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742 Part VI: The Erythrocyte Chapter 48: The Thalassemias: Disorders of Globin Synthesis 743

SPLENOMEGALY: DILUTIONAL ANEMIA own siderophore and hence can thrive in iron excess. Transfusion-
Constant exposure of the spleen to red cells with inclusions consisting dependent patients with thalassemia are at particular risk for blood-
of precipitated globin chains gives rise to the phenomenon of “work borne infections including hepatitis B, hepatitis C, HIV/AIDS, and, in
hypertrophy.” Progressive splenomegaly occurs in both α- and β-thalas- some parts of the world, malaria.
semia and may worsen the anemia. A large spleen acts as a sump for
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red cells, sequestering a considerable proportion of the red cell mass. COAGULATION DEFECTS
Furthermore, splenomegaly may cause plasma volume expansion, a
complication that can be exacerbated by massive expansion of the ery- The increasing knowledge about the potential hypercoagulable state
throid marrow. The combination of pooling of the red cells in the spleen in some forms of thalassemia has been reviewed in detail. 174–176,190 Evi-
and plasma volume expansion can exacerbate the anemia in both α- and dence indicates that patients, particularly after splenectomy and with
β-thalassemia. high platelet counts, may develop progressive pulmonary arterial dis-
ease as a result of platelet aggregation in the pulmonary circulation.
Furthermore, using thalassemic red cells as a source of phospholipids,
ABNORMAL IRON METABOLISM enhanced thrombin generation has been demonstrated in a prothrom-
β-Thalassemia homozygotes that are anemic manifest increased intes- binase assay. The procoagulant effect of thalassemia cells appears to
tinal iron absorption that is related to the degree of expansion of the result from increased expression of anionic phospholipids on the red
red cell precursor population. Iron absorption is decreased by blood cell surface (Chap. 33). Normally, neutral or negatively charged phos-
transfusion. Increased absorption causes a steady accumulation of pholipids are confined to the inner leaflet of the red cell membrane, an
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iron, first in the Kupffer cells of the liver and the macrophages of the effect that is mediated by the action of aminophospholipid translocase,
spleen and later in the parenchymal cells of the liver. Most patients an enzyme sometimes known as flippase. In effect, this enzyme flips
homozygous for β-thalassemia require regular blood transfusion; thus, aminophospholipids that are diffused to the outer leaflet back to the
transfusional siderosis adds to the iron accumulation. Iron accumu- inner leaflet (Chaps. 31 and 46). The current belief is that these amin-
lates in the endocrine glands, 7,186 particularly in the parathyroids, pitu- ophospholipids in thalassemic red cells are moved to the outer leaflet,
itary, pancreas, skin leading to increased pigmentation, liver, and, most thus providing a surface on which coagulation can be activated. Other
important, in the myocardium. 7,187 Iron accumulation in the myocar- nonspecific changes in the coagulation pathway and its antagonists have
dium leads to death by involving the conducting tissues or by causing been observed in patients with different forms of thalassemia.
intractable cardiac failure. Other consequences of iron loading include There is increasing evidence that, as in the case of sickle cell anemia
diabetes, hypoparathyroidism, hypothyroidism, and abnormalities of (Chap. 49), the hemolytic component of the anemia of β-thalassemia
hypothalamic–pituitary function leading to growth retardation and is associated with the release of hemoglobin and arginase resulting in
hypogonadism. 7,186 Recent work on the mechanisms of hepcidin down- impaired nitric oxide availability and endothelial dysfunction with pro-
191
regulation in association with marrow hypertrophy provides a much gressive pulmonary hypertension. There may be other contributions
better understanding of the mechanisms of iron loading in diseases like to this complication including increased coagulability and local struc-
thalassemia and may provide new therapeutic options for the future tural damage to the lungs relating to excess iron deposition.
(Chap. 43 and Ref. 188).
Accurate information is available regarding the levels of body CLINICAL HETEROGENEITY
iron, as reflected by hepatic iron, at which patients are at risk for seri-
ous complications of iron overload. 7,189 These studies, which extrapolate The pathophysiologic mechanisms described above provide the basis
data obtained from patients with genetic hemochromatosis, suggest that for the remarkably diverse clinical findings in the thalassemia syn-
patients with hepatic iron levels of approximately 80 μmol of iron per dromes. 7,192 All the manifestations of β-thalassemia can be related
gram of liver, wet weight (~15 mg of iron per gram of liver, dry weight), to excess α-chain production. Thus, any mechanism that reduces the
are at increased risk for hepatic disease and endocrine organ damage. excess of α chains should reduce the clinical severity of the disease. Sev-
Patients with higher body iron burdens are at particular risk for cardiac eral elegant “experiments of nature” have shown that this reasoning is
disease and early death (Chap. 43). true and, incidentally, have confirmed that globin-chain imbalance is
Disordered iron metabolism is less common in the adult forms of the major factor determining the severity of the thalassemias.
α-thalassemia. The milder degree of anemia, fewer transfusions, and the Coinheritance of α-thalassemia can reduce the severity of the more
less marked erythroid expansion of the marrow are likely explanations. severe forms of β-thalassemia. 193,194 The effect is much more marked in
The mechanisms whereby iron, and in particular non–transferrin- individuals who are homozygotes or compound heterozygotes for dif-
+
0
bound iron mediate tissue damage, and recent evidence about the cen- ferent forms of β -thalassemia. β -Thalassemia homozygotes who have
tral role of hepcidin in the abnormal regulation of iron absorption in inherited α-thalassemia seem to be protected little, if at all.
disorders like thalassemia are discussed in Chap. 42. Severe β-thalassemia can be modified by the coinheritance of
genetic determinants for enhanced production of γ chains. Several
determinants may be involved. For example, inheritance of a particular
INFECTION RFLP haplotype in the region 5′ to the β-globin gene may be an impor-
All forms of severe thalassemia appear to be associated with an increased tant factor. 195,196 This particular β-globin gene haplotype is associated
susceptibility to bacterial infection. The reason is not known. The rel- with a single base change, C→T, at position –158 relative to the γ-globin
G
7
atively high serum iron levels may favor bacterial growth. Another gene, an alteration that creates a cleavage site for the restriction enzyme
possible mechanism is blockade of the monocyte–macrophage system XmnI. An excess of individuals homozygous for T (XmnI+ +)
121
as a result of the increased rate of destruction of red cells. No consis- with the phenotype of thalassemia intermedia exist compared with
tent defects in white cell or immune function have been reported, and thalassemia major in different populations. 196–198 Whether this poly-
high serum iron levels as an important factor remain to be unequiv- morphism is the only factor that increases hemoglobin F production
ocally demonstrated. The one exception is infection with Yersinia in these cases is not absolutely clear. As discussed under “Hereditary
enterocolitica, a normally nonvirulent pathogen that can produce its Persistence of Fetal Hemoglobin” above, it is now clear that there are

Kaushansky_chapter 48_p0725-0758.indd 742 9/18/15 2:57 PM