Thalassaemias

• Thalassaemia is an inherited failure to make enough of one of the globin protein chains of adult haemoglobin, so the red cells that are made are small, pale and short-lived, producing chronic microcytic, hypochromic anaemia.
• Alpha thalassaemia comes from losing or inactivating some of the four alpha-globin genes on chromosome 16: one gene gives a silent carrier, two give alpha thalassaemia trait, three give HbH disease, and four produce lethal Hb Bart's hydrops fetalis. ^[3]
• Beta thalassaemia comes from mutations in the beta-globin gene on chromosome 11: heterozygotes have thalassaemia minor (trait), while homozygous or compound heterozygous severe mutations produce thalassaemia major (transfusion-dependent) or thalassaemia intermedia.
• Diagnosis is built on a full blood count and film, iron studies to exclude iron deficiency, and haemoglobin separation; molecular testing confirms alpha deletions and atypical cases.
• Transfusion-dependent thalassaemia requires a lifelong transfusion programme plus iron chelation, with splenectomy, erythropoiesis-stimulating drugs, stem-cell transplant and gene therapy used in selected patients.
• Prevention centres on carrier detection in pregnancy, partner screening and prenatal diagnosis, because beta thalassaemia is autosomal recessive; where both parents are carriers, planning a pregnancy needs prior counselling and testing.

By the end of this page you should be able to:

1. Explain how imbalanced globin chain production causes anaemia and its complications.
2. Classify alpha and beta thalassaemia by genetic lesion and severity, and link each genotype to its clinical picture.
3. Recognise the blood-film, red-cell index and Mentzer index clues that point to thalassaemia rather than iron deficiency.
4. Interpret haemoglobin electrophoresis in thalassaemia carriers and in HbH disease.
5. Outline the transfusion and iron-chelation programme of transfusion-dependent thalassaemia, including monitoring targets.
6. Describe the curative and novel options: stem-cell transplant, gene therapy and luspatercept.
7. Explain screening, carrier counselling and prenatal diagnosis.
8. Recognise the main complications and the priorities when resources are limited.

Thalassaemias are named by the chain that is underproduced: alpha, beta, and much rarer gamma, delta, delta-beta and epsilon-gamma-delta-beta. Alpha and beta are by far the most important clinically. They are usually recessive.

Clinically, patients are best split by what they need rather than by genotype alone. In transfusion-dependent thalassaemia (TDT), regular transfusions are required to survive and develop normally. In non-transfusion-dependent thalassaemia (NTDT), patients are anaemic but do not need lifelong regular transfusion, although they may need transfusion during illness, pregnancy or surgery. ^[1] This split decides follow-up: TDT brings iron overload and chelation, while NTDT brings chronic haemolysis, increasing intestinal iron absorption and its own complication set.

Thalassaemia is one of the commonest monogenic diseases worldwide. Population studies place the global prevalence of thalassaemia between 1.5% and 20%, with alpha thalassaemia at 5% to 20% and beta thalassaemia at around 1.6%. ^[3] It is concentrated in malaria-endemic regions: the Mediterranean, Middle East, South and Southeast Asia and sub-Saharan Africa. The carrier state probably persisted because heterozygotes have a survival advantage against malaria. Migration now carries the disease worldwide, so in countries where it was once rare it is increasingly seen in migrant communities. ^[2]

In some areas the burden is very high: thalassaemia mutations are common enough that carrier detection is a major public-health activity in, for example, Southeast Asia, where alpha-thalassaemia carrier rates can be 30% to 40% in parts of Thailand. ^[3] Family history alone is an unreliable guide, so community screening matters.

The alpha-globin genes are duplicated: two on each chromosome 16, so four in total (HBA1 and HBA2). ^[3] Most alpha thalassaemia comes from deletions of one or more of these genes (alpha-zero deletions remove both genes on a chromosome; alpha-plus deletions remove one). Non-deletional (point) mutations also occur. ^[1][3]

Beta thalassaemia comes from a wide range of mutations of the single beta-globin gene (HBB) on chromosome 11: point mutations, frameshifts, splicing defects and promoter mutations. ^[3] They are grouped as beta-zero, which abolish beta-chain production, and beta-plus, which reduce but do not abolish it.

Risk is increased by:

• ancestry from a high-prevalence region;
• consanguineous marriage, which raises homozygosity;
• family history, although many carriers are asymptomatic and undiagnosed;
• for severe alpha disease, both parents being carriers of an alpha-zero deletion.

The core problem is chain imbalance.

1. Reduced or absent globin synthesis. Fewer normal adult haemoglobin molecules are assembled.
2. Unpaired chain precipitation. The chain in excess (beta chains in alpha thalassaemia, alpha chains in beta thalassaemia) aggregates and precipitates, damaging the developing and circulating red cell.
3. Ineffective erythropoiesis. Most affected precursors die in the marrow before release; erythroid activity is hugely increased but yields few mature cells.
4. Haemolysis. Surviving cells are destroyed early, mainly in the spleen.
5. Compensatory changes. Erythropoietin rises, marrow expands, and extramedullary haematopoiesis can develop in liver, spleen and bones.

Extramedullary haematopoiesis produces the classical bony changes of severe disease: frontal bossing, maxillary overgrowth, dental malocclusion and osteoporosis, plus hepatosplenomegaly. It can form paravertebral masses that compress the cord.

Iron overload has two separate causes. In TDT, each unit of red cells adds a large load of iron and the body has no natural excretion route, so iron accumulates. In NTDT, anaemia and hypoxia suppress hepcidin, increasing intestinal iron absorption even without transfusion. Iron catalyses free-radical damage, so sustained overload damages the heart, liver, endocrine glands and skeleton. ^[1]

Patients with thalassaemia minor are usually well. Anaemia is mild (or absent) and often found incidentally on a full blood count, or it presents as tiredness or poor exercise tolerance. Some are mistakenly treated for iron deficiency. ^[4]

Thalassaemia intermedia presents with moderate anaemia, often worsening during infection, pregnancy or growth spurts. Fatigue, jaundice, abdominal discomfort from a large spleen, and bone pain are common.

Thalassaemia major declares itself in the first 6 to 12 months of life, when fetal haemoglobin falls and adult haemoglobin should take over. There is progressive pallor, poor feeding, failure to thrive, jaundice, irritability and recurrent infections. Without treatment, hepatosplenomegaly, growth failure and the characteristic facial bone changes develop. ^[3]

Look for:

• pallor, icterus and growth failure in children;
• tachycardia and flow murmurs from anaemia;
• hepatosplenomegaly;
• frontal bossing, depressed nasal bridge and maxillary prominence from marrow expansion;
• leg ulcers in older patients;
• features of iron overload: skin pigmentation, diabetes, short stature, delayed puberty.

Pregnancy can temporarily worsen anaemia in both TDT and NTDT.

The film in thalassaemia trait and disease shows:

• microcytosis and hypochromia;
• target cells (codocytes) and often elliptocytes;
• basophilic stippling and, in iron deficiency-like states, pencil cells;
• in HbH disease, "golf-ball" cells with multiple HbH inclusions seen with supravital stain (brilliant cresyl blue). The Thalassaemia International Federation guideline regards detection of HbH inclusion bodies as the hallmark finding. ^[1]

Key numbers for distinction:

• MCV and MCH are low, often strikingly so for the degree of anaemia.
• RDW is usually normal in thalassaemia, whereas it is high in iron deficiency because of mixed cell sizes. ^[4]
• RBC count tends to be raised or normal in thalassaemia relative to the haemoglobin, whereas it is low in iron deficiency.

The Mentzer index is the ratio of MCV (in fL) to the red-cell count (in million per microL). A value under 13 favours thalassaemia trait, while a value of 13 or more favours iron deficiency. ^[4] It is only a screen: it misclassifies many patients, particularly where iron deficiency coexists, and where possible it should be followed by HbA2 measurement or HPLC. ^[4]

Other red-cell indices (England-Fraser, Green-King and the rest) exist; none is perfect, and they all depend on the analyser. ^[4]

Separation and measurement of haemoglobin fractions is the basis for identifying beta-thalassaemia carriers. ^[1]

• Beta thalassaemia minor: HbA2 is raised above 3.5%, often with a small rise in HbF. ^[4]
• Beta thalassaemia major or severe intermedia: mainly HbF, with little or no HbA.
• HbH disease: a fast-moving band (HbH, beta4) on electrophoresis.
• Hb Bart's hydrops fetalis: Hb Bart's (gamma4) is the main haemoglobin.
• Alpha thalassaemia trait: HbA2 and HbF are usually normal, so the diagnosis often rests on a low MCV with a normal HbA2, exclusion of iron deficiency and, when needed, DNA analysis. ^[1]

Modern labs use HPLC or capillary electrophoresis, which are more reliable than simple electrophoresis for separating HbA2 and for picking up variant haemoglobins such as HbE.

Iron deficiency is the commonest cause of microcytic anaemia worldwide, and it must always be excluded in the work-up of hypochromic microcytosis. ^[1]

Iron deficiency tends to show:

• low serum ferritin;
• high total iron-binding capacity and low transferrin saturation;
• high RDW;
• a Mentzer index of 13 or more; ^[4]
• response to iron therapy. ^[4]

Thalassaemia trait tends to show:

• normal or high ferritin (it is not a deficiency state);
• normal RDW;
• target cells and a raised RBC count for the haemoglobin;
• a Mentzer index under 13; ^[4]
• raised HbA2 in beta trait, or a low MCV with normal HbA2 and normal iron in alpha trait. ^[4]

Where iron deficiency coexists, for example after repeated infections in a carrier, the indices can be misleading. The safe sequence is: treat confirmed iron deficiency first, then recheck; if the MCV stays low with normal iron studies, measure HbA2 or arrange DNA testing. Inflammation, anaemia of chronic disease, sideroblastic anaemia and lead poisoning also produce microcytosis and should be kept in mind. ^[4]

Diagnosis of thalassaemia should be considered in anyone with hypochromic microcytic anaemia, and iron deficiency must be excluded in the work-up. ^[1] A useful diagnostic sequence:

1. Full blood count and film.
2. Iron studies (ferritin, serum iron, TIBC, transferrin saturation).
3. Haemoglobin separation (HPLC or electrophoresis), including HbA2 and HbF.
4. Molecular testing: for alpha deletions, methods such as gap-PCR, reverse dot blot or MLPA; beta-globin sequencing for atypical beta cases or when ancestry is not high risk. ^[1]

Alpha thalassaemia carrier status particularly needs molecular confirmation, because routine indices can be normal and the HbA2 is not raised. ^[1] A beta carrier does not need molecular testing for diagnosis, though it is useful for prenatal diagnosis. ^[1] Gene triplication or quadruplication should also be considered when a heterozygous beta patient has an intermedia phenotype. ^[1]

Severity is defined by the need for transfusion rather than by genotype tables:

• TDT: confirmed thalassaemia with transfusion criteria met (below).
• NTDT: anaemia (often Hb 70-100 g/L) without fixed transfusion need; transfusion used only at times. ^[3]
• For TDT, treatment is planned in specialist centres with a multidisciplinary team: haematology, paediatrics or adult medicine, iron-chelation nurse, endocrinology, cardiology and psychosocial support. ^[1]

For TDT the aims are simple to state and hard to deliver lifelong:

• enough transfusion to support growth, energy and suppression of ineffective erythropoiesis;
• not so much as to provoke dangerous iron overload;
• effective, tolerable iron chelation from early in life;
• early detection and treatment of complications (heart, liver, endocrine, bone). ^[1][2]

Blood transfusion is decided on confirmed diagnosis plus:

• Laboratory criterion: haemoglobin under 70 g/L on two occasions more than two weeks apart, after excluding other causes such as infection; or
• Clinical criterion, irrespective of haemoglobin: haemoglobin above 70 g/L with any of significant symptoms of anaemia, poor growth or failure to thrive, pathological fractures or facial changes from excessive intramedullary haematopoiesis, or clinically significant extramedullary haematopoiesis. ^[1]

Once started, transfuse every 2 to 4 weeks, keeping the pre-transfusion haemoglobin above 90-105 g/L, or 110-120 g/L if cardiac complications are present, and the post-transfusion haemoglobin below 140-150 g/L. ^[1]

Practical standards that protect the patient:

• confirmed diagnosis before any transfusion, with informed consent;
• extended red-cell antigen typing at least for D, C, c, E, e and Kell before the first transfusion, with RBC genotyping where available; ^[1]
• ABO- and Rh(D)-compatible units at every transfusion, and units compatible for C, c, E, e and Kell wherever possible;
• antibody screening and cross-match (electronic cross-match where regulated) before each transfusion;
• leucodepleted packed red cells, pre-storage filtered where available, washed cells for patients with severe allergic reactions;
• records of antibodies, reactions and annual iron loading. ^[1]

Starting transfusions based only on haemoglobin is now thought to miss morbidity: clinical features such as poor growth, bone changes and vital signs should prompt transfusion too, and there is evidence that late transfusion increases alloimmunisation. ^[2]

Iron overload is inevitable once regular transfusion begins, because humans cannot excrete excess iron. Iron chelation is highly effective: it improves survival, lowers heart failure risk and reduces morbidity from transfusional iron overload. ^[1]

Monitoring drives dosing:

• serum ferritin every 1 to 3 months, aiming for 500-1000 microg/L; ^[1]
• liver iron concentration (LIC) by MRI: normal up to 1.8 mg/g dry weight, with sustained levels above 15 mg/g dry weight linked to worsening prognosis; total body iron can be estimated as 10.6 times LIC; ^[1]
• cardiac iron by T2-star MRI: above 20 ms every 2 years, 10-19 ms yearly, below 10 ms every 6 months, with urgent intensification when it is under 10 ms; ^[1]
• organ function (heart, liver, endocrine) screened regularly. ^[1]

Three chelators are licensed:

• Deferoxamine: parenteral, no minimum age. In children, doses are started low and titrated, and the limit often quoted is up to 40 mg/kg on 5-7 days a week; high doses in young children caused bone toxicity and sensorineural hearing loss in the past. ^[2]
• Deferiprone: oral, three divided doses, 75-100 mg/kg a day (FDA-approved regimens include 75-99 mg/kg in two divided doses). It is useful for cardiac iron and is the chelator that can be started early in children, though it requires regular blood counts because of neutropenia and agranulocytosis. ^[2]
• Deferasirox: oral once daily, up to 28 mg/kg a day in TDT, from age 2 years. It is the most commonly used paediatric chelator for practical reasons, but renal function, creatinine and proteinuria need monitoring. ^[2]

In practice dose and drug are chosen by iron burden, organ distribution on MRI, side effects, cost and age, not by age alone. Cardiac iron lags behind liver iron and is rare before 8 years. Chelation response is dose- and exposure-dependent, so adherence is a clinical priority. Over-chelation risks drug toxicity and should be avoided, particularly when MRI is unavailable. ^[1][2]

Children carry higher iron intake per kilogram for the transfusion they receive, so they should not automatically get lower doses, but children with low or absent iron accumulation need careful dosing. ^[2]

Chronic haemolysis increases folate consumption, so folic acid supplementation is commonly used in thalassaemia. Trace minerals and vitamins may also need attention. The main nutritional clinical issue is that adult heights are achievable with good transfusion and chelation, while poor control produces short stature and osteoporosis. ^[2]

Splenectomy is used when hypersplenism worsens cytopenias, or when transfusion requirements rise sufficiently. It improves red-cell survival and reduces transfusion need. The risks are significant: postsplenectomy sepsis from encapsulated organisms, so vaccination and, in many centres, antibiotic prophylaxis are standard, and young children are splenectomised as late as feasible. Splenectomy is particularly relevant in HbH disease. ^[2][3]

Luspatercept is a fusion protein that traps ligands in the TGF-beta superfamily and promotes erythroid maturation. It is approved for TDT in adults and reduces transfusion burden: in the BELIEVE trial, 21.4% of treated patients (vs 4.5% on placebo) had at least a 33% fall in transfusion requirement in weeks 13-24, with the effect seen in any 12-week period in 70.5% vs 29.5%. ^[1] Side effects include bone pain, arthralgia, dizziness, hypertension and hyperuricemia; hypertension was reported in 10.7% and thromboembolic events in 3.6%. ^[1] It should only be considered in patients needing regular transfusion aged 18 years or older. ^[1] It is not a cure and does not remove the need for chelation.

Allogeneic haematopoietic stem-cell transplant is the established curative option for thalassaemia major: more than 3000 transplants have been performed. In an EBMT survey of 1061 matched-sibling transplants, long-term overall survival was about 91% and thalassaemia-free survival about 83%. ^[1] Transplant should be offered early, before iron-overload damage, if a suitable donor is available: an HLA-identical sibling is best, with matched unrelated donors used when compatibility is high. ^[1] Myeloablative conditioning is standard. Transplant is also cost-effective compared with lifelong transfusion and chelation. ^[1]

Gene therapy aims to provide durable cure by correcting haematopoietic stem cells. Two approaches exist: gene addition with a viral vector and gene editing (CRISPR/Cas9 to reactivate fetal haemoglobin or repair the defect). Lentiviral gene therapy (adding a working beta-globin gene) is the most mature, approved in the USA, Europe and elsewhere as a one-off treatment for eligible patients. Treated patients are followed for 15 years for long-term safety and durability. ^[1][2] Independence from transfusion is achieved in many but not all patients, and availability remains restricted.

Iron overload remains the dominant threat: heart failure, cirrhosis, hepatocellular carcinoma, growth failure, delayed puberty and multiple endocrine deficits (diabetes, hypothyroidism, hypoparathyroidism, hypogonadism). ^[1]

Cardiac involvement is the lethal complication. Iron deposition reduces myocardial compliance and systolic function, with arrhythmia and heart failure. T2-star MRI predicts risk well, and chelation can rapidly normalise labile iron while storage iron clears over months to years. ^[1]

Endocrine damage is common in poorly chelated children: growth hormone deficiency, hypogonadism, diabetes mellitus and hypothyroidism.

Bone disease includes osteoporosis from marrow expansion and hypogonadism, and the facial and skull changes of untreated major disease.

Infection risk rises after splenectomy and in transfused patients (Yersinia is a particular chelation-related concern).

Gallstones occur from chronic haemolysis.

Pulmonary hypertension can complicate NTDT.

Ineffective erythropoiesis itself drives skeletal changes before transfusion starts.

With modern transfusion, chelation and complication screening, survival into late adulthood is expected and quality of life is good. Where these are unavailable, death in adolescence or early adulthood from heart failure or severe anaemia is still common, which is why resource differences matter so much. ^[2]

Thalassaemia is autosomal recessive, so the centre of prevention is identifying carriers before or early in pregnancy.

• Carrier detection: full blood count showing a low MCV/MCH with normal iron studies, followed by HbA2 measurement or HPLC. In pregnancy, screening programmes usually test in the first trimester. ^[1][4]
• Partner screening: if one partner is a carrier, the other must be tested before any risk counselling. ^[3]
• Counselling: when both parents are carriers, each pregnancy carries a risk of an affected child, a carrier child or an unaffected non-carrier child, in autosomal recessive inheritance. Decisions about prenatal diagnosis are for the couple.
• Prenatal diagnosis: chorionic villus sampling or amniocentesis with DNA analysis in high-risk pregnancies. For Hb Bart's hydrops fetalis, early identification allows informed decisions. ^[3]
• Newborn screening for haemoglobinopathies exists in some countries and identifies severe forms early.
• Family outreach: once a case is diagnosed, siblings and relatives should be offered testing.

Screening is the most cost-effective intervention in thalassaemia and is far cheaper than lifelong treatment.

Children: initiation of transfusion is based on clinical as well as laboratory criteria, and facial bone deformity is no longer accepted. Growth is monitored closely. Start chelation late rather than early to avoid bone toxicity, but do not delay too long once accumulation begins. Cardiac MRI can usually wait until around 8 years in well-chelated children. ^[2]

Pregnancy: minor and intermedia patients may develop worse anaemia and need transfusion; genetic counselling and carrier testing of the partner are essential. ^[2]

** Older adults:** cardiac iron and endocrine disease dominate; ensure monitoring continues lifelong.

Much of the world's thalassaemia burden sits where transfusion and chelation are inconsistent. Practical priorities:

• Diagnose early with a full blood count, film and RDW; the Mentzer index and simple iron studies (ferritin if available) can guide care where HPLC is not. ^[4]
• Treat confirmed iron deficiency first, but do not withhold transfusion from children with clinical criteria. ^[1][2]
• Keep blood safe: ABO/Rh compatibility, leucodepletion where possible, record antibodies and reactions. ^[1]
• Chelation choices are driven by availability and cost; deferiprone is cheaper, deferoxamine requires pumps, deferasirox is once daily but costly. ^[2]
• Where MRI is unavailable, serum ferritin trends plus transfusion history and, if possible, non-transferrin-bound iron estimates guide chelation; beware both under- and over-chelation. ^[1][2]
• Splenectomy can reduce transfusion needs where chelators are scarce, but infection risk must be managed. ^[2]
• Referral pathways to a transplant centre should be known in advance. ^[1]
• Population carrier screening and prenatal diagnosis are the only sustainable answer in high-prevalence settings. ^[3]

• Thalassaemia is underproduction of globin chains causing chronic microcytic hypochromic haemolytic anaemia.
• Alpha: 4 genes on chromosome 16; deletion count determines phenotype from silent carrier to lethal Hb Bart's hydrops.
• Beta: HBB mutations produce minor, intermedia or major disease.
• HbH disease comes from loss of 3 alpha genes; HbH inclusion bodies are its hallmark on supravital staining.
• Beta minor is diagnosed by HbA2 above 3.5%; carrier RDW is usually normal.
• Iron deficiency must always be excluded in microcytic anaemia; ferritin and RDW help, and the Mentzer index under 13 favours thalassaemia but is not diagnostic.
• TDT transfusion criteria include Hb under 70 g/L on two occasions two weeks apart, or clinical criteria above 70 g/L. ^[1]
• Transfuse every 2-4 weeks with pre-transfusion Hb 90-105 g/L (110-120 if cardiac disease) and post-transfusion under 140-150 g/L.
• Ferritin target 500-1000 microg/L; LIC normal up to 1.8 mg/g dry weight and dangerous above 15; cardiac T2-star under 10 ms is high risk. ^[2]
• Chelators: deferoxamine up to 40 mg/kg on 5-7 days/week; deferiprone 75-100 mg/kg/day; deferasirox up to 28 mg/kg/day in TDT.
• Luspatercept reduces transfusion burden in adult TDT but needs monthly blood-pressure awareness; HSCT cures most eligible patients; gene therapy is a one-off curative option.
• Complications are dominated by iron overload: heart, liver, endocrine, bone.
• Prevention rests on carrier testing, partner testing and prenatal diagnosis.

Iron deficiency anaemia; haemolytic anaemias; sickle cell disease; anaemia of chronic disease; haematopoietic stem-cell transplantation; gene therapy for haemoglobinopathies; prenatal diagnosis for Mendelian disorders.