Beta Thalassemia Major

Beta thalassaemia major is severe transfusion dependent anaemia from absent beta globin chain synthesis.

• Homozygous or compound heterozygous HBB mutations (beta 0 / beta 0 or severe beta+), autosomal recessive; carriers in Mediterranean, Middle East, South and Southeast Asia, Africa.
• Presents at 6 to 24 months with severe anaemia as HbF declines.
• Pathophysiology: excess alpha chains precipitate causing ineffective erythropoiesis, haemolysis, and marrow expansion.
• Complications: iron overload (transfusional and increased absorption), skeletal deformity, hypogonadism, diabetes, osteoporosis, heart failure and arrhythmia, hepatic fibrosis, thrombosis, infections.

• Pallor, failure to thrive, jaundice, hepatosplenomegaly, irritability.
• Thalassaemic facies (frontal bossing, maxillary overgrowth), bone pain.
• Without transfusion: death in early childhood.
• Iron overload: bronzing, delayed puberty, heart failure.

• Severe microcytic hypochromic anaemia (haemoglobin 3 to 7 g/dL), target cells, nucleated red cells, reticulocytosis.
• Haemoglobin electrophoresis/HPLC: HbF 20 to 100%, absent or reduced HbA, raised HbA2.
• HBB sequencing; alpha globin gene status (modifies phenotype).
• Ferritin, liver and cardiac T2* MRI, endocrine screen (glucose, TSH, calcium, PTH, gonadotropins), echocardiography, hepatitis B/C, HIV, red cell antigen typing.
• Prenatal diagnosis in at risk couples.

• Regular transfusion every 2 to 4 weeks (leucodepleted, phenotype matched) to maintain pretransfusion haemoglobin 9 to 10.5 g/dL.
• Iron chelation from ferritin over 1000 µg/L or after 10 to 20 units: deferasirox 20 to 40 mg/kg daily, deferiprone 75 to 100 mg/kg/day in three doses (monitor neutrophils weekly), deferoxamine 40 to 50 mg/kg over 8 to 12 hours SC 5 to 7 nights weekly; combined therapy for cardiac siderosis (T2* under 20 ms).
• Haematopoietic stem cell transplantation from HLA matched sibling donor before iron damage (cure 90% in low risk children); haploidentical and unrelated donors in expert centres.
• Gene therapy: betibeglogene autotemcel and exagamglogene autotemcel (CRISPR) as transfusion independence strategies.
• Luspatercept 1 to 1.25 mg/kg SC every 3 weeks reduces transfusion burden in adults.
• Splenectomy for hypersplenism with rising transfusion need (after age 5, vaccinate, prophylactic penicillin, thromboprophylaxis).
• Endocrine replacement (insulin, levothyroxine, sex steroids, growth hormone), calcium and vitamin D, bisphosphonates for osteoporosis, folic acid 5 mg daily, hepatitis B vaccination.
• Annual monitoring of ferritin, liver iron, cardiac T2*, glucose, thyroid, bone density, audiology, ophthalmology.