Causes of abnormal hemoglobin A2 levels

Reduced Hb A2		Increased Hb A2
Condition	Comments	Condition	Comments
Alpha thalassemia	Reduction correlates with severity of thalassemia	Beta thalassemia	Typical level 4 to 6%; rarely up to 10% with 5' HBB gene deletions
Alpha globin gene variants	Hybrid Hb A2 might not separate	Sickle cell disease-alpha thalassemia	Typical level 4 to 5%; due to a posttranslational effect
Delta globin gene variants	Variant can be poorly expressed	Sickle cell trait	Artifact of some HPLC systems
Delta-beta thalassemia	Half normal in heterozygotes	Sickle cell disease	Artifact of some HPLC systems
Delta thalassemia	Usually approximately half normal	Unstable hemoglobins
Gene deletional HPFH	Half normal in heterozygotes	KLF1 gene mutations	Lower than in beta thalassemia
Hb Lepore	Half normal in heterozygotes	Hereditary spherocytosis	Not uniformly elevated
Sideroblastic anemia	Due to impaired alpha globin synthesis	Congenital dyserythropoietic anemia, type 1	Lower than in beta thalassemia
Iron deficiency	Reduction correlates with severity of iron deficiency	Megaloblastic anemia	Modest increases
Acute myeloid leukemia	Minor reduction	Hyperthyroidism	Lower than in beta thalassemia
Myelodysplastic syndrome	Only reduced in a minority of cases	Zidovudine treatment for HIV infection	Lower than in beta thalassemia
Juvenile chronic granulocytic leukemia	Only reduced in a minority of cases with increased Hb F

Hb A2 is a normal adult hemoglobin consisting of two alpha chains and two delta chains (alpha2/delta2). Normal Hb A2 levels are approximately 2.8% (range, 2.1 to 3.1%). Increased or reduced Hb A2 levels may indicated one of the conditions listed in the table (inherited conditions are listed first, followed by acquired conditions). Refer to UpToDate for further discussions of these disorders and their evaluation.

HPLC: high-performance liquid chromatography; HPFH: hereditary persistence of fetal hemoglobin; Hb F: fetal hemoglobin.

Adapted with permission from:

Steinberg MH, Nagel RL. Hemoglobins of the embryo, fetus, and adult. In: Disorders of Hemoglobin: Genetics, Pathophysiology, and Clinical Management, 2nd ed, Steinberg MH, Forget BG, Higgs DR, Weatherall DJ (Eds), Cambridge University Press, New York 2009. Copyright © 2009 Cambridge University Press.
Steinberg MH, Rodgers GP. HbA2: Biology, clinical relevance and a possible target for ameliorating sickle cell disease. Br J Haematol 2015; 170(6):781-7. https://onlinelibrary.wiley.com/doi/abs/10.1111/bjh.13570. Copyright © 2015 John Wiley & Sons Inc.

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Causes of abnormal hemoglobin A2 levels