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Beta Thalassemia

  • Author: Pooja Advani, MD; Chief Editor: Emmanuel C Besa, MD  more...
Updated: Dec 24, 2015


Beta thalassemia syndromes are a group of hereditary disorders characterized by a genetic deficiency in the synthesis of beta-globin chains. In the homozygous state, beta thalassemia (ie, thalassemia major) causes severe, transfusion-dependent anemia. In the heterozygous state, the beta thalassemia trait (ie, thalassemia minor) causes mild to moderate microcytic anemia. (See Etiology.)

Patients in whom the clinical severity of the disease lies between that of thalassemia major and thalassemia minor are categorized as having thalassemia intermedia. Several different genotypes are associated with thalassemia intermedia.

Hemoglobin (Hb) E, a common Hb variant found in Southeast Asia, is associated with a beta thalassemia phenotype, and this variant is included in the beta thalassemia category of diseases.

Complications associated with beta thalassemia

Complications associated with beta thalassemia, aside from the aforementioned anemia, are as follows (see Prognosis, Presentation, Workup, Treatment, and Medication):

  • Extramedullary hematopoiesis
  • Asplenia secondary to splenectomy
  • Medical complications from long-term transfusional therapy - Iron overload and transfusion-associated infections (eg, hepatitis)
  • Increased risk for infections resulting from asplenia (eg, encapsulated organisms such as pneumococcus) or from iron overload (eg, Yersinia species)
  • Cholelithiasis (eg, bilirubin stones)


Beta-globin gene mutations

Mutations in globin genes cause thalassemias. Beta thalassemia affects 1 or both of the beta-globin genes. (Alpha thalassemia affects the alpha-globin gene[s].) These mutations, by causing impaired synthesis of the beta-globin protein component of Hb, result in anemia.[1, 2]

Beta thalassemia is inherited as an autosomal recessive disorder. The defect can be a complete absence of the beta-globin protein (ie, beta-zero thalassemia) or a severely reduced synthesis of the beta-globin protein (ie, beta-plus thalassemia). (See the image below.)

Peripheral smear in beta-zero thalassemia minor sh Peripheral smear in beta-zero thalassemia minor showing microcytes (M), target cells (T), and poikilocytes.

Peripheral smear in beta-zero thalassemia minor showing microcytes (M), target cells (T), and poikilocytes.The genetic defect usually is a missense or nonsense mutation in the beta-globin gene, although occasional defects due to gene deletions of the beta-globin gene and surrounding regions also have been reported.

In beta thalassemia minor (ie, beta thalassemia trait or heterozygous carrier-type), one of the beta-globin genes is defective, resulting in an approximately 50% decrease in the synthesis of the beta-globin protein.

In beta thalassemia major (ie, homozygous beta thalassemia), the production of the beta-globin chains is severely impaired because both beta-globin genes are mutated. The severe imbalance of globin chain synthesis (alpha >> beta) results in ineffective erythropoiesis and severe microcytic hypochromic anemia. (See the image below.)

Peripheral smear from a patient with beta-zero tha Peripheral smear from a patient with beta-zero thalassemia major showing more marked microcytosis (M) and anisopoikilocytosis (P) than in thalassemia minor. Target cells (T) and hypochromia are prominent.

Peripheral smear from a patient with beta-zero thalassemia major showing more marked microcytosis (M) and anisopoikilocytosis (P) than in thalassemia minor. Target cells (T) and hypochromia are prominent. The excess unpaired alpha-globin chains aggregate to form precipitates that damage red cell membranes, resulting in intravascular hemolysis. Premature destruction of erythroid precursors results in intramedullary death and ineffective erythropoiesis. The profound anemia typically is associated with erythroid hyperplasia and extramedullary hematopoiesis.

Although beta thalassemia is caused by a genetic mutation in the beta-globin gene (which is located on chromosome 11), many additional factors influence the clinical manifestations of the disease. That is, the same mutations may have different clinical manifestations in different patients. The factors below are known to influence the clinical phenotype.

Intracellular fetal Hb concentrations

The level of expression of fetal Hb (ie, the expression level of the gamma-globin gene) in red blood cells determines, in part, the severity of the disease. Patients with high fetal Hb have milder disease.

Coinheritance of alpha thalassemia

Patients with coinheritance of alpha thalassemia have a milder clinical course because they have a less severe alpha-beta chain imbalance.

Coexistence of sickle cell trait

The coexistence of sickle cell trait and beta thalassemia is a major and symptomatic hemoglobinopathy with most of the symptoms and complications of sickle cell disease. Unlike sickle cell trait, in which most Hb-on-Hb electrophoresis is Hb A (AS), S is the dominant Hb (SA) and usually constitutes about 60% or more of the circulating Hb, depending on the transfusion status of the patient and the nature of the coexisting beta-thalassemia mutation (ie, beta-zero vs beta-plus).



Occurrence in the United States

The frequency of beta thalassemia varies widely, depending on the ethnic population. The disease is reported most commonly in Mediterranean, African, and Southeast Asian populations.

International occurrence

The disease is found most commonly in the Mediterranean region, Africa, and Southeast Asia, presumably as an adaptive association to endemic malaria. The incidence may be as high as 10% in these areas.

Race-related demographics

Beta thalassemia genes are reported throughout the world, although more frequently in Mediterranean, African, and Southeast Asian populations. Patients of Mediterranean extraction are more likely to be anemic with thalassemia trait than Africans because they tend to have beta-zero thalassemia rather than beta-plus thalassemia.

The genetic defect in Mediterranean populations is caused most commonly by (1) a mutation creating an abnormal splicing site or (2) a mutation creating a premature translation termination codon. Southeast Asian populations also have a significant prevalence of Hb E and alpha thalassemia. African populations more commonly have genetic defects leading to alpha thalassemia.

Age-related demographics

The manifestations of the disease may not be apparent until a complete switch from fetal to adult Hb synthesis occurs. This switch typically is completed by the sixth month after birth.



Individuals with thalassemia minor (thalassemia trait) usually have mild, asymptomatic microcytic anemia. This state does not result in mortality or significant morbidity.

The prognosis of patients with thalassemia major is highly dependent on the patient's adherence to long-term treatment programs, namely the hypertransfusion program and lifelong iron chelation. Allogeneic bone marrow transplantation may be curative.

Morbidity and mortality

The major causes of morbidity and mortality in beta thalassemia are anemia and iron overload. The severe anemia resulting from this disease, if untreated, can result in high-output cardiac failure; the intramedullary erythroid expansion may result in associated skeletal changes such as cortical bone thinning. The long-term increase in red-cell turnover causes hyperbilirubinemia and bilirubin-containing gallstones.

Increased iron deposition resulting from lifelong transfusions and enhanced iron absorption results in secondary iron overload. This overload causes clinical problems similar to those observed with primary hemochromatosis (eg, endocrine dysfunction, liver dysfunction, cardiac dysfunction).

A broad spectrum of neurological complications has also been reported in beta thalassemia complications, although most were subclinical. These have included cognitive impairment, abnormal findings on evoked potentials, cerebrovascular disease, and peripheral neuropathy.[3]  


Patient Education

Educate patients with thalassemia minor about the genetic (hereditary) nature of their disease, and inform them that their immediate family members (ie, parents, siblings, children) may be affected. The presence of beta-thalassemia minor in both parents implies that there is about a one fourth chance that a child will have thalassemia major. Careful genetic counseling is also appropriate for parents in whom one parent has beta-thalassemia minor and the other parent has some form of beta-globin–related disease, such as sickle cell carrier.

Inform patients with thalassemia minor that they do not have iron deficiency and that iron supplementation will not improve their anemia.

Contributor Information and Disclosures

Pooja Advani, MD Clinical Fellow, Department of Hematology/Oncology, Mayo Clinic

Pooja Advani, MD is a member of the following medical societies: American Society of Hematology, American Society of Clinical Oncology, Florida Society of Clinical Oncology

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Marcel E Conrad, MD Distinguished Professor of Medicine (Retired), University of South Alabama College of Medicine

Marcel E Conrad, MD is a member of the following medical societies: Alpha Omega Alpha, American Association for the Advancement of Science, American Association of Blood Banks, American Chemical Society, American College of Physicians, American Physiological Society, American Society for Clinical Investigation, American Society of Hematology, Association of American Physicians, Association of Military Surgeons of the US, International Society of Hematology, Society for Experimental Biology and Medicine, SWOG

Disclosure: Partner received none from No financial interests for none.

Chief Editor

Emmanuel C Besa, MD Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American Society of Clinical Oncology, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, New York Academy of Sciences

Disclosure: Nothing to disclose.


Kenichi Takeshita, MD Adjunct Associate Professor, Department of Medicine, Division of Hematology, New York University School of Medicine; Medical Director, Clinical Research and Development, Celgene

Kenichi Takeshita, MD is a member of the following medical societies: American Society of Hematology

Disclosure: Nothing to disclose.

  1. Rachmilewitz EA, Giardina PJ. How I treat thalassemia. Blood. 2011 Sep 29. 118(13):3479-88. [Medline].

  2. Galanello R, Sanna S, Perseu L, Sollaino MC, Satta S, Lai ME, et al. Amelioration of Sardinian beta0 thalassemia by genetic modifiers. Blood. 2009 Oct 29. 114(18):3935-7. [Medline]. [Full Text].

  3. Nemtsas P, Arnaoutoglou M, Perifanis V, Koutsouraki E, Orologas A. Neurological complications of beta-thalassemia. Ann Hematol. 2015 Aug. 94 (8):1261-5. [Medline].

  4. Pennell DJ, Udelson JE, Arai AE, Bozkurt B, Cohen AR, Galanello R. Cardiovascular function and treatment in ß-thalassemia major: a consensus statement from the American Heart Association. Circulation. 2013 Jul 16. 128(3):281-308. [Medline].

  5. Jacob HS, Winterhalter KH. The role of hemoglobin heme loss in Heinz body formation: studies with a partially heme-deficient hemoglobin and with genetically unstable hemoglobins. J Clin Invest. 1970 Nov. 49 (11):2008-16. [Medline]. [Full Text].

  6. Rivella S. β-thalassemias: paradigmatic diseases for scientific discoveries and development of innovative therapies. Haematologica. 2015 Apr. 100 (4):418-30. [Medline]. [Full Text].

  7. Rachmilewitz EA, Giardina PJ. How I treat thalassemia. Blood. 2011 Sep 29. 118(13):3479-88. [Medline].

  8. Hapgood G, Walsh T, Cukierman R, Paul E, Cheng K, Bowden DK. Erythropoiesis is not equally suppressed in transfused males and females with β-thalassemia major: are there clinical implications?. Haematologica. 2015 Aug. 100 (8):e292-4. [Medline]. [Full Text].

  9. Thomas ED, Buckner CD, Sanders JE, Papayannopoulou T, Borgna-Pignatti C, De Stefano P. Marrow transplantation for thalassaemia. Lancet. 1982 Jul 31. 2(8292):227-9. [Medline].

  10. Lucarelli G, Galimberti M, Polchi P. Marrow transplantation in patients with thalassemia responsive to iron chelation therapy. N Engl J Med. 1993 Sep 16. 329(12):840-4. [Medline]. [Full Text].

  11. Elalfy MS, Saber MM, Adly AA, Ismail EA, Tarif M, Ibrahim F, et al. Role of vitamin C as an adjuvant therapy to different iron chelators in young β-thalassemia major patients: efficacy and safety in relation to tissue iron overload. Eur J Haematol. 2015 May 28. [Medline].

  12. Ganz T. Hepcidin and iron regulation, 10 years later. Blood. 2011 Apr 28. 117(17):4425-33. [Medline]. [Full Text].

  13. Maggio A, Vitrano A, Lucania G, Capra M, Cuccia L, Gagliardotto F, et al. Long-term use of deferiprone significantly enhances left-ventricular ejection function in thalassemia major patients. Am J Hematol. 2012 Jul. 87(7):732-3. [Medline].

  14. Cassinerio E, Roghi A, Pedrotti P, Brevi F, Zanaboni L, Graziadei G, et al. Cardiac iron removal and functional cardiac improvement by different iron chelation regimens in thalassemia major patients. Ann Hematol. 2012 May 10. [Medline].

  15. Olivieri NF, Brittenham GM, McLaren CE, et al. Long-term safety and effectiveness of iron-chelation therapy with deferiprone for thalassemia major. N Engl J Med. 1998 Aug 13. 339(7):417-23. [Medline]. [Full Text].

  16. [Guideline] Angelucci E, Barosi G, Camaschella C, et al. Italian Society of Hematology practice guidelines for the management of iron overload in thalassemia major and related disorders. Haematologica. 2008 May. 93(5):741-52. [Medline].

  17. Taher AT, Porter J, Viprakasit V, Kattamis A, Chuncharunee S, Sutcharitchan P, et al. Deferasirox reduces iron overload significantly in nontransfusion-dependent thalassemia: 1-year results from a prospective, randomized, double-blind, placebo-controlled study. Blood. 2012 Aug 2. 120(5):970-7. [Medline].

  18. Taher AT, Porter JB, Viprakasit V et al. Deferasirox continues to reduce iron overload in non-transfusion-dependent thalassemia: a one-year, open-label extension to a one-year, randomized double-blind, placebo-controlled study (THALASSA). Poster presented at the 54th American Society of Hematology Annual Meeting and Exposition in Atlanta, GA (8-11 December 2012). Abstract #3258.

  19. Pennell DJ, Porter JB, Piga A, Lai Y, El-Beshlawy A, Belhoul KM, et al. A 1-year randomized controlled trial of deferasirox vs deferoxamine for myocardial iron removal in ß-thalassemia major (CORDELIA). Blood. 2014 Mar 6. 123(10):1447-54. [Medline]. [Full Text].

  20. Elalfy M et al, 55th Annual ASH Annual Meeting abstracts, 2013, abstract# 559.

  21. Yesim A et al, 55th ASH Annual Meeting abstracts, 2013, abstract # 2257.

  22. Italia KY, Jijina FJ, Merchant R, et al. Response to hydroxyurea in beta thalassemia major and intermedia: experience in western India. Clin Chim Acta. 2009 Sep. 407(1-2):10-5. [Medline].

  23. Wilber A, Nienhuis AW, Persons DA. Transcriptional regulation of fetal to adult hemoglobin switching: new therapeutic opportunities. Blood. 2011 Apr 14. 117(15):3945-53. [Medline]. [Full Text].

  24. Raechel P et al, 55th Annual ASH Meeting abstracts, 2013, abstract # 1022.

  25. Perrine SP, Pace BS, Faller DV. Targeted fetal hemoglobin induction for treatment of beta hemoglobinopathies. Hematol Oncol Clin North Am. 2014 Apr. 28(2):233-48. [Medline].

  26. Maria-Domenica C, 55th Annual ASH Meeting abstracts, 2013, abstract # 3448.

  27. Fibach E, Rachmilewitz EA. Does erythropoietin have a role in the treatment of ß-hemoglobinopathies?. Hematol Oncol Clin North Am. 2014 Apr. 28(2):249-63. [Medline].

  28. Cavazzana-Calvo M, Payen E, Negre O, et al. Transfusion independence and HMGA2 activation after gene therapy of human ß-thalassaemia. Nature. 2010 Sep 16. 467(7313):318-22. [Medline].

Peripheral smear in beta-zero thalassemia minor showing microcytes (M), target cells (T), and poikilocytes.
Peripheral smear from a patient with beta-zero thalassemia major showing more marked microcytosis (M) and anisopoikilocytosis (P) than in thalassemia minor. Target cells (T) and hypochromia are prominent.
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