What Is Sickle Cell Disease?

Sickle cell disease (SCD) is an inherited disease in which the haemoglobin genes become mutated (altered) causing the red blood cells shape to become rigid, sticking to the walls of the blood vessels and obstructing normal blood flow.6 The normal haemoglobin gene is called haemoglobin A while a mutated haemoglobin (sickled) gene is referred to as haemoglobin S. Symptoms can range from mild to severe and may eventually progress to multiple organ damage and death, so prompt screening and diagnosis is important to improve chances of survival.5 

Sickle cell disease is a huge public health burden. According to the World Health Organization (WHO), over 300 000 babies are born with severe haemoglobin disorders each year, while roughly about 5% of the global population have a type of haemoglobin disorder, mainly, sickle-cell disease and thalassaemia but there are healthy carriers, meaning they show no signs or symptoms.11 Though SCD mainly affects people of African or African-Caribbean origin, the sickle gene is found in all ethnic groups.3 It is the most common genetic disease in the UK.12 There are roughly 15,000 people living with SCD in the UK.1,3 Almost 300 babies are born with sickle cell each year and 1 in 79 babies are born with the sickle cell trait.1,3,8

The main symptom of SCD are episodes of severe pain, which are referred to as sickle cell crisis.1 This crisis can be triggered by different conditions such as infections, psychological stress, extreme exercise, cold temperatures, pregnancy, dehydration, and reduced oxygen in the blood (for example due to exertion, anaesthesia, and high altitude).3 

Overview

Every individual has a pair of haemoglobin genes in every cell in their body, except the eggs and sperm.4 One half of this gene is received from each parent. In sickle cell disease, there are two altered haemoglobin genes, so an affected individual will inherit one from each parent. In sickle cell trait, there is only one haemoglobin S gene, which the affected individual inherits from only one parent while getting the haemoglobin A from the other. Individuals with sickle cell trait are generally healthy though they are carriers of the haemoglobin S gene meaning they can pass it to their children. 

Sickle cell disease runs in families. To understand the inheritance pattern:4

If one parent has a sickle cell trait (HbAS) and the other has a normal haemoglobin gene (HbAA), then none of the children will have sickle cell anaemia, though there is 50% chance that any given child will get one copy of the HbS gene (and therefore have the sickle cell trait, HbAS) and a 50% chance any given child will get two HbA genes (and be completely unaffected, HbAA)

If both parents have sickle cell trait (HbAS), there is a 25% chance that any given child could be born with sickle cell anaemia (HbSS), a 25% chance that any given child could be completely unaffected (HbAA) and a 50% chance that any given child will get the sickle cell trait (HbAS).

If one parent has sickle cell trait (HbAS) and the other has sickle cell anaemia (HbSS), there is a 50% chance that any given child will get sickle cell trait (HbAS) and a 50% chance that any given child will get sickle cell anaemia (HbSS). No children will be completely unaffected.

If one parent has sickle cell anaemia (HbSS) and the other is unaffected (HbAA), then all the children will have sickle cell trait. None will have sickle cell anaemia. The parent with HbSS can only pass the sickle gene to each of their children.

Causes of sickle cell disease

Haemoglobin is the protein substance in red blood cells that binds to oxygen and carries it from the lungs to the rest of the body, while transporting carbon dioxide in the opposite direction. Red blood cells with normal haemoglobin are soluble so they do not clump together and flexibly pass through narrow blood vessels. Normal red blood cells can live up to 120 days.10

When the haemoglobin gene is altered, the red blood cells are unable to hold on to oxygen and form a sickle or crescent shape. The affected red blood cells stick together and can’t easily move through the blood vessels, subsequently blocking the movement of healthy, normal oxygen-carrying blood in small blood vessels. It is this blockage that leads to the episodes of pain. In addition, the rigid shape of sickle cells causes them to get stuck in the spleen, which eventually destroys them. In healthy individuals, the spleen helps filter the blood of infections, so sickled cells interfere with the protective actions of the spleen, and affected individuals are prone to infections. All these contribute to an average lifetime of 10 to 20 days for sickle cells.9 

Signs and symptoms of sickle cell disease

Infants generally do not show any signs and symptoms until they are 6 months old. If symptoms manifest in infants younger than 6 months, they may appear as jaundice, pallor, or with a rapid heartbeat.3 In people above 6 months, signs and symptoms vary and may change over time, and can include:3, 7, 9

  • Anaemia due to the short lifetime of sickled red blood cells (10 to 20 days). This manifests as feeling dizzy, shortness of breath, fatigue, and tiredness
  • Episodes of pain due to occlusion of blood flow through tiny blood vessels, especially in the chest, abdomen, and joints. The intensity, duration, and frequency of this crisis varies between individuals, and may require hospitalisation in some people
  • Swelling of hands and feet due to occlusion of blood flow in the hands and feet
  • Frequent infections due to damage to the spleen, increasing vulnerability to infections,manifesting as fever
  • Delayed growth or puberty due to insufficient oxygen and nutrients resulting from a shortage of healthy red blood cells
  • Vision problems due to occlusion of blood flow in the tiny blood vessels that supply the eyes leading to retinal damage. This can result in blindness
  • Jaundice (yellowing) of the skin, eyes, and mouth because the red blood cells die faster than they can be removed from the body by the liver leading to accumulation of bilirubin. (Bilirubin is the orange yellow pigment produced from the breakdown of red blood cells and which is removed by the liver from the body. In abnormal conditions, the blood levels build up2

Complications include:

  • Stroke due to occlusion of blood flow to an area of the brain. This can manifest as weakness or numbness of the arms and legs, sudden speech difficulties, seizures, and loss of consciousness
  • Acute chest syndrome due to lung infection or sickle cells blocking blood vessels in the lungs. This can appear as chest pain, fever and difficulty breathing
  • Organ damage when sickle cells block blood flow to organs and deprive them of blood and oxygen
  • Splenic sequestration due to a large number of sickle cells getting trapped in the spleen, causing it to enlarge. This appears as a protruding abdomen and can cause pain on the left side
  • Gallstones due to abnormally high levels of bilirubin
  • Priapism when the sickle cells block the blood vessels in the penis, causing painful, long-lasting erections which can lead to impotence over time
  • Pregnancy complications such as miscarriage, premature birth, high blood pressure, and having low birth weight babies

As symptoms may mimic other medical conditions, it is important to consult your doctor.9 The severity of symptoms vary, and in mild cases may have no impact on an individual's day-to-day life. Indeed, most people have happy and normal lives.10 A UK study estimated that the median survival is 67 years.3

Prompt diagnosis is key to improving chances of survival since symptoms can begin as early as six months. In the UK, the Sickle Cell and Thalassaemia (SCT) screening programme screens for genetic carriers for sickle cell, thalassaemia, and other haemoglobin disorders. Sickle cell disease screening is offered to all new-born babies (usually when they are 5 days old), all infants aged younger than 1 year (if newly arrived in the UK or yet to have a blood spot test), pregnant women (normally before the 10th week), and biological fathers (if the mother is a genetic carrier for sickle cell disease or thalassaemia).3,10  

Management and treatment for sickle cell disease

The most cost-effective strategy for reducing SCD is by complementing disease management with self-care prevention measures such as regular and adequate fluid intake, healthy diet, folic acid supplementation, pain medication, keeping warm, avoiding triggers, vaccinations and antibiotics.11 

Treatment is required for life and includes regular blood transfusions if symptoms persist or worsen, or complications develop and emergency blood transfusions if severe anaemia develops.10 Hydroxycarbamide (hydroxyurea) is a disease-modifying therapy which increases foetal haemoglobin and reduces red blood cell sickling.6 Second-line medications include L-glutamine, Crizanlizumab, and Voxelotor. The only cure for sickle cell disease is a stem cell or bone marrow transplant, but they're not carried out very often because of the risks involved.10 As the success of transplant is limited by donor availability, best results are seen in children with a matched sibling donor.6 

Normally, women with sickle cell disease without complications can use any method of contraception.3 However, due to higher typical-use failure rates, sole use of barrier methods or behaviour-based methods may not be suitable for the individual.3

FAQs

How is sickle cell disease diagnosed?

There are different ways to diagnose sickle cell disease.

Blood tests like the haemoglobin electrophoresis measure the type of haemoglobin in the blood. Normal haemoglobin include HbF (foetal haemoglobin) and HbA.13 High levels of HbS indicate sickle cell anaemia while trace levels suggest a sickle cell trait. Genetic testing is confirmatory and can determine the type of sickle cell disease and the number of sickle haemoglobin genes.8

Several screening programs help to promote early diagnosis. In prenatal screening, a sample from the amniotic fluid or placenta tissue is used to check for genetic abnormalities as early as the 8th week of pregnancy.8,14 In antenatal screening, the pregnant woman is tested for the defective gene. If positive, her partner is usually tested for the presence of sickle cell trait.14 In the new-born screening, the heel prick test (also called the new-born blood spot test) is completed.. Two positive tests are required to confirm the diagnosis.8

How can I prevent sickle cell disease?

Self-care measures include regular and adequate fluid intake, healthy diet, folic acid supplementation, pain medication, keeping warm, avoiding triggers and vaccinations and antibiotics.11  

Who is at risk of sickle cell disease?

People with an African or Caribbean family background are at high risk of SCD.10 Other groups at risk include Hispanic-Americans from Central and South America and people of Middle Eastern, Asian, Indian, and Mediterranean descent.15

How common is sickle cell disease?

There are almost 15,000 people living with SCD in the UK. An estimated 300 babies are born with sickle cell each year.1, 3, 8

When should I see a doctor?

You should seek medical advice from your GP or care team immediately if you develop fever, breathing difficulties, drowsiness, confusion, severe headache, dizziness, pale skin or lips, seizures, severe pain that does not respond to home treatments, sudden tummy swelling, weakness on one or both sides of your body, changes in vision, or sudden vision loss.16 

Summary

The burden of sickle cell both individually and collectively is huge. In addition to research , it is important to increase awareness of the global burden of these disorders and promote equitable access to health services.11

References

  1. About sickle cell » sickle cell society [Internet]. Sickle Cell Society. [cited 2023 Feb 12]. Available from: https://www.sicklecellsociety.org/about-sickle-cell/
  2. Bilirubin test - mayo clinic [Internet]. [cited 2023 Feb 12]. Available from: https://www.mayoclinic.org/tests-procedures/bilirubin/about/pac-20393041
  3. CKS is only available in the UK [Internet]. NICE. [cited 2023 Feb 12]. Available from: https://www.nice.org.uk/cks-uk-only
  4. Inheritance of sickle cell anaemia » sickle cell society [Internet]. Sickle Cell Society. [cited 2023 Feb 12]. Available from: https://www.sicklecellsociety.org/resource/inheritance-sickle-cell-anaemia/
  5. Kato GJ, Piel FB, Reid CD, Gaston MH, Ohene-Frempong K, Krishnamurti L, et al. Sickle cell disease. Nat Rev Dis Primers. 2018 Mar 15;4:18010. Available from: https://pubmed.ncbi.nlm.nih.gov/29542687/
  6. Kavanagh PL, Fasipe TA, Wun T. Sickle cell disease: a review. JAMA. 2022 Jul 5;328(1):57–68. Available from: https://pubmed.ncbi.nlm.nih.gov/35788790/#:~:text=Abstract,multiorgan%20damage%2C%20and%20increased%20mortality
  7. Sickle cell anemia - Symptoms and causes [Internet]. Mayo Clinic. [cited 2023 Feb 12]. Available from: https://www.mayoclinic.org/diseases-conditions/sickle-cell-anemia/symptoms-causes/syc-20355876
  8. Sickle cell disease - causes and risk factors | nhlbi, nih [Internet]. [cited 2023 Feb 12]. Available from: https://www.nhlbi.nih.gov/health/sickle-cell-disease/causes
  9. Sickle cell disease [Internet]. 2019 [cited 2023 Feb 12]. Available from: https://www.hopkinsmedicine.org/health/conditions-and-diseases/sickle-cell-disease
  10. Sickle cell disease [Internet]. nhs.uk. 2017 [cited 2023 Feb 12]. Available from: https://www.nhs.uk/conditions/sickle-cell-disease/
  11. Sickle cell disease [Internet]. WHO | Regional Office for Africa. [cited 2023 Feb 12]. Available from: https://www.afro.who.int/health-topics/sickle-cell-disease
  12. Sickle cell disease | ukoss | npeu [Internet]. [cited 2023 Feb 12]. Available from: https://www.npeu.ox.ac.uk/ukoss/completed-surveillance/scd  
  13. Hassell, Kathryn L. “Chapter 56 - Sickle Cell Disease.” Critical Care Secrets (Fourth Edition), edited by Polly E. Parsons and Jeanine P. Wiener-Kronish, Mosby, 2007, pp. 355–59. ScienceDirect, https://doi.org/10.1016/B978-1-4160-3206-9.10056-4.
  14. Screening for sickle cell and thalassaemia [Internet]. nhs.uk. 2020 [cited 2023 Feb 13]. Available from: https://www.nhs.uk/pregnancy/your-pregnancy-care/screening-for-sickle-cell-and-thalassaemia/
  15. Sickle cell disease [Internet]. [cited 2023 Feb 13]. Available from: https://www.hematology.org:443/education/patients/anemia/sickle-cell-disease 
This content is purely informational and isn’t medical guidance. It shouldn’t replace professional medical counsel. Always consult your physician regarding treatment risks and benefits. See our editorial standards for more details.

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