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  • Microcytosis disproportionate to the degree of anemia.

  • Positive family history.

  • Lifelong personal history of microcytic anemia.

  • Normal or elevated RBC count.

  • Abnormal RBC morphology with microcytes, hypochromia, acanthocytes, and target cells.

  • In beta-thalassemia, elevated levels of hemoglobin A2 and F.


The thalassemias are hereditary disorders characterized by reduction in the synthesis of globin chains (alpha or beta). Reduced globin chain synthesis causes reduced hemoglobin synthesis and a hypochromic microcytic anemia because of defective hemoglobinization of RBCs. Thalassemias can be considered among the hyperproliferative hemolytic anemias, the anemias related to abnormal hemoglobin, and the hypoproliferative anemias, since all of these factors play a role in their pathophysiology. The hallmark laboratory features are small (low MCV) and pale (low mean corpuscular hemoglobin [MCH]) RBCs, anemia, and a normal to elevated RBC count (ie, a large number of the small and pale RBCs are being produced). Although patients often exhibit an elevated reticulocyte count, generally the degree of reticulocyte output is inadequate to meet the degree of RBC destruction (hemolysis) occurring in the bone marrow and the patients remain anemic.

Normal adult hemoglobin is primarily hemoglobin A, which represents approximately 98% of circulating hemoglobin. Hemoglobin A is formed from a tetramer of two alpha-globin chains and two beta-globin chains—and is designated alpha2beta2. Two copies of the alpha-globin gene are located on each chromosome 16, and there is no substitute for alpha-globin in the formation of adult hemoglobin. One copy of the beta-globin gene resides on each chromosome 11 adjacent to genes encoding the beta-like globins delta and gamma (the so-called beta-globin gene cluster region). The tetramer of alpha2delta2 forms hemoglobin A2, which normally composes 1–3% of adult hemoglobin. The tetramer alpha2gamma2 forms hemoglobin F, which is the major hemoglobin of fetal life and which composes less than 1% of normal adult hemoglobin.

The thalassemias are described as thalassemia trait when there are laboratory features without significant clinical impact, thalassemia intermedia when there is an occasional RBC transfusion requirement or other moderate clinical impact, and thalassemia major when the disorder is life-threatening and the patient is transfusion-dependent. Most patients with thalassemia major die of the consequences of iron overload from RBC transfusions.

Alpha-thalassemia is due primarily to gene deletions causing reduced alpha-globin chain synthesis (Table 15–4). Each alpha-globin gene produces one-quarter of the total alpha-globin quantity, so there is a predictable proportionate decrease in alpha-globin output with each lost alpha-globin gene. Since all adult hemoglobins are alpha containing, alpha-thalassemia produces no change in the proportions of hemoglobins A, A2, and F on hemoglobin electrophoresis. In severe forms of alpha-thalassemia, excess beta chains may form a beta-4 tetramer called hemoglobin H. In the presence of reduced alpha chains, the excess beta chains are unstable and precipitate, causing damage to RBC membranes. This leads to both ...

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