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 transfusion. The terms β- thalassemia minor and β-thalassemia trait describe asymptomatic heterozygotes for 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 Bart's, with all four loci deleted (Table 99-4). Nondeletion forms of α-thalassemia also exist. Table 99-4 The αThalassemias Conditio n Hemoglo bin A, % Hemoglo bin H (β 4 ), % Hemoglo bin Level, g/L (g/dL) MC V, fL Normal 97 0 150 (15) 90 Silent thalassemia: – α/αα 98–100 0 150 (15) 90 Thalasse mia trait: –α/– α homozygous α- thal-2 a or – – /αα heterozygous α- thal-1 a 85–95 Rare red blood cell inclusions 120–130 (12–13) 70– 80 Hemoglo bin H disease: – –/–α heterozygous α- thal-1/α-thal-2 70–95 5–30 60–100 (6–10) 60– 70 Hydrops fetalis: – –/– – 0 5–10 b Fatal in utero or at birth homozygous 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 is called 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 doubly heterozygous for α-thalassemia-2 and α-thalassemia-1 exhibit a more severe phenotype called HbH disease. Heterozygosity for a deletion that removes both genes from the same chromosome (cis deletion) is common in Asians and in those from the Mediterranean region, as is homozygosity for α-thalassemia-2 (trans deletion). Both produce asymptomatic hypochromia and microcytosis. In HbH disease, HbA production is only 25–30% normal. Fetuses accumulate some unpaired βchains. In adults, unpaired β-chains accumulate and are soluble enough to form β 4 tetramers called HbH. HbH forms few inclusions in erythroblasts and precipitates in circulating RBC. Patients with HbH disease have thalassemia intermedia characterized by moderately severe hemolytic anemia but milder ineffective erythropoiesis. Survival into mid-adult life without transfusions is common. . 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 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. 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