Thalassemias are genetic disorders of ineffective hemoglobin synthesis, resulting in a microcytic anemia with a normal RDW. There are two types of thalassemia, alpha and beta. Whereas thalassemias result in a low production of globulin chain levels, hemoglobinopathies occur when abnormal globin chains are produced. Common laboratory abnormalities of thalassemias include the above-mentioned microcytic anemia with hyperbilirubinemia and normal serum iron and ferritin levels. Characteristic changes noted on the peripheral blood smear include the presence of numerous erythroblasts, target cells, microcytic and hypochromic RBCs along with diffuse basophilia. The MCV in thalassemia is often depressed out of proportion to the degree of anemia, as opposed to iron deficiency anemia, in which the decreases of both the hemoglobin and the MCV are proportional. The distinction between iron deficiency anemia and thalassemia is further supported by the RDW, which is characteristically elevated with iron deficiency but normal with thalassemia. Arterial and venous thrombosis may complicate alpha or beta thalassemia major.

Beta thalassemia refers to impaired synthesis of hemoglobin beta chains, resulting in a relative excess of alpha chains. The excess alpha chains tend to aggregate and form insoluble complexes within RBCs and their precursors. These intracellular aggregates cause impaired cellular deformability, leading to increased destruction of RBCs by splenic macrophages. Shortened RBC survival with resultant anemia leads to increased erythropoietin secretion, which stimulates bone marrow growth causing invasion into the bone cortex and impaired bone growth. Extramedullary hematopoiesis occurs in the liver and spleen. Patients with beta thalassemia have increased absorption of dietary iron and are therefore predisposed to secondary hemochromatosis. Abnormalities on physical exam include splenomegaly, and depending on the severity of the thalassemia, jaundice, hepatomegaly, leg ulcerations, and a characteristic facial deformity known as chipmunk facies. There are two types of beta thalassemia, major (Cooley anemia) and minor (trait). Persons from Mediterranean countries, Arabs, and blacks manifest this disorder. Diagnosis is made by finding increased levels of hemoglobin A2 and sometimes hemoglobin F on serum hemoglobin electrophoresis. If there is coexistent iron deficiency, the hemoglobin A2 level may be falsely suppressed. Patients with this disorder should not receive iron therapy, and they should be monitored for signs of end organ damage secondary to iron overload. Genetic counseling should be offered to all patients with this diagnosis, and family members should be counseled not to start iron therapy without undergoing an appropriate workup.

Another form of beta thalassemia, seen mostly in persons from Southeast Asia, is hemoglobin E. This is diagnosed when hemoglobin electrophoresis shows hemoglobin E running behind hemoglobin A. Patients are asymptomatic, and the diagnosis is suspected when the blood smear shows a normal hemoglobin/hematocrit with microcytosis. Hemoglobin E is of concern only when patients with this form of disease produce children with persons suffering from other forms of beta thalassemia. The resulting offspring suffer beta thalassemia major and all of its complications.

Alpha thalassemias occur secondary to gene deletions on chromosome 16 and are characterized by impaired synthesis of hemoglobin alpha chains, resulting in a relative excess of beta chains. Beta chains then tend to aggregate forming tetramers called hemoglobin H. Patients with a single alpha globulin gene deletion are silent carriers of the disorder, two-gene deletions result in alpha thalassemia trait, three-gene deletions result in alpha thalassemia intermedia (HbH disease), and four gene deletions cause thalassemia major (Hb  Bart's). Both hemoglobin H and Barts have a high affinity for oxygen, and are therefore ineffective in tissue oxygenation. Alpha thalassemia major with Hb Bart's may result in nonimmune hydrops fetalis in utero. Alpha thalassemia is seen more commonly in blacks and Asians. Laboratory abnormalities noted with alpha thalassemia include microcytosis with minimal or no anemia, and a normal hemoglobin electrophoresis (excludes beta thalassemia) plus normal serum iron and ferritin (excludes iron deficiency anemia). During the newborn period, the hemoglobin electrophoresis may prove diagnostic by showing Hb Bart's or HbH. In the adult patient there is no good single lab test to diagnose alpha thalassemia. The diagnosis may be made by exclusion or by restriction endonuclease mapping. Mild alpha thalassemias require no treatment or close follow-up. Hemoglobin H disease is managed by close follow up so that drastic changes in the hemoglobin level can be treated.

Patients with thalassemia trait usually require no treatment other than preconception genetic counseling as two parents with beta thalassemia trait have a one in four chance of producing an offspring with beta thalassemia major. Parents with alpha thalassemia trait require genetic counseling because if the fetus has Hb Bart's, the pregnancy may be complicated by toxemia of pregnancy and postpartum hemorrhage. The treatment of patients afflicted with thalassemia major can be complex. Hematopoietic stem cell transplantation may prove curative in appropriate cases. Transfusion therapy offers relief from severe anemia with its associated complication of high out put heart failure. However, transfusion therapy also induces iron overload with resultant secondary hemochromatosis. Splenectomy may be performed to help reduce the frequency of transfusions. Iron chelation therapy with intravenous or subcutaneous desferrioxamine or oral deferasirox may be instituted to prevent hemochromatosis.

If both the mother and father of an unborn child have a family history of thalassemia, the fetus is consider at risk for thalassemia major and should be subjected to screening. If beta thalassemia is suspected, the amniotic fluid may be subjected to DNA probing to determine if the fetus suffers Beta thalassemia major. When alpha thalassemia is suspected, a Southern blot of the parental DNA is made. If one parent lacks two alpha globin genes from one chromosome and the other parent is lacking at least a single gene, then fetal DNA mapping should be undertaken.