What are the types of thalassemia, how is it diagnosed, and what are the management strategies?

Thalassemia: Types, Diagnosis, and Management

Types of Thalassemia

Thalassemia is classified into two major categories—alpha and beta—based on which globin chain is deficient, with clinical severity ranging from asymptomatic carrier states to life-threatening transfusion-dependent disease.

Beta-Thalassemia

• Beta-thalassemia results from mutations in the HBB gene on chromosome 11, with over 200 pathogenic variants identified, producing either β⁺ (reduced synthesis) or β⁰ (absent synthesis) phenotypes. 1
• Beta-thalassemia trait (carrier state) presents with microcytic hypochromic anemia (MCV < 80 fL) that does NOT respond to iron supplementation—this is the critical distinguishing feature from iron deficiency. 2
• Beta-thalassemia major (Cooley's anemia) is defined by requiring more than 8 transfusion events per year in adults and becomes life-threatening by age 1-2 years without treatment. 3, 1
• Beta-thalassemia intermedia represents a milder phenotype with variable transfusion needs, generally not requiring regular transfusions but may need them later to prevent cardiovascular complications. 3

Alpha-Thalassemia

• Alpha-thalassemia results from reduced or absent alpha-globin chain synthesis and is most prevalent in Southeast Asian populations. 1
• Alpha-thalassemia trait (two-gene deletion) causes mild microcytic anemia with MCV < 80 fL; carriers are asymptomatic. 1
• Hemoglobin H disease (three-gene deletion) requires complete blood count monitoring every 3-6 months to detect worsening hemolytic anemia. 1
• Alpha-thalassemia major (four-gene deletion/Hb Bart's) leads to hydrops fetalis and fetal demise, accounting for 28-55% of non-immune hydrops cases in Southeast Asian populations. 1, 3

Diagnosis

Clinical Presentation Timeline

• Newborns are asymptomatic because fetal hemoglobin (α₂γ₂) does not require beta-globin chains. 1
• Clinical symptoms emerge between 1-2 years of age as fetal hemoglobin declines and adult hemoglobin synthesis begins. 1, 4

Diagnostic Approach

• Suspect thalassemia in patients with microcytic anemia (MCV < 80 fL) and normal or elevated ferritin levels. 5
• The hallmark of beta-thalassemia trait is persistent mild anemia that fails to improve after 4 weeks of adequate iron therapy (no 1 g/dL hemoglobin increase or 3% hematocrit increase). 2
• Always check serum ferritin first to rule out concurrent iron deficiency before attributing findings solely to thalassemia trait. 2
• Hemoglobin electrophoresis reveals characteristic patterns for different subtypes, but genetic testing is required for definitive diagnosis. 5
• Consider ethnicity in the diagnostic approach—thalassemia is significantly more common in Mediterranean, Middle Eastern, Southeast Asian, and African populations. 2

Management Strategies

Beta-Thalassemia Major

• Lifelong regular red-cell transfusions are essential starting before age 2, maintaining pre-transfusion hemoglobin of 9-10 g/dL and post-transfusion hemoglobin of 13-14 g/dL to suppress ineffective erythropoiesis. 3, 1
• Lifelong iron chelation therapy is mandatory because each transfused unit delivers approximately 200-250 mg of elemental iron and humans lack physiological iron excretion mechanisms. 3, 1, 4
• Cardiac iron deposition accounts for roughly 70% of mortality in transfusion-dependent thalassemia—early detection and treatment of cardiac disease is safer than late-stage intervention. 3, 1, 4
• For cardiac iron overload without overt dysfunction, deferiprone shows superior efficacy versus deferoxamine, and combined deferiprone with deferoxamine is superior to deferoxamine alone; deferasirox is equivalent to deferoxamine. 3
• Hematopoietic stem cell transplantation is the only curative treatment for beta-thalassemia major; with optimal chelation, survival into the seventh decade is now achievable. 3, 4

Beta-Thalassemia Intermedia

• Patients generally do not require regular transfusions but may need them as they age to prevent cardiovascular complications (pulmonary hypertension, thrombosis). 3
• Iron chelation becomes necessary when transfusions are initiated due to progressive iron loading. 3

Alpha-Thalassemia

• Hemoglobin H disease requires monitoring with complete blood counts every 3-6 months; transfusions are given episodically based on symptoms. 1
• Alpha-thalassemia major is typically fatal; prenatal diagnosis via chorionic villus sampling should be offered to at-risk couples. 3

Critical Management Pitfalls to Avoid

• NEVER prescribe iron supplementation to patients with confirmed thalassemia trait—it provides no therapeutic benefit and promotes unnecessary iron accumulation. 1, 2
• Do not miss the diagnosis in pregnant women of appropriate ancestry with persistent mild anemia unresponsive to prenatal iron—evaluate with MCV, RDW, and hemoglobin electrophoresis. 2
• Cardiac disease must be identified and treated early; late-stage heart failure carries high mortality risk in thalassemia major. 3
• Monitor for iron overload complications affecting skeletal, endocrine, cardiac, and hepatic systems in all transfusion-dependent patients. 5
• Refer all patients with thalassemia for preconception genetic counseling to assess reproductive risks. 6