Thalassaemia
Definition
Thalassaemia is a group of inherited blood disorders characterized by the reduced or absent synthesis of one or more of the globin chains that constitute the haemoglobin molecule. Haemoglobin, the oxygen-carrying protein within red blood cells, is a tetramer composed of four globin chains. In adults, the predominant form is Haemoglobin A (HbA), which consists of two alpha (α) and two beta (β) chains. As an autosomal recessive condition, the primary genetic defect in thalassaemia results in an imbalanced production of these globin chains, leading to two core pathological processes: ineffective erythropoiesis (defective red blood cell production in the bone marrow) and haemolysis (premature destruction of circulating red blood cells), which culminates in chronic anaemia of varying severity (1).
Epidemiology
Thalassaemia is the most common single-gene disorder in Malaysia, posing a significant public health challenge. The national carrier rate is estimated to be between 4.5% and 6.8%, meaning approximately 1 in every 20 Malaysians carries a thalassaemia gene, creating a large reservoir for severe forms of the disease (4, 5). According to the Malaysian Thalassaemia Registry report, there were 7,984 registered patients alive in 2018, a testament to improved survival with modern care but also an indicator of the significant healthcare burden (5). The distribution follows distinct ethnic and geographical lines, a crucial clue in clinical diagnosis. Malays form the majority of registered patients (63.95%), followed by the indigenous Kadazan-Dusun of Sabah (11.36%) and Chinese (11.75%) (5). In Peninsular Malaysia, HbE/β-thalassaemia is the most common severe genotype, particularly prevalent among Malays, reflecting gene flow from neighbouring Southeast Asian populations where the HbE gene is common. In contrast, Sabah has the highest number of patients per capita, where homozygous β-Thalassaemia Major is the predominant severe form, especially within the Kadazan-Dusun community, likely due to a higher frequency of a specific β-globin gene deletion and historical patterns of intermarriage within the community (4, 6). Globally, thalassaemia is most prevalent among populations of Mediterranean, South Asian, and Southeast Asian descent, a distribution that historically mirrors regions where malaria was endemic, as the carrier state is thought to confer a selective advantage against severe malaria (10).
Pathophysiology
The fundamental pathology of thalassaemia is the imbalance of globin chain synthesis, which triggers a cascade of cellular damage. In β-thalassaemia, deficient β-chain production leads to an excess of unpaired α-chains. These α-chains are highly unstable and insoluble, precipitating within red blood cell precursors (erythroblasts) in the bone marrow to form toxic intracellular inclusions (10). In α-thalassaemia, a lack of α-chains results in an excess of γ-chains during foetal life (forming Haemoglobin Barts) or β-chains postnatally (forming Haemoglobin H). While more soluble than free α-chains, these non-α chain tetramers are functionally useless for oxygen transport and are also unstable, eventually precipitating and causing red cell damage (10).
This imbalance drives two core destructive processes:
Ineffective Erythropoiesis: This is the hallmark of severe β-thalassaemia. The toxic globin precipitates induce severe oxidative stress, damaging the cell membranes and proteins of erythroblasts and triggering their premature death (apoptosis) within the bone marrow. This leads to a profound paradox: the bone marrow undergoes massive, frantic expansion (erythroid hyperplasia) in a desperate attempt to compensate for the chronic anaemia, yet the production of viable, functional red cells is severely impaired. This rampant marrow activity erodes and widens bone cortices, causing the classic skeletal deformities like "thalassaemic facies" (frontal bossing, maxillary overgrowth) and the "hair-on-end" appearance on a skull X-ray. It also leads to extramedullary haematopoiesis, where blood production occurs in the liver and spleen, contributing significantly to their enlargement (10).
Haemolysis: The few red cells that manage to mature and escape the bone marrow are abnormal. Laden with globin precipitates, they are rigid and their membranes are damaged. These defective erythrocytes are recognized as foreign and are rapidly cleared from circulation by macrophages, primarily in the spleen, a process known as extravascular haemolysis. This drastically shortens the red cell lifespan from a normal 120 days to as little as 30-50 days, perpetuating the state of chronic anaemia. This constant, high rate of red cell destruction causes persistent jaundice (due to high bilirubin turnover) and massive splenomegaly. The enlarged spleen can further worsen anaemia by sequestering a large volume of both normal and abnormal red cells (hypersplenism), creating a vicious cycle (9).
Clinical Presentation
The clinical presentation depends on the severity of the thalassaemia syndrome and, critically, the adequacy of management. A well-managed patient may appear almost normal, whereas an under-treated patient will display the classic, florid signs of the disease.
Diagnostic Clues: In an infant aged 3-6 months, the classic presentation of Transfusion-Dependent Thalassaemia (TDT) unfolds as protective foetal haemoglobin wanes. The houseman will encounter a child with progressive and marked pallor, increasing lethargy, poor feeding, and failure to thrive. The abdomen becomes progressively distended from developing hepatosplenomegaly. In an older child or adult, particularly of Chinese ethnicity, the combination of chronic moderate anaemia, persistent jaundice, and significant splenomegaly is highly suggestive of Haemoglobin H disease, a form of Non-Transfusion-Dependent Thalassaemia (NTDT).
Common Symptoms (>50%):
Profound fatigue, lethargy, and poor exercise tolerance due to chronic tissue hypoxia from anaemia.
Marked pallor of the skin, nail beds, and conjunctivae.
Jaundice (scleral icterus), which is typically mild to moderate and persistent, resulting from the chronic hyperbilirubinaemia of haemolysis.
Abdominal distension and a dragging sensation in the abdomen from progressive hepatosplenomegaly.
Less Common Symptoms (10-50%):
Shortness of breath on exertion.
Poor growth and delayed or absent puberty are classic signs of chronic anaemia and endocrine dysfunction from iron overload in inadequately treated children.
Bone pain, particularly in the long bones and back, or pathological fractures due to the combination of marrow expansion and severe osteoporosis.
⚠️ Red Flag Signs & Symptoms:
Severe dyspnoea, orthopnoea, or peripheral oedema: These are urgent signs of congestive heart failure, either from severe, high-output failure due to anaemia or, more ominously, from decompensated cardiomyopathy due to cardiac iron overload. This requires immediate assessment and careful management.
Fever in a splenectomised patient: This must be treated as a life-threatening medical emergency. The spleen is critical for clearing encapsulated bacteria; its absence leaves the patient vulnerable to overwhelming post-splenectomy infection (OPSI), which can progress to fatal septic shock within hours.
New-onset palpitations, pre-syncope, or syncope: These symptoms may indicate life-threatening cardiac arrhythmias secondary to myocardial siderosis and fibrosis, necessitating urgent cardiac evaluation.
Complications
Complications are multi-systemic and arise from the interplay of chronic anaemia, massive ineffective erythropoiesis, and, most importantly, iron overload from transfusions and increased gut absorption.
Cardiovascular: Iron-induced cardiomyopathy is the leading cause of death. Iron deposition in myocardial cells generates reactive oxygen species, disrupting mitochondrial function and leading to cell death, fibrosis, and ultimately, both systolic and diastolic dysfunction culminating in heart failure and arrhythmias. Pulmonary hypertension is a serious complication, especially in NTDT, driven by chronic haemolysis, endothelial dysfunction, and a hypercoagulable state.
Endocrine: The anterior pituitary gland is exquisitely sensitive to iron deposition, leading to a cascade of endocrinopathies. Hypogonadotropic hypogonadism causes delayed or arrested puberty and infertility. Iron damage to the pancreas leads to diabetes mellitus. Other common issues include hypothyroidism, hypoparathyroidism (causing hypocalcaemia and tetany), and adrenal insufficiency.
Hepatic: The liver is a primary site of iron storage. Chronic iron overload leads to progressive liver fibrosis and cirrhosis. This is often compounded by viral hepatitis (Hepatitis B or C) acquired from blood transfusions in the past. Patients with cirrhosis are at a significantly increased risk of developing hepatocellular carcinoma.
Skeletal: Patients suffer from severe osteoporosis due to a combination of factors: massive marrow expansion eroding bone, endocrine dysfunction (hypogonadism, hypothyroidism), and direct effects of iron on bone metabolism. This leads to a high risk of fragility fractures, chronic bone pain, and skeletal deformities.
Other: There is an increased risk of thromboembolism (venous and arterial), particularly in NTDT and post-splenectomy patients, due to a chronic hypercoagulable state. Chronic haemolysis leads to high bilirubin turnover, predisposing patients to the formation of pigment (bilirubinate) gallstones. Painful, chronic leg ulcers can occur, especially in NTDT.
Prognosis
With modern management, the prognosis for thalassaemia has been transformed. In the pre-transfusion era, death in early childhood was inevitable. Today, with regular, safe blood transfusions and effective iron chelation therapy, the prognosis is dramatically improved. Patients who are diagnosed early and adhere strictly to treatment can now survive well into their 5th or 6th decade, achieve normal development, pursue careers, and have families. The primary determinant of long-term survival and quality of life is the prevention and diligent management of cardiac iron overload, which remains the leading cause of mortality (1, 7). Compliance with chelation therapy is the single most important factor influencing a patient's outcome.
Differential Diagnosis
Iron Deficiency Anaemia (IDA)
This is the most common differential for any microcytic anaemia and must always be considered. It is suggested by the shared findings of low MCV and MCH. However, thalassaemia is more likely if the anaemia is disproportionately severe for the degree of microcytosis, or if it is accompanied by features of haemolysis like jaundice and splenomegaly. A serum ferritin test is the key differentiator; it is low in IDA, reflecting depleted iron stores, but is typically normal or high in thalassaemia due to chronic inflammation and iron loading (1).
Anaemia of Chronic Disease (ACD)
This can cause a normocytic or, in long-standing cases, microcytic anaemia. This should be considered in a patient with a known chronic inflammatory condition, such as rheumatoid arthritis, inflammatory bowel disease, or chronic kidney disease. The key distinguishing feature is the clinical context of an underlying inflammatory disorder. Iron studies in ACD are characteristic, showing a normal or high ferritin (as it is an acute phase reactant) but with low serum iron and low total iron-binding capacity (TIBC), reflecting iron sequestration (10).
Hereditary Spherocytosis
This is another common inherited haemolytic anaemia that can present with the triad of anaemia, jaundice, and splenomegaly. It is a key differential because of the overlapping signs of haemolysis. However, it is distinguished by a normocytic FBC with a characteristically high Mean Corpuscular Haemoglobin Concentration (MCHC), reflecting cellular dehydration. The definitive feature on the peripheral blood film is the presence of numerous small, dense, spherical red cells (spherocytes) without central pallor, which are not typical of thalassaemia (10).
Investigations
Investigations are guided by the Malaysian CPG for Management of Thalassaemia (1), progressing from screening to definitive diagnosis and long-term monitoring.
Immediate & Bedside Tests
Bedside ECG: This is mandatory and must be performed immediately in any thalassaemia patient presenting with chest pain, palpitations, syncope, or signs of heart failure. The goal is to immediately rule out life-threatening arrhythmias or signs of cardiac ischaemia/strain (the action), which are potentially fatal complications of severe anaemia or advanced cardiac iron overload (the rationale).
Diagnostic Workup
First-Line Investigations: The initial workup starts with a Full Blood Count (FBC) and Peripheral Blood Film (PBF). The FBC is crucial to identify the characteristic microcytic (MCV <80 fL) and hypochromic (MCH ≤27 pg) anaemia (the rationale), which serves as the primary screening indicator for thalassaemia as per the national screening programme (the action) (1). The PBF provides vital morphological clues, showing microcytic, hypochromic red cells with significant anisopoikilocytosis (variation in size and shape), numerous target cells, basophilic stippling, and, in severe forms, circulating nucleated red blood cells, which signify severe marrow stress.
Gold Standard: The definitive presumptive diagnosis is made with Haemoglobin Analysis via High-Performance Liquid Chromatography (HPLC) or Capillary Electrophoresis. This test is the cornerstone of diagnosis as it separates and quantifies the different haemoglobin fractions with high precision (the rationale), allowing for the accurate identification of specific thalassaemia syndromes like β-thalassaemia trait (elevated HbA2 >3.5%), β-thalassaemia major (predominantly HbF with absent or minimal HbA), or HbH disease (presence of a fast-moving HbH peak) (the action) (1).
Confirmatory Test: DNA analysis (Molecular Testing) is the ultimate confirmatory test that identifies the specific genetic mutation. It is essential to confirm the diagnosis of α-thalassaemia (as Hb analysis can be normal in carriers) and should be performed for all patients with a diagnosed thalassaemia disease to establish the exact genotype (the rationale). This information is critical for predicting disease severity, genetic counselling for the patient and family, and enabling prenatal diagnosis for at-risk couples (the action) (1).
Monitoring & Staging
Serum Ferritin: This is performed every 3 months in regularly transfused patients to track iron levels over time and guide chelation therapy (the action). While convenient, it must be interpreted with caution as it is an acute-phase reactant and can be falsely elevated by infection or liver inflammation. Crucially, it correlates poorly with cardiac iron deposition (the rationale) (1).
MRI T2* (Heart and Liver): This is the non-invasive gold standard for quantifying organ-specific iron deposition. An annual scan is essential for all TDT patients from age 10 onwards to directly and accurately measure cardiac and liver iron concentration (the rationale). The T2* value (a measure of signal decay time, which is shortened by iron) allows for the early detection of dangerous iron levels, enabling pre-emptive intensification of chelation therapy long before clinical heart failure develops (the action). A cardiac T2* <20ms indicates iron deposition and requires action (1).
Management
Management is lifelong, complex, and multidisciplinary, aiming to suppress ineffective erythropoiesis, meticulously manage iron overload, and treat complications according to the MOH CPG (1).
Management Principles
The management of thalassaemia focuses on two counterbalancing goals: maintaining adequate haemoglobin levels through regular blood transfusions to ensure normal growth, development, and quality of life, while diligently preventing and treating the inevitable and life-threatening iron overload that results from this very therapy.
Acute Stabilisation (The First Hour)
In a patient presenting with severe anaemic heart failure:
Airway/Breathing: Administer high-flow oxygen via a non-rebreather mask to maintain SpO2 >94% (the action). This is crucial to maximise arterial oxygen content and improve oxygen delivery to tissues, helping to alleviate the profound tissue hypoxia driven by the severe anaemia and cardiac compromise (the rationale).
Circulation: Secure IV access but administer fluids with extreme caution. The primary problem is often high-output cardiac failure, not hypovolemia. A gentle diuretic like IV Furosemide (e.g., 20-40mg) is often the first and most critical step to reduce the overwhelming preload on the failing heart (the action), as aggressive fluid boluses can precipitate acute pulmonary oedema (the rationale). A slow, cautious blood transfusion (e.g., 5ml/kg over 4 hours) should be commenced only once the patient is stabilized with diuretics.
Definitive Therapy
Blood Transfusion: This is the life-saving mainstay for TDT. The goal is to maintain a pre-transfusion haemoglobin of 9-10 g/dL using leucodepleted, phenotype-matched packed red cells (the action). Regular transfusions suppress the patient's own massive and ineffective erythropoiesis, which in turn prevents severe anaemia, promotes normal growth, suppresses bone deformities, and improves quality of life (the rationale) (1).
Iron Chelation Therapy: This is the cornerstone of survival in TDT. It is initiated after approximately 10-20 blood transfusions or when serum ferritin is consistently >1000 ng/mL (the action). Chelation therapy involves administering drugs that bind to iron, forming complexes that can be excreted from the body (in urine and/or faeces), thereby removing the excess iron deposited from transfusions and preventing fatal organ damage, particularly to the heart and liver (the rationale) (1). Options in Malaysia include:
Deferoxamine (DFO): The oldest chelator, given as a slow subcutaneous infusion over 8-12 hours, 5-7 nights a week.
Deferiprone (DFP): An oral agent taken three times a day, known for its excellent efficacy in removing cardiac iron.
Deferasirox (DFX): A convenient once-daily oral agent effective for both liver and cardiac iron.
Combination therapy (e.g., daily oral DFP combined with nightly DFO infusions) is a powerful strategy used for patients with severe iron overload, especially cardiac siderosis.
Haematopoietic Stem Cell Transplantation (HSCT): This is the only established curative therapy for thalassaemia. It involves replacing the patient's defective bone marrow with healthy stem cells from a donor, ideally an HLA-matched sibling. It is considered for young TDT patients before the onset of significant iron-related organ damage, as outcomes are best in this group (1).
Supportive & Symptomatic Care
Folic Acid: Daily supplementation (e.g., 5mg) is given to provide the necessary substrate for the massively expanded (though ineffective) red blood cell production in the bone marrow.
Nutrition: Advise a healthy, balanced diet. Crucially, patients should be educated to avoid iron-rich foods (like red meat and offal), iron-fortified cereals and vitamins, and high doses of Vitamin C (which can mobilize toxic iron forms) unless prescribed.
Bone Health: Proactive management is key. Monitor with DEXA scans and supplement with calcium and Vitamin D. Bisphosphonates may be required for established osteoporosis.
Vaccinations: Ensure patients, especially those who are splenectomised, are fully vaccinated against encapsulated organisms (S. pneumoniae, H. influenzae, N. meningitidis) and receive annual influenza vaccines (1).
Key Nursing & Monitoring Instructions
Strict monitoring of pre-transfusion haemoglobin levels to ensure the target of 9-10 g/dL is met.
For patients on Deferiprone, it is mandatory to monitor the Full Blood Count weekly due to the risk of neutropenia or agranulocytosis. The patient must be educated to stop the drug and seek immediate medical attention if they develop a fever or sore throat.
For patients on Deferasirox, monitor serum creatinine and liver function tests regularly as per protocol due to potential renal and hepatic toxicity.
Educate the patient and family on the critical importance of adherence to nightly subcutaneous Deferoxamine infusions if prescribed, including proper technique and site rotation to prevent skin reactions.
Inform the medical officer or specialist immediately if a splenectomised patient develops a fever >38°C, as this requires urgent assessment and empiric antibiotics.
Long-Term Plan & Patient Education
The long-term plan involves lifelong, regular follow-up in a dedicated multidisciplinary thalassaemia clinic, ideally with a haematologist, cardiologist, endocrinologist, specialist nurse, and social worker. Patient education is a continuous and vital process, focusing on empowering the patient to be an expert in their own condition. Key topics include the critical importance of adherence to transfusions and chelation, recognising the early symptoms of complications (e.g., signs of heart failure or diabetes), understanding the genetic basis of the disease for family planning, and accessing psychosocial support to manage the significant burden of a chronic illness.
When to Escalate
A house officer must recognize their limits and call for senior help in specific, high-risk situations.
Call Your Senior (MO/Specialist) if:
A patient presents with any signs of cardiac decompensation (heart failure, arrhythmia).
A splenectomised patient presents with a fever, regardless of how well they appear.
A patient on Deferiprone develops fever, sore throat, or has a neutrophil count <1.5 x 10⁹/L.
A patient has a serum ferritin that is persistently rising above 2500 ng/mL despite standard chelation, or a cardiac MRI T2* that has fallen to <20 ms (especially <10 ms, which is a critical value), as this requires urgent review and intensification of chelation therapy.
Referral Criteria:
Refer to Endocrinology for systematic annual screening and management of diabetes, hypothyroidism, hypoparathyroidism, or delayed puberty.
Refer to Cardiology for any abnormal ECG, echocardiogram, or MRI T2* result for expert interpretation and management.
Refer to a Genetic Counsellor for all newly diagnosed patients, carriers, and their partners for comprehensive counselling on reproductive risks and options, including prenatal diagnosis.
References
Ministry of Health Malaysia. (2024). Management of Thalassaemia (Second Edition). https://www.moh.gov.my/moh/resources/Penerbitan/CPG/Haematology/e-CPG_Management_of_Thalassaemia_(Second_Edition).pdf
Royal College of Obstetricians and Gynaecologists. (2014). Management of Beta Thalassaemia in Pregnancy. Green-top Guideline No. 66. https://www.rcog.org.uk/media/vz1g54xu/gtg_66_thalassaemia.pdf
National Institute for Health and Care Excellence. (2022). Luspatercept for treating anaemia in adults with beta-thalassaemia. Technology appraisal guidance [TA843]. https://www.nice.org.uk/guidance/ta843
George, E. (2001). Beta-Thalassemia Major in Malaysia, an On-Going Public Health Problem. Medical Journal of Malaysia, 56(4), 397-400. http://www.e-mjm.org/2001/v56n4/Beta-Thalassemia.pdf
Karunajeewa, Y., Ibrahim, H., & Ismail, F. D. (2020). Observational study on the current status of thalassaemia in Malaysia: a report from the Malaysian Thalassaemia Registry. BMJ Open, 10(6), e037974. https://bmjopen.bmj.com/content/10/6/e037974
Tan, J. A., Eng, K. H., & Lee, P. C. (2010). High prevalence of alpha-and beta-thalassemia in the Kadazandusuns in East Malaysia: challenges in providing effective health care for an indigenous group. Journal of biomedicine & biotechnology, 2010, 789012. [suspicious link removed]
Thalassaemia International Federation. (2021). Guidelines for the Management of Transfusion Dependent Thalassaemia (TDT) (4th ed.). https://thalassaemia.org.cy/wp-content/uploads/2022/04/TIF-Guidelines-for-the-Management-of-TDT-4th-Ed..pdf
Thalassaemia International Federation. (2017). Guidelines for the Management of Non Transfusion Dependent Thalassaemia (NTDT) (2nd ed.). https://thalassaemia.org.cy/wp-content/uploads/2017/10/NTDT-final-combined-1.pdf
Cappellini, M. D., & Taher, A. T. (2023). Beta-thalassemia. In T. W. Post (Ed.), UpToDate. Retrieved July 12, 2025, from https://www.uptodate.com/contents/beta-thalassemia
Muncie, H. L., & Campbell, J. S. (2024). Thalassemia. In StatPearls. StatPearls Publishing. Retrieved July 12, 2025, from https://www.ncbi.nlm.nih.gov/books/NBK545151/
