Anemia can be the first feature of sickle cell disease and thalassemia when the disease manifests from about the age of 6 months.

This happens because normally, at the age of about 6 months, the fetal  hemoglobin (hemoglobin F, HbF, or α₂γ₂) is replaced by the more common adult hemoglobin: Hemoglobin A (α ₂β₂) ( > 90 %) and in a smaller proportion Hemoglobin A2 (α2δ2)< 3,4 % , less than 1% of HbF remains.

Patients with SCD include those who are homozygous for sickle hemoglobin (HbSS, also called sickle cell anemia [SCA]) and those with one sickle hemoglobin gene plus a gene for another abnormal hemoglobin type (such as  Sß(0), SC, or Sß(+)).

High-performance liquid chromatography (HPLC) is the test to distinguish hemoglobinopathies, which could be used easily in reference and routine laboratories for diagnosing hemoglobinopathies.

Other tests that should be performed are:

Complete blood count including erythrocytes, leucocytes, platelets, hemoglobin, hematocrit, mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH).

Ferritin is in hemoglobinopathies elevated, to the contrary, the ferritin will be low when anemia is caused by iron deficiency.

When erythrocytes have a short survival rate, the bone marrow will become more active. Young erythrocytes, reticuloculocytes, will appear in larger amounts in the peripheral blood. Typically for sickle cell disease the erythrocytes shaped as a sickle can be seen under the microscope in a blood smear.

If available a DNA test to confirm the genetic diagnosis is recommended.