Thalassemia is caused by abnormalities in one or more globin genes, leading to reduced or absent synthesis of one or more types of globin chains. This results in an imbalance in the proportions of globin chains, which causes insufficient production of normal hemoglobin and aggregation of excess globin chains within red blood cells, forming unstable products. The former causes microcytic hypochromic anemia, while the latter can result in ineffective erythropoiesis (destruction within the bone marrow) and hemolysis. Based on the type of globin chain affected, thalassemia is classified into α, β, δ, δβ, and γβ types, with α-thalassemia and β-thalassemia being the most common. This disease has a global distribution but is more prevalent in Southeast Asia and the Mediterranean region.
α-Thalassemia
α-Thalassemia primarily arises from the deletion of α-globin genes, though, in rare cases, it can result from point mutations or the deletion of a few nucleotide bases in α-globin genes. These changes lead to complete or partial insufficiency in α-globin chain synthesis and exhibit autosomal recessive inheritance. In healthy individuals, two α-globin genes are inherited from each parent (αα/αα). The severity of clinical manifestations depends on the number of defective α genes inherited. A reduction in α-chain synthesis decreases the production of the three hemoglobin types that contain this chain (HbA, HbA2, and HbF). In fetuses and neonates, this leads to an excess of γ chains, resulting in the formation of Hb Bart (γ4). In adults, excess β chains form hemoglobin H (HbH, β4). Both types of hemoglobin have a high affinity for oxygen, resulting in tissue hypoxia. Because γ4 and β4 tetramers are soluble, noticeable precipitation in bone marrow erythrocytes does not occur, so α-thalassemia generally does not lead to severe ineffective erythropoiesis. However, HbH can precipitate in aged red blood cells, forming inclusions (target cells), which reduce red cell deformability and damage the membrane, resulting in hemolysis in the spleen. Based on the number of deleted α genes and clinical presentations, α-thalassemia is divided into the following types:
Silent Carrier (1 Abnormal α Gene) and Trait (2 Abnormal α Genes)
Silent carriers inherit one defective α gene (α/αα), maintaining an α/β chain synthesis ratio of 0.9, close to the normal ratio of 1.0, with no clinical symptoms. Individuals with the trait inherit two defective α genes (α/α or αα/--), with an α/β chain synthesis ratio of approximately 0.6. They exhibit no significant clinical symptoms but present with microcytic hypochromic red blood cells. A small proportion of red blood cells may contain HbH inclusions after incubation with brilliant cresyl blue. Hemoglobin electrophoresis typically does not show abnormalities.
HbH Disease (3 Abnormal α Genes)
In this condition, the α/β chain synthesis ratio ranges from 0.3 to 0.6, and individuals experience mild to moderate anemia. Affected children appear healthy at birth and develop normally until anemia and splenomegaly become apparent after the first year of life. Events such as pregnancy, infections, or the use of oxidative drugs can exacerbate the anemia.
Hypochromia is pronounced, with the presence of target cells and reduced red cell osmotic fragility. HbH inclusions are frequently observed, and hemoglobin electrophoresis reveals HbH accounting for 5% to 40% of the total hemoglobin.
Hb Bart Hydrops Fetalis Syndrome (4 Abnormal α Genes)
The complete absence of α chains leads to γ chains self-associating into Hb Bart (γ4). This is the most severe form of α-thalassemia. Fetuses often die in utero between 30 and 40 weeks of gestation. In rare cases, if the fetus is not stillborn, the neonate is poorly developed, with pale skin, generalized edema, mild jaundice, significant ascites, pleural and pericardial effusions, marked hepatosplenomegaly, and severe cardiac hypertrophy. This condition is referred to as Hb Bart Hydrops Fetalis Syndrome. Most affected neonates die within hours of birth due to severe hypoxia. Hemoglobin electrophoresis shows Hb Bart levels accounting for 80% to 100% of the total hemoglobin.
β-Thalassemia
β-Thalassemia occurs due to defects in β-globin genes, leading to inhibited synthesis of β-globin chains. This condition follows an autosomal recessive inheritance pattern. In healthy individuals, one β-globin gene is inherited from each parent. If an abnormal β-globin gene is inherited, the synthesis of β-globin chains is reduced or absent, directly impairing the production of normal hemoglobin. This results in a relative excess of α chains, with compensatory synthesis of γ chains and δ chains, leading to increased levels of HbA2 (α2δ2) and HbF (α2γ2). Unbound α chains are highly insoluble and precipitate within the precursor and progeny red blood cells, causing damage to the red cell membrane. This leads to destruction of erythroid precursor cells in the bone marrow (ineffective erythropoiesis). The few red blood cells that enter peripheral circulation are rapidly cleared by the spleen and liver. Progressive splenomegaly exacerbates anemia through blood pooling and dilution. Severe anemia caused by these processes results in elevated erythropoietin (EPO) levels in circulation, significantly increased erythropoiesis in bone marrow and extramedullary hematopoietic tissues, skeletal deformities, and varying degrees of growth and metabolic disturbances. Based on the severity of anemia, β-thalassemia is categorized into the following types:
Mild β-Thalassemia
Symptoms are often absent, or patients may present with mild anemia and occasional mild splenomegaly. Hemoglobin electrophoresis typically reveals HbA2 levels greater than 3.5% (4%–8%), with normal or slightly increased HbF levels (less than 5%).
Intermediate β-Thalassemia
This form is characterized by moderate anemia and splenomegaly. Occasional mild skeletal deformities and delayed sexual maturation may occur. Laboratory findings include target cells and microcytic hypochromic red blood cells. HbF levels may reach up to 10%.
Severe β-Thalassemia (Cooley's Anemia)
Individuals with this form are homozygous for the β-globin gene mutation. Symptoms begin to appear around six months after birth and include progressive pallor, worsening anemia, jaundice, and hepatosplenomegaly. Growth and development are delayed, and complications such as osteoporosis and pathological fractures may occur. Affected individuals may develop a characteristic facial appearance, including frontal bossing, a depressed nasal bridge, and widened orbital spacing. Hemoglobin levels are often below 60 g/L, and microcytic hypochromic anemia is evident. Target cells account for 10%–35% of red blood cells. Erythroid hyperplasia is significant in the bone marrow, with increased intracellular and extracellular iron deposition. Hemoglobin electrophoresis shows HbF levels as high as 30%–90%, with HbA levels often below 40% or completely absent. Red cell osmotic fragility is significantly reduced. X-ray imaging reveals widened diploic spaces in the skull, cortical thinning, and prominent trabecular striations, resembling "hair-on-end" patterns.
Thalassemia is a genetic disorder, and clinical diagnosis is not difficult when family history, clinical symptoms, and laboratory findings are considered. Genetic analysis using methods such as restriction endonuclease mapping, PCR, and oligonucleotide hybridization probes can provide further confirmation of the diagnosis.
Treatment and Prevention
Treatment primarily involves symptomatic management based on disease type and severity. Common measures include red blood cell transfusion, prevention and treatment of secondary hemosiderosis, and splenectomy. Proactive management of factors inducing hemolysis, such as infections, is essential. Splenectomy is appropriate for patients with increased transfusion requirements, hypersplenism, or significant splenic compression-related symptoms. Patients with iron overload may require iron chelation therapy. For transfusion-dependent adult patients with β-thalassemia, treatment with red cell maturation agents like the TGF-β inhibitor luspatercept has been used. Allogeneic hematopoietic stem cell transplantation remains the only curative treatment for β-thalassemia and should be the first-line option for patients with an HLA-matched donor. Gene therapy has also been successfully reported in some cases.
Although mild cases do not require treatment, marriages between individuals with mild β-thalassemia may result in offspring with severe forms of the disorder. Prenatal genetic diagnosis is an effective approach to preventing the birth of fetuses with severe thalassemia and plays a crucial role in genetic counseling and health.