What is thalassemia?

Thalassemia: A Genetic Blood Disorder

Thalassemia is a group of inherited genetic blood disorders characterized by abnormal hemoglobin production, resulting in ineffective erythropoiesis, premature red blood cell destruction, and anemia of varying severity depending on the type and number of affected genes. 1

Types of Thalassemia

Alpha Thalassemia

• Caused by mutations or deletions in one or more of the four α-globin genes located on chromosome 16 2, 3
• Severity depends on the number of affected genes:
  • Silent carrier (one gene affected): Asymptomatic
  • Alpha thalassemia minor/trait (two genes affected): Mild microcytic anemia
  • Hemoglobin H disease (three genes affected): Moderate to severe anemia
  • Alpha thalassemia major (all four genes affected): Results in hydrops fetalis, usually fatal at birth 1

Beta Thalassemia

• Caused by mutations in the β-globin genes located on chromosome 11 2, 3
• Classified based on severity:
  • Beta thalassemia minor/trait: Mild or no anemia, often asymptomatic
  • Beta thalassemia intermedia: Moderate anemia with variable clinical presentation
  • Beta thalassemia major: Severe transfusion-dependent anemia starting in early childhood (often before 2 years of age) 1

Pathophysiology

• Defective production of alpha or beta globin chains leads to imbalanced globin chain synthesis 3
• Excess unpaired chains precipitate in red blood cell precursors, causing:
  • Ineffective erythropoiesis in the bone marrow
  • Premature destruction of red blood cells
  • Chronic hemolytic anemia 1
• In beta thalassemia major, profound anemia is life-threatening from approximately 1-2 years of age 2
• Chronic severe anemia results in:
  • Bone marrow expansion
  • Extramedullary hematopoiesis
  • Skeletal deformities
  • Growth retardation 1, 3

Clinical Manifestations

Beta Thalassemia Major

• Severe anemia requiring lifelong transfusions starting in early childhood 1
• Growth retardation and skeletal abnormalities 3
• Iron overload complications affecting:
  • Heart (cardiomyopathy, arrhythmias)
  • Liver (hepatomegaly, fibrosis)
  • Endocrine organs (diabetes, hypothyroidism, hypoparathyroidism, hypogonadism) 4
• Class II malocclusion, maxillary protrusion, high caries index, severe gingivitis 5

Thalassemia Intermedia

• Variable presentation based on gene mutations
• Greater propensity to pulmonary hypertension and thrombosis 2
• May eventually require transfusions to prevent complications, including cardiovascular issues 2

Diagnosis

• Suspect thalassemia in patients with microcytic anemia and normal or elevated ferritin levels 1
• Hemoglobin electrophoresis reveals characteristic patterns for different thalassemia subtypes
• Genetic testing is required for definitive diagnosis 1
• T2* cardiovascular magnetic resonance (CMR) is the gold standard for cardiac iron assessment 4

Management

Transfusion Therapy

• For beta thalassemia major: Regular blood transfusions every 2-4 weeks 4
• Maintain pre-transfusion hemoglobin levels of 9-10 g/dL and post-transfusion target of 13-14 g/dL 4
• Monitor hemoglobin levels every 2 weeks during treatment 4

Iron Chelation Therapy

• Indicated in transfusion-dependent patients with serum ferritin >1000 ng/mL 4
• Available chelators:
  • Deferoxamine (parenteral)
  • Deferiprone (oral)
  • Deferasirox (oral)
  • Combination therapy for severe cases 4

Monitoring for Complications

• Regular assessment of iron overload:
  • Serum ferritin levels
  • Liver iron concentration via biopsy or MRI
  • Cardiac T2* MRI 4
• Screening for endocrine complications (diabetes, hypothyroidism, hypoparathyroidism, hypogonadism) 4
• Cardiac monitoring for arrhythmias and heart failure, especially in patients with T2* <10 ms 4

Advanced Therapies

• Hematopoietic stem cell transplantation - currently the only potential cure 1, 3
• Gene therapy - promising approach but still under investigation 2
• Luspatercept - recently approved medication that may reduce transfusion requirements 1

Prevention and Genetic Counseling

• Genetic counseling for couples at risk
• Screening programs in high-risk populations can reduce disease prevalence 1, 6
• Prenatal diagnosis available for at-risk pregnancies 6

Prognosis

Life expectancy for thalassemia patients has dramatically improved over the past 50 years due to:

• Increased availability of blood transfusions
• Improved iron chelation therapy
• Better monitoring of iron overload 1

However, inadequate chelation leading to iron-induced cardiac disease remains the primary cause of death in beta-thalassemia major 4.