Page 650 - Hematology_ Basic Principles and Practice ( PDFDrive )

552 Part V Red Blood Cells

player in determining the rate of erythroid iron intake, modulating
erythropoiesis. In turn, erythropoiesis influences hepcidin expression
in the liver. Therefore, reducing the saturation levels of Tf might
have beneficial effects in β-thalassemia, decreasing formation of
hemichromes in the RBCs as well as the florid erythropoiesis that
suppresses hepcidin expression in the liver. In fact, chronic treatment
with apo-Tf injections in Hbbth1/th1 mice (another murine model of
thalassemia intermedia) results in increased Hb production, decreased
reticulocytosis and serum EPO levels, reverses splenomegaly, and
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elevates hepcidin expression. Apo-Tf injections reduce hemichrome
formation and change the proportion of erythroid precursors to more
mature relative to immature precursors, lower the rates of apoptosis in
mature erythroid precursors, and reduce the amount of extramedullary
erythropoiesis in the liver and spleen in Hbbth1/th1 mice. Theses
injections also resulted in iron unloading in tissues, normalization
of anemia, transferrin saturation, and suppression nontransferrin
bound iron levels in plasma. The addition of exogenous apo-Tf
results in decreased Tf saturation and likely a shift toward more
monoferric-Tf molecules with more Tf molecules available to deliver
smaller amounts of iron to more erythroid precursors, resulting in Fig. 40.6 MORPHOLOGIC APPEARANCE OF THE PERIPHERAL
further decreased mean corpuscular hemoglobin (MCH) and fewer BLOOD FILM IN A CASE OF SEVERE β-THALASSEMIA. Note the
hemichromes. Apo-Tf injections also appear to alter erythroferrone bizarre cells, the hypochromia, nucleated red blood cells, target cells, and
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expression, HAMP, plasma hepcidin, and ferroportin. Future polychromasia.
studies of apo-Tf will be important in understanding iron regulation
in vivo.
Clinical Manifestations the first months of life. When the child becomes symptomatic, the
Hb level may be as low as 3–4 g/dL. RBC morphology is strikingly
abnormal, with many microcytes, bizarre poikilocytes, teardrop cells,
Clinical Findings at Diagnosis and target cells (Fig. 40.6). A characteristic finding is the presence of
extraordinarily hypochromic, often wrinkled and folded cells (lepto-
Protected by prenatal Hb F production, infants with β-thalassemia cytes) containing irregular inclusion bodies of precipitated α-globin
major are born free of significant anemia. Nevertheless, deficient β- chains.
chain synthesis can be demonstrated at birth. Clinical manifestations
usually emerge during the second 6 months of life as the consequences
of defective β-globin synthesis on overall Hb production become Clinical Heterogeneity of Thalassemia
more pronounced. The diagnosis is almost always evident by 2 years
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of age. Pallor, irritability, growth retardation, abdominal swelling The severity of β-thalassemia is remarkable for its variability in dif-
caused by enlargement of the liver and spleen, and jaundice are the ferent patients. Two siblings inheriting identical thalassemia muta-
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usual presenting features. Facial and skeletal changes caused by BM tions sometimes exhibit markedly different degrees of anemia and
expansion develop later. erythroid hyperplasia. Many factors contribute to this clinical hetero-
geneity. Individual alleles vary with respect to severity of the biosyn-
Clinical Findings in Untreated or thetic lesion. Other modifying factors ameliorate the burden of
unpaired α-globin. High levels of Hb F expression persist to widely
Undertreated Patients various degrees in β-thalassemia. Because γ-globin can substitute for
β-globin, simultaneously generating more functional Hbs and reduc-
Untreated patients die in late infancy or early childhood as a conse- ing the α-globin inclusion burden, this is a powerful modulating
quence of severe anemia. In a retrospective review from Italy, the factor. Theoretically, patients may also vary in their ability to solubi-
average survival of children with untreated thalassemia major was less lize unpaired globin chains by proteolysis. Occasional heterozygous
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than 4 years; approximately 80% died in the first 5 years of life. patients have had more severe anemia than expected, possibly because
Patients who receive transfusions sporadically may live somewhat of defects in these proteolytic systems or because of the type of thalas-
longer than untransfused patients, but their quality of life is extremely semic mutation. Inheritance of more than the usual complement of
poor as a result of both the chronic anemia and the IE. The low Hb α-globin genes may also increase with severity of β-thalassemia
level and massive organomegaly are usually disabling, and the changes because of additional production of unpaired α-globin chains. All of
in the facial bones are disfiguring. After 10 to 20 years of weakness, these factors emphasize the essential role of α-globin inclusions in
stunted growth, and impaired activity, the undertransfused patients the pathophysiology of β-thalassemia.
usually succumb to congestive heart failure. Nucleated RBCs are frequently present in peripheral circula-
This disastrous symptom constellation, so prevalent in the past, tion. The reticulocyte count is 2% to 8% lower than would be
is now rare in North America and most industrialized countries. expected in view of the extreme erythroid hyperplasia and hemolysis.
Nonetheless, the clinical manifestations and complications of The low count reflects the severity of intramedullary erythroblast
untreated or undertreated β-thalassemia major illustrate the principles destruction. The white blood cell count is elevated. A moderate
of the pathophysiology. Furthermore, these descriptions accurately polymorphonuclear leukocytosis and normal platelet count are
characterize the disease that is still prevalent in many parts of the typical unless hypersplenism has developed. The BM exhibits marked
world. hypercellularity caused by erythroid hyperplasia. The RBC precur-
sors show defective hemoglobinization and reduced amounts of
cytoplasm.
Initial Laboratory Findings The osmotic fragility is strikingly abnormal. The RBCs are so
markedly resistant to hemolysis in hypotonic sodium chloride solu-
The anemia of thalassemia major is characterized by severe hypochro- tion that some are not entirely hemolyzed even in distilled water.
mia and microcytosis. The Hb level decreases progressively during Before transfusion therapy is initiated, the serum iron and transferrin