Pathophysiology of alpha thalassemia
- Stanley L Schrier, MD
Stanley L Schrier, MD
- Editor-in-Chief — Hematology
- Section Editor — Myeloproliferative Disorders; Red Cell Disorders
- Professor of Medicine
- Stanford University School of Medicine
- Section Editors
- William C Mentzer, MD
William C Mentzer, MD
- Section Editor — Red Cell Disorders
- Professor of Pediatrics
- University of California, San Francisco
- Donald H Mahoney, Jr, MD
Donald H Mahoney, Jr, MD
- Section Editor — Pediatric Hematology
- Professor of Pediatrics
- Baylor College of Medicine
The major hemoglobin in children and adults is hemoglobin A (adult hemoglobin, HbA), a heterotetramer consisting of one pair of alpha globin chains and one pair of beta globin chains. These chains are derived from two copies of the alpha globin gene on chromosome 16 and a single beta globin gene on chromosome 11 (figure 1). In normal adults, globin chain synthesis is very tightly controlled such that the ratio of production of alpha to beta globin chains is 1.00±0.05. (See "Structure and function of normal hemoglobins".)
The pathophysiology of alpha thalassemia, in which this delicate balance is disrupted, will be reviewed here. This discussion will focus on the mechanisms by which the excess unmatched beta globin chain synthesis in alpha thalassemia leads to increased red blood cell destruction (hemolysis). The accumulation of excess beta chains in erythroid precursors within the bone marrow and in extramedullary sites, such as the liver and spleen, also leads to a certain amount of ineffective erythropoiesis.
The molecular pathology of the thalassemias and the pathophysiology of beta thalassemia are discussed separately. (See "Molecular pathology of the thalassemic syndromes" and "Pathophysiology of beta thalassemia".)
OVERVIEW OF THE THALASSEMIAS
Thalassemia refers to a spectrum of disorders characterized by reduced or absent production of one (or, rarely, two or more) of the globin chains, thus disrupting the delicate balance between the production of alpha and non-alpha (eg, gamma or beta) globin chains. The two most common forms are:
●Alpha thalassemia – Alpha thalassemia is due to impaired or absent production of alpha globin chains, which leads to a relative excess of gamma globin chains in the fetus and newborn, and excess beta globin chains in children and adults. While the excess beta globin chains are capable of forming soluble homotetramers (beta-4, HbH), they are unstable and some precipitate within the cell, leading to a variety of clinical manifestations. Since all normal hemoglobins of postnatal life contain alpha chains, homozygous alpha (0) thalassemia, in which no alpha globin chains can be produced, is incompatible with extrauterine life, leading to hydrops fetalis and death shortly after delivery.
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- OVERVIEW OF THE THALASSEMIAS
- Alpha (0) thalassemia
- Alpha (+) thalassemia
- Complex alpha thalassemia variants
- Protection against severe malaria
- HEMOGLOBIN H DISEASE
- Consequences of impaired alpha globin synthesis
- - Red blood cell size and shape
- - Red blood cell hydration
- - Hemolytic anemia
- Removal of alpha thalassemic red blood cells by spleen and macrophages
- - Reduced RBC deformability
- - Abnormal RBC membrane features
- Increased membrane rigidity
- Increased RBC membrane stability
- Red blood cell inclusions
- Phosphatidylserine signaling
- Membrane IgG and complement
- Macrophage colony-stimulating factor
- Biochemical and cellular alterations leading to hemolysis
- - Membrane bound beta globin chains
- - Role of oxidant injury
- - Other evidence of RBC membrane damage
- Ineffective erythropoiesis
- HYDROPS FETALIS AND HEMOGLOBIN BART'S