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Clinical Nomenclature Genotype Disease Molecular Genetics

b-Thalassemias

Thalassemia major Homozygous b0 -thalassemia (b0 /b0 ) Severe; requires blood transfusions

Rare gene deletions in b0 /b0

Defects in transcription, processing, or

translation of b-globin mRNA

Homozygous b+ -thalassemia (b+ /b+ )

Thalassemia intermedia b0 /b Severe, but does not require regular blood transfusions

b+ /b+

Thalassemia minor b0 /b Asymptomatic with mild or absent anemia; red cell

abnormalities seen

b+ /b

a-Thalassemias

Hydrops fetails -/- -/- Lethal in utero without transfusions

Mainly gene deletions

HbH disease -/- -/a Severe; resembles b-thalassemia intermedia

a-Thalassemia trait -/- a/a (Asian) Asymptomatic, like b-thalassemia minor

-/a -/a (black African)

Silent carrier -/a a/a Asymptomatic; no red cell abnormality

the following discussions of thalassemia major and minor ( Table 13-3 ).

Thalassemia Major.

b-Thalassemia is most common in Mediterranean countries and parts of Africa and Southeast Asia. In the United States, the incidence is highest in immigrants from these areas. As

indicated in Table 13-3 , the genotype of affected patients can be b+ /b+ , b0 /b0 , or b0 /b+ . With all these genotypes, the anemia manifests 6 to 9 months after birth, as hemoglobin

synthesis switches from HbF to HbA. In untransfused patients, hemoglobin levels range between 3 and 6 gm/dL. The peripheral blood smear shows severe red cell morphologic

abnormalities, including marked anisocytosis and poikilocytosis (variation in size and shape, respectively), microcytosis (small size), and hypochromia (poor hemoglobinization). Target

cells (so called because hemoglobin collects in the center of the cells), basophilic stippling, and fragmented red cells are also common. Inclusions of aggregated a chains are efficiently

removed by the spleen and not easily found in peripheral blood smears. The reticulocyte count is elevated, but because of ineffective erythropoiesis is lower than expected for the severity

of anemia. Variable numbers of poorly hemoglobinized normoblasts are seen in the peripheral blood due to "stress" erythropoiesis and abnormal release of progenitors from sites of

extramedullary hematopoiesis. The red cells can completely lack HbA (b0 /b0 genotype) or contain small amounts (b+ /b+ or b0 /b+ genotypes). HbF is markedly increased and indeed

constitutes the major red cell hemoglobin. HbA2 levels may be normal, low, or high.

Morphology.

The major morphologic alterations, in addition to those found in all hemolytic anemias, involve the bone marrow and spleen. In the untransfused patient, there is striking expansion of

hematopoietically active marrow, particularly in facial bones. This erodes existing cortical bone and induces new bone formation, giving rise to a "crew-cut" appearance on X-rays ( Fig. 13-

15 ). Both mononuclear phagocytic cell hyperplasia and extramedullary hematopoiesis contribute to enlargement of the spleen, which can weigh up to 1500 gm.



Figure 13-15Thalassemia: x-ray film of the skull showing new bone formation on the outer table, producing perpendicular radiations resembling a crew-cut. (Courtesy of Dr. Jack

Reynolds, Department of Radiology, University of Texas Southwestern Medical School, Dallas, TX.)

Figure 13-16Two kinds of membrane proteins: transmembrane and glycosyl phosphatidyl inositol (GPI)-linked. The latter are anchored to cell membranes through a covalent attachment

to a glycosyl phospatidyl inositol moiety. In PNH, GPI cannot be synthesized, leading to a global deficiency of GPI-linked membrane proteins.

TABLE 13-4-- Classification of Immunohemolytic Anemias

Warm Antibody Type

The antibody is of the IgG type, does not usually fix complement, and is active at 37°C.

Primary (idiopathic)

Secondary

••Lymphomas and leukemias

••Other neoplastic diseases

••Autoimmune disorder (particularly systemic lupus erythematosus)

••Drugs


Date: 2016-04-22; view: 609


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