Last reviewed: 23 Aug 2023
Last updated: 11 Jul 2023



History and exam

Key diagnostic factors

  • symptoms of anemia
  • splenomegaly
More key diagnostic factors

Other diagnostic factors

  • childhood or young adulthood
  • family history of alpha-thalassemia
  • symptoms of gallstones
  • growth retardation
  • history of prior iron supplementation
  • jaundice
  • mild dysmorphic facial features
  • extramedullary hematopoiesis
Other diagnostic factors

Risk factors

  • ethnicity from a geographic malarial area
  • positive family history
More risk factors

Diagnostic investigations

1st investigations to order

  • hemoglobin (Hb)
  • mean corpuscular volume (MCV)
  • mean corpuscular hemoglobin (MCH)
  • red blood cell count
  • peripheral smear
  • reticulocyte percentage
  • serum iron
  • serum ferritin
More 1st investigations to order

Investigations to consider

  • brilliant cresyl blue staining of red blood cells
  • Hb electrophoresis
  • Hb fractionation by high-performance liquid chromatography (HPLC)
  • gap-polymerase chain reaction (gap-PCR)
  • multiplex ligation-dependent probe amplification (MLPA)
  • direct sequencing/reverse dot blot
  • MRI (hepatic or cardiac)
  • superconducting quantum interference devices (SQUID)
  • liver biopsy
More investigations to consider

Treatment algorithm


acute hemolytic episodes: pregnant or nonpregnant

transient aplastic crisis: pregnant or nonpregnant






Janet L. Kwiatkowski, MD, MSCE


Thalassemia Program

Children’s Hospital of Philadelphia

Professor of Pediatrics

Perelman School of Medicine

University of Pennsylvania




JLK has participated in research trials of gene therapy sponsored by bluebird bio, Sangamo, Vertex, and Editas, and has participated in studies of pyruvate kinase activators sponsored by Agios and Forma Therapeutics. She has consulted for Agios, Forma, Chiesi, Biomarin, Regeneron, and Bristol Myers Squibb (Celgene).


Dr Janet L. Kwiatkowski would like to gratefully acknowledge Dr Elizabeth A. Price and Dr Stanley L. Schrier, the previous contributors to this topic.


EAP declares that she has no competing interests. SLS has received National Institutes of Health (NIH) research funds, has received funds for organizing an educational symposium, and is an author of a number of references cited in this topic.

Peer reviewers

David H. K. Chui, MD, FRCPC

Professor of Medicine

Boston University School of Medicine




DHKC is an author of a number of references cited in this topic. He has received research grants or salary from the US National Institutes of Health greater than 6 figures USD.

Piero Giordano, PhD

Professor of Clinical Biochemical Molecular Genetics

Human and Clinical Genetics Department

Leiden University Medical Center


The Netherlands


PG declares that he has no competing interests.

Cornelis Harteveld, PhD

Clinical Molecular and Biochemical Geneticist

Department of Clinical Genetics

Leiden University Medical Center


The Netherlands


CH declares that he has no competing interests.

  • Alpha-thalassemia images
  • Differentials

    • Iron-deficiency anemia
    • Beta-thalassemia
    • Variant hemoglobins (Hb E, Hb Lepore)
    More Differentials
  • Guidelines

    • Hemoglobinopathies in pregnancy: ACOG practice advisory
    • Consensus statement for the perinatal management of patients with alpha-thalassemia major
    More Guidelines
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