Thalassemia — Causes, Alpha & Beta Types, Symptoms & Treatment Guide — Symptoms, Causes & Treatment | MyMedicPlus

Thalassemia is a group of inherited haemoglobin disorders in which genetic mutations reduce or eliminate the production of one or more globin chain subunits of haemoglobin, leading to chronic haemolytic anaemia of varying severity. The two principal types are alpha-thalassemia (reduced alpha-globin chain production — predominantly from gene deletions on chromosome 16) and beta-thalassemia (reduced beta-globin chain production — predominantly from point mutations on chromosome 11). Both cause imbalanced globin chain synthesis, red blood cell destruction, and compensatory ineffective erythropoiesis with progressive bone marrow expansion. Thalassemia is most prevalent in Mediterranean countries, the Middle East, the Indian subcontinent, and Southeast Asia — geographic regions historically associated with malaria endemicity, as the heterozygous carrier state confers partial malaria protection. Approximately 300,000 infants with severe thalassemia are born globally each year.

Alpha-thalassemia results from deletions in the alpha-globin gene cluster (HBA1 and HBA2 on chromosome 16). The four clinical subtypes depend on the number of alpha genes affected: silent carrier (1 gene affected — no clinical effect), alpha-thalassemia trait (2 genes — mild microcytic anaemia), HbH disease (3 genes — moderate haemolytic anaemia), and Hb Bart's hydrops fetalis (4 genes — lethal in utero or shortly after birth). Beta-thalassemia results from over 200 point mutations in the HBB gene on chromosome 11, causing reduced (beta+) or absent (beta0) beta-globin production. Beta-thalassemia minor (trait) is the heterozygous carrier state with mild microcytosis; beta-thalassemia intermedia causes moderate anaemia without regular transfusion need; beta-thalassemia major (Cooley's anaemia) is the severe homozygous or compound heterozygous form requiring lifelong transfusions. Family history and ethnicity are the primary risk factors.

Beta-thalassemia major (most severe form): symptoms appear in the first year of life when foetal haemoglobin (HbF) declines. Severe hypochromic microcytic anaemia (Hb typically below 7 g/dL without treatment), pallor, jaundice, hepatosplenomegaly (from extramedullary haematopoiesis and haemolysis), frontal bossing and facial bone deformities (from bone marrow expansion), growth retardation, delayed puberty, recurrent infections, and high-output cardiac failure if untreated. Beta-thalassemia intermedia: moderate anaemia (Hb 7–10 g/dL), splenomegaly, bone changes, iron overload from increased gastrointestinal absorption — transfusion-independent but complications develop over decades. Thalassemia trait/minor: mild microcytic anaemia (Hb above 10 g/dL), often entirely asymptomatic and detected only on routine FBC or antenatal screening.

Full blood count (FBC) shows microcytic hypochromic anaemia with low MCV (below 75 fL) and MCH (below 25 pg) in thalassemia trait — often misidentified as iron deficiency. Peripheral blood film shows target cells, hypochromic red cells, and nucleated red blood cells in severe disease. Iron studies: serum ferritin, transferrin saturation — normal or elevated in thalassemia (unlike iron deficiency). Haemoglobin electrophoresis (or HPLC — high-performance liquid chromatography): the definitive diagnostic test. In beta-thalassemia major, HbA is absent or markedly reduced, with elevated HbF and HbA2 (above 3.5%). Alpha-thalassemia diagnosis requires molecular genetic testing (gap-PCR for common deletions). Prenatal diagnosis by chorionic villus sampling (CVS at 10–12 weeks) or amniocentesis (15–18 weeks) is offered when both parents are carriers.

Beta-thalassemia major requires regular red blood cell transfusions every 2–4 weeks to maintain pre-transfusion Hb above 9–10.5 g/dL, preventing ineffective erythropoiesis, bone disease, and cardiac failure. Chronic transfusions cause progressive iron overload, requiring iron chelation therapy: deferasirox (Exjade) 20–40 mg/kg/day oral; deferoxamine (Desferal) 25–40 mg/kg subcutaneous infusion 5–7 nights per week; deferiprone 25 mg/kg TDS oral — particularly effective for cardiac iron. Splenectomy reduces transfusion requirements in hypersplenism. Allogeneic haematopoietic stem cell transplantation (HSCT) from an HLA-matched sibling donor is potentially curative — best outcomes in younger patients with low ferritin and no hepatomegaly. Betibeglogene autotemcel (Zynteglo) — gene therapy using autologous haematopoietic stem cells transduced with a functional beta-globin gene — approved in EU (2019) and US (2022); achieves transfusion independence in >90% of patients with non-beta0/beta0 genotype. Luspatercept (Reblozyl) reduces transfusion burden in thalassemia by promoting late-stage erythropoiesis.

Untreated beta-thalassaemia major causes severe anaemia, cardiac failure from compensatory haematopoiesis, skeletal deformities from extramedullary haematopoiesis expanding facial bones, and death in childhood. Chronic blood transfusion prevents anaemia but causes progressive iron overload — each unit of blood deposits 200-250 mg of iron that cannot be excreted. Iron overload damages the heart (cardiomyopathy — leading cause of death in adults), liver (cirrhosis), and endocrine organs (diabetes mellitus, hypogonadism causing infertility, hypothyroidism, and osteoporosis). Iron chelation therapy with deferasirox, deferoxamine, or deferiprone is essential to prevent organ failure. Hepatitis C infection from older blood products compounds liver disease risk.

Carrier screening is the cornerstone of thalassemia prevention — offered to at-risk ethnic groups and all antenatal couples in high-prevalence regions. When both parents carry beta-thalassemia trait, each pregnancy has a 25% chance of beta-thalassemia major. Genetic counselling is essential for carrier couples to discuss reproductive options: natural conception with prenatal diagnosis, preimplantation genetic testing (PGT) with IVF, gamete donation, or adoption. National screening programmes in Mediterranean countries, Iran, and Southeast Asia have dramatically reduced the incidence of new thalassemia major births. For established patients: avoid iron supplementation without haematological assessment (worsens iron overload); maintain folic acid supplementation (5 mg daily); age-appropriate vaccinations (including pneumococcal, meningococcal, and annual influenza — particularly post-splenectomy); calcium and vitamin D supplementation for bone disease; and regular endocrine and cardiac monitoring.

Seek urgent medical assessment if a child has persistent pallor, jaundice, progressive abdominal swelling, or failure to thrive — these may indicate undiagnosed thalassemia major. Adults of at-risk ethnicities (South Asian, Mediterranean, Middle Eastern, Southeast Asian) with unexplained microcytic anaemia that does not respond to iron treatment should be evaluated for thalassemia trait. Consult a haematologist before pregnancy if you are a known thalassemia carrier, to assess the risk to offspring and arrange partner screening. Established patients should report any sudden worsening of anaemia, fever (post-splenectomy sepsis emergency), chest pain, or heart failure symptoms promptly. Regular haematology reviews, annual cardiac MRI (T2*), and endocrine assessments are essential for all patients on chronic transfusion therapy.