Sections View Full Chapter Figures Tables Videos Annotate Full Chapter Figures Tables Videos Supplementary Content + Download Section PDF Listen ++ For further information, see CMDT Part 13-04: The Thalassemias + Key Features Download Section PDF Listen +++ +++ Essentials of Diagnosis ++ Microcytosis out of proportion to degree of anemia Positive family history or lifelong personal history of microcytic anemia Normal or elevated red blood cell (RBC) count Abnormal RBC morphology with microcytes, hypochromia, acanthocytes, and target cells In beta-thalassemia, elevated levels of hemoglobin A2 and F +++ General Considerations ++ Hereditary disorders characterized by reduction in synthesis of globin chains (alpha or β), causing reduced hemoglobin synthesis and eventually hypochromic microcytic anemia Normal adult hemoglobin is primarily hemoglobin A, a tetramer of two alpha-chains and two beta-chains (alpha2beta2) Thalassemias are described as Trait, when there are laboratory features without clinical impact Intermedia, when there is a RBC transfusion requirement or other moderate clinical impact Major, when the disorder is life-threatening Alpha-thalassemia syndromes are determined by the number of functional alpha-globin genes Normal (four alpha-globin genes, normal hematocrit) Silent carrier (three alpha-globin genes, normal hematocrit) Alpha-thalassemia minor or trait (two alpha-globin genes, hematocrit 28–40%, mean cell volume [MCV] 60–75 fL) Hemoglobin H disease (one alpha-globin gene, hematocrit 22–32%, MCV 60–70 fL) Hydrops fetalis (0 alpha-globin genes, fatal in utero) Beta-thalassemia: Reduced beta-globin chain synthesis results in relative increase in proportions of hemoglobins A2 and F compared with hemoglobin A, because beta-like globins (delta and gamma) substitute for missing beta-chains With reduced beta-chains Excess alpha-chains precipitate, causing hemolysis Bone marrow becomes hyperplastic, resulting in bony deformities, osteopenia, and pathologic fractures +++ Demographics ++ Alpha-thalassemia occurs primarily in persons from southeast Asia and China and, less commonly, in blacks and persons of Mediterranean origin Beta-thalassemia affects persons of Mediterranean origin (Italian, Greek) and to lesser extent Asians and blacks + Clinical Findings Download Section PDF Listen +++ +++ Symptoms and Signs ++ Alpha-thalassemia silent carriers: asymptomatic Alpha-thalassemia trait: clinically normal with mild microcytic anemia Hemoglobin H disease Chronic hemolytic anemia of variable severity Pallor Splenomegaly Hydrops fetalis Only hemoglobin species made is called hemoglobin Bart's (γ4) All four alpha-globin genes are deleted, no normal hemoglobin is produced and the affected fetus is stillborn Heterozygotes for beta-thalassemia (thalassemia minor): mild microcytic anemia Homozygotes for mild beta-thalassemia (thalassemia intermedia): chronic hemolytic anemia Homozygotes for major beta-thalassemia (thalassemia major) Severe anemia requiring transfusion Growth failure Bony deformities (abnormal facial structure, pathologic bone fractures) Hepatosplenomegaly and jaundice +++ Differential Diagnosis ++ Iron deficiency anemia (thalassemia has lower MCV, normal iron studies, more normal RBC count, more abnormal peripheral blood smear at modest levels of anemia, and usually reticulocytosis) Other hemoglobinopathy (eg, sickle thalassemia, hemoglobin C disorders) Sideroblastic anemia Anemia of chronic disease + Diagnosis Download Section PDF Listen +++ +++ Laboratory Tests +++ Alpha-thalassemia trait ++ Mild or no anemia (hematocrit 28–40%) with strikingly low MCV (60–75 fL) RBC count normal or increased Peripheral blood smear mildly abnormal Microcytes Hypochromia Occasional target cells Acanthocytes Reticulocyte count and iron studies normal Hemoglobin electrophoresis: normal See Table 13–4 ++Table Graphic Jump LocationTable 13–4.Alpha-thalassemia syndromes.View Table||Download (.pdf) Table 13–4. Alpha-thalassemia syndromes. Number of Alpha-Globin Genes Transcribed Syndrome Hematocrit MCV 4 Normal Normal Normal 3 Silent carrier Normal Normal 2 Thalassemia minor (or trait) 28–40% 60–75 fL 1 Hemoglobin H disease 22–32% 60–70 fL 0 Hydrops fetalis1 < 18% < 60 fL 1Die in utero.MCV, mean corpuscular volume. +++ Hemoglobin H disease ++ Variably severe anemia (hematocrit 22–32%) with remarkably low MCV (60–70 fL) Peripheral blood smear markedly abnormal: hypochromia, microcytosis, target cells, poikilocytosis Reticulocyte count elevated and RBC count is normal or elevated Hemoglobin electrophoresis: shows hemoglobin H comprises 10–40% of the hemoglobin +++ Beta-thalassemia minor ++ Mild anemia (hematocrit 28–40%) with MCV 55–75 fL RBC count normal or increased Peripheral blood smear mildly abnormal Hypochromia Microcytosis Target cells Basophilic stippling Reticulocyte count normal or slightly elevated Hemoglobin electrophoresis: elevated hemoglobin A2 to 4–8% and occasionally elevated hemoglobin F to 1–5% +++ Beta-thalassemia intermedia ++ Modest anemia with hematocrit between 17% and 33% MCV ranges from 55 fL to 75 fL RBC count is normal or increased The reticulocyte count is elevated The peripheral blood smear is abnormal with hypochromia, microcytosis, basophilic stippling, and target cells Hemoglobin electrophoresis shows up to 30% hemoglobin A and an elevation of hemoglobin A2 up to 10% and elevation of hemoglobin F from 6% to 10% +++ Beta-thalassemia major ++ Severe anemia (hematocrit sometimes < 10% without transfusion) Peripheral blood smear bizarre Severe poikilocytosis Hypochromia Microcytosis Target cells Basophilic stippling Nucleated RBCs Hemoglobin electrophoresis Little or no hemoglobin A Variable amounts of hemoglobin A2 Predominant hemoglobin present is hemoglobin F See Table 13–5 ++Table Graphic Jump LocationTable 13–5.Beta-thalassemia syndromes.View Table||Download (.pdf) Table 13–5. Beta-thalassemia syndromes. Beta-Globin Genes Transcribed Hb A Hb A2 Hb F Transfusions Normal Homozygous beta 97–99% 1–3% < 1% None Thalassemia minor Heterozygous beta0 80–95% 4–8% 1–5% None Heterozygous beta+ 80–95% 4–8% 1–5% None Thalassemia intermedia Homozygous beta+ (mild) 0–30% 4–8% 6–10% Occasional Thalassemia major Homozygous beta0 0% 4–10% 90–96% Dependent Homozygous beta+ 0–10% 4–10% 90–96% Dependent Hb, hemoglobin; beta0, no beta-globin produced; beta+, some beta-globin produced. + Treatment Download Section PDF Listen +++ +++ Medications ++ Mild thalassemias (alpha-thalassemia trait or beta-thalassemia minor) Usually require no treatment Should be identified to avoid repeated evaluations for iron deficiency and inappropriate administration of supplemental iron Alpha-thalassemia trait and thalassemia intermedia may require transfusion during infection or other stress Hemoglobin H disease Folic acid supplementation (1 mg/day orally) Avoid medicinal iron and oxidative drugs, such as sulfonamides Severe thalassemia Regular transfusions Folate supplementation Iron chelation (oral or parenteral) For patients who require regular transfusions Prevents or delays life-limiting organ damage from iron overload +++ Surgery ++ Splenectomy indicated if hypersplenism causes marked increase in transfusion requirement or refractory symptoms +++ Therapeutic Procedures ++ Prenatal diagnosis and genetic counseling should be offered Blood transfusions as above Allogeneic stem cell transplantation for beta-thalassemia major in children who have not yet experienced iron overload and chronic organ toxicity + Outcome Download Section PDF Listen +++ +++ Complications ++ Bony deformities, osteopenia, and pathologic fractures in beta-thalassemia Complications of blood transfusions as below Splenomegaly may result from chronic hemolysis +++ Prognosis ++ Mild thalassemia (alpha-thalassemia trait or beta-thalassemia minor): normal life expectancy Thalassemia intermedia Transfusional iron overload may develop Patients survive into adulthood but with hepatosplenomegaly and bony deformities Beta-thalassemia major Clinical course modified significantly by transfusion therapy, but transfusional iron overload causes heart failure, cirrhosis, and endocrinopathies, usually after > 100 units of transfusion Death from cardiac failure usually occurs between ages 20 and 30 in the absence of effective iron chelation and allogeneic stem cell transplantation Long-term survival is > 80% in cases undergoing allogeneic bone marrow transplantation +++ When to Refer ++ All patients with thalassemia intermedia or major should be referred to a hematologist Any patient with an unexplained microcytic anemia should be referred to help establish a diagnosis Patients with thalassemia minor or intermedia should be offered genetic counseling because offspring of thalassemic couples are at risk for inheriting thalassemia major + References Download Section PDF Listen +++ + +Cappellini MD et al. New therapeutic targets in transfusion-dependent and -independent thalassemia. Hematology Am Soc Hematol Educ Program. 2017 Dec 8;2017(1):278–83. [PubMed: 29222267] + +Di Maggio R et al. The new era of chelation treatments: effectiveness and safety of 10 different regimens for controlling iron overloading in thalassaemia major. Br J Haematol. 2017 Sep;178(5):676–88. [PubMed: 28439891] + +Jagannath VA et al. Hematopoietic stem cell transplantation for people with B-thalassaemia major. Cochrane Database Syst Rev. 2016 Nov 30;11:CD008708. [PubMed: 27900772] + +Kwiatkowski JL. Current recommendations for chelation for transfusion-dependent thalassemia. Ann N Y Acad Sci. 2016 Mar;1368(1):107–14. [PubMed: 27186943] + +Porter J. Beyond transfusion therapy: new therapies in thalassemia including drugs, alternate donor transplant, and gene therapy. Hematology Am Soc Hematol Educ Program. 2018 Nov 30;2018(1):361–70. [PubMed: 30504333] + +Srivastava A et al. Cure for thalassemia major—from allogeneic hematopoietic stem cell transplantation to gene therapy. Haematologica. 2017 Feb;102(2):214–23. [PubMed: 27909215] + +Taher AT et al. Thalassaemia. Lancet. 2018 Jan13;391(10116):155–67. [PubMed: 28774421] + +Thompson AA et al. Gene therapy in patients with transfusion-dependent β-thalassemia. N Engl J Med. 2018 Apr 19;378(16):1479–93. [PubMed: 29669226]