Each year, 19 June marks World Sickle Cell Day – an event established in 2008 by the United Nations General Assembly to raise awareness of sickle cell disease at a national and international level.
Sickle cell disease (of which a common form is sickle cell anaemia) is a devastating inherited blood disorder. People suffering from sickle cell disease around the world may have endured a particularly challenging time during the COVID-19 pandemic; in the UK, people with sickle cell disease are categorised as ‘clinically extremely vulnerable’ to COVID-19 [1].
Although it is rare, sickle cell disease is the fastest growing genetic disorder in the UK [2], and there is an urgent need for increased awareness of the disease 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 acute and chronic symptoms of sickle cell disease are often debilitating, taking their toll on the patient’s physical and mental health. Patients with sickle cell disease experience chronic pain and fatigue, which have severe impacts on their productivity and quality of life. The term ‘sickle cell crises’ refers to acute episodes of intense pain, which can be life-threatening and require hospital admission. The most common sickle cell crisis is a vaso-occlusive crisis (VOC), characterised by very intense pain as the patient’s blood vessels become obstructed by sickled cells. 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 shielding 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. Although there are limited data, you can also find statistics on COVID-19 outcomes for patients with sickle cell disease [11].
Treatment options
The pillars of treatment for sickle cell disease are blood transfusions and the oral medication hydroxyurea. Blood transfusions are an important intervention used to treat both chronic and acute complications of sickle cell disease by increasing the oxygen-carrying capacity of the blood and reducing the sickle cell load, thereby reducing the risk of vaso-occlusions [14]. Originally developed as a chemotherapy agent, low doses of hydroxyurea have a proven benefit in patients with sickle cell disease by increasing the amount of foetal haemoglobin, which in turn reduces the chance of red blood cell sickling. Hydroxyurea has been used to treat adult patients with sickle cell disease for decades; in recent years, the drug has also been approved for use in children with sickle cell disease [17].
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].
However, curative approaches are not widely used. Conventional treatment aims to reduce the frequency of painful episodes and infections associated with the disease, with most patients taking antibiotics and antivirals daily to ward off infections, as well as vitamins and dietary supplements (such as folic acid). Environmental factors can also trigger VOCs in patients with sickle cell disease, so keeping warm and hydrated are also important preventative measures [12].
What can you do to help?
You can visit the NHS Blood and Transplant sickle cell awareness website for information on how to get involved in fundraising activities [2].
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].
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. National Health Service. Who’s at higher risk from coronavirus? Available at: https://www.nhs.uk/conditions/coronavirus-covid-19/people-at-higher-risk/who-is-at-high-risk-from-coronavirus-clinically-extremely-vulnerable/. Accessed June 2021.
2. 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 2021.
3. 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 2021.
4. Kato GJ, Piel FB, Reid CD et al. Sickle cell disease. Nat Rev Dis Primers 2018; 4: 18010.
5. Piel FB, Patil AP, Howes RE et al. Nat Commun 2010; 1: 104.
6. Centers for Disease Control and Prevention. Data & statistics on sickle cell disease. Available at: https://www.cdc.gov/ncbddd/sicklecell/data.html. Accessed June 2021.
7. Grosse SD, Odame I, Atrash HK et al. Am J Prev Med 2011; 41 (6 Suppl 4): S398–S405.
8. National Health Service. Symptoms: Sickle cell disease. Available at: https://www.nhs.uk/conditions/sickle-cell-disease/symptoms. Accessed June 2021.
9. Verduzco LA and Nathan DG. Blood 2009; 114 (25): 5117–5125.
10. GOV.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 2021.
11. Sickle Cell Society. Coronavirus (COVID-19) & sickle cell disorder. Available at: https://www.sicklecellsociety.org/coronavirus-and-scd. Accessed June 2021.
12. National Health Service. Treatment: Sickle cell disease. Available at: https://www.nhs.uk/conditions/sickle-cell-disease/treatment. Accessed June 2021.
13. Ribeil J-A, Hacein-Bey-Abina S, Payen E et al. N Engl J Med 2017; 376 (9): 848–855.
14. Howard J. Hematology Am Soc Hematol Educ Program 2016; 2016 (1): 625–631.
15. Sickle Cell Society. Available at: https://www.sicklecellsociety.org. Accessed June 2021.
16. 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 2021.
17. Hydroxyurea for Sickle Cell Disease, Treatment information from ASH. Available at: https://www.hematology.org/-/media/Hematology/Files/Education/Hydroxyurea-Booklet.pdf
Author: Luke Smith, Medical Writer, Porterhouse Medical
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