Sickle cell disease is a genetic blood disorder characterised by deficient haemoglobin. It prevents haemoglobin from carrying oxygen in red blood cells. Sickle cells tend to stick together, obstructing tiny blood vessels which leads to painful and detrimental effects.

The disease was first described in the scientific literature as a case report by Herrick, JB. in 1910 in a young male from Grenada with severe anaemia and other symptoms, noting that the “red corpuscles varied much in size with very irregular shape and a large number of elongated sickle-shaped forms”.

According to Kato, GJ. et al.) Sickle Cell Disease (SCD) is an “umbrella term” for a group of inherited diseases, including Sickle Cell Anemia (SCA), HbSC and HbSBeta-thalassemia. The mutation is in the Beta-globin gene of the haemoglobin molecule (Hb), leading to a substitution of glutamic acid for valine at position 6.

Commonly, haemoglobin is expressed at different stages of life as embryonic, fetal and adult (HbA); the most abundant form of adult haemoglobin (>90%) is HbA and comprises two alpha globin subunits (HBA1 and HBA2) and two beta globin subunits (HBB1 and 2). Each globin subunit is associated with the cofactor haem, which can carry a molecule of oxygen.

How is Sickle Cell Disease Inherited?

A single nucleotide substitution in HBB results in the Sickle Hb (HbS) as a predominant production of HbS (allele BS). Its most common form occurs in individuals with homozygous SCD-SS. Compound heterozygous forms result from co-inheritance with other HBB variants, including C (SCD-SC), the second most common and Beta-thalassemia (SCD-SBeta0 and SCD-SBeta+).

The genotypes SS and SBeta0 are classified as sickle cell anaemia (SCA). They are associated with the most severe clinical manifestations characterised by chronic hemolytic anaemia, unpredictable pain episodes, and widespread organ damage, with vast clinical severity and survival variability.

Under deoxygenation conditions, when the Hb is not bound to oxygen, the mutant HbS can polymerise and cause the erythrocytes to assume a sickled shape, leading to recurrent vaso-occlusive episodes, the hallmark of SCD.

Individuals who are heterozygous for the BetaS allele carry the sickle cell trait (HbAS) but don’t have SCD, whereas individuals who are homozygous for the BetaS allele have SCA. As mentioned, the most common form of Sickle Cell Disease is Sickle Cell Anemia, a lifelong illness.

Global newborn estimates suggest that about 300,000 babies are born with SCA annually, and it is projected that such an annual number will exceed 400,000 by 2050. Also, it has been estimated that 50% to 90% of children born with SCA in sub-Saharan Africa, India, part of the Mediterranean and the Middle East will die before five years of age.

By contrast, in high-income countries, with less than 5% of the global disease burden, over 95% of children will survive beyond 18 years.

The reasons for better survival are newborn screening, early interventions, and comprehensive care.

Managing Sickle Cell Disease

Many basic science studies were conducted during the 80s on the Hb polymer structure and the HbS sickle-shaped red cells; the key sickle pathophysiology event is polymerisation (only occurs when HbS is deoxygenated). As the polymer fibres extend, the shape and physical properties of erythrocytes change, making them less deformable and abnormal, resulting in occlusion of blood flow at the level of capillaries and post-capillary vessels and hemolysis.

HbS polymerisation can also occur in reticulocytes, which account for approximately 20% of the red blood cells in individuals with SCA. In addition, vascular endothelial activation and injury results from functional nitric oxide deficiency, inflammatory mediators, excess oxidant generation and reperfusion, hypercoagulability, platelet activation, tissue injury and end-organ damage.

HbS polymerisation alters the erythrocyte membrane’s typical lipid bilayer and proteins, reducing cellular hydration, increased hemolysis, and abnormal interactions with other blood cells.

Vaso-occlusion causes ischemic tissue damage, resulting in severe pain and other acute complications like hypo-splenia-related infections, acute chest syndrome (ACS), splenic sequestration, stroke, and priapism. Some chronic complications include cerebrovascular damage, anaemia, pulmonary hypertension, cardiac conditions, kidney disease, avascular necrosis of bone, retinopathy, and gallstones.

Children may be asymptomatic until they present acute illness, like bacterial infections (pneumonia, sepsis, and meningitis), which can result in death. In these pediatric patients, early signs include dactylitis (hand-foot syndrome), jaundice, pallor, splenomegaly and functional asplenia.

A key observation was that fetal Hb (HbF) had beneficial effects; later studies starting in the late 70s demonstrated that SCD was milder in those patients with higher levels of HbF. A genetic variation called heterocellular hereditary persistence of fetal haemoglobin (HPFH) produces modest increases in HbF. This situation in healthy adults is irrelevant, but co-inheritance of heterocellular HPFH in SCD leads to significant increases in HbF with major clinical benefits.

Recent genetic studies showed that common HbF variation behaves as a quantitative trait, and the levels are genetically controlled.

How is Sickle Cell Treated? Effective Approaches

The beneficial effect of HbF led to studies with Hydroxyurea (HU) in patients with the HbSS form. Initially an anti-neoplastic agent -ribonucleotide reductase inhibitor- for myeloproliferative diseases, this drug demonstrated that measurable and sustainable increases of HbF could be achieved with minimal toxicity. The primary beneficial effect of HbF is to dilute the intracellular concentration of HbS and improve oxygen transportation to tissues.

So, Sickle Cell Disease is a complex, multisystem condition characterised by acute and chronic complications. Three therapies modify the natural history of Sickle Cell Anemia: hydroxyurea (highly effective disease-modifying therapy), erythrocyte transfusions and hematopoietic stem cell transplantation.

HU significantly reduces the incidence of vaso-occlusive crisis/acute pain episodes in children and adults, Acute Chest Syndrome (ACS), dactylitis, the need for blood transfusions, hospitalisations, and mortality compared to placebo with an excellent safety profile. Some patients do not show an integral beneficial response, usually because of problems of adherence to treatment and in a small proportion because of pharmacogenomic reasons.

Nevertheless, HU is underutilised because of healthcare infrastructure deficiencies in low- and high-resource countries and wrong perceptions of carcinogenicity, teratogenicity, and fertility based mainly on outdated experimental models and treatment experiences with myeloproliferative disorders.

Results of genotoxicity studies demonstrated that Hydroxyurea is not mutagenic and does not directly bind DNA. Its genotoxic effects are limited to indirect clastogenicity (an agent capable of causing breakage of chromosomes) occurring in select cell types and only when high dose and time thresholds are exceeded. The absence of mutagenic activity is consistent with the lack of compelling carcinogenic potential.

Empowering Individuals & Communities Impacted By Sickle Cell Disease

Both children and adults with SCD have significantly impaired quality of life compared to healthy individuals in nearly every domain, especially in pain, fatigue, and physical functioning. Adolescents and adults report poor sleep quality and moderate levels of fatigue.

The baseline physical functioning quality of life (QOL) of many individuals with SCD is worse or comparable to that of patients with chronic diseases such as cancer. Daily pain can affect the ability to attend school or work and is predictive of worse QOL; nearly 35 % of adults with SCD report pain almost every day, and over half of patients have pain 50% of the time.

Hydroxyurea improves general health and reduces pain in adults; similar results have been observed in children who received Hydroxyurea in addition to reducing the chronic red blood cell transfusion therapy.

An available way to enhance the use of a proven therapy, such as Hydroxyurea, is a 100mg and 1000mg scored tablets (Siklos®) for precision dosing, which contributes to much better management of the disease, particularly when patients can follow the proven method of maximum tolerated dose.

On the other hand, given its curative potential despite the possibility of graft versus host disease, a case can be made that all patients with a suitable donor be offered hematopoietic stem cell transplantation, a curative therapy. Donor sources are now being expanded using haploidentical donors, and transplant-related toxicities are reduced by employing less intense conditioning regimens and better graft versus host disease prevention strategies.

Gene therapy based on gene modification of autologous hematopoietic stem cells has also been considered a promising cure. They include gene addition and genome editing to modify or replace the defective sickle gene or induce high HbF expression; with these therapies, the barrier posed by the limited availability of matched sibling donors is removed, as no donor is required. Several clinical trials are currently under development for such therapies.

Integrating SCD Hydroxyurea treatment into primary care, linked with evidence-based guidelines, will help improve survival and quality of life for many more patients. However, apart from being a complex disorder, there is considerable variability among individuals and accumulating morbidities associated with ageing, which challenge its management.

In addition, even if comprehensive programs exist for pediatric patients, there is an essential need for improved transition of care to reduce early mortality in young adults. Until these patients with SCD have access to acceptable preventive treatment and specialised management centres, they will continue receiving inadequate care at a high cost.

It may seem exaggerated, but patients with SCD should be advised to dress appropriately, especially in cold or windy weather, depending on the geography. Also, they should be encouraged to exercise regularly.

Improving Accessibility To Sickle Cell Medication With Masters

Dedicated to enhancing patient access to sickle cell and other rare disease medication, Masters is a leading global pharmaceutical company that understands the difficulties posed by these conditions. We are skilled pharmaceutical drug suppliers, making medications for rare ailments available in developing markets. Through the power of medicine, we continuously work to transform lives.