By: Mint Suetrong, Contributing Writer
Edited by: Olivia Storti, Editor; Elias Azizi, Editor in Chief
What is sickle cell anaemia?
As defined by the CDC, sickle cell anaemia is an inherited genetic condition that results in abnormal haemoglobin. Patients with this condition have sticky, crescent-shaped red blood cells (RBCs) that resemble a sickle, as opposed to the normal biconcave discs. The change in shape decreases its ability to perform a crucial task: supplying all cells in your body with sufficient oxygen. Furthermore, patients with sickle cell disease (SCD) have a heightened risk of developing blood clots, such as a deep vein thrombosis (DVT) which is a clot occurring in the large veins found in the legs or arms. These clots can not only inhibit blood flow to certain tissues, resulting in cell death, but they can break off and block critical blood vessels within the lungs.
What is the cause of sickle cell anaemia?
Sickle cell anaemia is caused by a change in the primary sequence of the globin protein. As a quaternary protein, haemoglobin is composed of 2 α-globin and 2 β-globin proteins. The irregular shape is caused by a change in the primary structure, a single base substitution (CTC to CAC) causing a change in the amino acid sequence (Glu to Val), in the HBB gene in the β-globin protein, cited The Lancet. The change in the primary sequence causes knock-on effects in the secondary and tertiary structures, changing the bonding and folding of the protein affecting its shape. The shape of a protein is vital to its performance: receptors and binding sites are remarkably specific to each molecule. The sickle cell haemoglobin decreases the surface area in which oxygen molecules can bind to the iron complex within its structure.
Sickle cell anaemia is a recessive condition. This means that patients must inherit the sickle cell allele, HbS or abnormal haemoglobin, from both parents. A patient with sickle cell disease would have a genotype of HbSHbS meaning sickle cell haemoglobin (HbSS). A patient who is heterozygous for this condition (HbAHbS), however, is said to have sickle cell trait (SCT). In patients with sickle cell trait, approximately ⅔ of the haemoglobin produced is normal while ⅓ is abnormal. SCT provides these individuals with resistance against malaria and therefore is genetically favoured in malarial regions such as Central Africa. Individuals with normal haemoglobin would be more susceptible to large outbreaks of malaria while patients with SCD would also have a poor prognosis due to secondary infections and fatigue. The competitive advantage of SCT in malarial regions is reflected in the high incidence. Nevertheless, it should be understood that individuals with SCT would be outcompeted by individuals with normal haemoglobin in malarial-free zones and therefore would have a lower incidence.
What are the effects of sickle cell anaemia on patients?
Targeted by sickle cell disease, the shape of erythrocytes or red blood cells is changed, meaning they are not as effective in delivering oxygen to cells within the body. The New England Journal of Medicine stated that patients born with this condition have a shortened life expectancy of 42 years for males and 48 years for females. Patients are in a constant state of pain, 23 per cent of sickle cell mortality is due to an ‘acute sickle crisis’, 78 per cent of patients had pain, chest syndrome, or both; 22 per cent had a stroke. 18 per cent of death during adulthood is due to overt organ failure, predominantly renal. Increased risk of early death has been associated with acute chest syndrome, renal failure, seizures, a baseline white-cell count above 15,000 cells per cubic millimetre, and a low level of fetal haemoglobin. On a day-to-day aspect, patients with SCD are more easily fatigued and require a longer recovery period. Episodes of pain can interfere with a person’s daily routine which could not only be physically exhausting but also emotionally draining. Sickle cell anaemia is a chronic disease that requires comprehensive and life-long management which aims to tackle all complications associated.
How can we treat sickle cell anaemia?
Traditionally, most treatments for sickle cell anaemia are supportive. This means that the target is not to cure the person, but to help alleviate pain and the symptoms presented by this disease. Various pain medications can be administered according to the severity and frequency of pain crises. These medications, however, often come with unpleasant side effects such as nausea, vomiting, or even more pain. Vaccinations and extended periods of antibiotics may be reinforced in children to prevent minor infections that could prove to be fatal. Blood transfusions can also be used to prevent SCD related complications such as strokes, but this increases the risk of an immune response to the donors’ blood which may make the patient more susceptible to diseases. Overall, most treatments for SCD have been given to maintain or improve the quality of life.
Novel research, on the other hand, has been working to improve the effectiveness of curative procedures including hematopoietic stem cell transplants and gene therapy. Stem cell or bone marrow transplants replace the bone marrow of an SCD patient with a healthy, matched donor, such as a sibling. As the risk of death is high and this procedure is only available for patients with matched donors, scientists have explored gene therapy as another cure for sickle cell anaemia.
Although it is still experimental, the gene-editing tool, CRISPR, has been investigated into correcting the mutation which causes sickle cell disease. While HSCT requires a donor, gene therapy allows each patient to be their own donor. The BBC covered the journey of CRISPR in changing the life of a sickle cell patient. By first extracting the patient’s hematopoietic stem cells and turning off the BCL11A gene that was responsible for producing the sickle cell haemoglobin, the genetically modified stem cells were reintroduced into the patients’ body. Jimi Olaghere, the SCD patient, recounts that although the process of harvesting the stem cells from his body was mentally and physically draining, he emerged from this procedure with a pain-free life, living as the person he ‘always felt inside’.
Link to cover image: https://ec.europa.eu/research-and-innovation/sites/default/files/styles/w1108/public/hm/field/image/sickle_cells-head.jpg?itok=Jz0Fqt5p
Sources:
Ware, R. E., de Montalembert, M., Tshilolo, L., & Abboud, M. R. (2017). Sickle cell disease. The Lancet, 390(10091), 311-323.
WELLS, I. C., & ITANO, H. A. (1951). Ratio of sickle-cell anemia hemoglobin to normal hemoglobin in sicklemics. The Journal of biological chemistry, 188(1), 65–74.
Platt, O. S., Brambilla, D. J., Rosse, W. F., Milner, P. F., Castro, O., Steinberg, M. H., & Klug, P. P. (1994). Mortality in sickle cell disease--life expectancy and risk factors for early death. New England Journal of Medicine, 330(23), 1639-1644.
Chakravorty, S., & Williams, T. N. (2015). Sickle cell disease: a neglected chronic disease of increasing global health importance. Archives of disease in childhood, 100(1), 48–53. https://doi.org/10.1136/archdischild-2013-303773