Page 665 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 40 Thalassemia Syndromes 567

Clinical Manifestations pH demonstrates a fast-moving component amounting to 3% to
30% of the total Hb. Concomitant iron deficiency may reduce the
468
amount of Hb H in the patient’s RBCs. A syndrome of Hb H
+
Silent Carrier (α -Thalassemia Trait) disease associated with mental retardation, other congenital anoma-
lies, and large deletions on chromosome 16 has been noted in several
+
α -Thalassemia trait has no consistent hematologic manifestations. white families. 469,470
The RBCs are not microcytic, and Hb A 2 and Hb F are normal. The degree of deletions in Hb H is also relevant to clinical pre-
During the newborn period, small amounts (≤3%) of Hb Bart (γ 4) sentation. Deletional HbH occurs when three deletional alpha (0)
can be seen by electrophoresis or other techniques. This condition is mutations occur. Non-deletional HbH occurs when two deletional
most often recognized when an apparently normal individual becomes alpha(0) mutations occur with an alpha (+) mutation (e.g. Constant
the parent of a child with Hb H disease after mating with a person Spring). Nondeletional Hb H genotypes are more likely to have
with α°-thalassemia trait. The mild excess of β-globin chains is prob- higher percentage Hb H, more splenomegaly, and more advanced
+
458
ably removed in erythroblasts by proteolysis. α -Thalassemia is disease. 455
particularly common in Melanesia, as well as in Southeast Asia and
in African Americans, reaching a prevalence of more than 80% in
+
North coastal Papua New Guinea. At the molecular level, α - Hydrops Fetalis With Hb Bart
thalassemia has been found to be associated with two common gene
deletions resulting from different nonhomologous crossing-over Hydrops fetalis with Hb Bart occurs almost exclusively in Asians,
events between the two linked α-globin genes: a 3.7-kb rightward especially Chinese, Cambodians, Thais, and Filipinos. Affected
3.7
deletion (-α ) resulting in a fused α2α1-globin gene and a 4.2-kb fetuses are usually born prematurely and are either stillborn or die
1–4
4.2
leftward deletion (-α ) resulting in loss of the 5′ (α2) gene. 452,453,459 shortly after birth. Marked anasarca and enlargement of the liver
The level of α-globin gene expression differs in the two conditions, and spleen are present. Severe anemia is usually present, with Hb
as discussed in the following section. levels of 3–10 g/dL. The RBCs are markedly microcytic and hypo-
chromic and include target cells and large numbers of circulating
nucleated RBCs. These morphologic abnormalities and a negative
α-Thalassemia Trait (α-Thalassemia Trait) Coombs test result exclude hemolytic diseases caused by blood group
incompatibility. Hb electrophoresis reveals predominantly Hb Bart,
Levels of Hb A 2 in the low to low normal range (1.5–2.5%) and β/α with a smaller amount of Hb H. A minor component identified as
synthetic ratios averaging 1.4 : 1 characterize α°-thalassemia trait. Hb Portland (ζ 2 γ 2 ) migrating in the position of Hb A is also seen.
During the perinatal period, elevated amounts of Hb Bart are noted Normal Hb A and Hb F are totally absent. 471
(3–8%). Microcytosis is present in cord blood erythrocytes. Hydropic infants have massive hepatosplenomegaly. Extreme
Studies of newborns from the archipelago of Vanuatu in the extramedullary erythropoiesis occurs in response to the profound
Southwest Pacific and from Papua New Guinea indicate that homo- hypoxia and hemolytic anemia characteristic of this disease. The
zygotes for the rightward -α 3.7III deletion (where only a fused α2α1- universal edema characteristic of the hydrops fetalis syndrome is a
globin gene, mostly of the α2 type, remains) have lower Hb Bart levels reflection of severe congestive heart failure and hypoalbuminemia in
(3.5% ± 0.8%) than those of infants homozygous for the leftward utero. This is partly a consequence of anemia, but the strikingly
4.2
-α deletion (in whom only the α1-globin gene remains) (6.0% ± abnormal oxygen affinity of the tetrameric Hb Bart is probably the
1.4%). These results suggest that the 5′ α2-globin gene has a higher most important determinant of the severe tissue hypoxia. The oxygen
output than the 3′ α1-globin gene, a conclusion supported by direct dissociation curve of Hb Bart lacks the normal sigmoid form because
measurement of α2/α1 mRNA ratios. 460,461 of noncooperativity during oxygen loading and unloading and is
Hb H is not detected in hemolysates of peripheral RBCs, probably markedly shifted to the left. The shift is so great that little oxygen is
because of rapid proteolysis of Hb H or free β-globin chains. However, released under conditions of low oxygen concentration in the tissues.
approximately 1% of erythroblasts and BM reticulocytes have inclu- Infants with this syndrome do not die in an earlier trimester of
sions. When an α-thalassemia gene occurs in persons who are also pregnancy because of the presence of Hb Portland (ζ 2 γ 2 ). This Hb
heterozygous for α-globin chain variant Hbs, such as Hb S, Hb C, does display cooperativity in a manner similar to that of Hb F and
or Hb E, the proportion of the abnormal Hb is lower than that seen therefore has a much more favorable oxygen dissociation pattern than
462
in simple heterozygotes. The lower level of the abnormal Hb is that of Hb Bart. A high incidence of toxemia of pregnancy has been
attributable to posttranslational control because of higher affinity of described in women carrying severely affected infants, providing an
A
β chains for a limited pool of α-globin chains coupled with prote- increased rationale for prenatal diagnosis of this condition.
olysis of the uncombined β variant chains. 463
Prenatal Diagnosis of α-Thalassemia
Hemoglobin H Disease
472
Using molecular hybridization technology, Dozy and associates
Hb H disease is associated with a moderately severe but variable detected the complete absence of α-globin genes in fetal fibroblasts
anemia resembling thalassemia intermedia, with osseous changes and obtained by amniocentesis in a pregnancy at risk of homozygous
464
splenomegaly. However, the clinical phenotype may be consider- α-thalassemia and the hydrops fetalis syndrome. A quantitative
ably milder in some patients and severe enough to cause hydrops polymerase chain reaction (PCR) method provides similar informa-
473
fetalis in others. 465,466 It occurs predominantly in Asians and occasion- tion rapidly and accurately. The presence of hydrops can also be
ally in whites (Mediterranean) but is rare in persons of African detected by ultrasonography. DNA studies or globin synthesis evalu-
ancestry. Exacerbations of anemia during febrile illnesses are common ation may be used to confirm the diagnosis in utero. PCR-based
and are usually characterized by increasing fatigue and jaundice. assays are available for the detection of the common α-thalassemia
Adults with Hb H develop some of the same complications as deletions. 473–476
β-thalassemia including osteoporosis, cholelithiasis, and iron
overload. 467
Because Hb H is unstable and precipitates within the circulating Therapy
RBCs, hemolysis occurs. Hb H can be demonstrated by incubation
of blood with supravital oxidizing stains such as 1% brilliant cresyl Fetuses with homozygous α°-thalassemia usually die in utero because
blue. Multiple small inclusions form in the RBCs (see Fig. 40.15). of severe hydrops fetalis and are stillborn. However, some infants
Electrophoresis of a freshly prepared hemolysate at alkaline or neutral have had successful blood exchange transfusion immediately after