Pathophysiology
Clinical meaning
Thalassemias are inherited hemoglobin disorders characterized by reduced or absent synthesis of one of the globin chains that make up the hemoglobin molecule. Normal adult hemoglobin (HbA) consists of 2 alpha and 2 beta globin chains (α₂β₂). In thalassemia, the imbalance between alpha and beta chain production causes the excess unpaired chains to precipitate within red blood cell precursors, causing ineffective erythropoiesis (RBC precursor destruction in the bone marrow) and hemolytic anemia (premature destruction of circulating RBCs). Alpha-thalassemia results from deletions of alpha-globin genes (chromosome 16; normally 4 copies — 2 from each parent): silent carrier (1 gene deleted, -α/αα — asymptomatic with normal CBC), alpha-thal trait (2 genes deleted, --/αα or -α/-α — mild microcytic anemia), HbH disease (3 genes deleted — moderate hemolytic anemia, HbH tetramers [β₄] on electrophoresis), and hydrops fetalis (all 4 deleted — incompatible with life, Hb Bart's [γ₄], fetal death from severe anemia). Beta-thalassemia results from point mutations in beta-globin genes (chromosome 11; 2 copies): beta-thal minor/trait (one mutant gene — mild microcytic anemia, elevated HbA2 >3.5% on electrophoresis), beta-thal intermedia (two mutations with...