Thalassemias

Overview

• Core defect: an imbalance between the amounts of α and β globin chains, from mutations that partially or completely inactivate production of one chain.
• Typical lesions: α-thalassemia is usually caused by full deletions of α genes; β-thalassemia is usually caused by point mutations in the β genes.
• Clinical categories:
  • Minor: very mild or no symptoms; symptoms (if any) come from hypoproliferation, not hemolysis.
  • Intermedia: between minor and major; not necessarily transfusion-dependent.
  • Major: severe; patients are transfusion-dependent; hemolysis is prominent.
• Hemoglobin phenotype naming: some forms are named for the abnormal hemoglobin produced (e.g., Hemoglobin Barts, Hemoglobin H).

β-Thalassemia

• Genetics: only 2 β-globin alleles (chromosome 11). β0 mutation = absent β globin; β+ mutation = decreased β globin. Can be heterozygous, homozygous, or compound with another β mutation.
• Distribution: most common in southern Europe (Mediterranean); also SE Asia, Africa, Middle East.
• Pathophysiology: deficiency of β chains leaves a relative excess of free α chains that are highly unstable and precipitate as intracellular inclusions (α chains do not form stable α4 tetramers) → ineffective erythropoiesis (intramedullary hemolysis) plus destruction of circulating RBCs. Anemia drives ↑ EPO and more ineffective erythropoiesis, splenomegaly (worsens anemia by sequestration), marrow expansion (frontal bossing, thinned cortex, fractures), and iron overload (transfusions plus increased gut iron absorption).

β-Thalassemia Major and Intermedia

• β-thal major (Cooley): β0/β0 (no HbA), or severe β0/β+ or β+/β+ (β+ alleles make some HbA); transfusion-dependent from childhood.
• β-thal intermedia (β+/β0 or β+/β+): β markedly ↓ so HbA ~15 to 65%; non-transfusion-dependent (NTDT) that may convert to TDT later in life.
• Timing: severe anemia develops between 2 and 12 months (first year of life). Infants are well at birth because HbF predominates and needs no β chains (HbA2 is only a trace at birth and rises afterward) and little HbA is needed; disease emerges once the γ to β switch would normally occur (~6 months) but β is not produced. Typically Mediterranean descent.
• Diagnosis: hemoglobin electrophoresis/HPLC showing predominant HbF with absent or minimal HbA.

β-Thalassemia Minor (trait: β0/β or β+/β)

• Genetics: heterozygous, one normal allele and one usually β+ allele.
• Clinically asymptomatic: enough β chains pair with α, so little excess free α chain is left to precipitate.
• Labs: microcytic (MCV ~60 to 70); may be non-anemic or only mildly anemic; RBC count typically very elevated; RDW normal (all cells uniformly microcytic/hypochromic).
• Diagnosis in adults: hemoglobin electrophoresis with HbA2 >3.5% (delta chains increase, HbA2 rises to ~4 to 8%). Not seen in newborns (fetal Hb predominates).
• Management: usually no treatment; partner testing is important given the risk of a severely affected child.

β-Thalassemia Intermedia: Complications and Splenectomy

• Complications increase with age: osteoporosis; hypercoagulability and thrombosis; pulmonary hypertension; cerebrovascular disease; leg ulcers; extramedullary hematopoiesis (hepatosplenomegaly, paraspinal masses); HCC; renal abnormalities; iron overload.
• Splenectomy (formerly standard of care) increases the chance of thrombosis, silent cerebral infarcts, extramedullary hematopoiesis, pulmonary hypertension, leg ulcers, iron-related endocrinopathies, and infection; only do it if absolutely necessary.
• Key management shift: transfusions reduce complications in β-thal intermedia, so follow patients and convert them from NTDT to TDT when disease progresses.

Transfusion, Iron Overload, and Chelation

• Chronic regular transfusion (TDT): for severe anemia (Hb <7 g/dL, as in thal major or progressive β-thal intermedia) or symptoms of worsening disease pathology.
• Intermittent transfusion (NTDT): individualized to symptoms, baseline Hb, acute illness, surgery, and pregnancy, not a fixed Hb <6 g/dL cutoff; in pregnancy when transfusing aim Hb about 10 g/dL (e.g., β-thal intermedia, non-deletional HbH).
• Goals: correct severe anemia, prevent complications of anemia, and control ineffective erythropoiesis.
• Transfusion targets: regular transfusions to keep pre-transfusion Hb ~9 to 10.5 g/dL every 2 to 4 weeks.
• Alloimmunization: risk is high (up to 37%); prevent by transfusing C, E, and Kell matched RBCs.
• Iron loading: each unit of packed RBCs carries ~275 mg iron; there is no excretion mechanism, so iron deposits in liver (fibrosis, cirrhosis, HCC), heart (heart failure, arrhythmia), and endocrine organs (hypogonadotropic hypogonadism, low bone density, diabetes, hypothyroidism, hypoparathyroidism, growth failure).

• Iron chelators: deferasirox (oral, preferred), deferoxamine (parenteral), deferiprone (oral).

Disease-Modifying and Curative Therapy (β-thalassemia)

• Hydroxyurea: can raise HbF in β-thal intermedia and may improve Hb in a few patients, and may reduce transfusion needs in some NTDT patients, though the evidence is largely observational (no large randomized trials).
• Luspatercept (Reblozyl): modified activin receptor type IIB (ActRIIB) fusion protein that binds TGF-β superfamily ligands (e.g., GDF11) to reduce SMAD2/3 signaling → ↓ erythroid hyperplasia and ↑ RBC differentiation. In transfusion-dependent β-thalassemia (phase 3 BELIEVE) it significantly reduced transfusion requirements vs placebo. FDA Nov 2019 for β-thalassemia (also approved for MDS-RS). Side effects: headache, bone/joint pain, fatigue, dizziness, thrombosis, hypertension.
• Mitapivat (Pyrukynd): pyruvate kinase activator. ENERGIZE phase 3 in non-transfusion-dependent α/β-thalassemia (Kuo, Lancet 2025) met its primary endpoint (Hb increase ≥1.0 g/dL in 42% vs 2% placebo); ENERGIZE-T in TDT also met its transfusion-reduction endpoint; FDA approved Dec 2025 (Aqvesme) for anemia in adults with α- or β-thalassemia (TDT and NTDT), boxed warning for hepatocellular injury with REMS liver monitoring. Also approved Feb 2022 for PK deficiency (Pyrukynd).
• Splenectomy: can improve Hb but carries increased risk of infection, thromboembolism, and pulmonary hypertension; increasing reluctance to use it.
• Allogeneic HSCT: an established curative option; approved autologous gene therapies (beti-cel/Zynteglo, exa-cel/Casgevy) are also potentially curative in eligible TDT patients. Pretransplant organ function and iron status are important prognosticators; younger patients do better; best outcomes with a matched sibling donor (overall survival ~90 to 95%, thalassemia-free survival ~85 to 90%). Non-myeloablative regimens and alternative-donor options are evolving: well-matched unrelated-donor HSCT is accepted at experienced centers, whereas cord blood and haploidentical approaches remain more investigational.
• Gene therapy:
  • Gene addition (beti-cel, Zynteglo): lentiviral vector encoding adult Hb A^T87Q; achieves transfusion independence in TDT β-thalassemia with adverse events typical of myeloablative conditioning; well tolerated in pediatric and adult patients. FDA Aug 2022 for transfusion-dependent β-thalassemia.
  • Gene editing (exa-cel, Casgevy): targets BCL11A to raise fetal hemoglobin; FDA expanded Jan 2024 for transfusion-dependent β-thalassemia (age ≥12), then to age ≥2 in July 2026.

α-Thalassemia

• Distribution: mostly SE Asia and West Africa.
• Defect: decreased production of α globin chains. There are 4 α alleles (2 on each chromosome 16); ~90% of cases are deletions and ~10% are non-deletional mutations (e.g., Constant Spring).
• Chain consequences:
  • In the fetus, low α means excess γ chains combine as Hb Barts (γ4), which has very high O2 affinity → hypoxia and increased erythropoietic drive.
  • After ~6 months and in adulthood, excess β chains form β4 tetramers (HbH), which are very unstable and toxic and cause hemolysis and ineffective erythropoiesis.

α-Thalassemia: Details

• Why the electrophoresis is normal in α-thal trait: in β-thalassemias the β-chain proportions change, so electrophoresis percentages change; in α-thalassemia the β-chain proportions do NOT change, so the ratios of HbA to HbA2 to HbF stay normal. (Sandwich analogy: α chains are the bread; reducing bread does not change the filling ratio, just the number of sandwiches.)
• HbH disease diagnosis: Hb usually 7 to 11 (as low as 3 to 4); low MCV ~50 to 60 and low MCH; high RDW; brilliant cresyl blue stain shows β4 inclusions precipitating on the cell membrane; HPLC shows a fast-moving HbH peak (~5 to 40%); confirm with hemoglobin identification plus molecular studies.
• Hb Barts hydrops fetalis: extramedullary hematopoiesis (hepatosplenomegaly), interference with organogenesis (congenital anomalies, impaired cognitive development), and increased placental size (maternal preeclampsia, hypertension, bleeding, retained placenta). Most common in SE Asia, China, Greece, Turkey, Cyprus. Can be treated in utero with exchange transfusions as early as ~18 weeks, then every ~3 weeks, to reverse anemia and reduce hydrops and preterm delivery; survivors may have growth retardation, neurodevelopmental delay, and limb abnormalities; after delivery HSCT can be considered for cure.
• Atypical α-thalassemias:
  • ATRX syndrome (α-thalassemia X-linked intellectual disability): mutations in ATRX on the X chromosome (a chromatin-remodeling protein); X-linked; craniofacial and genital anomalies, developmental delay in young boys; α-thalassemia (mild HbH disease) in ~75%.
  • ATR-16 syndrome: contiguous deletion of both α genes on the distal short arm of chromosome 16; α-thalassemia plus intellectual disability; variable phenotype.
  • α-thalassemia-MDS: acquired α-thalassemia in myelodysplastic syndrome.

Distinguishing the Trait (labs)

• Mentzer index (MCV/RBC count): <13 favors thalassemia trait; >13 favors iron deficiency.
• β-thal trait: ↑ HbA2 (>3.5%); microcytic with ↑ RBC count; Mentzer <13.
• α-thal trait: normal HbA2 (key to distinguish from β-thal); DNA testing required for diagnosis.

High Yield (thalassemia)

• β-thal trait: ↑ HbA2 (>3.5%), microcytosis with high RBC count, normal RDW, Mentzer <13.
• α-thal trait: normal HbA2; diagnose by DNA testing.
• HbH disease (3-gene α deletion): moderate hemolysis with HbH on electrophoresis.
• Hb Barts hydrops fetalis (4-gene α deletion): lethal in utero unless treated with intrauterine transfusion.
• β-thal major (Cooley): transfusion-dependent, iron overload; HSCT or gene therapy curative.
• Cis vs trans 2-gene α-thal trait: cis (Asian, αα/−−) is more concerning for offspring (HbH or Hb Barts).
• Transfusion target: pre-transfusion Hb ~9 to 10.5 g/dL; start chelation once ferritin >1000 ug/L or after ~20 units.
• Luspatercept: for β-thal and MDS-RS; beti-cel and exa-cel approved for transfusion-dependent β-thalassemia.
• Splenectomy: increasing reluctance because of thrombosis and infection risk.