Currently, roughly 1,200 patients have undergone HSCT since

Currently,
over 5 million people of the world’s population are affected by sickle cell
disease (SCD) and over a quarter million live births every year (Piel et al,
2013). SCD remains one of the most common severe monogenic disorders which
plagues 70% of cases in populations of the East African ethnic origin and
manifests itself through erythrocyte rigidity, tissue ischemia and cerebral infarction
(Ware et al, 2017).  Sickle cell disease
is mostly characterised by intermittent vaso-occlusive complications, chronic
haemolytic anaemia, and progressive organ depletion, which is why mortality
rates in individuals with sickle cell disease are elevated. Research
investigations lend some support into the understanding of sickle cell disease
but current approaches and prevention treatments are limited only to
hydroxycarbamide (also known as hydroxyurea) and transfusions, despite all the
extensive studies the clinical management of the disease, no specific drug has
yet been developed to target the pathophysiology. 

The
use of haematopoietic stem-cell transplantation, on the other hand, offers a
promising potential curative therapy, yielding a significant 92% chance of cure
when matched with a human leukocyte antigen(HLA) -sibling donor. The International Blood and Marrow Transplant Research,
give stats that roughly 1,200 patients have undergone HSCT since the first
report of treatment in 1984 (Bhatia et al, 2015). Successful stem cell
transplants resulted in lower toxicity, reduced organ damage and increased
lifespan, nonetheless, transplantation comes with several complications and is
often only confined to children. The role of haematopoietic stem cell transplantation
is imperative to the future of sickle cell sufferers. (Rees et al, 2010).

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Sickle
cell disease is the name given to the group of inherited conditions that effect
the red blood cells and is associated with occurrences of acute illness and progressive
organ damage (Rees et al, 2010). 1910, saw the first publication where the description
of abnormally elongated red blood cells was documented in an anaemic patient by
Herrick becoming one of the firsts links of sickle cells to the clinical symptoms
of Sickle Cell anaemia (Herrick JB, 1910). The sickle shape reduces the ability
of RBC’s to carry oxygen, in reaction the body undertakes the destruction and
removal of sickled red blood cells at elevated rates, thus causing anaemia (Lonergan
et al, 2001. The abnormal qualitative production of haemoglobin S is caused by
a point mutation in the beta globin gene which resulted in a single amino acid
substitution, where valine replaced glutamic acid at the sixth position in the
beta globin chain of haemoglobin A (Douglas R et al, 2008). The substitution
results in both crystallisation between B1 and B2 chains of the haemoglobin
molecules and polymerisation. Polymerisation is reversible to an extent when
under well oxygenated levels, however numerous cycles of deoxygenation cause
the red cells to become permanently sickled.

The
process of polymerisation complements the definition for the term ‘sickle cell’
due to the rigid strands that cause physical distortion of erythrocytes, loss
of solubility via deoxygenation, and decrease its formability and increases the
membrane cation ion permeability which causes an egress of water, resulting in
erythrocyte dehydration. (Pace et al, 2012) This
deformation impairs the capability of the cell to travel through small vascular
channels; which increases the number of sickled erythrocytes to accumulate and
adhere in the endothelium to further worsen the vaso-occlusion and risk of
infarction, this can be seen in Figure 1, (Rees et al, 2010).  A therapy for decreasing the adhesion to the
endothelium is currently under investigation, specific agents like E- and P-
have been tested were promising results have shown in a Phase 3 trial. Clinical
agents that don’t compromise the immune system when active can effectively
decrease the adhesion to the cell endothelium (Ataga et al, 2017).

Existing treatment for sickle cell anaemia includes the use of
hydroxyurea therapy which has reduced the prevalence of acute chest syndrome,
splenic sequestration and aplastic crisis, but research shows that hydroxyurea yields
more toxic side effects. Blood transfusions on the other hand are more beneficial
than hydroxyurea by decreasing stroke factor likelihood in patients with
chronic anaemia (Kassim et al, 2017). Often sufferers of sickle cell disease
are more suited for haematopoietic stem cell transplantation (HSCT). HSCT
explores the use of healthy stems cells derived from bone marrow and the umbilical
cord. A phase one and two study from a transplant in adults by Mathew M Hsieh returned
positive results. The procedure wasn’t related to any serious adverse effects
and there were no treatment related deaths (Hsieh et al, 2009). Bilirubin
levels decreased from 3.03 to 0.69 mg per decilitre, total haemoglobin counts progressively
improved, and acute or chronic graft versus host disease did not develop in any
patient. This study shows how rapidly the field of HSCT has expanded, before treatment
on adults was high risk due to initial regimes that conceded concerning levels
of toxicity. However, advances in HSCT has made it possible for older
individuals to undergo this treatment and alleviate symptoms (Bender et al,
2017).

Sickle cell conditions like anaemia and thalassemia have an
autosomal recessive pattern of inheritance, either two copies of HbS allele
(homozygous) or one copy (heterozygous) of Hb S allele and another beta=globin
variant is required for the disease to be expressed (Ashley-Koch et al, 2000).
If both parents carry the pathological haemoglobin they are usually
asymptomatic the chances of passing on the defected gene are 25%.
Co-inheritance of HbS with other mutant beta globin chain variants give rise to
two types of sickle B- thalassemia and sickle c haemoglobin disease (Bender et
al, 2003). Fortunately, carriers of haemoglobin S are protected from malaria
infections, although they still exhibit significant morbidity and mortality.

Hematopoietic stem cell transplantations also link into the genetics
of SCD. The use of HSCT is limited due to the lack of HLA corresponding donors
and not enough monozygotic twins (Kassim et al, 2017). All sufferers with
homozygosity of SCD should be evaluated irrespective of symptomatology. Controversy
remains around the use of HSCT due to the emphasis on the balance between the
severity of SCD and the dangers of the procedure (Bhatia et al, 2015). but new research
investigations sheds light on the use of alternate non-familial donors;
including the increasing success of haploidentical donor transplants which can
broaden the number of potential cures.

Individuals with Sickle Cell disease clinically present
jaundice, pallor, periodic episodes of severe pain, non-iron deficient related
anaemia, anaemia with severe splenic growth and infants present swelling of the
hands and feet or even stroke. At birth SCD sufferers are healthy, these
features become symptomatic later in childhood after foetal haemoglobin levels
drop (Bender et al,2003). Screening programs for sickle cell disease in
newborns have been implemented in all states in America since 2005 (MP Adam et
al, 2003). These programs perform isoelectric focusing or high-performance
liquid chromatography (HPLC) where identification of HbS if established against
normal fetal haemoglobin (Hb F) or adult haemoglobin (HbA) on an assay. Genetic
single gene testing can also be performed, this analyses the sequence in order
to locate any pathogenic variant, however, gene panel testing is quite
expensive considering that some panels are not associated with the genes linked
to sickle cell disease, therefore this is an inadequate procedure for
diagnosis. Clinicians need to determine a reasonably priced gene methodology
whilst limiting the identification of mutant variants in genes which aren’t
concurrent to the phenotype (Kato, 2016).