Beta-Thalassemia
(Mediterranean Anemia, Cooley Disease)

Article written and reviewed by Dr Luca Moretti

Beta-thalassemia is the most clinically relevant form of the thalassemia syndromes and comprises a group of genetic disorders characterized by reduced (beta+) or absent (beta0) synthesis of the beta-globin chains of adult hemoglobin (HbA). This condition creates an imbalance between alpha- and beta-chain production, with consequences of variable severity for erythropoiesis and red blood cell survival; these consequences are marked in clinically significant forms, whereas they are generally mild in the trait.

In historical terminology and clinical practice, beta-thalassemia major is often called Mediterranean anemia or Cooley disease. These terms reflect both the typical geographic distribution of the disease, which is highly prevalent in the Mediterranean basin, and the name of pediatrician Thomas Benton Cooley, who first described its most severe variant in the early decades of the twentieth century. Today, the term “Mediterranean anemia” properly refers only to the major, transfusion-dependent form, whereas “beta-thalassemia” also includes intermediate and minor forms.

Clinical manifestations are extremely heterogeneous and range from asymptomatic forms (trait, or beta-thalassemia minor), through intermediate phenotypes, to severe transfusion-dependent forms (beta-thalassemia major, or Mediterranean anemia, Cooley disease). The historical terminology major/intermedia/minor remains descriptive, but contemporary management increasingly uses the functional distinction between transfusion-dependent thalassemia (TDT) and non-transfusion-dependent thalassemia (NTDT), which does not correspond perfectly to the historical categories. The impact on patients’ quality of life and life expectancy depends closely on genotype, coexisting mutations, access to care and management of chronic complications.

Beta-thalassemia, particularly common in the Mediterranean basin, the Middle East, Southeast Asia and the Indian subcontinent, is an important public health problem in high-prevalence areas, where screening, prevention and treatment programs are essential components of public health.

Etiology and Genetics

Beta-thalassemia is caused by mutations in the beta-globin gene (HBB), located on chromosome 11. These mutations reduce (beta+) or abolish (beta0) production of the beta-globin chain, an essential component of adult hemoglobin (HbA, consisting of two alpha and two beta chains: α2β2).

More than 300 mutations responsible for beta-thalassemia have been described to date, predominantly point mutations (substitutions, deletions or insertions of a few nucleotides) that may interfere with several stages of beta-globin synthesis:

• Mutations in the promoter or regulatory regions, with reduced transcription
• Mutations that alter exon splicing, producing aberrant and unstable transcripts
• Nonsense mutations that introduce premature stop codons, blocking chain synthesis
• Frameshift mutations with loss of protein function

Classic beta-thalassemia major and intermedia are generally inherited in an autosomal recessive pattern: heterozygous carriers (trait) have a single mutated allele, whereas the more severe clinical forms are usually due to pathogenic mutations of both HBB alleles (homozygosity or compound heterozygosity). Rare autosomal dominant forms of beta-thalassemia intermedia due to specific heterozygous HBB variants do, however, exist. It is important to emphasize that coexistence of other mutations, particularly in alpha-globin genes or quantitative modifiers of fetal hemoglobin, may significantly influence clinical phenotype severity.

In Mediterranean and Middle Eastern populations, a small number of mutations account for most cases (for example, IVS-I-110, IVS-I-6, codon 39, IVS-II-1), whereas distribution is more heterogeneous in other geographic regions.

Pathogenesis and Pathophysiology

Understanding the pathogenetic mechanisms of beta-thalassemia requires a review of the physiology of hemoglobin synthesis. Normal adult hemoglobin (HbA) consists of two alpha and two beta chains, produced in rigorously balanced amounts during erythropoiesis. The balance between alpha- and beta-globin is essential for correct assembly of the hemoglobin tetramer, oxygen transport and red blood cell membrane stability.

Hemoglobin composition changes throughout life:

• During embryonic life, Gower and Portland hemoglobins, composed of zeta, epsilon, alpha and gamma chains, predominate.
• During fetal life, the principal hemoglobin is HbF (alpha2-gamma2), which has high oxygen affinity and is fundamental for placental oxygen transfer.
• After birth, production of HbA (alpha2-beta2) progressively replaces HbF. A small proportion (<5%) of hemoglobin A2 (alpha2-delta2) is present in healthy adults.

This transition explains the progressive appearance of symptoms in severe forms: protected by HbF, newborns develop clinical signs of disease only after the first months of life, when beta-globin production becomes essential.

In beta-thalassemia, the genetic defect reduces or abolishes beta-chain production, creating a relative excess of alpha chains that cannot associate stably and precipitate in erythroid precursors. Free alpha chains are highly unstable and cytotoxic: they aggregate and form inclusions that damage erythroid precursor membranes, generating extensive intramedullary apoptosis (ineffective erythropoiesis), with destruction of cells before they reach the peripheral circulation.

The red blood cells that do enter the circulation are nevertheless abnormal, fragile and readily hemolyzed because of persistent protein inclusions and membrane instability, and undergo chronic extravascular hemolysis primarily in the spleen. The combination of ineffective erythropoiesis and hemolysis causes chronic hyporegenerative anemia, which stimulates a compensatory marrow response with expansion of erythroid tissue and attempts at extramedullary hematopoiesis.

Another key feature in clinically significant forms, especially non-transfusion-dependent forms, is increased intestinal iron absorption: ineffective erythropoiesis suppresses hepcidin and may cause progressive iron overload even in the absence of transfusions. In transfusion-dependent forms (Mediterranean anemia, Cooley disease), the combination of dietary iron and transfusional iron dramatically accelerates accumulation and organ injury.

In forms with clinically significant anemia, hemoglobin deficiency reduces oxygen-carrying capacity and may cause tissue hypoxia, with systemic effects on metabolism, growth and organ function.

Clinical Features

The clinical phenotype of beta-thalassemia is extremely variable and depends closely on the type and combination of genetic mutations, residual beta-globin synthesis, age at onset and the presence of modifying factors (for example, persistence of fetal hemoglobin or involvement of alpha-globin genes).

Beta-thalassemia major (Mediterranean anemia, Cooley disease)

This form typically presents during the first 6-24 months of life, when the physiologic transition from fetal hemoglobin (HbF) to adult hemoglobin (HbA) reveals beta-globin deficiency. Infants rapidly develop progressively severe anemia, mucocutaneous pallor, mild jaundice due to indirect hyperbilirubinemia, poor linear and weight growth and irritability. Hepatosplenomegaly is almost always present and progressive, caused by increased red blood cell destruction and expansion of extramedullary hematopoiesis. In untreated cases, skeletal changes progressively develop with characteristic craniofacial abnormalities of thalassemia (frontal bossing, malar prominence, depressed nasal bridge and maxillary hypertrophy), macrocrania, osteopenia and increased susceptibility to fractures.

The clinical course of beta-thalassemia major (Mediterranean anemia, Cooley disease), in the absence of regular transfusions, progresses toward severe anemia, erythroid expansion, growth delay, high-output heart failure and early death; in patients receiving chronic transfusions, inadequate chelation may cause iron overload with cardiomyopathy, diabetes and other endocrinopathies.

Beta-thalassemia intermedia

This form has a broad spectrum of severity, with onset after age 2: more severe forms often present between 2 and 6 years, whereas mild forms may be recognized later, even in adulthood. Patients have chronic anemia of variable degree, hepatosplenomegaly and mild jaundice and, in the absence of transfusion regimens, may develop complications similar to those of the major form (skeletal changes, extramedullary hematopoiesis, gallstones, hypercoagulability), but generally more slowly and less severely. Transfusion dependence may develop over time in relation to physiologic stress (infections, pregnancy, surgery) or worsening erythropoietic function.

Beta-thalassemia minor (trait)

This form is generally asymptomatic. Heterozygous carriers may have persistent microcytosis and mild anemia (often unrecognized), without clinically significant manifestations. It is typically identified during population screening, prenatal testing or hematologic assessments for other reasons. In carriers, however, distinction from iron-deficiency anemia is important both for clinical management and genetic counseling, especially when reproductive partners are both carriers.

Common manifestations and clinical complications:

In clinically significant forms, some manifestations may occur to varying degrees:

• Chronic jaundice due to persistent hemolysis
• Gallstones and biliary complications
• Delayed puberty and impaired growth (moderate to severe forms)
• Skeletal abnormalities (osteopenia, deformities)
• Symptoms of chronic tissue hypoxia (fatigue, dyspnea, tachycardia)
• Complications of iron overload in transfusion-dependent forms or those with marked ineffective erythropoiesis
• Increased susceptibility to infections due to splenic dysfunction or splenectomy
• Thromboembolic tendency, especially after splenectomy or in nontransfused intermediate forms

Overall, the natural history of beta-thalassemia (particularly Mediterranean anemia, Cooley disease) is closely intertwined with available treatment strategies: regular transfusion and chelation therapy have radically altered the prognosis of severe forms, while early identification of carriers and genetic counseling remain the pillars of prevention in high-prevalence areas.

Investigations and Diagnosis

The diagnosis of beta-thalassemia is based on a sequential, integrated process that begins with clinical and laboratory suspicion, continues with hemoglobin characterization and, when indicated, is completed by molecular analysis. The objective is to distinguish precisely among the different clinical forms (major, intermedia, minor), differentiate them from other causes of microcytic anemia and promptly identify carriers for genetic counseling.

Suspicion generally arises in the presence of microcytic anemia (MCV below the age-specific reference limit, generally < 80 fL in adults), often with only mildly increased RDW, normal or elevated iron stores and a personal or family history of anemia or splenomegaly.
In children, the typical presentation of beta-thalassemia major (Mediterranean anemia, Cooley disease) occurs during the first two years of life with progressive anemia, poor growth, pallor and splenomegaly.

First-line laboratory evaluation:

• Complete blood count: microcytic, hypochromic anemia with reduced MCV and MCH, normal or mildly increased reticulocytes, and possible apparent leukocytosis on automated analyzers because nucleated red blood cells may be counted.
• Peripheral smear: findings vary with severity; in major and intermedia forms, marked anisopoikilocytosis, microcytes, target cells, polychromasia and circulating erythroblasts may occur, whereas in the trait microcytosis, hypochromia and target cells predominate without typical erythroblasts.
• Serum iron, ferritin, transferrin and transferrin saturation: generally normal or increased, a key feature in the differential diagnosis with iron-deficiency anemia.

Hemoglobin analysis (electrophoresis or HPLC): The most informative test for identifying minor forms and characterizing major/intermediate forms (Mediterranean anemia, Cooley disease). Typical results are:

• Beta-thalassemia major: absent or markedly reduced HbA, pronounced increase in HbF (up to 90-100%), and variably increased HbA2.
• Beta-thalassemia intermedia: variable HbA that may sometimes be absent, variably increased HbF, and variable and often increased HbA2.
• Beta-thalassemia minor: normal or mildly reduced HbA, increased HbA2 (>3.5%, often 4-8%), and normal or mildly increased HbF, generally below 5%; higher values may reflect specific genotypes or modifiers.

Integrated with the history and hematologic findings, these data enable accurate diagnosis in most cases.

Additional investigations: When the diagnosis is uncertain or atypical cases must be identified, molecular analysis of the HBB gene (testing for the principal mutations) is indicated. This investigation is essential:

• For prenatal diagnosis and genetic counseling of carrier partners
• In atypical intermediate forms or when alpha-globin abnormalities coexist
• For planning innovative treatments (transplantation, gene therapy)

Instrumental assessment and follow-up: In major (Mediterranean anemia, Cooley disease) and intermediate forms, these are essential for evaluating organ complications and monitoring therapy:

• Cardiac and hepatic T2* MRI to quantify tissue iron
• Echocardiography and electrocardiography to assess cardiac function
• Hormonal testing, bone densitometry, hepatic, renal and endocrine function to screen for complications
• Abdominal ultrasonography to assess splenomegaly, extramedullary masses and gallstones

Differential diagnosis: Beta-thalassemia minor must be distinguished from iron-deficiency anemia (iron studies, lack of response to iron therapy, HbA2 levels), from other hemoglobin disorders (e.g. delta-beta thalassemia, structural hemoglobin variants) and, in major/intermediate forms (Mediterranean anemia, Cooley disease), from other causes of chronic hemolytic anemia and dyserythropoiesis.

Genetic counseling: For carriers and at-risk couples, genetic counseling and possible prenatal diagnosis (amniocentesis, chorionic villus sampling and, only in specialist settings using validated methods, noninvasive prenatal diagnosis) play a central role in preventing severe forms and supporting informed family planning.

Timely diagnosis, precise phenotypic definition and assessment of complications are essential foundations for personalized treatment and prevention of the long-term consequences of the disease.

Treatment and Prognosis

Treatment of beta-thalassemia is based on an individualized strategy that takes into account clinical severity, transfusion dependence, patient age and the presence of organ complications. The primary objective is to prevent or correct chronic anemia, avoid iron overload, ensure normal growth and development in children, prevent systemic complications and improve quality and duration of life. Over recent decades, treatment has advanced substantially with the introduction of innovative therapies and multidisciplinary care pathways.

Transfusion therapy: Regular transfusion of leukoreduced packed red blood cells is the cornerstone of management for major forms (Mediterranean anemia, Cooley disease) and many intermediate forms. The aim is to maintain pretransfusion hemoglobin levels of 9.5–10.5 g/dL in order to achieve the objectives listed below. In patients with heart disease or pulmonary hypertension, clinically significant extramedullary hematopoiesis or insufficient suppression of erythropoiesis, a target of 10–11 g/dL may be appropriate; during pregnancy the pretransfusion target is approximately 10 g/dL.

• Prevent manifestations of severe anemia
• Suppress extramedullary hematopoiesis and skeletal abnormalities
• Support growth and development in children
• Prevent cardiovascular and metabolic complications

Initiation of a regular transfusion program during the first years of life is decided on the basis of clinical phenotype and persistence of transfusion need, not a single isolated hemoglobin threshold. In patients with TDT, transfusions continue chronically for as long as necessary unless transfusion independence is achieved through transplantation or curative therapies. Before the first transfusion, typing should include at least Rh C/c/D/E/e and Kell; during the transfusion program, units must be prophylactically matched at least for C, c, E, e and K, in addition to ABO/RhD, with irregular-antibody screening. This reduces the risk of alloimmunization and transfusion reactions.

Iron chelation therapy: Iron overload secondary to chronic transfusions and increased intestinal absorption requires early and continuous iron chelation. In TDT, chelation is generally started after approximately 10–20 transfusions or when ferritin exceeds approximately 1000 ng/mL, always integrating these parameters with iron burden and the clinical context. Available agents include:

• Deferoxamine (continuous subcutaneous infusion)
• Deferasirox (oral, daily administration)
• Deferiprone (oral, 2-3 administrations daily)

Choice and combination of agents depend on tolerability, safety profile and the extent of organ siderosis. Monitoring includes serum ferritin at least every 3 months and iron quantification with liver and cardiac MRI generally annually from 8–10 years of age, with frequency adjusted according to iron burden and response to chelation, as well as assessment of organ complications.

Supportive therapy: Treatment of complications and support of growth and development include:

• Folic acid supplementation when indicated, particularly in non-transfusion-dependent forms or in the presence of low pretransfusion levels; vitamin D and calcium when indicated
• Prevention and treatment of infections (vaccination, antibiotic prophylaxis after splenectomy)
• Management of endocrine complications (screening and replacement therapy for hypogonadism, hypothyroidism, diabetes, adrenal insufficiency)
• Assessment and treatment of osteoporosis and skeletal abnormalities

Splenectomy: Indicated in patients with severe hypersplenism (increased transfusion requirements, severe cytopenias) or symptomatic splenomegaly. It should be reserved for selected cases after careful assessment of infectious and thrombotic risks and must always be preceded by appropriate vaccination coverage.

Innovative therapies: In recent years, therapeutic options targeting modulation of erythropoiesis and globin synthesis have been developed:

• Luspatercept (erythroid maturation agent): in authorized populations and indications, it may increase hemoglobin or reduce transfusion requirements; it does not guarantee discontinuation of transfusions.
• Mitapivat (red blood cell pyruvate kinase activator): in the European Union it is authorized in adults for anemia associated with beta-thalassemia, both transfusion-dependent and non-transfusion-dependent; eligibility, dose and continuation criteria follow the product information.
• Gene therapy: addition of a functional copy of beta-globin using lentiviral vectors is authorized for selected patients with transfusion-dependent beta-thalassemia in some jurisdictions and may produce durable transfusion independence in a proportion of treated patients.
• Genome editing (CRISPR/Cas9): in the European Union exagamglogene autotemcel is indicated for transfusion-dependent beta-thalassemia from 12 years of age when hematopoietic stem cell transplantation is appropriate and an HLA-matched related donor is not available; availability and operational criteria require assessment at authorized centers.

Hematopoietic stem cell transplantation (HSCT): Allogeneic hematopoietic stem cell transplantation is an established potentially curative therapy for selected patients with transfusion-dependent thalassemia (TDT) and for some severe non-transfusion-dependent forms. Success depends on donor availability and suitability, age, risk profile and prevention of post-transplant complications (GVHD, infections, organ toxicity). The choice among transplantation, conventional treatment and, when available and indicated, gene therapies must be individualized according to risk, accessibility and patient preferences.

Prognosis: The prognosis of beta-thalassemia major (Mediterranean anemia, Cooley disease) has improved radically over recent decades through transfusion therapy, iron chelation and multidisciplinary monitoring and is not adequately described by a single generalizable survival threshold. In health systems with continuous access to safe transfusions, effective chelation and surveillance for complications, many patients reach advanced adulthood. Quality of life and survival depend on birth cohort, access to and adherence to care, control of iron overload and prevention of organ complications. Residual risk of premature mortality is related mainly to heart failure caused by hemosiderosis, infectious complications and hepatic malignancies in chronically affected patients.

Intermediate forms have a slower and more variable course but remain at risk over time for complications of iron overload, hypercoagulability and endocrine disorders. Minor forms have an excellent prognosis, with normal life expectancy and no significant complications.

Prevention of beta-thalassemia major (Mediterranean anemia, Cooley disease) and severe forms relies on carrier-screening programs, genetic counseling and prenatal diagnosis, which have substantially reduced disease incidence in at-risk areas.

Complications

Complications of beta-thalassemia are the principal cause of morbidity and mortality, especially in severe transfusion-dependent forms (Mediterranean anemia, Cooley disease). The risk of complications depends on the severity of dyserythropoiesis, age and clinical phenotype, transfusion exposure, iron overload and its management, as well as other individual factors. No less relevant is the contribution of the therapies themselves (transfusions, chelation, splenectomy) to the development of complex clinical conditions requiring continuous monitoring and multidisciplinary care.

Complications of iron overload: Iron overload is the principal long-term threat in transfusion-dependent forms (Mediterranean anemia, Cooley disease) and those with marked ineffective erythropoiesis. Progressive iron accumulation causes multiorgan injury:

• Iron-overload heart disease (dilated cardiomyopathy, arrhythmias, heart failure), historically one of the principal causes of death; in settings with MRI monitoring and adequate chelation, cardiac mortality has fallen significantly, although it remains a serious complication.
• Chronic liver disease (fibrosis, cirrhosis, increased risk of hepatocellular carcinoma, viral infections transmitted by blood products).
• Endocrine disorders (hypogonadism, hypothyroidism, diabetes mellitus, hypoparathyroidism), often causing infertility, osteoporosis and growth impairment.

Timely and adequate chelation therapy is essential to prevent these outcomes.

Infectious complications: Splenectomy, siderosis and transfusions increase the risk of severe infections, particularly with encapsulated bacteria (Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae). Viral infections (HBV, HCV, HIV) remain a risk despite screening, especially in resource-limited countries. Vaccination and prompt antibiotic therapy are essential.

Cardiovascular and thromboembolic complications: Iron-overload heart disease and chronic hypoxia promote arrhythmias and heart failure and, in splenectomized patients or those with active extramedullary hematopoiesis, increase the risk of venous and arterial thromboembolic events.

Musculoskeletal complications: Expansion of hematopoietic marrow, endocrine dysfunction and iron overload contribute to osteopenia, osteoporosis and skeletal deformities (frontal and zygomatic bossing, spinal abnormalities), with increased risk of fractures and chronic pain.

Metabolic and nutritional complications: Malnutrition, altered intestinal absorption, impaired growth and vitamin deficiencies (especially vitamin D) are common in children and adolescents and require targeted supplementation.

Psychosocial and quality-of-life complications: The need for chronic transfusions, dependence on complex therapies, physical and social limitations and the cosmetic impact of skeletal changes may profoundly affect patients’ psychological well-being and quality of life, especially during childhood and adolescence.

Malignant complications: The risk of hepatic malignancies (hepatocellular carcinoma) is increased in patients with chronic liver disease and hepatitis C virus infection, while secondary hematologic malignancies have also been increasingly reported in patients treated with transplantation and/or immunosuppressive therapies.

Overall, management of complications in beta-thalassemia (particularly Mediterranean anemia, Cooley disease) requires careful balance between treatment of the underlying disease, prevention and treatment of iron overload, systematic surveillance and multidisciplinary care, with the objective of ensuring long survival and good quality of life.

References
1. Rund D, Rachmilewitz E. Beta-thalassemia. N Engl J Med. 2005;353(11):1135–1146.
2. Musallam KM, Rivella S, Vichinsky E, et al. Non-transfusion-dependent thalassaemias. Haematologica. 2013;98(6):833–844.
3. Galanello R, Origa R. Beta-thalassemia. Orphanet J Rare Dis. 2010;5:11.
4. Cappellini MD, Farmakis D, Porter J, Taher A, et al. Guidelines for the Management of Transfusion-Dependent Thalassaemia (TDT). Thalassaemia International Federation. 4th ed. 2021.
5. Porter JB, Garbowski MW. Interaction of Transfusion and Iron Chelation in Thalassemias. Hematol Oncol Clin North Am. 2018;32(2):247–259.
6. Thompson AA, Walters MC, Kwiatkowski J, et al. Gene therapy in patients with transfusion-dependent beta-thalassemia. N Engl J Med. 2018;378(16):1479–1493.
7. Cappellini MD, Viprakasit V, Taher AT, et al. A phase 3 trial of luspatercept in patients with transfusion-dependent beta-thalassemia. N Engl J Med. 2020;382(13):1219–1231.
8. Weatherall DJ, Clegg JB. The Thalassaemia Syndromes. Blackwell Science. 4th ed. 2001.
9. Borgna-Pignatti C, Rugolotto S, De Stefano P, et al. Survival and complications in patients with thalassemia major treated with transfusion and deferoxamine. Haematologica. 2004;89(10):1187–1193.
10. Taher AT, Musallam KM, Cappellini MD. β-Thalassemias. N Engl J Med. 2021;384(8):727-743.
11. European Medicines Agency. Pyrukynd (mitapivat): EPAR and product information. 2022, updated 2026.