eMedicine Specialties > Hematology > Red Blood Cells and Disorders

Thalassemia, Alpha: Differential Diagnoses & Workup

Author: Samer A Bleibel, MD, Staff Physician, Department of Internal Medicine, Wayne State University, St John's Hospital and Medical Centers
Coauthor(s): Robert J Leonard, MD, Clinical Assistant Professor, Department of Medicine, Wayne State University School of Medicine; Jennifer L Jones-Crawford, MD, Fellow, Department of Hematology/Oncology, Medical College of Georgia; Abdullah Kutlar, MD, Director of Sickle Cell Center, Fellowship Program Director, Professor, Department of Internal Medicine, Section of Hematology and Oncology, Medical College of Georgia; Linda K Hendricks, MD, Assistant Professor, Department of Internal Medicine, Section of Hematology and Oncology, Mercer University School of Medicine
Contributor Information and Disclosures

Updated: Aug 26, 2009

Differential Diagnoses

Hemoglobin C Disease
Hemolytic Anemia
Iron Deficiency Anemia
Thalassemia, Beta

Other Problems to Be Considered

Beta thalassemia major
Hemoglobin E thalassemia
Hemoglobin S thalassemia syndrome
Hemoglobinopathies
Hereditary persistence of fetal hemoglobin
High hemoglobin F syndromes
Sideroblastic anemia
Thalassemia intermedia
Thalassemia minima
Thalassemia minor

Workup

Laboratory Studies

  • Trait -a/aa
    • Hemoglobin level is within the reference range.
    • Reticulocyte count is normal. 
    • Mean corpuscular volume (MCV) ranges between 75 and 85 fL. 
    • Mean corpuscular hemoglobin (MCH) is around 26 pg.
  • Alpha1 thalassemia minor
    • Hemoglobin level is within the reference range. 
    • Reticulocyte count is normal. 
    • MCV is 65-75 fL. 
    • MCH is around 22 pg.
  • Hemoglobin H disease
    • Hemoglobin level is 7-10 g/dL. 
    • Reticulocyte count is 5-10%. 
    • MCV is 55-65 fL. 
    • MCH is 20 pg. 
    • The peripheral blood smear shows small misshapen red cells, hypochromia, microcytosis, and targeting. 
    • Brilliant cresyl blue stain demonstrates hemoglobin H inclusion bodies.
  • Hydrops fetalis 
    • Hemoglobin is 4-10 g/dL.
    • MCV is 110-120 fL. 
    • The peripheral blood smear shows severe anisopoikilocytosis, severe hypochromia, and nucleated red blood cells. 
  • Alpha thalassemia combined with sickle cell anemia causes a higher hemoglobin concentration and improved red blood cell survival. The alpha gene deletion is associated with improved red cell deformability, but the improved rheologic benefits often are overcome by the greater viscosity of a higher hematocrit. Clinically, this is observed as a greater number of painful vasoocclusive crises. Interestingly, however, the incidence of stroke is lower than that in sickle cell disease alone.

Imaging Studies

    • Imaging studies are not useful in these disorders.

Other Tests

  • Hemoglobin electrophoresis separates hemoglobin into different types. Hemoglobin Bart is elevated at birth in patients with alpha thalassemia. In hemoglobin H disease, 20-40% of total hemoglobin is of hemoglobin Bart; however, in the silent carrier alpha thalassemia condition, the percentage is only 1-2% with low or normal amounts of hemoglobin A2.5 Hemoglobin electrophoresis is generally not sufficiently sensitive to diagnose silent carrier alpha thalassemia.
  • The imbalance between the quantities of α- and β-globin chains initially was used to define the thalassemias. β to α synthetic ratios are altered in both alpha and beta thalassemias. Increasing ratios of β- to α-globin chains are observed in alpha-2 thalassemia, alpha-1 thalassemia, and hemoglobin H disease, respectively. Tests are performed by incubation of red blood cells with radiolabeled amino acid and subsequently separating α- and β-globin chains using urea carboxymethyl cellulose (CMC) chromatography.
  • Currently, genetic testing is used to establish the diagnosis in patients with a suggestive family history and/or hematologic findings suggestive of alpha thalassemia.6,7,8
    • Recombinant DNA technology can be diagnostic but is still a research tool.
    • Gene mapping
    • Polymerase chain reaction (PCR)
    • Restriction endonucleases
    • Anti-L globin monoclonal antibodies

Procedures

  • Bone marrow aspiration and biopsy are not helpful in establishing the precise diagnosis and are not indicated unless other confounding problems exist.

Histologic Findings

Peripheral blood smear may reveal target cells, microcytosis, hypochromia, and anisopoikilocytosis. Most individuals with alpha2 thalassemia (trait) have only mild microcytosis, which can be differentiated from other common causes of microcytosis based on serum iron and ferritin concentrations within the reference range.

Peripheral smear from a patient with hemoglobin H...

Peripheral smear from a patient with hemoglobin H disease showing target cells, microcytosis, hypochromia, and anisopoikilocytosis. Morphological abnormalities are similar to those observed in beta thalassemia. In alpha2 thalassemia (silent trait), only mild microcytosis is observed.

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Peripheral smear from a patient with hemoglobin H...

Peripheral smear from a patient with hemoglobin H disease showing target cells, microcytosis, hypochromia, and anisopoikilocytosis. Morphological abnormalities are similar to those observed in beta thalassemia. In alpha2 thalassemia (silent trait), only mild microcytosis is observed.

More on Thalassemia, Alpha

Overview: Thalassemia, Alpha
Differential Diagnoses & Workup: Thalassemia, Alpha
Treatment & Medication: Thalassemia, Alpha
Follow-up: Thalassemia, Alpha
Multimedia: Thalassemia, Alpha
References
Further Reading
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References

  1. Muncie HL Jr, Campbell J. Alpha and beta thalassemia. Am Fam Physician. Aug 15 2009;80(4):339-44. [Medline].

  2. Higgs DR, Weatherall DJ. The alpha thalassaemias. Cell Mol Life Sci. Apr 2009;66(7):1154-62. [Medline].

  3. Singer ST. Variable clinical phenotypes of alpha-thalassemia syndromes. ScientificWorldJournal. Jul 13 2009;9:615-25. [Medline].

  4. Haas PS, Roy NB, Gibbons RJ, Deville MA, Fisher C, Schwabe M, et al. The role of X-inactivation in the gender bias of patients with acquired alpha-thalassaemia and myelodysplastic syndrome (ATMDS). Br J Haematol. Feb 2009;144(4):538-45. [Medline].

  5. Giambona A, Passarello C, Renda D, Maggio A. The significance of the hemoglobin A(2) value in screening for hemoglobinopathies. Clin Biochem. Jul 8 2009;[Medline].

  6. Liu J, Tang N, Liu Q, Wang L, Han H, Cai R, et al. Improvement in the Detection of alpha0- and Deletional alpha-Thalassemia by Real-Time PCR Combined with Dissociation Curve Analysis. Acta Haematol. Aug 15 2009;122(1):17-22. [Medline].

  7. Chen YL, Shih CJ, Ferrance J, Chang YS, Chang JG, Wu SM. Genotyping of alpha-thalassemia deletions using multiplex polymerase chain reactions and gold nanoparticle-filled capillary electrophoresis. J Chromatogr A. Feb 13 2009;1216(7):1206-12. [Medline].

  8. Ribeiro DM, Sonati MF. Regulation of human alpha-globin gene expression and alpha-thalassemia. Genet Mol Res. Oct 14 2008;7(4):1045-53. [Medline].

  9. Arcasoy MO, Gallagher PG. Hematologic disorders and nonimmune hydrops fetalis. Semin Perinatol. Dec 1995;19(6):502-15. [Medline].

  10. Benz EJ. Clinical Manifestations of the thalassemias. UpToDate. 2006.

  11. Bernini LF, Harteveld CL. Alpha-thalassaemia. Baillieres Clin Haematol. Mar 1998;11(1):53-90. [Medline].

  12. Bunn HF, Forget BG. Hemoglobin. In: Molecular, Genetic and Clinical Aspects. Philadelphia, Pa: WB Saunders; 1986.

  13. Chui DH, Fucharoen S, Chan V. Hemoglobin H disease: not necessarily a benign disorder. Blood. Feb 1 2003;101(3):791-800. [Medline].

  14. Chui DH, Waye JS. Hydrops fetalis caused by alpha-thalassemia: an emerging health care problem. Blood. Apr 1 1998;91(7):2213-22. [Medline].

  15. Clegg JB, Weatherall DJ. Thalassemia and malaria: new insights into an old problem. Proc Assoc Am Physicians. Jul-Aug 1999;111(4):278-82. [Medline].

  16. Higgs DR. Hamm-Wasserman LectureGene Regulation in Hematopoiesis: New Lessons from Thalassemia. Hematology. 2004.

  17. Kazazian HH Jr, Dowling CE, Hurwitz RL, Coleman M, Stopeck A, Adams JG 3rd. Dominant thalassemia-like phenotypes associated with mutations in exon 3 of the beta-globin gene. Blood. Jun 1 1992;79(11):3014-8. [Medline].

  18. Lee R, Foerster J, Lukens J. The thalassemias and related disorders:. In: quantitative disorders of hemoglobin synthesis. In: Wintrobe's Clinical Hematology. Philadelphia, Pa: Lippincott, Williams, and Wilkins; 1999:1405-1448.

  19. Schell T, Kulozik AE, Hentze MW. Integration of splicing, transport and translation to achieve mRNA quality control by the nonsense-mediated decay pathway. Genome Biol. 2002;3(3):REVIEWS1006. [Medline].

  20. Schrier SL. Pathophysiology of alpha thalassemia. UpToDate. 2006.

  21. Schrier SL. Thalassemia: pathophysiology of red cell changes. Annu Rev Med. 1994;45:211-8. [Medline].

  22. Sgourou A, Routledge S, Antoniou M, Papachatzopoulou A, Psiouri L, Athanassiadou A. Thalassaemia mutations within the 5'UTR of the human beta-globin gene disrupt transcription. Br J Haematol. Mar 2004;124(6):828-35. [Medline].

  23. Steensma DP, Gibbons RJ, Higgs DR. Acquired alpha-thalassemia in association with myelodysplastic syndrome and other hematologic malignancies. Blood. Jan 15 2005;105(2):443-52. [Medline].

  24. Vichinsky EP, MacKlin EA, Waye JS, Lorey F, Olivieri NF. Changes in the epidemiology of thalassemia in North America: a new minority disease. Pediatrics. Dec 2005;116(6):e818-25. [Medline].

  25. Weatherall D. The molecular basis for phenotypic variability of the common thalassaemias. Mol Med Today. Apr 1995;1(1):15-20. [Medline].

  26. Weatherall DJ, Clegg JB. The Thalassaemia Syndromes Fourth Edition. 2004.

  27. Weatherall, DJ, Clegg, JB, Higgs, DR, et al. The hemoglobinopathies. In:. In: Scriver, CR, Beaudet, AL, Sly, WS, Valle, D (Eds). The Metabolic and Molecular Bases of Inherited Disease. 7th edition. New York: McGraw-Hill; 1995:p.3417.

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Further Reading

Related eMedicine Topics

Clinical Trials
 National Guideline Clearinghouse

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Keywords

alpha thalassemia, hemoglobin H disease, hydrops fetalis, alpha thalassemia minor, alpha thalassemia major, thalassemia intermedia, alpha globin chains, beta thalassemia, beta globin chains, silent carrier state, homozygous alpha+ thalassemia, heterozygous alpha0 thalassemia, hemoglobin H, hemoglobin Bart, hemoglobin Bart’s

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Contributor Information and Disclosures

Author

Samer A Bleibel, MD, Staff Physician, Department of Internal Medicine, Wayne State University, St John's Hospital and Medical Centers
Samer A Bleibel, MD is a member of the following medical societies: American College of Physicians
Disclosure: Nothing to disclose.

Coauthor(s)

Robert J Leonard, MD, Clinical Assistant Professor, Department of Medicine, Wayne State University School of Medicine
Disclosure: Nothing to disclose.

Jennifer L Jones-Crawford, MD, Fellow, Department of Hematology/Oncology, Medical College of Georgia
Jennifer L Jones-Crawford, MD is a member of the following medical societies: American College of Physicians and American Society of Hematology
Disclosure: Nothing to disclose.

Abdullah Kutlar, MD, Director of Sickle Cell Center, Fellowship Program Director, Professor, Department of Internal Medicine, Section of Hematology and Oncology, Medical College of Georgia
Abdullah Kutlar, MD is a member of the following medical societies: American Society of Hematology
Disclosure: Nothing to disclose.

Linda K Hendricks, MD, Assistant Professor, Department of Internal Medicine, Section of Hematology and Oncology, Mercer University School of Medicine
Linda K Hendricks, MD is a member of the following medical societies: American Society of Hematology
Disclosure: Nothing to disclose.

Medical Editor

Wadie F Bahou, MD, Chief, Division of Hematology, Hematology/Oncology Fellowship Director, Professor, Department of Internal Medicine, State University of New York at Stony Brook
Wadie F Bahou, MD is a member of the following medical societies: American Society of Hematology
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Marcel E Conrad, MD, (Retired) Distinguished Professor of Medicine, University of South Alabama
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, and Southwest Oncology Group
Disclosure: No financial interests None None

CME Editor

Rajalaxmi McKenna, MD, FACP, Consulting Staff, Department of Medicine, Southwest Medical Consultants, SC, Good Samaritan Hospital, Advocate Health Systems
Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis
Disclosure: Nothing to disclose.

Chief Editor

Emmanuel C Besa, MD, Professor, Department of Medicine, Division of Hematologic Malignancies, Kimmel Cancer Center, Thomas Jefferson University
Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, and New York Academy of Sciences
Disclosure: Nothing to disclose.

 
 
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