Sickle cell disease (SCD) is the most commonly inherited single gene disorder among millions of people worldwide. This hereditary red cell disorder affects individuals from diverse ethnic backgrounds, i.e., Mediterranean, African, Caribbean, Middle East, South America, and South Asian. In Ontario, over 3500 people are affected by SCD with a total of more than 6,000 Canadians; predominantly in individuals who identify as Black.¹

A group of genetic disorders characterized by the production of abnormal hemoglobin S (Hb S) is known generically as SCD. The severity of the disease varies widely, depending on the person’s genes, e.g., heterozygous, homozygous, or compound heterozygous.

Hemoglobin

Four subunits compose hemoglobin (Hb), each containing a molecule of heme and a globin chain.² The major adult hemoglobin is called Hb A (alpha_2/beta_2).³ Minor amounts of two additional hemoglobin fractions are normally present in adults, Hb A₂ (alpha₂/delta₂)  and Hb F (alpha₂/gamma₂). The Hb F fraction is the major hemoglobin detected in newborns but is replaced by Hb A during the first six months after birth.⁴ The hemoglobinopathies are genetic disorders of globin that can be divided into two broad categories, the hemoglobin variants, in which structurally abnormal globin chains are produced, and the thalassemia, resulting in reduced production of normal globin chains.^5,6

In SCD, the abnormality is a substitution of valine for glutamic acid at the 6th amino acid of the β-globin chain. This results in the production of sickle hemoglobin (Hb S), which is unstable and polymerizes in the deoxygenated state – the presence of hemoglobin S (in homozygous form) distorts the erythrocyte architecture into the distinctive crescent moon-shaped sickle cells. These cells have increased rigidity, interfering with their ability to pass through small blood vessels and can result in several types of crises. 

Characteristics of sickle cell disease and trait

Sickle cells are red blood cells that have been deformed by polymerized Hb S. The classic sickle cell is elongated and crescentic, with pointed and tapered ends (Figure 1). However, there are variations on the sickle cell form and include cells with more blunted ends, the “holly-leaf” variant and the “blister-cell” variant. Common to all forms is the lack of central pallor and increased density.

Figure 1: Sickle cells (arrows) demonstrating some variation in morphology. All cells lack central pallor and appear dense compared with surrounding cells. The tapered ends are easily noted, though some do not demonstrate the typical curvature. (Wright-Giemsa stain, ×60 magnification) (From MORP-1810-SB Committee Comments).⁷

Sickle cell anemia is the most common type of sickle cell disease and represents the homozygous form, in which the individual inherits a double dose of the abnormal gene that codes for hemoglobin S.  Combination of hemoglobin S with other inherited hemoglobin disorders including beta thalassemia trait, Hb C, Hb D and Hb O also leads to a sickling disorder.

In the heterozygous form of the disease, known as sickle cell trait, individuals inherit both a normal β-globin gene and a sickle-globin gene (β^ss). As a result, individuals with sickle cell trait produce both normal Hb A and Hb S, with a predominance of Hb A in an approximate ratio 60:40.^8. 

Symptoms

An individual with sickle cell disease may experience painful vaso-occlusive events, visceral sequestration crises often presenting with dyspnea (also known as acute sickle chest syndrome), aplastic crises and/or hemolytic crises. Lower leg ulcers are also common. Patients with sickle cell anemia are often prone to infections such as pneumococcal septicemia and meningitis. As well, excessive exercise can lead to a significant buildup of lactic acid, resulting in sickling and subsequent infarction.

Individuals affected by the heterozygous form of SCD are usually asymptomatic, but occasionally episodes of hematuria and hyposthenuria occur as a complication of sickle cell trait because of sickling in the kidney.

Sickle cell disease is associated with an increased risk of death from sepsis or stroke in infants and potentially serious morbidity in adulthood.

Conclusion

With increasing diversity in Ontario’s population, laboratories may encounter an individual affected by a clinically significant sickling disorder, often in the absence of a clear history or previous laboratory results. Familiarity with the typical features of sickling disorders (including CBC parameters and morphology) will aid in the timely identification of these conditions.

The IQMH Hematology committee, acknowledges the health disparities for patients with a sickling disorder. Structural discrimination is widespread in the health care system, affecting access to appropriate care for sickling disorder patients. View the recommended readings below for further information.^9,10,11.

IQMH Red Cell Disorders and Morphology programs include proficiency testing surveys that ensure the quality and reliability of test results used to diagnose sickle cell disease. For more information on the survey program, view the IQMH Proficiency Testing Catalogue.

References

1. Sickle Cell Awareness Group of Ontario. Addressing the Health Equity Gap in Sickle Cell Disease in Ontario. 2023. Available from: https://sicklecellanemia.ca/health-equity-gap-in-sickle-cell-disease-in-ontario-canada.
2. Consensus Practice Recommendations for the Laboratory Investigation of Hemoglobinopathies, revised 2020-12-18.
3. Traeger-Synodinos J, Harteveld CL, Old JM, Petrou M, Galanello R, Giordano P, et al. EMQN Best Practice Guidelines for molecular and haematology methods for carrier identification and prenatal diagnosis of the haemoglobinopathies. Eur J Hum Genet. 2015;23(4):560.
4. Ryan K, Bain BJ, Worthington D, James J, Plews D, Mason A, et al; British Committee for Standards in Haematology. Significant haemoglobinopathies: guidelines for screening and diagnosis. Br J Haematol. 2010; 149:35–49.
5. Trent RJ. Diagnosis of haemoglobinopathies. Clin Biochem Rev. 2006; 27:27–38.
6. Kutlar F. Diagnostic Approach to Hemoglobinopathies. Hemoglobin 2007; 31:243–50.
7. Institute for Quality Management in Healthcare (IQMH). MORP-1810 Committee Comments. 2018.
8. Lee, GR. Wintrobe’s Clinical Hematology. Lea & Febiger. Philadelphia, 1993.

Recommended Reading

9. https://www.cdcfoundation.org/sites/default/files/files/SickleCellDisease-HealthDisparities-FactSheet021618.pdf

10. Lee L, Smith-Whitley K, Banks S, Puckrein G. Reducing Health Care Disparities in Sickle Cell Disease: A Review. Public Health Reports. 2019;134(6):599-607. doi:10.1177/0033354919881438.

11. Power-Hays A, McGann PT. When Actions Speak Louder Than Words — Racism and Sickle Cell Disease. 2020; 383:1902-1903. doi: 10.1056/NEJMp2022125.

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