Thalassemia Syndromes

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Chapter 13 Thalassemia Syndromes

Patricia J. Giardina, Stefano Rivella

Table 13-1 Common β-Thalassemia Mutations in Different Racial Groups

Racial Group	Description
Mediterranean	IVS-1, position 110 (G → A)
	Codon 39, nonsense (CAG → TAG)
	IVS-1, position 1 (G → A)
	IVS-2, position 745 (C → G)
	IVS-1, position 6 (T → C)
	IVS-2, position 1 (G → A)
Black	-34 (A → G)
	-88, (C → T)
	Poly(A), (AATAAA → AACAAA)
Southeast Asian	Codons 41/42, frameshift (-CTTT)
	IVS-2, position 654 (C → T)
	-28 (A → T)
Asian Indian	IVS-1, position 5 (G → C)
	619-bp deletion
	Codons 8/9, frameshift (++G)
	Codons 41/42, frameshift (–CTTT)
	IVS-1, position 1 (G → T)

Data from Kazazian HH Jr, Boehm CD: Molecular basis and prenatal diagnosis of beta-thalassemia. Blood 72(4):1107, 1988; and Kazazian HH Jr, Boehm CD: personal communication, 1993.

Figure 13-1 PATHOPHYSIOLOGY OF SEVERE FORMS OF β-THALASSEMIA.

The diagram outlines the pathogenesis of clinical abnormalities resulting from the primary defect in β-globin chain synthesis. RBC, Red blood cell.

Clinical Heterogeneity of Thalassemia

The severity of β-thalassemia is remarkable for its variability in different patients. Two siblings inheriting identical thalassemia mutations sometimes exhibit markedly different degrees of anemia and erythroid hyperplasia. Many factors contribute to this clinical heterogeneity. Individual alleles vary with respect to severity of the biosynthetic lesion. Other modifying factors ameliorate the burden of unpaired α-globin. High levels of Hb F expression persist to widely various degrees in β-thalassemia. Because γ-globin can substitute for β-globin, simultaneously generating more functional hemoglobins and reducing the α-globin inclusion burden, this is a powerful modulating factor. Theoretically, patients may also vary in their ability to solubilize unpaired globin chains by proteolysis. Occasional heterozygous patients have had more severe anemia than expected, possibly because of defects in these proteolytic systems or because of the type of thalassemic mutation. Inheritance of more than the usual complement of α-globin genes may also increase with severity of β-thalassemia because of additional production of unpaired α-globin chains. All of these factors emphasize the essential role of α-globin inclusions in the pathophysiology of β-thalassemia.

Figure 13-2 MORPHOLOGIC APPEARANCE OF THE PERIPHERAL BLOOD FILM IN A CASE OF SEVERE β-THALASSEMIA.

Note the many bizarre cells, the hypochromia, nucleated red blood cells, target cells, and leptocytes.

(From Pearson HA, Benz EJ Jr: Thalassemia syndromes. In Miller DR, Baehner RL, McMillan CW, editors: Smith’s blood diseases of infancy and childhood, ed 5, St. Louis, 1984, CV Mosby, p 439.)

Guidelines for Transfusion Therapy

Although some of the details of a transfusion program for patients with thalassemia major vary from center to center, the following guidelines are important for achieving the benefits while controlling the risks of a transfusion program. The rationales for these guidelines are discussed in the text.

1. Obtain a complete RBC antigen profile before the first transfusion.

2. Administer 10 to 15 mL/kg of RBCs every 2 to 4 weeks to maintain the pretransfusion hemoglobin level above 9 to 10.5 g/dL.

3. Use leukoreduced RBCs that have been stored for less than 7 to 10 days.

4. Avoid the use of first-degree relatives as blood donors.

5. For patients who come to a new center after receiving transfusions elsewhere, contact the previous blood bank for information about alloantibodies.

Deciding to Begin Transfusion Therapy in Patients With Thalassemia

The decision to initiate regular RBC transfusions is one of the most important—and sometimes most difficult—steps in the management of patients with thalassemia. Regular RBC transfusions not only distinguish thalassemia major from thalassemia intermedia but also commit the patient to long-term chelation therapy to control the transfusional iron loading. The decision should include consideration of both clinical and laboratory findings. Children who are growing poorly and developing disfiguring bone changes will benefit from regular transfusions even if their hemoglobin levels are 8 to 9 g/dL. On the other hand, children who are asymptomatic at hemoglobin levels of 7 to 8 g/dL may have little to gain from transfusions. Hemoglobin levels below 7 g/dL are usually associated with problems related to both the anemia and the compensatory erythropoiesis. When the hemoglobin level is consistently less than 7 g/dL, there is usually little to be gained from delaying transfusion.

Benefits of Iron Chelation Therapy

More than 30 years of experience using iron chelation therapy with deferoxamine in thalassemia major patients have demonstrated that:

1. Liver iron concentrations can be maintained at normal or mildly elevated levels.

2. Hepatic fibrosis is slowed or prevented.

3. The risk of iron-induced cardiac disease, including heart failure and serious arrhythmias, is markedly decreased.

4. Normal growth and sexual development are common but not universal.

5. Long-term survival is substantially improved. These benefits are directly related to compliance and generally require the prolonged administration of deferoxamine at least five times per week.

6. Long-term safety and efficacy studies of the oral iron chelators deferiprone and deferasirox are ongoing.

Assessment of Iron Stores

Because excess transfusional iron cannot be actively excreted it is deposited in the macrophages of the RES. When the RES is overwhelmed, iron spills over into parenchymal tissue, generating free radical damage with cellular membrane lipid peroxidation and leading to end-organ dysfunction, especially of the liver, endocrine system, and myocardium.

The best strategy for monitoring iron accumulation in patients with thalassemia remains controversial. Multiple approaches should be considered to assess iron stores, including transfusion requirements, ongoing transfusion burdens, serum ferritin, and liver and cardiac iron concentration. Before chelation therapy is begun, careful recording of transfusion volumes provides an accurate assessment of iron loading. Each milliliter of RBCs contains approximately 1.1 mg of iron. Therefore, each unit of blood contains approximately 200 mg of iron. The total transfusional iron intake can be calculated from the transfusion record and should be as useful in determining the need to begin chelation therapy as indirect or direct measures of body iron stores. Chelation therapy is initiated after approximately 10 to 25 units of blood have been transfused, serum ferritin levels are above 1000 mg/mL, and liver iron concentration is greater than 3 mg Fe/g dry weight. However, when chelation therapy has been initiated, iron is going out as well as coming in. Under these circumstances, regular assessment of iron stores is needed to determine the severity of iron overload and to achieve an optimal treatment program.

Measurement of liver iron concentration by biopsy provides a direct assessment of tissue iron loading and reflects total body iron stores but liver biopsy requires a skilled technician, at least 1 mg of tissue at least 2.5 cm in length with five portal tracts and has the risk of hemorrhage. MRI changes in R2 reflects liver iron concentration comparable to that on liver biopsy. The use of MRI to estimate hepatic and cardiac iron in patients with transfusional siderosis has largely replaced liver biopsy for liver iron concentration quantification at the start of chelation therapy and with annual assessments. Future MRI use may involve the quantification of iron concentration of endocrine glands to predict or monitor dysfunction.¹^–³ Levels between 3 and 7 mg Fe/g dry weight appear to be associated with minimal toxicity. Levels greater than 15 mg Fe/g dry weight are associated with an increased risk of heart disease. Recent experience with cardiac magnetic resonance imaging suggests that changes in T2* reflect levels of iron in the heart and may predict adverse changes in cardiac function.

Serum ferritin levels are safe, inexpensive, and readily available, and serial measurements are predictive both of critical complications such as iron-induced heart disease and of adverse effects of chelation therapy such as impairment of vision and hearing. However, single ferritin levels may correlate poorly with liver iron concentration because it is an acute phase reactant and may be influenced by inflammation, vitamin C deficiency, hepatitis, and other infectious states. Transferrin saturation is not very useful in evaluating the severity of iron overload in patients with thalassemia because the massive IE usually results in a transferrin saturation greater than 60% even in the absence of iron overload.⁴

Noninvasive hepatic MRI of liver iron by R2 changes correlates with liver iron concentration by biopsy but cannot be used in patients with pacemakers or those who are claustrophobic.

Figure 13-3 BONY ABNORMALITIES IN A PATIENT WITH SEVERE β-THALASSEMIA.

A and B, “Hair-on-end” appearance of the skull, especially obvious in the close-up view shown in part B. C, Distortion of the maxillary bones, as well as poor development of the sinus cavities caused by opaque masses of extramedullary erythropoiesis. D, Squaring and convexity abnormalities of the hands.

(From Pearson HA, Benz EJ Jr: Thalassemia syndromes. In Miller DR, Baehner RL, McMillan CW, editors: Smith’s blood diseases of infancy and childhood, ed 5, St. Louis, 1984, CV Mosby, p 439.)

Figure 13-4 COMPRESSION FRACTURE OF L2 VERTEBRA IN A PATIENT WITH SEVERE β-THALASSEMIA.

(From Pearson HA, Benz EJ Jr: Thalassemia syndromes. In Miller DR, Baehner RL, McMillan CW, editors: Smith’s blood diseases of infancy and childhood, ed 5, St. Louis, 1984, CV Mosby, p 439.)

Table 13-2 Survival by Birth Cohort at Different Ages of Patients With Transfusion-Dependent Thalassemia

Data from Borgna Pignatti C, Rugolotto S, De Stefano X, et al: Survival and disease complications in thalassemia major. Ann N Y Acad Sci 850:227, 1998.

Figure 13-5 MORPHOLOGY OF THE PERIPHERAL BLOOD FILM IN A PATIENT WITH HETEROZYGOUS β-THALASSEMIA (A) AND A PATIENT WITH HETEROZYGOUS α-THALASSEMIA (B).

Note the profound hypochromia and microcytosis and the many target cells.

(From Pearson HA, Benz EJ Jr: Thalassemia syndromes. In Miller DR, Baehner RL, McMillan CW, editors: Smith’s blood diseases of infancy and childhood, ed 5, St. Louis, 1984, CV Mosby, p 439.)

Figure 13-6 PATHOPHYSIOLOGY OF HEMOGLOBIN (HB) H DISEASE AND HYDROPS FETALIS WITH HB BART.

(Adapted from Benz EJ Jr: The hemoglobinopathies. In Kelly WN, DeVita VT, editors: Textbook of internal medicine, Philadelphia, 1988, JB Lippincott, p 1423.)

References

1 Wood JC. Impact of iron assessment by MRI. Hematology Am Soc Hematol Educ Program. 443, 2011.

2 Au WY, Lam WW, Chu W, et al. A T2* magnetic resonance imaging study of pancreatic iron overload in thalassemia major. Haematologica. 2008;93:116.

3 Noetzli LJ, Papudesi J, Coates TD, et al. Pancreatic iron loading predicts cardiac iron loading in thalassemia major. Blood. 2009;114:4021.

4 Finch CA, Huebers H. Perspectives in iron metabolism. N Engl J Med. 1982;306:1520.