Sickle cell disease (SCD) is an inherited life-long blood disorder where the haemoglobin (Hb) in red blood cells (RBCs) is abnormal and causes the RBCs to become hard and sticky. This abnormality makes the RBCs inflexible and look C-shaped or like a sickle, rather than round, flexible and healthy.

One of the consequences of SCD is that the irregular RBCs have a shorter lifespan, which leads to an ongoing shortage of RBCs.

• Normal RBCs survive for 90-120 days
• RBCS associated with SCD last 10-20 days.Unhealthy shaped RBCs also increase the chance of getting stuck in the blood vessels, leading to blockages and impeding blood flow. This can cause pain and increase the risk of infection, acute chest syndrome and stroke.

SCD is also thought to be a prothrombotic state, playing a vital role in promoting venous thrombosis. This can result from a boost in platelet function, impaired fibrinolysis and the chronic activation of the coagulation cascade.

Statistics

Sickle cell disease is the most common monogenic (one gene) disease globally, which is caused by the mutation in the ꞵ-globin gene (a haemoglobin subunit gene). The Global Burden of Disease Study 2021 found there were 7.74 million people globally living with SCD; an increase from 5.46 million in 2000.

SCD is more prevalent among certain population groups:

• People whose ancestors are from sub-Saharan Africa.
• Regions in the Western Hemisphere (South America, Caribbean and Central America).
• Saudi Arabia, India.
• The Mediterranean (Turkey, Greece and Italy).

It is estimated that approximately 275,000 babies are born with SCD every year, with this number hypothesised to grow to over 400,000 by 2050. A child will inherit SCD by receiving one abnormal haemoglobin gene from each parent. There are many different forms or varieties of SCD, and the type a child is born with depends on the type of genes inherited.

The most common types of SCD are:

HbSS – this is when you receive one gene from each parent that code for haemoglobin ‘S’, which is an irregular class of haemoglobin which causes the RBCs to become sickle shaped. Another term used for this type of SCD is sickle cell anaemia which is the most severe variety of the condition.

HbSC – this is milder version of SCD as it involves receiving the haemoglobin ‘S’ gene from one parent and another type of abnormal haemoglobin called ‘C’.

HbS beta thalassemia – this is also a milder form of SCD; with the haemoglobin ‘S’ gene coming from one parent, the gene coming from the other parent is for beta thalassemia. However, there are two types of Hbs – the milder version is Hbs beta0 (zero), and the more severe form is HbS+ (plus).

Signs and symptoms

As there are a diverse range SCD, signs and symptoms will also vary. Here are some general presentations, which usually begin to appear at 5-6 months of age.

• Jaundice – a yellowish colour to the skin.
• Icterus – a yellowish colour of the whites of the eyes.
• Painful swelling of the hands and feet.
• Fatigue or fussiness from anaemia.

Treatment options

The main cure for SCD is a blood and bone marrow transplant, however there are several treatments available to help reduce symptoms.

Medications

• to help prevent RBCs from developing into the sickle shape
• to reduce the destruction of RBCs which may reduce the risk of anaemia and improve blood flow
• to prevent RBCs sticking to the blood vessel walls – which may help reduce blockage

SCD, pregnancy and the risk of thromboembolism

As pregnancy is thought to be a prothrombotic state, and SCD can involve elevated coagulation events, pregnant women with SCD are shown to be at a higher risk of thromboembolism.

A 2023 study found that thromboembolism during pregnancy and 1-year post-partum was significantly higher in pregnant women with SCD when compared to pregnant women without SCD. The study results also found that thromboembolism was more prevalent during the third trimester and 3-months post-partum.

Oxidative stress and SCD

With SCD, sickle RBCs are the main cause of the disease and sickle RBCs are a prime source of oxidative stress. Oxidative stress is an imbalance between the production of reactive oxygen species (ROS), also called free radicals, and antioxidant defences in the body.

One of the most noticeable observed events associated with sickle RBCs is that they contain elevated levels of ROS and oxidative stress.

Image: Potential contributions of sickle RBCs to venous thrombosis in SCD (Wang & Zennadi, 2021)

High levels of ROS in sickle RBCs impair the structure and function of blood vessel walls (endothelium) causing damage. This can then lead to reduced flow of sickle RBCs causing blood stasis, slowly increased the formation of thrombi.

You can read more about oxidative stress HERE.

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References

• What is Sickle Cell Disease? | CDC
• Sickle Cell Disease - What Is Sickle Cell Disease? | NHLBI, NIH
• Genetic Disorders (genome.gov)
• Sickle Cell Disease | Sickle Cell Anemia | MedlinePlus
• Data & Statistics on Sickle Cell Disease | CDC
• Global, regional, and national prevalence and mortality burden of sickle cell disease, 2000–2021: a systematic analysis from the Global Burden of Disease Study 2021 - The Lancet Haematology
• Agarwal, S., Stanek, J.R., Vesely, S.K., Creary, S.E., Cronin, R.M., Roe, A.H., & O’Brien, S.H. (2023). Pregnancy-related thromboembolism in women with sickle cell disease: An analysis of National Medicaid Data. American Journal of Hematology, 98(11), 1677–1684. https://doi.org/10.1002/ajh.27045
• Nelson, A., Ho, P. J., Haysom, H., Waters, N., Wellard, C., Chee, M., Teo, J., Greenway, A., Mason, K., Kidson-Gerber, G., Kaplan, Z., Carter, T., Cole-Sinclair, M. F., Barbaro, P., & Wood, E. M. (2023). Sickle cell disease in Australia: a snapshot from the Australian Haemoglobinopathy Registry. Internal Medicine Journal. https://doi.org/10.1111/imj.16297.
• Osunkwo, I. et al. (2021). Impact of sickle cell disease on patient’s daily lives, symptoms reported, and disease management strategies: results from the International Sickle Cell World Assessment Survey (SWAY).” American journal of hematology,  96.4: 404–417.
• Pincez, T., Lo, K.S., D’Orengiani, A.-L. P. H. d’Alexandry, Garrett, M.E., Brugnara, C., Ashley-Koch, A.E., Telen, M.J., Galacteros, F., Joly, P., Bartolucci, P., & Lettre, G. (2023). Variation and impact of polygenic hematologic traits in monogenic sickle cell disease. Haematologica (Roma), 108(3), 870–881. https://doi.org/10.3324/haematol.2022.281180.
• Wang, Q., & Zennadi, R. (2021). The role of rbc oxidative stress in sickle cell disease: From the molecular basis to pathologic implications. Antioxidants, 10(10), 1608-. https://doi.org/10.3390/antiox10101608