Thalassemias: Alpha & Beta

What goes wrong in thalassemia

A quantitative defect. In the thalassemias, α- or β-globin chains are made in normal form but reduced amount. Less hemoglobin per cell produces a microcytic, hypochromic anemia, and the unpaired partner chains either precipitate or pair into abnormal tetramers, destroying red cells in the marrow (ineffective erythropoiesis) and in the circulation (hemolysis). Hemoglobinopathies such as HbS are the opposite problem: a normal amount of a structurally abnormal chain. Carrier states cluster where falciparum malaria was endemic (the Mediterranean, Africa, the Middle East, South and Southeast Asia), because heterozygosity protects against severe malaria.

Laboratory signature. Thalassemia trait causes microcytosis out of proportion to the anemia, with target cells and basophilic stippling, a normal or high RBC count, a normal RDW and normal iron studies. The Mentzer index (MCV divided by RBC count in millions/μL) below 13 favors thalassemia; above 13 favors iron deficiency.

Iron deficiency lowers HbA2 and can hide β-thalassemia trait: replete iron first, then repeat electrophoresis.

Alpha thalassemia

Genetics. Each chromosome 16 carries two α-globin genes (αα/αα), and α-thalassemia usually results from gene deletions. Severity tracks the number of genes lost. Because α chains are needed both before and after birth, the most severe form strikes the fetus.

Silent carrier and trait. One deletion causes no anemia. Two deletions cause mild microcytic anemia with target cells, but adult electrophoresis is normal (HbA2 and HbF are not raised, unlike β-thalassemia trait), so α-thal trait is diagnosed by excluding iron deficiency and confirmed by DNA testing. Newborns with trait show a little Hb Barts (γ₄) on the screen, which disappears as β chains replace γ chains.

Cis vs trans. Cis deletions (--/αα, both genes lost from one chromosome) are common in Southeast Asian ancestry. When both parents carry a cis deletion, each passes the empty chromosome half the time, so a pregnancy has a 25% (1/2 × 1/2) chance of Hb Barts hydrops. Trans deletions (-α/-α), typical of African ancestry, always transmit one working α gene, so offspring cannot have Hb Barts.

HbH disease. With one α gene left, excess β chains form β₄ tetramers (HbH). HbH is unstable and binds O₂ very tightly; it precipitates into inclusions that give a golf-ball pattern on brilliant cresyl blue staining and appears as a fast-moving band on electrophoresis. Patients have chronic moderate hemolytic anemia, splenomegaly, jaundice and gallstones, worsened by oxidant drugs and infection.

Hb Barts hydrops fetalis. With no α genes, fetal γ chains form γ₄ tetramers whose extreme O₂ affinity prevents oxygen delivery, causing severe fetal hypoxia, high-output heart failure and hydrops. Embryonic Hb Portland (ζ₂γ₂), which needs no α chains, sustains the fetus in early gestation. Death usually occurs in utero or soon after birth unless intrauterine transfusions are given, and the mother is at risk of preeclampsia and obstetric hemorrhage.

Beta thalassemia

Genetics and mechanism. The β-globin gene (HBB, chromosome 11) is usually disrupted by point mutations rather than deletions: splice-site mutations are common, along with promoter and nonsense mutations. β⁰ alleles make no β chain; β⁺ alleles make a reduced amount. Unpaired α chains cannot form stable tetramers and precipitate inside erythroid precursors, so β-thalassemia is dominated by ineffective erythropoiesis in the marrow, with additional hemolysis. Because fetal hemoglobin (α₂γ₂) needs no β chains, disease appears only after birth.

β-Thalassemia minor. One affected allele (β/β⁰ or β/β⁺) causes mild microcytic anemia with target cells and a high RBC count but few symptoms. HbA2 (α₂δ₂) rises above 3.5% because δ chains take the place of missing β chains, sometimes with slightly raised HbF. No treatment is needed, and iron should not be given without proven deficiency.

β-Thalassemia major. β⁰/β⁰ or severe β⁺ disease appears around 6 months of age as HbF falls, with severe anemia (hemoglobin often below 7 g/dL), failure to thrive, and jaundice. Anemia drives EPO, and the expanding marrow thins cortical bone: crew-cut (hair-on-end) skull radiographs, frontal bossing and maxillary overgrowth (chipmunk facies). Extramedullary hematopoiesis enlarges the liver and spleen. The smear shows target cells and nucleated RBCs; electrophoresis shows very high HbF with HbA absent (β⁰/β⁰) or scant. Survival depends on regular transfusion.

β-Thalassemia intermedia. Moderate anemia (hemoglobin about 7–10 g/dL) without regular transfusion needs, from milder β⁺ alleles or modifiers that ease the chain imbalance, such as coinherited α-thalassemia or high HbF. Ineffective erythropoiesis releases erythroferrone, which suppresses hepcidin, so gut iron absorption rises and iron accumulates even without transfusions. Extramedullary masses, gallstones, leg ulcers and thrombosis are common.

Complications and treatment

Transfusion. Transfusion-dependent β-thalassemia is treated with RBCs every 2–5 weeks to keep the pre-transfusion hemoglobin around 9–10.5 g/dL, which also suppresses ineffective erythropoiesis and prevents bone deformity; folate is supplemented. Splenectomy is reserved for hypersplenism that raises transfusion needs.

Iron overload. Each unit of RBCs adds about 200–250 mg of iron that the body cannot excrete. Iron deposits in the heart (cardiomyopathy and arrhythmias, the leading cause of death), the liver (fibrosis, cirrhosis) and endocrine glands (diabetes, hypogonadism, hypothyroidism, growth failure). Ferritin and MRI T2* of heart and liver guide chelation.

• Deferoxamine: subcutaneous or IV infusion; ototoxicity, retinopathy, and Yersinia infection because the iron-bound drug acts as a siderophore.
• Deferasirox: oral; kidney and liver injury, GI upset.
• Deferiprone: oral; agranulocytosis, so the ANC is checked weekly.

Aplastic crisis. Patients with shortened red cell survival, such as those with HbH disease or β-thalassemia intermedia, rely on constant high marrow output. Parvovirus B19, the cause of the slapped-cheek rash of erythema infectiosum, infects erythroid progenitors through the P antigen and halts production for about 7–10 days, causing abrupt, severe anemia with reticulocytes near zero; transfusion bridges the gap.

Cure. Allogeneic stem cell transplant from a matched sibling can cure transfusion-dependent thalassemia, and gene therapies either add a functional β-globin gene or edit the BCL11A enhancer to raise HbF.