Sections View Full Chapter Figures Tables Videos Annotate Full Chapter Figures Tables Videos Supplementary Content + DEFINITION Download Section PDF Listen +++ ++ Each of these disorders results from an inherited defect in the rate of synthesis of one or another of globin chains. Resultant imbalance of globin chain production may cause ineffective erythropoiesis, defective hemoglobin production, red cell hemoglobin precipitates, hemolysis, anemia of variable degree and propensity to iron overload. + ETIOLOGY AND PATHOGENESIS Download Section PDF Listen +++ +++ Genetic Control and Synthesis of Hemoglobin ++ Each hemoglobin (Hb) molecule consists of two separate pairs of identical globin chains. All normal human Hb molecules found in an adult have one pair of α-chains. The α-chains can combine with β-chains (α2β2), δ-chains (α2δ2), and γ-chains (α2γ2). Adult Hb is ~97% Hb A (α2β2), ~0.5% Hb F α2γ2, and ~2.5% Hb A2 (α2δ2). In fetal life, Hb F (α2γ2) predominates. Position 136 of some γ-chains is occupied by glycine and in others by alanine. These are designated Gγ and Aγ, respectively. At birth Hb F is a mixture of α2Gγ2 and α2Aγ2 in a ratio of 3:1. In embryonic life, Hb Gower 1 is composed of dimers of zeta (ζ) and epsilon (ε) globins (ζ2ε2). Hb Gower 2 (α2ε2) and Hb Portland (ζ2γ2) are only present before the 8th week of intrauterine life. During fetal life, globin gene expression switches occur from ζ- to α- and from ∈- to γ-chain production, followed by β- and δ-chain production at perinatal life. +++ Globin Gene Clusters ++ α-Gene cluster (chromosome 16) consists of one functional ζ gene and two α genes (α2 and α1). Exons of the two α-globin genes have identical coding sequences; however, they differ in second intron. Production of α2 mRNA exceeds that of α1, by factor of 1.5 to 3. β-Gene cluster (chromosome 11) consists of one functional ∈ gene, a Gγ gene, an Aγ gene, a pseudo β gene, a δ gene, and a β gene. Flanking regions contain conserved sequences essential for gene expression. +++ Regulation of Globin Gene Clusters ++ Primary transcript is a large mRNA precursor, with both intron and exon sequences, which is extensively processed in the nucleus to yield the final mRNA. Expression of the globin genes is regulated by complex control mechanisms. +++ Developmental Changes in Globin Gene Expression ++ β-Globin produced at low levels beginning at 8 to 10 weeks of fetal life increases considerably at about 36 weeks gestation. γ-Globin produced at high levels early starts to decline at ~36 weeks. At birth, β-globin and γ-globin production are approximately equal. By age 1 year, γ-globin production is less than 1% of total non–α-globin production. Mechanism of switches is being elucidated and involve BCL11A and leukemia-related factor encoded by the ZBTB7A gene. Fetal Hb synthesis may be reactivated in adults in some disease states by a yet unknown mechanism. + MOLECULAR BASIS OF THE THALASSEMIAS Download Section PDF Listen +++ ++ A large number of mutations cause thalassemia (eg, more than 200 for β-thalassemia). The molecular basis of the thalassemias is discussed in detail in Chap. 48 in Williams Hematology, 9th ed. + DIFFERENT FORMS OF THALASSEMIA Download Section PDF Listen +++ ++ β-Thalassemias are of two main varieties: (Table 15–1) — The two types are β0-thalassemia, with total absence of β-chain production and β+-thalassemia, with partial deficiency of β-chain production. — The hallmark of the common forms of β-thalassemias is elevation of Hb A2 in heterozygotes. δβ-Thalassemias are heterogeneous: — In some cases, no δ- or β-chains are produced. — In other cases, the non-α chains are fusion δβ-chains: N-terminal residue of δ-chain fused to C-terminal residues of the β-chain. Fusion variants are called Lepore hemoglobins. — Levels of Hb F, but not HbA2, are elevated in heterozygotes. Hereditary persistence of fetal Hb (HPFH): — HPFH is heterogeneous genetically (deletion and nondeletion forms). — It is characterized by persistence of Hb F in adult life. — Although it has no clinical significance, it may have mild thalassemic changes. α-Thalassemias are usually caused by deletion of one or more of the four α genes (two globin genes per haploid chromosome): — If one of the two α-globin loci on chromosome 16 is deleted, the designation α– is used. If both are deleted, the designation αα/– – is used. Thus, a patient with two α locus deletions would be designated α–/α– or αα/– – depending on the arrangement of the deletions on the chromosomes. — α-Thalassemias also arise from a variety of other mechanisms, such as an elongated α-chain because of a mutated stop codon (Hb Constant Spring) or missense or nonsense mutations. ++Table Graphic Jump LocationTABLE 15–1THALASSEMIAS AND RELATED DISORDERSView Table||Download (.pdf) TABLE 15–1 THALASSEMIAS AND RELATED DISORDERS α-Thalassemia α0 α+ Deletion (–α) Nondeletion (αT) β-Thalassemia β0 β+ Normal hemoglobin A2 Dominant Unlinked to β-globin genes δβ-Thalassemia (δβ)+ (δβ)0 (Aγ δβ)0 γ-Thalassemia δ-Thalassemia δ0 δ+ εγδβ-Thalassemia Hereditary Persistence of Fetal Hemoglobin Deletion (δβ)0, (Aγ δβ)0 Nondeletion Linked to β-globin genes Gγ β+,Aγ β+ Unlinked to β-globin genes Source: Williams Hematology, 9th ed, Chap. 48, Table 48–1. + PATHOPHYSIOLOGY Download Section PDF Listen +++ +++ Imbalanced Globin Chain Synthesis (The Major Problem) ++ Homozygous β-thalassemia (Figure 15–1): — β-Globin synthesis is absent or greatly reduced, resulting in hypochromic microcytic red cells. — Because excess α-chains are incapable of forming viable Hb tetramers, they precipitate in red cell precursors, resulting in intramedullary destruction of the abnormal erythroid cells (ineffective erythropoiesis) and hemolysis. — Clinical manifestations appear after neonatal switch from γ-chain to β-chain production. Heterozygous β-thalassemia: — Usually only mild hypochromic microcytic anemia with elevated Hb A2 is apparent. — Some are more severe because of poor heme-binding properties and instability, with red cell inclusions containing precipitated β-chains as well as excess α-chains. These are sometimes designated as hyperunstable hemoglobins. α-Thalassemias: — There is defective α-chain production. Manifestations occur in both fetal and adult life because α-chains are present in both fetal and adult hemoglobin molecules. — In the newborn, excess γ-chains become soluble γ4 homotetramers designated Hb Bart’s. — After infancy, as the switch from γ- to β-chains takes place, excess β-chains if sufficiently large become β4 homotetramer (Hb H). — Because both γ4 and β4 homotetramers are soluble, they do not precipitate to any significant degree, explaining the less severe degree of ineffective erythropoiesis in α-thalassemias compared to β-thalassemias. — However, Hb H is unstable and precipitates readily, forming inclusion bodies. — Both Hb Bart’s and Hb H have high oxygen affinity. — Defect in Hb synthesis leads to hypochromic, microcytic cells. ++ FIGURE 15–1 Pathophysiology of β-thalassemia. HgbF, hemoglobin F; RBC, red blood cell. (Source: Williams Hematology, 9th ed, Chap. 48, Fig. 48–13.) Graphic Jump LocationView Full Size||Download Slide (.ppt) +++ Persistent Fetal Hemoglobin Production and Cellular Heterogeneity ++ In β0-thalassemias, Hb F is the only Hb produced except for small amounts of Hb A2. In thalassemias, as in normal individuals, Hb F is heterogeneously distributed among the red cells. Because of elevated Hb F levels in β-thalassemias, red cells have high oxygen affinity. The mechanism of persistent γ-chain synthesis in thalassemias is incompletely understood. +++ Consequence of Compensatory Mechanisms for the Anemia of Thalassemia ++ Severe anemia and the high oxygen affinity of Hb F in homozygous β-thalassemia produce severe tissue hypoxia. High oxygen affinity of Hb Bart’s and Hb H accentuates hypoxia in severe forms of α-thalassemia. Erythropoietin production and consequent expansion of marrow lead to deformities of skull with frequent sinus and ear infections, porous long bones, and pathologic fractures. Massive erythropoiesis diverts calories and also leads to hyperuricemia, gout, and folate deficiency. +++ Splenomegaly; Dilutional Anemia ++ Constant exposure of the spleen to red cells of precipitated globin chains leads to “work hypertrophy” of spleen, ultimately leading to splenomegaly. The enlarged spleen may sequester red cells and expand plasma volume, exacerbating anemia. +++ Abnormal Iron Metabolism ++ β0-Thalassemia homozygotes accumulate large amounts of iron because of increased absorption and red cell transfusions. Iron accumulates in endocrine glands, liver and, most importantly, myocardium. Consequences are diabetes, hypoparathyroidism, hypogonadism, and death from heart failure. The role of hepcidin of erythroferrone in the abnormal regulation of iron absorption in thalassemias is discussed in Chap. 9 of this Manual. +++ Infection ++ All forms of severe thalassemia appear to be associated with an increased susceptibility to bacterial infection; the iron overload may be one of the contributing factors. See Chap. 9 of this Manual. +++ Coagulation Defects ++ Patients with thrombocytosis after splenectomy may develop progressive pulmonary hypertension with platelet aggregation in the pulmonary circulation. +++ Clinical Heterogeneity ++ Most manifestations of β-thalassemia are related to excess α-chains. Degree of globin-chain imbalance determines severity. Coinheritance of α-thalassemia or of genes for enhanced γ-chain production may reduce the severity of β-thalassemias. + POPULATION GENETICS Download Section PDF Listen +++ ++ β-Thalassemias: Mediterranean populations, Middle East, India and Pakistan, Southeast Asia, southern Russia, China — Rare in Africa, except Liberia and parts of North Africa — Occurs sporadically in all races α-Thalassemias: widespread in Africa, Mediterranean populations, Middle East, Southeast Asia — Loss of both functional α-globin loci on the same chromosome. This occurs in Mediterranean and Asian populations but is extremely rare in Africa and the Middle East. Thus, Hb Bart’s hydrops syndrome and Hb H disease are largely restricted to Southeast Asia and Mediterranean populations. Thalassemic red cells: less likely to be infected with the plasmodial organisms of malaria + CLINICAL FEATURES Download Section PDF Listen +++ +++ β-Thalassemias ++ β-Thalassemia major: clinically severe, requiring transfusions β-Thalassemia intermedia: milder, later onset, requiring either few or no transfusions but at risk of iron overload β-Thalassemia minor: heterozygous carrier, clinically asymptomatic +++ β-Thalassemia Major ++ Homozygous or compound heterozygous state Infant well at birth; anemia developing in first few months of life, becoming progressively more severe, and coinciding with switch from γ to β-chains; failure to thrive Onset of symptoms after first year of life more typical of β-thalassemia intermedia Inadequately transfused child — Stunted growth; expanded marrow leads to bossing of skull, expanded maxilla, widened diploë, gross skeletal deformities — Grossly enlarged liver and spleen; secondary thrombocytopenia and leukopenia — Skin pigmentation; chronic leg ulceration — Hypermetabolic state: fever, wasting, hyperuricemia — Frequent infections, folate deficiency, spontaneous fractures, dental problems — Symptoms of iron loading by time of puberty; poor growth; endocrine problems (diabetes mellitus, adrenal insufficiency); cardiac problems, death by the third decade as a result of cardiac siderosis Adequately transfused child — Grows and develops normally until effects of iron loading appear by end of first decade +++ β-Thalassemia Intermedia ++ Wide spectrum of disability: — Severe forms: later-appearing anemia than β-thalassemia major; usually requires transfusion. There is retarded growth and development, skeletal deformities, and splenomegaly. — Milder forms: asymptomatic, transfusion-independent, Hb levels 10 to 12 g/dL. +++ β-Thalassemia Minor ++ Often slight anemia without functional impairment; discovered by blood cell examination +++ α-Thalassemias ++ Interactions of α-thalassemia haplotypes result in four broad phenotypic categories: — Normal (αα/αα). — Silent carrier (α–/αα). — α-Thalassemia trait (α–/α–) or αα/– –); mild hematologic changes, but no clinical abnormality; low mean cell volume (MCV) and low mean cell hemoglobin (MCH). There are varying levels of Hb Bart’s (γ4) at birth. — Hb H disease (– –/α–); hypochromic, severe to moderately severe hemolytic anemia often with marked splenomegaly. Red cells contain precipitates of Hb H(β4), which is an unstable hemoglobin. Hb Bart’s hydrops fetalis syndrome (– –/– –) is incompatible with extrauterine life. — Frequent cause of stillbirth in Southeast Asia. If alive at birth, infant dies within hours. — Pallor, massive edema, hepatosplenomegaly. Hydrops resembles that of Rh incompatibility. — High incidence of maternal toxemia of pregnancy, with enlarged placenta. — At autopsy: massive extramedullary hematopoiesis. + LABORATORY FEATURES Download Section PDF Listen +++ +++ β-Thalassemias ++ (Figure 15–2) ++ FIGURE 15–2 Blood films in β-thalassemia. A. β-Thalassemia minor. Anisocytosis, poikilocytosis, hypochromia. Occasional spherocytes and stomatocytes. B. Scanning electron micrograph of cells in A showing more detail of the poikilocytes. Note the knizocyte (pinch-bottle cell) at the lower right. C. β-Thalassemia major. Marked anisocytosis with many microcytes. Marked poikilocytosis. Anisochromia. Nucleated red cell on the right. Small lymphocyte on the left. (Reproduced with permission from Lichtman’s Atlas of Hematology, www.accessmedicine.com.) Graphic Jump LocationView Full Size||Download Slide (.ppt) +++ β-Thalassemia Major ++ Severe anemia: Hb 2 to 3 g/dL; blood film: marked anisopoikilocytosis, hypochromia, target cells, basophilic stippling, large poikilocytes; nucleated red cells numerous; reticulocytes moderately increased; inclusions of Hb in hypochromic red cells (these can be supravitally stained by methyl violet) After splenectomy: more inclusions; large, flat macrocytes; small, deformed microcytes Leukocyte and platelet counts normal or slightly elevated Marrow: marked erythroid hyperplasia, abnormal erythroblasts with stippling, increased sideroblasts; markedly increased storage iron Markedly ineffective erythropoiesis; shortened red cell survival Hb: Hb F increased, from less than 10% to greater than 90%; Hb A absent in β0-thalassemia. Hb A2 levels are low, normal, or high; always invariably elevated, however, if expressed as a proportion of Hb A +++ β-Thalassemia Minor ++ Mild anemia: Hb 9 to 11 g/dL Microcytic hypochromic red cells: MCV 50 to 70 fL (MCV a valuable screen for thalassemia trait); MCH 20 to 22 pg Hb A2 level: increased to 3.5% to 7% +++ α-Thalassemias +++ Hemoglobin Bart’s Hydrops Fetalis Syndrome ++ Blood film: severe thalassemic changes; many nucleated red blood cells Hb: Hb Bart’s predominates; Hb Portland (ζ2γ2) 10% to 20% +++ Hemoglobin H Disease ++ Blood film: hypochromic microcytic red blood cells, increased polychromasia Mild reticulocytosis (~5%) Hb H inclusions demonstrable in almost all red blood cells in blood incubated with brilliant cresyl blue +++ α0-Thalassemia Trait (αα/– – or α–/α–) ++ Similar appearance of blood film and cell counts as in β-thalassemia trait 5% to 15% Hb Bart’s at birth, disappears during maturation Rare cells with Hb H inclusions can be demonstrated in some cases +++ Silent Carrier or α+-Thalassemia Trait (αα/α–) ++ 1% to 2% Hb Bart’s at birth in some but not all cases Gene mapping analysis is only certain method of diagnosing α-thalassemia carrier states + DIFFERENTIAL DIAGNOSIS Download Section PDF Listen +++ ++ For an approach to the diagnosis of thalassemia syndromes, see Figure 15–3. In childhood, hereditary sideroblastic anemias may resemble thalassemia, but marrow examination should permit differentiation (see Chap. 11). High fetal Hb levels found in juvenile chronic myelomonocytic leukemia rarely can cause confusion, but examination of the marrow should be definitive (see Chap. 46). Diagnosis of the rarer forms of thalassemia is discussed in Chap. 48, of Williams Hematology, 9th ed. ++ FIGURE 15–3 A flowchart showing an approach to the diagnosis of the thalassemia syndromes. MCH, mean cell hemoglobin; MCV, mean corpuscular volume; RBC, red blood cell count. (Source: Williams Hematology, 9th ed, Chap. 48, Fig. 48–20.) Graphic Jump LocationView Full Size||Download Slide (.ppt) + THERAPY, COURSE, AND PROGNOSIS Download Section PDF Listen +++ +++ β-Thalassemia Major +++ General Considerations ++ High standard of pediatric care is required with adequate transfusions. Early treatment of infections is necessary. Folate supplements are warranted. Careful attention to respiratory infections and dental care must be taken because of bony deformities of skull. Preventive measures of iron overload are essential. When iron-loading is present, endocrine replacement therapy may be needed. +++ Allogeneic Hematopoietic Stem Cell Transplantation ++ Very good results are obtained with human leukocyte antigen (HLA)–identical sibling donors if performed early. In the absence of risk factors (irregular chelation, hepatomegaly, portal fibrosis), approximately 90% of children have 5-year, event-free survival with a mortality risk of 4%. For patients with one or two risk factors, the disease-free survival rate is 82%; with all three risk factors, the disease-free survival rate is 51%. No case of hematologic malignancy has been observed after transplantation. +++ Transfusion ++ In children, maintain Hb at 9.5 to 14 g/dL by transfusing red cells every 4 weeks to ensure normal growth and development. Use washed, filtered, or frozen cells to avoid transfusion reactions. Children maintained at high Hb level do not develop hypersplenism. +++ Iron Chelation ++ Rationale: Every child on high-transfusion regimen will develop and die of myocardial siderosis. Subcutaneous infusion of deferoxamine, 12 hours, overnight: determine dose to achieve adequate urinary iron excretion. Continue nightly infusions of deferoxamine on outpatient basis and monitor by measurements of urinary iron excretion. Ascorbic acid administered orally, 50 to 100 mg/d, increases iron excretion but should be given only after deferoxamine infusion has been started. +++ Experimental Approaches ++ Increase γ-globin synthesis in patients with β-thalassemia or sickle cell anemia using demethylating or cytotoxic agents, or arginine butyrate. Somatic gene therapy is discussed in Chap. 29 in Williams Hematology, 9th ed. +++ α-Thalassemia +++ Hydrops Fetalis (– –/– –) ++ There is no treatment. Genetic counseling and prenatal diagnosis are encouraged. +++ Hb H Disease (α –/– –) ++ Avoid “oxidant” drugs. Splenectomy may be needed if anemia and splenomegaly are severe. + PREVENTION Download Section PDF Listen +++ ++ For prenatal diagnosis, screen mothers at first prenatal visit; if mother is a thalassemia carrier, screen father. If both are carriers of gene for severe form of thalassemia, offer prenatal diagnostic testing and termination of pregnancy. Chorionic villus sampling at 9 to 10 weeks and fetal DNA analysis. + PROGNOSIS Download Section PDF Listen +++ +++ β-Thalassemia +++ Thalassemia Major ++ Cardiac complications have decreased dramatically in patients who are adequately treated by transfusion and iron chelation. Hematopoietic stem cell transplantation done early in life with HLA–identical sibling donors can lead to cure. +++ Thalassemia Intermedia ++ Patients may develop iron loading and severe bone disease in 3 to 4 decades. There is a high incidence of diabetes mellitus due to iron loading of pancreas. ++ For a more detailed discussion, see Stan Gerson: Gene Transfer Therapy, Chap. 29; Tomas Ganz: Iron Deficiency and Overload, Chap. 43; Sir David Weatherall: The Thalassemias, Chap. 48 in Williams Hematology, 9th ed.