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Group III Anemias: Defects of Hemoglobin Synthesis
Group III anemias, or anemias due to defects of hemoglobin synthesis, comprise a broad category of inherited disorders in which the primary defect involves the qualitative or quantitative production of the globin chains of hemoglobin. In these conditions, normal hematopoiesis is impaired by genetic abnormalities that compromise hemoglobin synthesis or stability, resulting in chronic anemia of variable severity, often associated with hemolysis, altered erythroid maturation and systemic complications.
Hemoglobinopathies include quantitative defects of globin chains, such as thalassemias, which are often microcytic and hypochromic, and structural hemoglobin variants, which may have a normal MCV and very diverse manifestations.
The genetic defects may affect the quantity, as in thalassemias, or the quality, as in sickle cell disease and unstable hemoglobins, of globin chains.
The group of thalassemias includes numerous variants, distinguished according to the type of chain involved (α, β, δβ, γδβ, εγδβ) and molecular characteristics (regulatory, compound or mixed forms), each of which has different clinical, genetic and prognostic features. Other relevant conditions are sickle cell disease (sickle cell anemia) and hemoglobinopathies due to molecular instability.
Precise identification of these forms, their distinction from other congenital anemias and targeted management of complications represent a central challenge in clinical hematology.
Definition and general overview
Anemias due to hemoglobin defects are a group of inherited disorders in which red blood cell production is altered because of a genetic defect in hemoglobin synthesis or structure. The impairment may involve quantitative synthesis of globin chains, as in thalassemias, or their stability or function, as in sickle cell disease.
Common features include:
- Anemia of variable severity and morphology; microcytosis and hypochromia are typical particularly of thalassemias
- Signs of chronic hemolysis or ineffective hematopoiesis
- Presence of erythrocytes with altered morphology (poikilocytosis, target cells, sickle cells)
- Possible systemic manifestations (iron overload, splenomegaly, skeletal deformities)
These features clearly distinguish hemoglobin disorders from erythroblastopenias and from anemias due to maturation defects (group II).
Several forms are recognized within the thalassemia group, including β thalassemia, α thalassemia, δβ thalassemia, γδβ thalassemia, εγδβ thalassemia and mixed or compound forms. Hereditary persistence of fetal hemoglobin is a distinct but related condition, relevant to differential diagnosis and phenotype modulation. A summary of the differential features is available in the comparative table of thalassemias.
Etiology, pathogenesis and pathophysiology
The etiology of anemias due to hemoglobin defects consists of inherited genetic mutations that alter globin-chain synthesis or the structure of the hemoglobin molecule. In thalassemias, the defect involves reduced or absent production of one or more globin chains, predominantly α or β, whereas in sickle cell disease and unstable hemoglobins, mutations alter the amino acid sequence, conferring an unstable structure or a tendency toward pathological polymerization.
The main risk factors for clinical disease are genetic: belonging to populations with a high carrier prevalence (Mediterranean region, Africa, Middle East and Southeast Asia for thalassemias; sub-Saharan Africa and India for sickle cell disease) and familial transmission, whose pattern depends on the specific hemoglobinopathy: thalassemias and sickle cell disease are typically recessive or codominant, whereas some unstable hemoglobins are autosomal dominant. Risk increases with consanguinity or a family history of non-iron-deficiency microcytic anemia.
The pathogenesis of thalassemias is dominated by insufficient production of a specific globin chain, for example the β chain in β thalassemia, which causes an imbalance among the chains produced and accumulation of free chains. This causes oxidative damage, death of erythroid precursors in the bone marrow (ineffective erythropoiesis) and peripheral hemolysis. In hemoglobin S, polymerization under deoxygenated conditions deforms erythrocytes and causes vaso-occlusion. Other structural variants may instead alter stability, oxygen affinity or globin production without causing sickling.
From a pathophysiological perspective, thalassemias are characterized by ineffective erythropoiesis, microcytosis and variable hemolysis; structural hemoglobinopathies may instead cause hemolysis, altered oxygen affinity or vaso-occlusion with normal erythrocyte indices. Splenomegaly, erythroid expansion and iron overload depend on the specific disorder, severity and transfusion exposure.
Risk factors and prevention
The risk factors for hemoglobin disorders mainly involve carrier status for globin mutations, family history and belonging to ethnic groups with a high prevalence. Prevention and control of severe forms are based on carrier screening, genetic counseling for at-risk couples and, in selected settings, the option of prenatal diagnosis to identify severe forms during fetal life.
Some healthcare systems provide newborn or preconception screening in regions with high prevalence. Timely identification of carriers enables genetic counseling, information on reproductive risk and family planning based on informed, nondirective choices. At present, there are no pharmacological or environmental prevention strategies for these disorders because of their genetic nature.
Clinical manifestations
The clinical picture of anemias due to hemoglobin defects is extremely variable, depending on the mutation, the type and number of genes involved and the presence of associated variants. Onset may occur from childhood to adulthood, with manifestations ranging from mild chronic anemia and asymptomatic disease in heterozygous forms to transfusion-dependent and complicated syndromes in homozygous or compound forms.
In β thalassemia major and severe α thalassemias, symptoms include:
- Pallor, asthenia, mild jaundice due to chronic hemolysis
- Splenomegaly and sometimes hepatomegaly
- Bone deformities (typical facies, frontal bossing, maxillary hypertrophy)
- Growth delay, poor growth in children
- Symptoms of iron overload (heart disease, diabetes, skin pigmentation)
In sickle cell disease, the clinical picture is dominated by painful vaso-occlusive crises, hemolysis, susceptibility to infections and the risk of neurological or organ complications.
In thalassemia minor and in many carriers, the clinical picture may be mild or subclinical; unstable hemoglobins instead have variable severity.
Investigations and diagnosis
Diagnosis is based on a rational sequence of clinical and laboratory investigations. Suspicion arises in the presence of microcytic anemia not responsive to iron, sometimes associated with family history, splenomegaly or a history of hemolytic crises. The hematologic pattern depends on the defect: microcytosis with a relatively high red blood cell count chiefly suggests thalassemia, whereas many structural hemoglobinopathies have normal red cell indices.
The specific tests include:
- Hemoglobin electrophoresis (or HPLC) to identify abnormal fractions
- Molecular analysis to characterize mutations (β, α, δβ, γδβ, etc.)
- Ferritin measurement and assessment of iron status to distinguish iron deficiency anemias and monitor secondary iron overload
In unstable hemoglobins, stability tests (precipitation, Heinz bodies) and functional tests may be used. Prenatal diagnosis is possible by molecular analysis of chorionic villi or amniotic fluid.
The differential diagnosis includes deficiency anemias, sideroblastic anemias and other causes of microcytosis; distinction is based on hematologic data, response to iron, family pattern and genetic-molecular analyses.
Treatment and prognosis
The therapeutic management of hemoglobin disorders is closely related to the specific form, severity and patient age. In thalassemia major, treatment is based on regular transfusions, iron chelation therapy to prevent siderosis and assessment for hematopoietic stem cell transplantation in selected cases. In intermediate forms, agents that modulate globin synthesis may be used, for example hydroxyurea in thalassemia intermedia or sickle cell disease, together with nutritional support and monitoring of complications.
Among pharmacological options for thalassemias, luspatercept is authorized in specific adults with beta thalassemia according to its regulatory indication; mitapivat is authorized in the European Union for adults with anemia associated with alpha or beta thalassemia, in both transfusion-dependent and non-transfusion-dependent forms.
In mild forms, treatment is disease-specific: folic acid is reserved for cases with increased requirements or significant hemolysis, whereas vaccination and antibiotic prophylaxis depend on asplenia, splenectomy or indications specific to the individual hemoglobinopathy. Iron monitoring is indicated in patients at risk of overload or deficiency. Sickle cell disease: prevention of dehydration, pain management, hydroxyurea, transfusions and specific therapies as indicated.
Prognosis is extremely variable: severe forms require continuous treatment and carry a risk of cardiac, hepatic, pancreatic and endocrine complications, whereas mild forms have a benign course and normal life expectancy. Gene therapy and gene editing are no longer only experimental: authorized products exist for selected indications of transfusion-dependent beta thalassemia and sickle cell disease, available in specialized centers under strict criteria.
Complications
- Secondary siderosis (hepatic, cardiac, endocrine) due to iron overload from repeated transfusions
- Heart failure due to chronic anemia or iron overload
- Bone deformities in children due to marrow hyperplasia
- Recurrent infections due to functional asplenia or splenectomy
- Vaso-occlusive crises and organ damage in sickle cell diseases
- Complications of chelating drugs (renal toxicity, hepatic toxicity, allergic reactions)
- Progression to multiorgan failure in untreated or severe forms
Patients’ quality of life is strongly influenced by the need for continuous therapies, management of complications and the necessary psychological support, especially in childhood and adolescence.
- Taher AT, Musallam KM, Cappellini MD. β-Thalassemias. N Engl J Med. 2021;384(8):727–743.
- Origa R. β-Thalassemia. Genet Med. 2017;19(6):609–619.
- Ware RE, de Montalembert M, Tshilolo L, Abboud MR. Sickle cell disease. Lancet. 2017;390(10091):311–323.
- Kassebaum NJ, et al. The global burden of anemia. Hematol Oncol Clin North Am. 2016;30(2):247–308.
- Musallam KM, Rivella S, Vichinsky E, Rachmilewitz EA. Non-transfusion-dependent thalassemias. Haematologica. 2013;98(6):833–844. doi:10.3324/haematol.2012.066845.
- Kattamis A, Kwiatkowski JL, Aydinok Y. Thalassaemia. Lancet. 2022;399(10343):2310–2324. doi:10.1016/S0140-6736(22)00536-0.
- Bain BJ, Daniel Y, Henthorn J, de la Salle B, Hogan A, Roy NBA, et al.; British Society for Haematology. Significant haemoglobinopathies: A guideline for screening and diagnosis. Br J Haematol. 2023;201(6):1047-1065.
- Forget BG, Bunn HF. Classification of the disorders of hemoglobin. Cold Spring Harb Perspect Med. 2013;3(2):a011684.
- Thom CS, Dickson CF, Gell DA, Weiss MJ. Hemoglobin variants: biochemical properties and clinical correlates. Cold Spring Harb Perspect Med. 2013;3(3):a011858.
- Higgs DR, Engel JD, Stamatoyannopoulos G. Thalassaemia. Lancet. 2012;379(9813):373–383.
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