19 June 2024

World Sickle Cell Day: Shining a light on sickle cell disease

 

World Sickle Cell Day (19 June) is observed annually with the aim of increasing public knowledge of sickle cell disease, and the challenges experienced by patients, their families and caregivers. To help improve understanding of sickle cell disease, our article looks at the pathology of the disease, its prevalence and available treatment.

Sickle cell disease (also called sickle cell anaemia) is a devastating inherited blood disorder that affects millions of people throughout the world. Although still rare in the UK, it is the fastest growing genetic disorder in the country [2]

The disease is particularly prevalent in people with an African or Caribbean background and there is an urgent need for increased awareness to help address the shortage of blood donors of Black, Asian and/or minority ethnic heritage [3].

Genetics

Sickle cell disease is often used as an archetypal example of an inherited disorder; many school and university biology students will be familiar with its aetiology. The disease is caused by a mutation in the HBB gene encoding the beta subunit of haemoglobin (HBB), which is combined in a 1:1 ratio with the alpha subunits of haemoglobin (HBA) to form the tetrameric protein haemoglobin [4].

The mutation results in a single amino acid substitution within the 147 residues that comprise the wild-type HBB protein, but it has dramatic effects on the properties of haemoglobin.

Individuals inherit the disease only if they have two copies of the mutant allele, meaning that both parents must either be carriers of the mutated allele or themselves sufferers of sickle cell disease. Carrying one copy (sickle cell trait) is not usually associated with any symptoms of the disease and, as we will discover later, can actually be advantageous to the carrier [4].

Haemoglobin and red blood cells

The role of haemoglobin is to deliver oxygen from the lungs to the tissues of the body. Each haemoglobin molecule is capable of binding four oxygen molecules (one to each subunit) that are donated to tissues as haemoglobin travels through the circulation, meaning it exists in an oxygenated (oxyhaemoglobin) and deoxygenated (deoxyhaemoglobin) form [4].

Oxyhaemoglobin in patients with sickle cell disease is indistinguishable from the normal protein, but deoxyhaemoglobin in these patients sticks together (polymerises). Polymerisation of deoxyhaemoglobin causes the red blood cells to morph from a normal pliant disc-shaped cell to a stiff, sickle-shaped cell. These deformed cells do not travel well within the circulation, tending to aggregate within blood vessels. In addition, because of their abnormal properties, they are prone to rupturing in a process called haemolysis [4].

The malaria hypothesis

Sickle cell disease is common within populations originating from tropical regions and, of course, sickle cell trait is even more prevalent within these populations. Knowing that untreated children born with sickle cell disease do not usually reach adulthood, geneticists in the early 20th century were presented with a paradox. In the absence of a suitable explanation, the prevalence of sickle cell disease was simply incompatible with Darwin’s theory of natural selection; with such a strong selective pressure against the mutant allele, it should not have survived, let alone remained so common [5].

The apparent paradox was resolved in 1949 by John Burdon Sanderson ‘JBS’ Haldane, considered to be one of the fathers of modern genetics, who proposed that alleles responsible for blood diseases in homozygotes offer heterozygotes protection against the parasite that causes malaria. This ‘balancing selection’ was later confirmed in many locations where sickle cell disease is still common and was more recently confirmed globally [5].

Prevalence

The HBB mutation that causes sickle cell disease is common among people originating from areas where malaria is endemic, including parts of Africa, the Mediterranean, the Middle East, India, the Caribbean, and Central and South America [5].

In the UK, the disease is increasing in prevalence because of historic and continuing immigration. There are approximately 15,000 people in the UK living with sickle cell disease, and approximately 300 babies are born with the disease each year [2].

In the US, the Centers for Disease Control and Prevention (CDC) estimates that roughly 1 in 13 Black or African American babies are born with the sickle cell trait, and sickle cell disease affects approximately 1 of every 365 babies born to these populations [6].

The disease is more common in Africa, affecting up to 3% of births in some countries in the continent. In this region, sickle cell disease is associated with a very high rate of child mortality (50%–90% mortality rate before the age of five years) and remains a neglected disease [7].

Disease symptoms

The most common symptoms associated with sickle cell disease include pain caused by vaso-occlusive episodes (blood vessels becoming obstructed by sickled cells), increased vulnerability to infections and, of course, anaemia. As you might imagine given the essential role of red blood cells within the circulation, there is a very long list of severe complications associated with the disease [8], with stroke and chronic cerebral ischaemia among the most debilitating. It has been reported that 24% of patients with sickle cell disease have a stroke by the age of 45 years [9].

Sickle cell disease and COVID-19

Patients with sickle cell disease are at a high risk of infections and are consequently in the highest risk group for COVID-19 [1]. For more information, see the Government’s guidance on getting vaccinated and protecting clinically extremely vulnerable people from COVID-19 [10].

The Sickle Cell Society provides more specific information on sickle cell disease and COVID-19, as well as various links to official guidance. [11].

Treatment options

As is common with many inherited diseases, curing sickle cell disease is not usually an option, although curative approaches are possible. Stem cell therapy and bone marrow transplants offer potential cures but are rarely considered because they carry significant risks, particularly graft-versus-host disease [12]. One way around this is to extract and modify a patient’s own stem cells before transplanting them back into the patient. A group in France used gene therapy to introduce an anti-sickling HBB gene variant into a patient’s haematopoietic stem cells before reimplantation. The patient, a 13-year-old boy with a long history of sickle cell–related complications, was reported to be symptom-free 15 months after treatment [13].

These approaches are not widely used, and conventional treatment aims to reduce the painful episodes and infections associated with the disease, with most patients taking antibiotics daily to ward off bacterial infections. They may also require dietary supplements (such as folic acid) to address anaemia [12].

Blood transfusions are another important intervention used to treat both chronic and acute complications of sickle cell disease. Blood transfusions increase the oxygen-carrying capacity of the blood and reduce the sickle cell load, which reduces the risk of vaso-occlusions [14].

What can you do to help?

Fundraising

You can visit the NHS Blood and Transplant sickle cell awareness website for information on how to get involved in fundraising activities [2].

Spread awareness

The Sickle Cell Society is calling for volunteers to help raise awareness of the need for more blood donors of Black heritage as part of the Give Blood, Spread Love, England awareness project, which sprang from the successful South London Gives project [15].

Become a blood donor

The background to this campaign is that transfusions, especially when received regularly, are typically more successful when patients receive blood from donors of the same ethnic background. There is a particular need for blood donors with the Ro subtype, which is more common in people from Black ethnic backgrounds. [16] If you can help address this need, visit the NHS Blood and Transplant website today to register to become a blood donor: https://www.nhsbt.nhs.uk/.

References

  1. NHS Blood and Transplant. Sickle cell awareness. Available at: https://www.nhsbt.nhs.uk/how-you-can-help/get-involved/download-digital-materials/sickle-cell-awareness-day-2020. Accessed June 2022.
  2. NHS Blood and Transplant. Black, Asian and minority ethnic communities. Available at: https://www.nhsbt.nhs.uk/how-you-can-help/get-involved/key-messages-and-information/why-black-asian-and-minority-ethnic-donors-are-needed/. Accessed June 2022.
  3. Kato GJ, Piel FB, Reid CD et al. Sickle cell disease. Nat Rev Dis Primers 2018; 4: 18010.
  4. Piel FB, Patil AP, Howes RE et al. Nat Commun 2010; 1: 104.
  5. Centers for Disease Control and Prevention. Data & statistics on sickle cell disease. Available at: https://www.cdc.gov/ncbddd/sicklecell/data.html. Accessed June 2022.
  6. Grosse SD, Odame I, Atrash HK et al. Am J Prev Med 2011; 41 (6 Suppl 4): S398–S405.
  7. National Health Service. Symptoms: Sickle cell disease. Available at: https://www.nhs.uk/conditions/sickle-cell-disease/symptoms. Accessed June 2022.
  8. Verduzco LA and Nathan DG. Blood 2009; 114 (25): 5117–5125.
  9. UK. Guidance on shielding and protecting people who are clinically extremely vulnerable from COVID-19. Available at: https://www.gov.uk/government/publications/guidance-on-shielding-and-protecting-extremely-vulnerable-persons-from-covid-19/guidance-on-shielding-and-protecting-extremely-vulnerable-persons-from-covid-19. Accessed June 2022.
  10. Sickle Cell Society. Coronavirus (COVID-19) & sickle cell disorder. Available at: https://www.sicklecellsociety.org/coronavirus-and-scd. Accessed June 2022.
  11. National Health Service. Treatment: Sickle cell disease. Available at: https://www.nhs.uk/conditions/sickle-cell-disease/treatment. Accessed June 2022.
  12. Ribeil J-A, Hacein-Bey-Abina S, Payen E et al. N Engl J Med 2017; 376 (9): 848–
  13. Howard J. Hematology Am Soc Hematol Educ Program 2016; 2016 (1): 625–631.
  14. Sickle Cell Society. Available at: https://www.sicklecellsociety.org. Accessed June 2021.
  15. Why we need Black donors. Available at: https://www.blood.co.uk/why-give-blood/demand-for-different-blood-types/why-more-black-blood-donors-are-needed. Accessed June 2022.