What is the pathophysiology of thalassemia?

Pathophysiology of Thalassemia

Thalassemia results from inherited mutations that reduce or eliminate globin chain synthesis, creating a critical imbalance between alpha and beta globin chains that drives the disease through two primary mechanisms: accumulation of unpaired globin chains that precipitate and destroy red blood cells, and profound ineffective erythropoiesis with hemolytic anemia. 1

Genetic Basis

• Beta-thalassemia is caused by mutations in the HBB gene on chromosome 11, with over 200 disease-causing mutations identified, predominantly single nucleotide substitutions, small deletions, or insertions 2, 3, 4
• Mutations result in either β+ (reduced production) or β0 (complete absence) of beta-globin chain synthesis 2
• Alpha-thalassemia results from reduced or absent synthesis of alpha-globin chains, most commonly in individuals of Southeast Asian descent 5, 6
• The condition follows autosomal recessive inheritance, requiring homozygosity or compound heterozygosity for severe disease 2

Core Pathophysiologic Mechanisms

Primary Defect: Globin Chain Imbalance

• The fundamental problem is defective biosynthesis of one or more globin chain subunits, creating an imbalance in globin chain production 1
• In beta-thalassemia, the absence or reduction of beta chains leads to excess unpaired alpha chains 1, 4
• These unpaired globin chains are insoluble and precipitate within developing erythroblasts and mature erythrocytes 1

Consequences of Chain Precipitation

• Precipitated chains cause direct damage and destruction of developing erythroblasts in the bone marrow, producing ineffective erythropoiesis 1
• Precipitated chains also damage mature red blood cells, causing hemolytic anemia 1, 6
• The clinical severity directly correlates with the extent of imbalance between alpha and non-alpha globin chains 4

Clinical Expression Timeline

• Infants are healthy at birth because fetal hemoglobin (HbF, composed of α2γ2 chains) does not require beta-globin chains 2, 3
• Symptoms emerge at approximately 1-2 years of age as fetal hemoglobin production declines and the switch to adult hemoglobin (requiring beta chains) occurs 2, 3
• Beta-thalassemia major becomes life-threatening by age 1-2 years without intervention 3

Secondary Pathophysiologic Complications

Bone Marrow Response

• Ineffective erythropoiesis and hemolytic anemia trigger chronic bone marrow overstimulation attempting to compensate for the anemia 7
• This leads to skeletal abnormalities during infancy in severe cases 6

Transfusion-Related Iron Overload

• Each unit of transfused blood contains approximately 200-250 mg of elemental iron 2, 3
• Humans lack physiological mechanisms for iron excretion, leading to progressive iron accumulation 2
• Cardiac iron loading becomes the leading cause of death, accounting for approximately 70% of mortality in transfusion-dependent patients 2, 3
• Before modern chelation therapy, patients died by age 10 from cardiac complications; now survival into the 7th decade is possible with optimal care 3

Spectrum of Disease Severity

Beta-Thalassemia Trait (Heterozygous)

• Clinically asymptomatic with specific hematological features 4
• Characterized by microcytic hypochromic anemia that does NOT respond to iron supplementation, with MCV typically <80 fL 8, 3
• Patients have normal life expectancy 6

Beta-Thalassemia Major (Homozygous)

• Requires more than 8 transfusion events per year in adults over 16 years of age 2, 3
• Causes severe transfusion-dependent anemia with hemolytic anemia, poor growth, and skeletal abnormalities 4, 6
• Requires lifelong regular red blood cell transfusions for survival and lifelong iron chelation therapy 2

Alpha-Thalassemia Major

• Severe hemolytic anemia typically leads to hydrops fetalis and fetal demise 5

Critical Clinical Pitfall

• Do not prescribe iron supplementation to patients with confirmed thalassemia trait—the anemia does not respond to iron therapy despite compliance, and iron supplementation provides no benefit while potentially contributing to unnecessary iron accumulation 8, 3