Pathophysiology
Clinical meaning
Thalassemias are inherited hemoglobin disorders caused by reduced or absent production of one or more globin chains (alpha or beta). Normal adult hemoglobin (HbA) consists of two alpha and two beta globin chains. Alpha thalassemia results from gene deletions on chromosome 16 (4 alpha genes total; severity depends on number deleted). Beta thalassemia results from point mutations on chromosome 11 reducing or abolishing beta chain synthesis. Unpaired globin chains precipitate within RBC precursors, causing ineffective erythropoiesis and intramedullary hemolysis. The bone marrow expands dramatically to compensate, causing skeletal deformities (frontal bossing, maxillary hyperplasia, 'chipmunk facies,' 'hair-on-end' skull x-ray). Extramedullary hematopoiesis causes hepatosplenomegaly. Alpha thalassemia spectrum: silent carrier (1 gene deleted, asymptomatic), alpha thalassemia trait (2 genes deleted, mild microcytic anemia), HbH disease (3 genes deleted, moderate hemolytic anemia with HbH inclusions), and Hb Bart hydrops fetalis (4 genes deleted, incompatible with life without in-utero transfusion). Beta thalassemia spectrum: beta thalassemia minor/trait (one mutant gene, mild anemia, often asymptomatic), beta thalassemia intermedia (moderate anemia, variable transfusion needs), and beta thalassemia major (Cooley anemia—both genes affected, severe transfusion-dependent anemia presenting at 6-12...