Pancytopenia Resulting from Destruction of Cells. Pancytopenia resulting from destruction of cells may be caused by intramedullary destruction of hematopoietic elements (myeloproliferative disorders, deficiencies of folic acid and vitamin B12) or by the peripheral destruction of mature cells. The usual site of peripheral destruction of blood cells is the spleen, although the liver and other parts of the reticuloendothelial system may participate. Hypersplenism maybe the result of anatomic causes (portal hypertension or splenic hypertrophy from thalassemia); infections (including malaria); or storage diseases (Gaucher disease, lymphomas, or histiocytosis). Splenectomy is indicated only when the pancytopenia is of clinical significance.
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Etiology. Because alpha chains are needed for fetal erythropoiesis and production of hemoglobin F (α2γ2), alpha chain hemoglobinopathies are present in utero. Four alpha genes are present on the two number 16 chromosomes (see Fig. 150-3 and Table 150-5). Single gene deletions produce no disorder (silent carrier state), but can be detected by measuring the rates of α and β synthesis or by using molecular biologic techniques. Deletion of two genes produces α-thalassemia minor with mild or no anemia and microcytosis. In individuals of African origin, the gene deletions occur on different chromosomes (trans), and the disorder is benign. In the Asian population, deletions may occur on the same chromosome (cis),and infants may inherit two number 16 chromosomes lacking three or even four genes. Deletion of all four genes leads to hydrops fetalis, severe intrauterine anemia, and death, unless intrauterine transfusions are administered. Deletion of three genes produces moderate hemolytic anemia with γ4 tetramers (Bart hemoglobin) in the fetus and β4 tetramers (hemoglobin
H) in older children and adults (see Table 150-5).
Beta chain hemoglobinopathies in the United States are more prevalent than alpha chain disorders, possibly because these abnormalities are not symptomatic in utero. The major beta hemoglobinopathies include those that alter hemoglobin function, including hemoglobins S, C, E, and D, and those that alter beta chain production, the β-thalassemias. Because each RBC has two copies of chromosome 11 and they express both β-globin genes, most disorders of beta chains are not clinically severe, unless both beta chains are abnormal. By convention, when describing β-thalassemia genes, β0 indicates a thalassemic gene resulting in absent beta chain synthesis, whereas β+ indicates a thalassemic gene that permits reduced but not absent synthesis of normal β chains. Disorders of the beta chain usually manifest themselves clinically between 4 and 12 months of age, unless they have been detected prenatally or by cord blood screening.
β-Thalassemia Major (Cooley Anemia) Etiology and Epidemiology. β-Thalassemia major is caused by mutations that impair beta chain synthesis. Because of unbalanced synthesis of alpha and beta chains, alpha chains precipitate within the cells, resulting in RBC destruction either in the bone marrow or in the spleen. β-Thalassemia major is seen most commonly in individuals of Mediterranean or Asian descent. The clinical severity of the illness varies on the basis of the molecular defect.