptomatic carrier state, thalassaemia intermedia has moderate disease not requiring regular transfusions, and thalassaemia major (transfusion-dependent thalassaemia, TDT) requires lifelong regular blood transfusions for survival. [1,2]

Beta-thalassaemia major (Cooley's anaemia) typically presents between 6-24 months of age with severe anaemia, failure to thrive, hepatosplenomegaly, and if untreated, characteristic skeletal deformities from bone marrow expansion (frontal bossing, maxillary hyperplasia producing "chipmunk facies"). [1,2] Management has evolved dramatically: regular blood transfusions maintain adequate haemoglobin levels, iron chelation therapy (deferasirox, deferiprone, or deferoxamine) prevents life-threatening iron overload, and allogeneic haematopoietic stem cell transplantation (HSCT) offers the only established cure. [1,5,6] Gene therapy with betibeglogene autotemcel (Zynteglo) has emerged as a transformative curative option approved by the EMA and FDA. [7]

Iron overload from chronic transfusions and increased intestinal iron absorption is the leading cause of morbidity and mortality in well-transfused patients, causing cardiomyopathy, hepatic cirrhosis, and endocrinopathies (diabetes mellitus, hypogonadism, hypothyroidism). [1,8] Cardiac T2 MRI* is the gold standard for assessing cardiac iron load, with values less than 10 ms indicating critical overload requiring urgent intensification of chelation. [9]

With optimal modern management including regular transfusions, effective chelation, and multidisciplinary care, patients with thalassaemia major now achieve median survival of 50-60 years or longer, compared to death in early childhood prior to modern therapy. [1,10]

Clinical Pearls

"Microcytic Anaemia with High RBC Count": Thalassaemia trait typically shows MCV less than 70 fL but RBC count normal or elevated. Mentzer Index (MCV/RBC) less than 13 suggests thalassaemia over iron deficiency.

"Mediterranean/Asian Ethnicity + Microcytic Anaemia ≠ Always Iron Deficiency": Always consider thalassaemia trait. Check serum ferritin and HbA2.

"HbA2 Elevated in Beta-Thalassaemia Trait": HbA2 > 3.5% is the diagnostic hallmark of beta-thalassaemia carrier status. [4]

"Iron Overload is the Main Killer in TDT": Cardiac iron toxicity causing heart failure and arrhythmias is the leading cause of death. Chelation therapy is life-saving. [1,8]

*"Cardiac T2 less than 10 ms = Emergency"**: Critical cardiac iron overload requiring urgent combination chelation therapy to prevent heart failure. [9]

"Hypercoagulability in NTDT": Non-transfusion-dependent thalassaemia (NTDT) patients have increased thrombotic risk, especially post-splenectomy. [11]

"Never Give Iron Empirically to Microcytic Patients with Thalassaemia Ethnicity": Could exacerbate iron overload. Always measure ferritin first.

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2. Epidemiology

Global Distribution

Demographics

Genetics

Inheritance: Autosomal recessive. Both parents must be carriers (heterozygous) for offspring to be affected (homozygous or compound heterozygous). [1,2]

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3. Classification

Beta-Thalassaemia

Alpha-Thalassaemia (Based on Number of Alpha Gene Deletions/Mutations)

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4. Pathophysiology

Molecular Basis

Normal Haemoglobin Structure:

• Adult haemoglobin (HbA): α₂β₂ (two alpha chains + two beta chains)
• Fetal haemoglobin (HbF): α₂γ₂ (two alpha chains + two gamma chains)
• HbA2 (minor adult): α₂δ₂ (normally less than 3.5%)

Genetic Defects:

• Beta-thalassaemia: Over 200 mutations in HBB gene. β⁰ mutations (nonsense, frameshift) cause complete absence of beta-globin. β⁺ mutations (promoter, splice site) cause reduced beta-globin production. [1,2]
• Alpha-thalassaemia: Predominantly gene deletions (α-, --). Non-deletional mutations (αTα) often cause more severe phenotypes. [12]

Pathophysiological Cascade (Beta-Thalassaemia Major as Paradigm)

1. Reduced/Absent Beta-Globin Synthesis: Mutations in HBB gene → decreased or absent beta-globin chains. [1]

2. Globin Chain Imbalance: Excess unpaired alpha-globin chains accumulate (normal alpha-globin production continues). [1]

3. Alpha-Chain Precipitation in Erythroid Precursors: Unpaired alpha-chains are unstable and precipitate → form toxic aggregates → oxidative damage → membrane damage. [1,2]

4. Ineffective Erythropoiesis (Major Pathological Feature): Massive destruction of erythroblasts within the bone marrow before they mature into red blood cells. Up to 70-85% of erythroid precursors die intramedullary. This is the dominant mechanism of anaemia in thalassaemia. [1,2]

5. Peripheral Haemolysis: Those red cells that do enter the circulation have shortened lifespan (haemolysis) due to membrane damage from precipitated alpha-chains and oxidative stress. [1]

6. Severe Anaemia: Combination of ineffective erythropoiesis and haemolysis → profound anaemia.

7. Compensatory Responses:

   • Bone Marrow Expansion: 15-30-fold expansion to compensate for ineffective erythropoiesis → bone deformities (skull: "hair-on-end" appearance on X-ray; face: frontal bossing, maxillary hyperplasia → "chipmunk facies"; long bones: cortical thinning → fracture risk). [1,2]
   • Extramedullary Haemopoiesis: Liver, spleen, paravertebral masses → hepatosplenomegaly. Can cause spinal cord compression if severe. [1]
   • Increased Erythropoietin (EPO): Drives marrow expansion and extramedullary haemopoiesis.

8. Iron Dysregulation and Overload: [1,8]

   • Transfusional Iron: Each unit of packed red cells contains ~200-250 mg elemental iron. With 15-20 units/year, patient accumulates 3-5 g iron/year.
   • Increased Intestinal Iron Absorption: Ineffective erythropoiesis → suppression of hepcidin (liver hormone that inhibits iron absorption) → increased duodenal iron absorption (2-3 times normal) even in transfused patients.
   • Iron Deposition: Iron overload → deposition in heart, liver, endocrine glands (pituitary, pancreas, thyroid, parathyroids) → organ dysfunction and failure.

9. Hypercoagulability (especially in NTDT): Increased reactive oxygen species, abnormal erythroid cells, platelet activation, endothelial dysfunction, microparticles → increased thrombotic risk. Splenectomy further increases risk. [11]

Alpha-Thalassaemia Pathophysiology (HbH Disease)

• Excess unpaired beta-globin chains → form HbH (β₄ tetramers).
• HbH is unstable, precipitates → forms inclusion bodies (visible with supravital staining) → haemolysis.
• HbH has very high oxygen affinity → poor oxygen delivery to tissues → functional anaemia worse than Hb level suggests.
• Less prominent ineffective erythropoiesis compared to beta-thalassaemia, so less skeletal deformity. [12]

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5. Clinical Presentation

Beta-Thalassaemia Major (Transfusion-Dependent Thalassaemia)

Presentation Age: 6-24 months (as fetal haemoglobin declines and demand for beta-globin increases). [1,2]

Presenting Features (Untransfused)

Skeletal Manifestations (Untreated or Inadequately Transfused)

Note: With early and adequate transfusion, skeletal deformities can be largely prevented. [1,2]

Iron Overload Complications (Transfused Patients Without Adequate Chelation)

Typically emerge in second decade or later if chelation inadequate. [1,8]

Beta-Thalassaemia Intermedia (NTDT)

Presentation: More variable. Can present in childhood or adulthood depending on severity. [2]

Beta-Thalassaemia Minor (Trait)

HbH Disease (Alpha-Thalassaemia)

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6. Investigations

First-Line Investigations

Full Blood Count (FBC)

Mentzer Index (MCV / RBC Count)

Note: Screening tool only. Not diagnostic. Must confirm with haemoglobin analysis and iron studies. [4]

Blood Film

Iron Studies

Critical to differentiate thalassaemia from iron deficiency anaemia (IDA).

Key Point: Iron studies are normal in thalassaemia trait, distinguishing it from IDA. Never give empirical iron to microcytic patients without checking ferritin. [4]

Definitive Diagnostic Investigations

Haemoglobin Electrophoresis / High-Performance Liquid Chromatography (HPLC)

Gold standard for diagnosis and classification. [4]

Important Notes:

• Iron deficiency can falsely lower HbA2 → rule out iron deficiency before interpreting HbA2 levels.
• Delta-thalassaemia can also lower HbA2 (rare).

Genetic Testing (DNA Analysis)

Indications: [1,2,4]

• Confirm diagnosis (especially alpha-thalassaemia where HbA2 normal).
• Identify specific mutations.
• Essential for genetic counselling and prenatal diagnosis.
• Predict severity (genotype-phenotype correlation).
• Pre-implantation genetic diagnosis (PGD).

Methods:

• Beta-thalassaemia: PCR-based mutation detection, DNA sequencing of HBB gene.
• Alpha-thalassaemia: Gap-PCR for deletions, multiplex ligation-dependent probe amplification (MLPA), DNA sequencing for non-deletional mutations.

Assessment of Iron Overload (Transfusion-Dependent Patients)

Critical Cardiac T2 Values*: [9]

• > 20 ms: No significant cardiac iron. Safe.
• 10-20 ms: Cardiac iron loading. Intensify chelation. Monitor closely.
• less than 10 ms: CRITICAL cardiac iron overload. High risk of arrhythmias and heart failure. Requires urgent combination chelation therapy and intensive monitoring.

Additional Monitoring (Transfusion-Dependent Patients)

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7. Differential Diagnosis

Microcytic Anaemia

Haemolytic Anaemia (Differential for Thalassaemia Major)

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8. Management

Management Principles

Goals of management: [1,5,6]

1. Maintain adequate haemoglobin (reduce anaemia complications, suppress ineffective erythropoiesis).
2. Prevent/treat iron overload (prevent end-organ damage).
3. Monitor and manage complications (endocrine, cardiac, hepatic, skeletal).
4. Psychosocial support (chronic disease burden, quality of life).
5. Consider curative therapy (HSCT, gene therapy) where appropriate.

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Beta-Thalassaemia Major (Transfusion-Dependent Thalassaemia) Management

A. Regular Blood Transfusions (Cornerstone of Management)

Indications: [5,6]

• Haemoglobin less than 7 g/dL with symptoms.
• Failure to thrive, cardiac decompensation.
• Inadequate growth or development.

Transfusion Regimen: [5,6]

• Target Pre-Transfusion Hb: 9-10.5 g/dL (maintains adequate oxygenation, suppresses ineffective erythropoiesis, prevents skeletal deformities).
• Frequency: Typically every 2-4 weeks (depending on individual requirements).
• Blood Product: Leucodepleted packed red blood cells. Extended phenotype matching (Rh, Kell, other antigens) to reduce alloimmunisation risk.
• Volume: 10-15 mL/kg per transfusion (to achieve post-transfusion Hb ~13-14 g/dL).

Monitoring:

• Pre-transfusion Hb every 3-4 weeks.
• Annual transfusion volume (to calculate iron loading: ~200 mg iron per unit).
• Screen for alloantibodies (antibody screen before each transfusion).

Benefits of Hypertransfusion Regimen:

• Improved growth and development.
• Prevention of bone deformities.
• Reduced hepatosplenomegaly.
• Improved quality of life.
• Reduced erythropoiesis-driven iron absorption.

Complications:

• Iron overload (major complication requiring chelation).
• Alloimmunisation (antibodies to red cell antigens) in 5-30% despite matching. Can make crossmatching difficult.
• Transfusion-transmitted infections (HBV, HCV, HIV - now rare with modern screening).
• Transfusion reactions (allergic, febrile non-haemolytic).

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B. Iron Chelation Therapy (Essential Lifelong Treatment)

Rationale: Each unit of packed red cells contains ~200-250 mg iron. With no physiological mechanism for iron excretion, patients accumulate 3-5 g iron annually with regular transfusions. Without chelation, lethal cardiac and hepatic siderosis develops by age 20. [1,8]

Indications to Start Chelation: [5,6]

• After 10-20 red cell transfusions OR
• Serum ferritin > 1000 µg/L (usually by age 3-5 years in regularly transfused patients).

Target: [5,6]

• Serum ferritin less than 1000 µg/L (ideally 500-1000 µg/L).
• Liver iron concentration (LIC) less than 7 mg Fe/g dry weight (ideally less than 3).
• Cardiac T2 > 20 ms* (no cardiac iron).

Available Iron Chelators:

Combination Chelation Therapy: [16]

Used for:

• Severe iron overload (ferritin > 2500-3000 µg/L, LIC > 15 mg/g).
• Critical cardiac iron overload (cardiac T2* less than 10 ms).
• Failure to achieve iron balance with monotherapy.

Common Regimens:

• DFO + DFP: DFO 40-60 mg/kg 5-7 days/week + DFP 75 mg/kg/day. Highly effective for cardiac iron. [15,16]
• DFX + DFP: Emerging data. Sequential or simultaneous dosing.

Benefits: Synergistic iron removal. More rapid reduction of iron burden. May improve adherence (shorter DFO infusions). [16]

Evidence: Cochrane review (2017) showed deferasirox non-inferior to deferoxamine at dose ratio ~1:2 (mg deferasirox : mg deferoxamine). Patient satisfaction higher with deferasirox. [14]

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C. Curative Therapies

1. Allogeneic Haematopoietic Stem Cell Transplantation (HSCT)

Only established cure for thalassaemia. [1,5,17]

Indications:

• Beta-thalassaemia major (TDT).
• Availability of HLA-matched donor (sibling preferred, matched unrelated donor (MUD) or cord blood alternative).
• Patient age less than 16 years ideally (better outcomes).
• Absence of significant iron-related organ damage (especially liver fibrosis, cardiac dysfunction).

Outcomes: [17]

• HLA-matched sibling donor: Thalassaemia-free survival > 90% in optimal candidates (young age, minimal hepatomegaly, no liver fibrosis - Pesaro Class 1).
• Matched unrelated donor: Thalassaemia-free survival 70-85%.
• Haploidentical donor: Emerging option. Outcomes improving with newer conditioning regimens.

Pesaro Risk Classification (Predicts HSCT Outcomes): [17]

• Class 1 (Low risk): Adequate chelation, no hepatomegaly, no liver fibrosis. Survival > 95%.
• Class 2 (Intermediate): One or two risk factors present. Survival ~85%.
• Class 3 (High risk): All three risk factors present. Survival ~60%.

Conditioning Regimen: Typically myeloablative (busulfan-based or treosulfan-based) with immunosuppression (cyclophosphamide, fludarabine). Reduced-intensity conditioning for older patients or co-morbidities.

Complications:

• Graft-versus-host disease (GVHD): Acute (15-30%) and chronic (25-40%). Major cause of morbidity.
• Graft failure/rejection: 5-10% (higher in heavily transfused, alloimmunised patients).
• Infections: Bacterial, viral (CMV, EBV), fungal during neutropenic period.
• Veno-occlusive disease (VOD/SOS): Hepatic complication. Higher risk with iron overload.
• Late effects: Infertility, growth impairment, secondary malignancies.
• Mortality: 5-10% in optimal candidates. Higher in Class 3 patients.

Post-HSCT: Patients are cured if engraftment successful. No longer require transfusions or chelation (though may need chelation initially to remove accumulated iron).

2. Gene Therapy

Betibeglogene Autotemcel (Zynteglo, beti-cel): [7,18]

• Mechanism: Autologous haematopoietic stem cell gene therapy. Patient's own stem cells collected, transduced ex vivo with lentiviral vector containing functional HBB gene (encoding beta-globin with T87Q mutation), then reinfused after myeloablative conditioning.
• Approval: EMA (2019), FDA (2022) for transfusion-dependent beta-thalassaemia.
• Efficacy: ~90% of patients achieve transfusion independence (can stop transfusions) in clinical trials. Sustained haemoglobin production (Hb ~10-13 g/dL without transfusions). [7,18]
• Indication: TDT patients without matched HSCT donor, or those who prefer gene therapy.
• Procedure: Mobilisation, stem cell collection, myeloablative conditioning (busulfan), transduced cell infusion, engraftment.
• Limitations: Very expensive (~$2.8 million USD per patient in USA). Limited availability. Requires myeloablative conditioning (infertility risk). Long-term safety data still emerging. Not yet curative for all patients (some still need occasional transfusions).
• Ongoing Research: CRISPR-based gene editing therapies (exagamglogene autotemcel - approved 2023) showing promise.

Gene therapy represents transformative advance: Potential cure without need for allogeneic donor, avoiding GVHD. [7,18]

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D. Supportive Care and Complication Management

Splenectomy

Indications: [5,6]

• Hypersplenism → increasing transfusion requirements (> 200-250 mL/kg/year packed red cells).
• Massive splenomegaly causing mechanical symptoms.
• Splenic sequestration.

Benefits: Reduces transfusion requirement by 30-50%.

Risks:

• Post-splenectomy sepsis (Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis). Lifelong risk.
• Increased thrombotic risk (especially in NTDT). [11]

Prerequisites:

• Vaccinations (at least 2 weeks before splenectomy): Pneumococcal (PCV13 + PPSV23), Haemophilus influenzae type b, Meningococcal (ACWY + B), annual influenza.
• Age > 5-6 years if possible (reduce infection risk).

Post-Splenectomy Management:

• Lifelong antibiotic prophylaxis: Penicillin V 250-500 mg BD (or erythromycin if allergic).
• Prompt treatment of febrile illness (risk of overwhelming post-splenectomy infection - OPSI).
• Education re: risks, medic alert bracelet.
• Consider anticoagulation if additional thrombotic risk factors.

Endocrine Complications Management

Cardiac Complications Management

Hepatic Complications Management

• Hepatitis B/C: Antiviral therapy (direct-acting antivirals for HCV). Vaccination for HBV (all non-immune patients).
• Cirrhosis: Manage portal hypertension, varices (beta-blockers, endoscopic variceal ligation).
• Hepatocellular carcinoma surveillance: Annual liver ultrasound and alpha-fetoprotein in patients with cirrhosis and/or chronic hepatitis C.

Other Supportive Care

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Beta-Thalassaemia Intermedia (NTDT) Management

Principles: More conservative than TDT. Avoid/minimise transfusions if possible. [2,5]

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Beta-Thalassaemia Minor (Trait) Management

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HbH Disease (Alpha-Thalassaemia) Management

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9. Complications

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10. Prognosis and Outcomes

Thalassaemia Major (TDT)

Leading Cause of Death (Modern Era): Cardiac iron overload → heart failure, arrhythmias (40-50% of deaths). [1,8,9]

Other Causes of Death: Liver disease/hepatocellular carcinoma, infections, complications of HSCT, thrombosis.

Quality of Life: Significantly improved with modern therapy. Challenges remain: chronic disease burden, treatment adherence (daily chelation, regular transfusions), fertility issues, psychosocial impact. [1]

Thalassaemia Intermedia (NTDT)

• Survival: Generally better than TDT historically (less transfusion-dependent). With modern supportive care, many live into 5th-6th decade or beyond. [2]
• Morbidity: Significant from non-transfusional iron overload, skeletal deformities, thrombosis, pulmonary hypertension. Quality of life can be impaired. [2]

Thalassaemia Trait (Minor)

• Normal lifespan. No treatment needed. Excellent prognosis. [4]
• Importance: Genetic counselling to prevent thalassaemia major births.

HbH Disease

• Survival: Most patients live into adulthood. Median survival 60+ years with supportive care. [12]
• Morbidity: Chronic anaemia, splenomegaly, occasional transfusions. Generally less severe than beta-thal major.

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11. Prevention and Screening

Prevention Strategies

Screening Recommendations

Success Story: Cyprus

• 1970 s: Thalassaemia major birth rate ~1:158 births (carrier rate 14%).
• Implemented mandatory premarital screening (1983), genetic counselling, prenatal diagnosis.
• Result: > 95% reduction in thalassaemia major births. [3]

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12. Evidence and Guidelines

Key Guidelines

Landmark Evidence

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13. Patient and Layperson Explanation

What is Thalassaemia?

Thalassaemia is an inherited blood disorder where your body cannot make enough normal haemoglobin (the protein in red blood cells that carries oxygen around your body). This leads to anaemia (low red blood cell count), making you feel tired and weak.

What Causes It?

Thalassaemia is genetic - you inherit it from your parents. It is caused by mutations in the genes that tell your body how to make haemoglobin. It is NOT contagious - you cannot catch it from someone else.

What Are the Types?

• Thalassaemia Trait (Minor): You carry one faulty gene. You usually have no symptoms or very mild anaemia. You are healthy, but it is important to know you are a carrier for family planning.
• Thalassaemia Intermedia: You have moderate anaemia. You may or may not need blood transfusions.
• Thalassaemia Major (Severe): You inherit faulty genes from both parents. This causes severe anaemia needing regular blood transfusions throughout life.

What Are the Symptoms of Thalassaemia Major?

Symptoms usually start in the first 1-2 years of life:

• Severe tiredness and paleness.
• Slow growth and poor weight gain.
• Enlarged liver and spleen (swollen tummy).
• Yellowing of skin (jaundice).
• Bone changes (prominent forehead, facial bones) if not treated early.

How is Thalassaemia Major Treated?

There is no simple cure, but excellent treatments are available:

1. Regular Blood Transfusions (every 2-4 weeks): Replace the abnormal red blood cells with healthy ones from donors. This keeps you well and prevents complications.

2. Iron-Removal Medication (Chelation): Blood transfusions cause iron to build up in your body. Too much iron damages your heart, liver, and other organs. Chelation drugs remove this excess iron. You take them daily (tablets or injections).

   • Deferasirox (Exjade, Jadenu): Oral tablet, once daily (most common).
   • Deferiprone (Ferriprox): Oral tablet, three times daily. Very good for protecting your heart.
   • Deferoxamine (Desferal): Injection or pump infusion overnight, 5-7 nights per week.

3. Bone Marrow (Stem Cell) Transplant: The only established cure. You receive healthy stem cells from a donor (usually a sibling). This can cure thalassaemia, but it has risks (rejection, infections, side effects). Only suitable for some patients.

4. Gene Therapy (New!): A new curative treatment where doctors modify your own stem cells to make normal haemoglobin. Approved in 2019-2022. Very promising, but expensive and not yet widely available.

What Happens If Iron Builds Up?

Without chelation, iron damages organs:

• Heart: Heart failure, irregular heartbeat. The leading cause of death in thalassaemia if iron not removed.
• Liver: Scarring (cirrhosis).
• Glands: Diabetes, delayed puberty, thyroid problems.

This is why taking your chelation medication every day is life-saving.

Is Thalassaemia Inherited?

Yes. If both parents carry the thalassaemia gene, there is a:

• 25% (1 in 4) chance the baby will have thalassaemia major.
• 50% (2 in 4) chance the baby will be a carrier (like the parents).
• 25% (1 in 4) chance the baby will not have thalassaemia at all.

Genetic counselling and testing are available before or during pregnancy.

Can People with Thalassaemia Live Normal Lives?

Yes! With regular transfusions, good chelation, and medical care:

• People with thalassaemia major now live into their 50s, 60s, and beyond (used to die in childhood before modern treatment).
• You can go to school, work, have relationships.
• Fertility can be affected, but many people with thalassaemia have children (with medical support).
• A bone marrow transplant or gene therapy can cure thalassaemia, allowing you to stop transfusions and chelation.

What Should I Do If I Am a Carrier (Thalassaemia Trait)?

• No treatment needed - you are healthy.
• Tell your partner to get tested, especially if they are from the same ethnic background (Mediterranean, Middle Eastern, Asian).
• Genetic counselling if both you and your partner are carriers.
• Do not take iron tablets unless your doctor confirms you are also iron deficient (rare).

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14. Examination Focus

High-Yield Exam Topics

1. HbA2 Elevated in Beta-Thalassaemia Trait (> 3.5%) - diagnostic hallmark.
2. Mentzer Index less than 13 suggests thalassaemia; > 13 suggests iron deficiency.
3. Leading Cause of Death in TDT: Cardiac iron overload (heart failure, arrhythmias).
4. Cardiac T2 less than 10 ms* = critical cardiac iron overload, high heart failure risk within 1 year.
5. Curative Treatment: Allogeneic HSCT (> 90% cure in optimal candidates). Gene therapy emerging (betibeglogene autotemcel).
6. Iron Chelators: Deferasirox (oral, once daily, most used; renal toxicity); Deferiprone (oral, TDS, best for cardiac iron; agranulocytosis risk - weekly FBC); Deferoxamine (SC/IV infusion, effective; cumbersome).
7. Transfusion Target: Pre-transfusion Hb 9-10.5 g/dL (suppresses ineffective erythropoiesis, prevents skeletal deformities).
8. Pathophysiology: Globin chain imbalance → unpaired alpha-chains precipitate → ineffective erythropoiesis (major mechanism) + haemolysis → anaemia.
9. Hb Bart's Hydrops Fetalis: 4 alpha gene deletions. Incompatible with life. Hydrops, stillbirth.
10. HbH Disease: 3 alpha gene deletions. HbH (β₄ tetramers) on electrophoresis. Moderate haemolytic anaemia.
11. Chipmunk Facies, Hair-on-End Skull: Bone marrow expansion from undertreated thalassaemia major.
12. Iron Overload in NTDT: Non-transfusional iron overload from increased intestinal absorption (hepcidin suppression).
13. Hypercoagulability in NTDT: Increased thrombotic risk, especially post-splenectomy.
14. Splenectomy Indications: Hypersplenism (increasing transfusion requirement > 200-250 mL/kg/year packed red cells).
15. Post-Splenectomy Care: Lifelong penicillin prophylaxis, vaccinations (pneumococcal, Hib, meningococcal), prompt treatment of fever (OPSI risk).

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Common Exam Questions (MCQ/SBA)

Q1: A 3-year-old child of Mediterranean descent presents with severe anaemia (Hb 6 g/dL), hepatosplenomegaly, and frontal bossing. Blood film shows microcytic hypochromic red cells, target cells, and nucleated red blood cells. HbA is absent, HbF is 95%. What is the most likely diagnosis?

• Answer: Beta-thalassaemia major (Cooley's anaemia).

Q2: A 25-year-old woman has Hb 11 g/dL, MCV 62 fL, RBC count 5.8 × 10¹²/L. Ferritin is 120 µg/L. Mentzer Index is 10.7. What investigation will confirm the diagnosis?

• Answer: Haemoglobin electrophoresis showing elevated HbA2 (> 3.5%) → Beta-thalassaemia trait.

Q3: What is the leading cause of death in well-transfused patients with beta-thalassaemia major?

• Answer: Cardiac iron overload causing cardiomyopathy, heart failure, and arrhythmias.

Q4: A patient with transfusion-dependent thalassaemia has a cardiac MRI T2* of 8 ms. What is the most appropriate management?

• Answer: Urgent intensive combination iron chelation therapy (e.g., deferoxamine + deferiprone). T2* less than 10 ms indicates critical cardiac iron overload.

Q5: What is the gold standard investigation for assessing cardiac iron overload in thalassaemia?

• Answer: Cardiac MRI T2* (T2-star).

Q6: Which iron chelator requires weekly FBC monitoring due to the risk of agranulocytosis?

• Answer: Deferiprone (Ferriprox).

Q7: A couple are both carriers of beta-thalassaemia trait. What is the risk their child will have beta-thalassaemia major?

• Answer: 25% (1 in 4) per pregnancy.

Q8: What is the only established curative treatment for beta-thalassaemia major?

• Answer: Allogeneic haematopoietic stem cell transplantation (HSCT).

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Viva Points

Opening Statement: "Thalassaemia is a group of inherited haemoglobinopathies characterised by reduced or absent synthesis of globin chains, resulting in globin chain imbalance, ineffective erythropoiesis, and chronic haemolytic anaemia. Beta-thalassaemia, caused by mutations in the HBB gene on chromosome 11, is the commonest clinically significant form, ranging from asymptomatic carriers (trait) to severe transfusion-dependent disease (thalassaemia major)."

Key Facts to Mention:

1. Epidemiology: Most common monogenic disorder worldwide. ~270 million carriers. Prevalent in Mediterranean, Middle East, South/Southeast Asia.
2. Pathophysiology: Reduced beta-globin → excess unpaired alpha-chains precipitate → ineffective erythropoiesis (dominant mechanism) + haemolysis.
3. Classification: Trait (heterozygous, HbA2 > 3.5%, asymptomatic), Intermedia (NTDT), Major (TDT, presents 6-24 months, requires lifelong transfusions).
4. Diagnosis: FBC (microcytic anaemia, high RBC count), blood film (target cells, nucleated RBCs), haemoglobin electrophoresis (HbA2 elevated in trait, HbF elevated in major), genetic testing (confirm, prenatal diagnosis).
5. Management: TDT requires (a) regular transfusions (pre-Hb target 9-10.5 g/dL), (b) lifelong iron chelation (deferasirox, deferiprone, or deferoxamine; target ferritin less than 1000 µg/L, cardiac T2* > 20 ms), (c) multidisciplinary monitoring (cardiac MRI annually, endocrine function, growth), (d) curative therapy (HSCT in suitable candidates - > 90% cure; gene therapy - betibeglogene autotemcel - emerging).
6. Complications: Iron overload (cardiac - leading cause of death, hepatic, endocrine - diabetes, hypogonadism, hypothyroidism, osteoporosis), infections (post-splenectomy, transfusion-transmitted), thrombosis (NTDT), alloimmunisation.
7. Prognosis: Modern management → median survival 50-60+ years (previously death in childhood). HSCT curative.
8. Prevention: Carrier screening, genetic counselling, prenatal diagnosis. Cyprus model: > 95% reduction in affected births.

Model Viva Answer:

Examiner: "Tell me about thalassaemia."

Candidate: "Thalassaemia is an inherited haemoglobinopathy caused by reduced or absent globin chain synthesis, leading to an imbalance in the alpha-to-beta globin ratio. This results in ineffective erythropoiesis - the major pathological mechanism - and chronic haemolytic anaemia. Beta-thalassaemia, caused by mutations in the HBB gene on chromosome 11, is the most clinically important form globally, with 270 million carriers worldwide, particularly in Mediterranean, Middle Eastern, and Asian populations.

Clinically, beta-thalassaemia ranges from asymptomatic carriers (trait) with mild microcytic anaemia and elevated HbA2 greater than 3.5%, to transfusion-dependent thalassaemia major presenting in infancy with severe anaemia, hepatosplenomegaly, and skeletal deformities if untreated.

Management of thalassaemia major involves lifelong regular blood transfusions targeting a pre-transfusion haemoglobin of 9 to 10.5 grams per decilitre, combined with iron chelation therapy to prevent cardiac, hepatic, and endocrine iron toxicity. Cardiac iron overload causing cardiomyopathy is the leading cause of death, and we monitor cardiac iron burden using T2-star MRI annually, with values below 10 milliseconds indicating critical overload requiring urgent intensive chelation.

Curative options include allogeneic haematopoietic stem cell transplantation, which achieves over 90% cure rates in optimal candidates, and gene therapy with betibeglogene autotemcel, recently approved by the FDA and EMA, which achieves transfusion independence in approximately 90% of patients."

Examiner: "What are the indications for splenectomy in thalassaemia?"

Candidate: "Splenectomy is indicated for hypersplenism causing increased transfusion requirements - typically when the annual packed red cell requirement exceeds 200 to 250 millilitres per kilogram body weight - or for massive splenomegaly causing mechanical symptoms. However, splenectomy carries significant risks including lifelong susceptibility to overwhelming post-splenectomy infection, particularly from encapsulated organisms like Streptococcus pneumoniae, and increased thrombotic risk especially in non-transfusion-dependent thalassaemia where hypercoagulability is already present.

Before splenectomy, we must ensure the patient is vaccinated at least 2 weeks prior with pneumococcal, Haemophilus influenzae type b, and meningococcal vaccines, and ideally delay surgery until age 5 to 6 years. Post-splenectomy, lifelong penicillin prophylaxis and prompt treatment of any febrile illness are essential to prevent overwhelming sepsis."

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Common Mistakes to Avoid

❌ Giving empirical iron to microcytic patients without checking ferritin: Could worsen iron overload in thalassaemia trait. Always measure ferritin first.

❌ Diagnosing iron deficiency based on MCV alone: Thalassaemia trait also causes microcytosis. Check Mentzer Index, ferritin, HbA2.

❌ Undertransfusing thalassaemia major: Pre-transfusion Hb less than 9 g/dL → bone marrow expansion, skeletal deformities, increased iron absorption. Target 9-10.5 g/dL.

❌ Not monitoring cardiac iron with T2 MRI*: Serum ferritin alone is inadequate. Cardiac T2* is gold standard. T2* less than 10 ms requires urgent action.

❌ Missing hypercoagulability in NTDT: NTDT patients have increased thrombotic risk, especially post-splenectomy. Consider anticoagulation.

❌ Forgetting genetic counselling in trait: Both parents must be tested. 25% risk of affected child if both carriers.

❌ Overlooking endocrine complications: Diabetes, hypogonadism, hypothyroidism, osteoporosis are common. Annual screening essential.

❌ Using wrong iron chelator without monitoring: Deferasirox - monitor renal function. Deferiprone - monitor FBC weekly (agranulocytosis risk).

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15. References

Primary Sources

1. Taher AT, Weatherall DJ, Cappellini MD. Thalassaemia. Lancet. 2018;391(10116):155-167. doi:10.1016/S0140-6736(17)31822-6. PMID: 28774421.

2. Langer AL. Beta-Thalassemia. 2000 Sep 28 [Updated 2024 Feb 8]. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. PMID: 20301599.

3. Kohne E. Hemoglobinopathies: clinical manifestations, diagnosis, and treatment. Dtsch Arztebl Int. 2011;108(31-32):532-540. doi:10.3238/arztebl.2011.0532. PMID: 21886666.

4. Brancaleoni V, Di Pierro E, Motta I, Cappellini MD. Laboratory diagnosis of thalassemia. Int J Lab Hematol. 2016;38 Suppl 1:32-40. doi:10.1111/ijlh.12527. PMID: 27183541.

5. Farmakis D, Porter J, Taher A, Domenica Cappellini M, Angastiniotis M, Eleftheriou A. 2021 Thalassaemia International Federation Guidelines for the Management of Transfusion-dependent Thalassemia. HemaSphere. 2022;6(8):e732. doi:10.1097/HS9.0000000000000732. PMID: 35928543.

6. Musallam KM, Cappellini MD, Porter JB, Farmakis D, Eleftheriou A, Angastiniotis M, Taher AT. TIF Guidelines for the Management of Transfusion-Dependent beta-Thalassemia. HemaSphere. 2025;9(3):e70095. doi:10.1002/hem3.70095. PMID: 40045934.

7. Locatelli F, Thompson AA, Kwiatkowski JL, et al. Betibeglogene autotemcel gene therapy for non-β0/β0 genotype β-thalassemia. N Engl J Med. 2022;386(5):415-427. doi:10.1056/NEJMoa2113206.

8. Farmakis D, Giakoumis A, Polymeropoulos E, Aessopos A. Pathogenetic aspects of immune deficiency associated with beta-thalassemia. Med Sci Monit. 2003;9(RA19-22). [Endocrine complications reference composite]

9. Anderson LJ, Holden S, Davis B, et al. Cardiovascular T2-star (T2*) magnetic resonance for the early diagnosis of myocardial iron overload. Eur Heart J. 2001;22(23):2171-2179. doi:10.1053/euhj.2001.2822.

10. Borgna-Pignatti C, Rugolotto S, De Stefano P, et al. Survival and complications in patients with thalassemia major treated with transfusion and deferoxamine. Haematologica. 2004;89(10):1187-1193. PMID: 15477202.

11. Cappellini MD, Taher AT, Motta I. Thalassemia and hypercoagulability. Hematology Am Soc Hematol Educ Program. 2025;2025(1):285-290. doi:10.1182/hematology.2025000716. PMID: 41348010.

12. Chui DHK, Fucharoen S, Chan V. Hemoglobin H disease: not necessarily a benign disorder. Blood. 2003;101(3):791-800. doi:10.1182/blood-2002-07-1975.

13. Olivieri NF, Nathan DG, MacMillan JH, et al. Survival in medically treated patients with homozygous beta-thalassemia. N Engl J Med. 1994;331(9):574-578. doi:10.1056/NEJM199409013310903.

14. Bollig C, Schell LK, Rucker G, et al. Deferasirox for managing iron overload in people with thalassaemia. Cochrane Database Syst Rev. 2017;8(8):CD007476. doi:10.1002/14651858.CD007476.pub3. PMID: 28809446.

15. Pennell DJ, Porter JB, Cappellini MD, et al. Deferiprone versus deferoxamine in thalassaemia major patients: cardiac protection. Eur Heart J. 2013;34(12):917-925. [Cardiac iron chelation reference]

16. Aydinok Y. Combination chelation therapy. Ann N Y Acad Sci. 2023;1529(1):33-41. doi:10.1111/nyas.15052. PMID: 37594980.

17. Sadelain M, Boulad F, Galanello R, et al. Therapeutic options for patients with severe β-thalassemia: the need for globin gene therapy. Hum Gene Ther. 2007;18(1):1-9. [HSCT outcomes reference]

18. Thompson AA, Walters MC, Kwiatkowski J, et al. Gene therapy in patients with transfusion-dependent β-thalassemia. N Engl J Med. 2018;378(16):1479-1493. doi:10.1056/NEJMoa1705342.

19. Cappellini MD, Viprakasit V, Taher AT, et al. A Phase 3 Trial of Luspatercept in Patients with Transfusion-Dependent β-Thalassemia. N Engl J Med. 2020;382(13):1219-1231. doi:10.1056/NEJMoa1910182.

20. Musallam KM, Rivella S, Vichinsky E, Rachmilewitz EA. Non-transfusion-dependent thalassemias. Haematologica. 2013;98(6):833-844. doi:10.3324/haematol.2012.066845.

21. Rund D, Rachmilewitz E. Beta-thalassemia. N Engl J Med. 2005;353(11):1135-1146. doi:10.1056/NEJMra050436.

22. Weatherall DJ. The inherited diseases of hemoglobin are an emerging global health burden. Blood. 2010;115(22):4331-4336. doi:10.1182/blood-2010-01-251348.

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Medical Disclaimer: MedVellum content is for educational purposes and clinical reference. Clinical decisions should account for individual patient circumstances. Always consult appropriate specialists and follow local guidelines. Thalassaemia management should be undertaken in specialist centres with multidisciplinary teams.

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Topic: Thalassaemia
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Citations: 22