Page 776 - Williams Hematology ( PDFDrive )

750 Part VI: The Erythrocyte Chapter 48: The Thalassemias: Disorders of Globin Synthesis 751

raised hemoglobin A levels is characterized by a clinical picture of been reported. 7,9,10 Particularly well-characterized disorders include the
2
0
+
severe transfusion-dependent β-thalassemia. Family data obtained in various interactions of α - and α -thalassemia with hemoglobin E 7,234
Italy and Sardinia suggest this condition represents the compound het- and hemoglobin S (Chap. 49). 254,255 Carriers for these hemoglobin vari-
erozygous state for both β-thalassemia and δ-thalassemia. 244,245 Most of ants who also have the α - or α -thalassemia traits have thalassemic
+
0
the δ-thalassemias have been observed trans to β-thalassemia. However, red cell indices and unusually low levels of the abnormal hemoglo-
the form of δ-thalassemia resulting from loss of an A in codon 59 occurs bin. Individuals with sickle cell anemia who have α-thalassemia show
on the same chromosome as the hemoglobin Knossos mutation, which thalassemic red cell changes, more persistent splenomegaly, and lower
246
is associated with a mild form of β-thalassemia. This finding explains hemoglobin F values than do patients without the thalassemia genes.
the normal level of hemoglobin A associated with this condition, which
2
is the most common form of normal hemoglobin A β-thalassemia in
2
the Mediterranean region. THERAPY, COURSE, AND PROGNOSIS
Several other conditions, mentioned earlier in this chapter in “Eti-
ology and Pathogenesis,” are associated with a phenotype that is indis- The only forms of treatment available for thalassemic children are reg-
tinguishable from normal A β-thalassemia. These conditions include ular blood transfusions, iron chelation therapy in an attempt to prevent
2
the heterozygous states for the Corfu form of δβ-thalassemia and iron overload, judicious use of splenectomy in cases complicated by
εγδβ-thalassemia. hypersplenism, and a good standard of general pediatric care. 7,9,256 Mar-
row transplantation has an important role in selected cases (Chap. 23).
OTHER UNUSUAL FORMS OF β-THALASSEMIA TRANSFUSION
The clinical features of the dominant β-thalassemias resemble the fea-
tures of thalassemia intermedia. Moderate anemia and splenomegaly Children with β-thalassemia who are maintained at a hemoglobin level
7
are seen, with a blood picture showing thalassemic red cell changes. of 9.5 to 14.0 g/dL grow and develop normally. They do not develop
The marrow shows erythroid hyperplasia with well-marked inclusion the distressing skeletal complications of thalassemia. 7,256 Maintaining a
bodies in the red cell precursors. The latter may be seen in the blood lower hemoglobin level than this range without any deleterious effects
after splenectomy. Hemoglobin analysis shows hemoglobins A and A on development and with the added advantage of reducing the level
2
are present, and the hemoglobin F level is not usually elevated much of iron loading may be possible. This regimen maintains a mean pre-
257
higher than that seen in β-thalassemia trait. Hemoglobin A levels are transfusion level that does not exceed 9.5 g/dL. A transfusion pro-
2
always raised. gram should not be started too early, and it should be initiated only
Other unusual varieties of β-thalassemia include those categorized when the hemoglobin level is too low to be compatible with normal
by unusually high hemoglobin F or A levels. Most of these conditions development. If transfusion is started too soon, thalassemia intermedia
2
result from deletions involving the β-globin gene and its promoter may be missed, and the child may be transfused unnecessarily. Usually
region. For example, the so-called Dutch form of β-thalassemia is blood transfusions are given every 4 weeks on an outpatient basis. To
247
associated with unusually high hemoglobin F levels in heterozygotes and avoid transfusion reactions, washed, filtered, or frozen red cells should
high hemoglobin A levels. Several other conditions of this type, which be used so that the majority of the white cells and plasma-protein com-
2
result from different-size deletions, have been reported (see Ref. 7). ponents are removed (Chap. 138).
δ -THALASSEMIA IRON CHELATION
0
0
δ -Thalassemia causes a complete absence of hemoglobin A in homozy- Every child who is maintained on a high-transfusion regimen ulti-
2
248
gotes and a reduced hemoglobin A level in heterozygotes. It is of no mately develops iron overload and dies of siderosis of the myocardium.
2
clinical significance except for its effect of reducing hemoglobin A lev- Therefore, such children must be started on a program of iron chelation
2
256
els in β-thalassemia heterozygotes. within the first 2 to 3 years of life. Deferoxamine (desferrioxamine)
was the first chelating agent of proven long-term value for treatment
of thalassemia. It is best administered by an 8- to 12-hour overnight
εγδβ-THALASSEMIA pump-driven infusion in the subcutaneous tissues of the anterior
This heterogeneous condition has been observed only in the hete- abdominal wall. 258,259 Chelation therapy should commence by the time
rozygous state in a few families. 7,108,109 It is characterized by neonatal the serum ferritin level reaches approximately 1000 mcg/dL. In practice,
hemolysis and, in adult life, by the hematologic picture of heterozygous this level usually is seen after the 12th to 15th transfusion. To prevent
β-thalassemia with normal hemoglobin A levels. toxicity, infants must not be overchelated when the iron burden is still
2
low. The initial dose usually is 20 mg/kg 5 nights per week, with 100
α-THALASSEMIA IN ASSOCIATION WITH mg of oral vitamin C (200 mg in older children and adults) on the day
of infusion, after the infusion has been initiated. Some evidence and
259
α- AND β-CHAIN HEMOGLOBIN VARIANTS widespread opinion indicate ascorbate precipitates myocardiopathy in
Several α-globin structural variants are caused by single amino acid these patients if it is given before deferoxamine infusion is started. 260,261
substitutions at α-chain loci on chromosomes that carry only a single In patients who are heavily iron loaded, particularly those patients with
α-chain gene. Individuals who inherit variants of this type and an α - cardiac or endocrine complications, the body iron stores can be effec-
0
thalassemia determinant have a form of hemoglobin H disease in which tively lowered by continuous intravenous infusion of deferoxamine at
the hemoglobin consists of the α-chain variant hemoglobin and hemo- a dose of up to 50 mg/kg body weight. The procedure usually entails
globin H. Well-documented examples include hemoglobin QH disease insertion of an intravenous delivery system.
(– –/–α ), hemoglobin G Philadelphia H disease (– –/–α ), Extensive experience with the use of deferoxamine and its toxic
G 251,252
Q 249,250
). Many examples of
and hemoglobin Hasharon H disease (– –/–α Hash 253 effects has been reported. No serious complications occur other than
189
the coexistence of the homozygous or heterozygous states for β-chain local erythema and painful subcutaneous nodules at the site of infu-
hemoglobin variants and different α-thalassemia determinants have sions and extremely rare severe allergic reactions. These reactions can

Kaushansky_chapter 48_p0725-0758.indd 751 9/18/15 2:58 PM