Chapter 099. Disorders of Hemoglobin (Part 11)

Severity is highly variable. Known modulating factors are those that ameliorate the burden of unpaired α-globin inclusions. Alleles associated with milder synthetic defects and co-inheritance of α-thalassemia trait reduce clinical severity by reducing accumulation of excess α globin. HbF persists to various degrees in β-thalassemias. γ-Globin gene chains can substitute for βchains, generating more hemoglobin and reducing the burden of α-globin inclusions. The terms β-thalassemia major and β-thalassemia intermedia are used to reflect the clinical heterogeneity. Patients with β-thalassemia major require intensive transfusion support to survive. Patients with β-thalassemia intermedia have a somewhat milder phenotype and can survive without...
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Chapter 099. Disorders of Hemoglobin (Part 11) Chapter 099. Disorders of Hemoglobin (Part 11) Severity is highly variable. Known modulating factors are those thatameliorate the burden of unpaired α-globin inclusions. Alleles associated withmilder synthetic defects and co-inheritance of α-thalassemia trait reduce clinicalseverity by reducing accumulation of excess α globin. HbF persists to variousdegrees in β-thalassemias. γ-Globin gene chains can substitute for βchains,generating more hemoglobin and reducing the burden of α-globin inclusions. Theterms β-thalassemia major and β-thalassemia intermedia are used to reflect theclinical heterogeneity. Patients with β-thalassemia major require intensivetransfusion support to survive. Patients with β-thalassemia intermedia have asomewhat milder phenotype and can survive without transfusion. The terms β-thalassemia minor and β-thalassemia trait describe asymptomatic heterozygotesfor βthalassemia. α-Thalassemia Syndromes The four classic α-thalassemias, most common in Asians, are α-thalassemia-2 trait, in which one of the four α-globin loci is deleted; α-thalassemia-1 trait, with two deleted loci; HbH disease, with three loci deleted;and hydrops fetalis with Hb Barts, with all four loci deleted (Table 99-4).Nondeletion forms of α-thalassemia also exist. Table 99-4 The αThalassemias Conditio Hemoglo Hemoglo Hemoglo MCn bin A, % bin H (β4), % bin Level, g/L V, fL (g/dL) Normal 97 0 150 (15) 90 Silent 98–100 0 150 (15) 90thalassemia: –α/αα Thalasse 85–95 Rare red 120–130 70–mia trait: –α/–α blood cell (12–13) 80homozygous α- inclusionsthal-2a or – –/ααheterozygous α-thal-1a Hemoglo 70–95 5–30 60–100 60–bin H disease: – (6–10) 70–/–αheterozygous α-thal-1/α-thal-2 Hydrops 0 5–10b Fatal infetalis: – –/– – utero or at birthhomozygous α-thal-1 a When both α-alleles on one chromosome are deleted, the locus is called α-thal-1; when only a single α-allele on one chromosome is deleted, the locus iscalled α-thal-2. b 90–95% of the hemoglobin is hemoglobin Barts (tetramers of γ-chains). α-Thalassemia-2 trait is an asymptomatic, silent carrier state. α-Thalassemia-1 trait resembles β-thalassemia minor. Offspring doublyheterozygous for α-thalassemia-2 and α-thalassemia-1 exhibit a more severephenotype called HbH disease. Heterozygosity for a deletion that removes bothgenes from the same chromosome (cis deletion) is common in Asians and in thosefrom the Mediterranean region, as is homozygosity for α-thalassemia-2 (transdeletion). Both produce asymptomatic hypochromia and microcytosis. In HbH disease, HbA production is only 25–30% normal. Fetusesaccumulate some unpaired βchains. In adults, unpaired β-chains accumulate andare soluble enough to form β4 tetramers called HbH. HbH forms few inclusions inerythroblasts and precipitates in circulating RBC. Patients with HbH disease havethalassemia intermedia characterized by moderately severe hemolytic anemia butmilder ineffective erythropoiesis. Survival into mid-adult life without transfusionsis common.