THALASSEMIA

THE THALASSEMIAS
Essentials of Diagnosis

Microcytosis out of proportion to the degree of anemia.

Positive family history or lifelong personal history of microcytic anemia.

Abnormal red blood cell morphology with microcytes, acanthocytes, and target cells.

In
-thalassemia, elevated levels of hemoglobin A2 or F.
General Considerations
The thalassemias are hereditary disorders characterized by reduction in the synthesis of globin chains (
or
). Reduced globin chain synthesis causes reduced hemoglobin synthesis and eventually produces a hypochromic microcytic anemia because of defective hemoglobinization of red blood cells. Thalassemias can be considered among the hypoproliferative anemias, the hemolytic anemias, and the anemias related to abnormal hemoglobin, since all of these factors play a role in pathogenesis.
Normal adult hemoglobin is primarily hemoglobin A, which represents approximately 98% of circulating hemoglobin. Hemoglobin A is formed from a tetramer—two
chains and two
chains—and can be designated
2
2. Two copies of the
-globin gene are located on chromosome 16, and there is no substitute for
-globin in the formation of hemoglobin. The
-globin gene resides on chromosome 11 adjacent to genes encoding the
-like globin chains,
and
. The tetramer of
2
2 forms hemoglobin A2, which normally comprises 1–2% of adult hemoglobin. The tetramer
2
2 forms hemoglobin F, which is the major hemoglobin of fetal life but which comprises less than 1% of normal adult hemoglobin.
The thalassemias are described as "trait" when there are laboratory features without significant clinical impact, "intermedia" when there is a red blood cell transfusion requirement or other moderate clinical impact, and "major" when the disorder is life-threatening.

-Thalassemia is due primarily to gene deletion causing reduced
-globin chain synthesis (Table 13–4). Since all adult hemoglobins are
containing,
-thalassemia produces no change in the percentage distribution of hemoglobins A, A2, and F. In severe forms of
-thalassemia, excess
chains may form a
4 tetramer called hemoglobin H.

MCV, mean cell volume.

-Thalassemias are usually caused by point mutations rather than deletions (Table 13–5). These mutations result in premature chain termination or in problems with transcription of RNA and ultimately result in reduced or absent
-globin chain synthesis. The molecular defects leading to
-thalassemia are numerous and heterogeneous. Defects that result in absent globin chain expression are termed
0, whereas those causing reduced synthesis are termed
+. The reduced
-globin chain synthesis in
-thalassemia results in a relative increase in the percentages of hemoglobins A2 and F compared to hemoglobin A, as the
-like globins (
and
) substitute for the missing
chains. In the presence of reduced
chains, the excess
chains are unstable and precipitate, leading to damage of red blood cell membranes. This leads to intramedullary and peripheral hemolysis. The bone marrow becomes hyperplastic under the drive of anemia and ineffective erythropoiesis resulting from the intramedullary destruction of the developing erythroid cells. In cases of severe thalassemia, the marked expansion of the erythroid element in the bone marrow may cause severe bony deformities, osteopenia, and pathologic fractures.

Clinical Findings
SYMPTOMS AND SIGNS
The
-thalassemia syndromes are seen primarily in persons from southeast Asia and China and, less commonly, in blacks. Normally, adults have four copies of the
-globin chain. When three
-globin genes are present, the patient is hematologically normal (silent carrier). When two
-globin genes are present, the patient is said to have
-thalassemia trait, one form of thalassemia minor. These patients are clinically normal and have a normal life expectancy and performance status, with a mild microcytic anemia. When only one
-globin chain is present, the patient has hemoglobin H disease. This is a chronic hemolytic anemia of variable severity (thalassemia minor or intermedia). Physical examination will reveal pallor and splenomegaly. Although affected individuals do not usually require transfusions, they may do so during periods of hemolytic exacerbation caused by infection or other stresses. When all four
-globin genes are deleted, the affected fetus is stillborn as a result of hydrops fetalis.

-Thalassemia primarily affects persons of Mediterranean origin (Italian, Greek) and to a lesser extent Chinese, other Asians, and blacks. Patients homozygous for
-thalassemia have thalassemia major. Affected children are normal at birth but after 6 months, when hemoglobin synthesis switches from hemoglobin F to hemoglobin A, develop severe anemia requiring transfusion. Numerous clinical problems ensue, including growth failure, bony deformities (abnormal facial structure, pathologic fractures), hepatosplenomegaly, and jaundice. The clinical course is modified significantly by transfusion therapy, but the transfusional iron overload (hemosiderosis) results in a clinical picture similar to hemochromatosis, with heart failure, cirrhosis, and endocrinopathies, usually after more than 100 units of red blood cells. These problems develop because of the body’s inability to excrete the iron (see above) from transfused red cells. Before the application of allogeneic stem cell transplantation and the development of more effective forms of iron chelation, death from cardiac failure usually occurred between the ages of 20 and 30 years. This has been profoundly changed.
Patients homozygous for a milder form of
-thalassemia (allowing a higher rate of globin gene synthesis) have thalassemia intermedia. These patients have chronic hemolytic anemia but do not require transfusions except under periods of stress. They may also develop iron overload because of periodic transfusion. They survive into adult life but with hepatosplenomegaly and bony deformities. Patients heterozygous for
-thalassemia have thalassemia minor and a clinically insignificant microcytic anemia.
Prenatal diagnosis is available, and genetic counseling should be offered and the opportunity for prenatal diagnosis discussed.
LABORATORY FINDINGS

-Thalassemia trait
Patients with two
-globin genes have mild anemia, with hematocrits between 28% and 40%. The MCV is strikingly low (60–75 fL) despite the modest anemia, and the red blood count is normal or increased. The peripheral blood smear shows microcytes, hypochromia, occasional target cells, and acanthocytes (cells with irregularly spaced bulbous projections) (see blood smear). The reticulocyte count and iron parameters are normal. Hemoglobin electrophoresis will show no increase in the percentage of hemoglobins A2 or F and no hemoglobin H.
-thalassemia trait is thus usually diagnosed by exclusion. Genetic testing to demonstrate
-globin gene deletion is available in research laboratories.

Fig.

-thalassemia trait. (Peripheral blood, 50 x.) Mildly hypochromic and microcytic cells with occasional target cells in a patient with
-thalassemia trait (the absence of two
-globin genes). Note that the red blood cells are slightly smaller than the small lymphocyte nucleus shown in the center of the field. (Courtesy of L Damon.)

Hemoglobin H disease
These patients have a more marked hemolytic anemia, with hematocrits between 22% and 32%. The MCV is remarkably low (60–70 fL) and the peripheral blood smear is markedly abnormal, with hypochromia, microcytosis, target cells, and poikilocytosis (see blood smear). The reticulocyte count is elevated. Hemoglobin electrophoresis will show the presence of a fast migrating hemoglobin (hemoglobin H), which comprises 10–40% of the hemoglobin. A peripheral blood smear can be stained with supravital dyes to demonstrate the presence of hemoglobin H.

Fig.

Hemoglobin H disease. (Peripheral blood, 50 x.) This smear from a patient with severe
-thalassemia shows hypochromic, microcytic cells, target cells, and bizarre shapes. These changes are the consequence of loss of three
-globin genes. The reticulocyte count is elevated since this is a hemolytic state due to the mispairing of
-globin units in the marrow compartment. Hemoglobin H is the tetramer of four
-globin units. Some red blood cells appear normal in this smear because this patient had recently received a blood transfusion. (Courtesy of L Damon.)

-Thalassemia minor
As in
-thalassemia trait, these patients have a modest anemia with hematocrit between 28% and 40%. The MCV ranges from 55 to 75 fL, and the red blood cell count is normal or increased. The peripheral blood smear is mildly abnormal, with hypochromia, microcytosis, and target cells (see blood smear). In contrast to
-thalassemia, basophilic stippling may be present. The reticulocyte count is normal or slightly elevated. Hemoglobin electrophoresis (using quantitative techniques) may show an elevation of hemoglobin A2 to 4–8% and occasional elevations of hemoglobin F to 1–5%.

Fig.

-thalassemia. (Peripheral blood, 50 x.) Microcytic red blood cells, most of which are target forms, consistent with beta thalassemia. These target cells are also hypochromic because they contain very little hemoglobin. (Courtesy of L Damon.)

-thalassemia major

-thalassemia major produces severe anemia, and without transfusion the hematocrit may fall to less than 10%. The peripheral blood smear is bizarre, showing severe poikilocytosis, hypochromia, microcytosis, target cells, basophilic stippling, and nucleated red blood cells (see blood smear). Little or no hemoglobin A is present. Variable amounts of hemoglobin A2 are seen, and the major hemoglobin present is hemoglobin F.

Fig.

Beta thalassmia major. (Peripheral blood, 50 x.) Microcytic, hypochromic target cells of severe beta thalassemia. Many red blood cell shapes are bizarre, consistent with severe thalassemia. There is intense reticulocytosis, as evidenced by a large number of nucleated red blood cells in the peripheral blood. The thalassemias are hyperproductive anemias manifested by hemolysis occurring in the bone marrow compartment due to mispairing of beta and globin units. (Courtesy of L Damon.)

Differential Diagnosis
Mild forms of thalassemia must be differentiated from iron deficiency. Compared to iron deficiency anemia, patients with thalassemia have a lower MCV, a more normal red blood count, and a more abnormal peripheral blood smear at modest levels of anemia. Iron studies are normal. Severe forms of thalassemia may be confused with other hemoglobinopathies. The diagnosis is made by hemoglobin electrophoresis.
Treatment
Patients with mild thalassemia (
-thalassemia trait or
-thalassemia minor) require no treatment and should be identified so that they will not be subjected to repeated evaluations and treatment for iron deficiency. Patients with hemoglobin H disease should take folate supplementation and avoid medicinal iron and oxidative drugs such as sulfonamides. Patients with severe thalassemia are maintained on a regular transfusion schedule and receive folate supplementation. Splenectomy is performed if hypersplenism causes a marked increase in the transfusion requirement. Deferoxamine is routinely given as an iron-chelating agent to avoid or postpone hemosiderosis. Deferasirox is a new oral iron chelator that has been approved for clinical use.
Allogeneic bone marrow transplantation is the treatment of choice for
-thalassemia major. Children who have not yet experienced iron overload and chronic organ toxicity do well, with long-term survival in more than 80% of cases.

Chaidos A et al. Treatment of beta-thalassemia patients with recombinant human erythropoietin: effect on transfusion requirements and soluble adhesion molecules. Acta Haematol. 2004;111(4):189–95. [PMID: 15153710]

Chui D et al. Hemoglobin H disease: not necessarily a benign disorder. Blood. 2003 Feb 1;101(3):791–800. [PMID: 12393486]

Cohen AR. New advances in iron chelation therapy. Hematology Am Soc Hematol Educ Program. 2006:42–7. [PMID: 17124038]

Cunningham MJ et al. Thalassemia Clinical Research Network. Complications of beta-thalassemia major in North America. Blood. 2004 Jul 1;104(1):34–9. [PMID: 14988152]

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