Sickle Cell Anaemia

Sickle cell anaemia is an autosomal recessive disorder caused by a point mutation in the ß globin gene. It refers specifically to the sickling disorder which arises from the ß^Sß^S genotype. Haemoglobin S is susceptible to deoxygenation, which triggers a conformational change that forms the basis for the pathogenic polymerisation of the variant haemoglobin.

The ß^S gene is most often found in individuals of African descent, but can also be found in Mediterranean and Middle Eastern descent.

Blood film features:

• Sickle cells (may be very rare)
• Boat-shaped cells
• Polychromasia
• Anisocytosis
• Basophilic stippling

Other features to look for:

• Features of hyposplenism (although acanthocytes are rare in such patients)
• Malaria infection
• Dimorphic picture (recent transfusion)
• Features of megaloblastic anaemia (concurrent folate deficiency)

Differential diagnosis:

• Hb S / ß thalassaemia (more circulating nRBCs, basophilic stippling and other dyseythropoeitic features). The sickle test in both is positive.
• Haemoglobin SC disease (will have characteristic SC poikilocytes, anaemia is less severe, less dyserythropoeitic features). The sickle test in both is positive.
• ß thalassaemia intermedia / major (lacks sickle cells and boat-shaped cells). The sickle test in ß thalassaemia intermedia / major is negative.

Other investigations:

• Sickle test: positive in Hb S / ß thalassaemia
• Haemoglobin electrophoresis
• HPLC

Haemoglobin electrophoresis:

Alkaline gel electrophoresis from a patient with sickle cell anaemia. The main haemoglobin has the mobility of haemoglobin S. There are other haemoglobins with the mobility of haemoglobin F and haemoglobin C. The band with the mobility of haemoglobin C is most likely haemoglobin A₂.

Acid gel electrophoresis from a patient with sickle cell anaemia. The main haemoglobin has the mobility of haemoglobin S. This confirms that the dominant band seen on the alkaline gel is haemoglobin S (Hb G, D and Lepore all have the mobility of Hb A on acid gel). There are other haemoglobins with the mobility of haemoglobin F and haemoglobin A. The band with the mobility of haemoglobin A is most likely haemoglobin A₂.

HPLC:

HPLC from a patient with sickle cell anaemia. There is no normal haemoglobin A. The major haemoglobin is haemoglobin S (red arrow). The haemoglobin F (green arrow) fraction is increased (10.9%, upper limit of normal usually ~1%), which helps to compensate for the severity of the disease. The low concentration of the variant haemoglobin in the A₂ window (blue arrow) confirms that it is haemoglobin A₂ (haemoglobin E can also occur in this window, but would be expected to have a higher fraction, with a lower fraction of Hb S).

Other resources:

• PHE Family Origin Questionnaire
• PHE Sickle Cell and Thalassaemia Screening Programme (2019)
• BCSH Guideline: Significant Haemoglobinopathies: Guidelines for Screening and Diagnosis (2010)
• BCSH Guideline: Management of Acute Chest Syndrome in SCD (2015)
• BCSH Guideline: Red Cell Transfusion in SCD Part I (2016)
• BCSH Guideline: Red Cell Transfusion in SCD Part II (2016)
• BCSH Guideline: Use of hydroxycarbamide in children and adults with SCD (2018)
• BCSH Guideline: Red blood cell specifications for patients with hemoglobinopathies: a systematic review and guideline (2020)
• RCOG Guideline: Management of SCD in Pregnancy (2011)