Sickle Cell Disease

Sickle cell disease is a group of inherited blood disorders affecting haemoglobin, a red oxygen carrying molecule found inside red blood cells. It is now one of the most common inherited diseases in the UK and there are currently believed to be around 12,500 sufferers^. It mainly effects people of African, African-Caribbean, Asian and Mediterranean decent.

Causes of sickle cell disease

There is a single cause for all sickle cell diseases, and that it is a mutation in the gene coding for beta haemoglobin. The most common form is sickle cell anaemia (also known as HbSS), it is caused by a single nucleotide substitution in the beta haemoglobin chain. In this case adenine is changed to thymine, resulting in the production of valine instead of glutamic acid. Valine is a non-polar amino acid, meaning that it repels aqueous environments.

Haemoglobin molecules are made up of four polypeptide chains, two alpha chains and two beta chains which are joined together by intermolecular forces between amino acids in neighbouring chains. Due to the non-polarity of valine it tends to clump together with other valine amino acids on other chains to avoid water. This causes the haemoglobin molecules to polymerise and form rod like strands instead of round balls. When erythrocytes have increased saturation of these strands they form sickled shapes.

Effects of sickle cell disease

Normal red blood cells are in the form of biconcave discs allowing their surface area to be increased and carry more oxygen. Whereas, the sickled red cells form an uneven crescent like shape with some visible strands. The sickled erythrocytes are then unable to pass through blood vessels easily and become trapped, causing tissue and organ damage.

Sickled erythrocytes can affect the body in a number of different ways. Firstly their shape means that they are unable to easily pass through blood vessels, resulting in blockages. This may then lead to tissue damage as there is a lack of blood reaching tissues, and therefore less oxygen and other necessary materials reach major organs. If this blockage happens in a vessel in the brain then it may lead to a stroke.

>Another effect is the reduced amount of oxygen that haemoglobin can carry. Due to the change in the shape of the erythrocyte its surface area to volume ratio decreases, meaning that there is less area for oxygen binding. The altered haemoglobin is also less efficient at carrying oxygen. This is means that less oxygen reaches parts of the body, also leading to tissue damage and fatigue, due to reduced aerobic respiration.

The painful episodes that suffers experience are known as crises. These crises can be put into a number of different categories, depending on the part of the body that it effects:

Vaso-occlusive crisis

Most common type of crisis

Caused by the obstruction of the microcirculatory system leading to Ischaemia (The restriction of blood flow to certain tissues of the body)

The severity mainly depends of the area of the body where the obstruction takes place

Effects include: loin pain, thrombotic strokes priaprisms, hyphaema and swollen, painful joints

Aplastic crisis

This is the temporary termination of erythropoiesis (the process which produces red blood cells or erythrocytes)

This is generally caused by parvovirus B19 infection

The result is usually a drop in haemoglobin over a period of a few days

If patients do not recover spontaneously then a blood transfusion may be given

In some cases it can lead to certain forms of heart failure

Sequestration crisis

This is the sudden enlargement of the spleen, which results in a decrease in the concentration of haemoglobin and eventually hypovolemic shock (when severe blood and fluid loss means that the heart cannot pump enough blood around the body)

May result in organ failure

Recurrent sequestration crises may be avoided through the use of a splenectomy

Acute chest syndrome

This is simply a vaso-occlusive crisis affecting the lungs only

Sickle Cell Sufferers have a general life expectancy of around 60 years in men and 68[1] in women in high income countries, but in lower income countries the life expectancy is much lower.

Inheritance of sickle cell disease

Sickle cell Disease is caused by recessive alleles. Sufferers are either homologous for the haemoglobin S allele or heterozygous for the S allele and another mutated form of haemoglobin. This means that in order for a child to be born with Sickle Cell Disease, either a sickle cell trait or the disease must be present in both parents.

In the case of figure 2 both of the parents have a sickle cell trait. The likely chances of each outcome are shown among their four children. Child one was normal meaning that they were homozygous for the normal haemoglobin gene, AA. Since one out of four of the children is likely to have normal haemoglobin there is a 25% chance of a couple who both have a sickle cell trait to have a normal child. Both children two and three had a sickle cell trait. This means that they were heterozygous for the sickle cell gene and would still be considered relatively normal. This means that the couple had a two in four, 50%, chance of giving birth to a child with the sickle cell trait, AS. The fourth child had sickle cell disease, meaning that she was homozygous for the mutated haemoglobin gene. This shows that the couple had one child out of the four who had the disease, this is 25%.

Treatment of sickle cell disease

Currently there is no widely available cure for sickle cell disease, meaning that most patients and healthcare professionals focus on managing the illness through a balance in medications and treatments.

One main drug used to treat sickle cell disease is hydroxyurea, also known as hydroxycabamide, which was first synthesised in 1869 and has been used as an antineoplastic (chemotherapy) drug since the late 1960s. It has been used to treat sickle cell since 1995. It is enclosed and administered as a capsule due to the high toxicity of the drug.

At the moment its mechanism of action is unclear, but in Sickle Cell Disease it is believed to increase the amount of foetal haemoglobin in the body. By increasing the amount of foetal haemoglobin in the blood the concentration of HbS (sickling haemoglobin) is reduced. This reduces the polymerisation of haemoglobin and therefore the sickling of red blood cells. Hydroxycarbamide is also known to reduce the levels of other blood components such as thrombocytes and leukocytes. This can lead to excessive bleeding at the site of a wound and reduced immune response.

Other effects include: infertility in men vomiting diahhoreah and hair loss.

Non-myeloablative/ myeloablative allogenic haematopoietic stem cell transplant

For the last 20 years myeloablative allogenic haematopoietic stem cell transplants have been used to cure paediatric Sickle Cell Disease. The treatment has been performed in around five hundred children worldwide, with a 93% success rate. Due to the Myeloablative conditioning used the treatment proved to be too toxic for adults. Myeloablative conditioning involves high dosages of chemotherapy drugs and radiation in order to destroy almost all of the patient’s bone marrow in order for new stem cells to be produced in the bone marrow.

It was later discovered that Non-myeloablative conditioning could also be used prior to the bone marrow transplant in adults. Non-myeloablative conditioning is when low doses of chemotherapy and radiation are used to deplete the bone marrow cells of the recipient. This is similar to myeloablative conditioning used with children, but instead the conditioning used is not enough to deplete all of the recipient’s bone marrow.A study was carried out by J. F. Tisdale, C. D. Fitzhugh et al, looking at the efficacy and outcome of a non-myeloablative HLA-matched sibling allogeneic haematopoietic stem cell transplantation for severe sickle cell. After a median follow up of 3.4 years, the results from the study were eventually collated and published. Overall, as of October 2013 twenty six patients had long-term stable donor engraftment without any form of Graft Versus Host Disease. This implies that the treatment has a success rate of around 87%

Currently this treatment is not widely available due to the fact that: it is very expensive, around £120,000 most patients are ineligible to part, in order for the treatment to have a high chance of success the patient needs to have a sibling that is both health and a match for their HLA protein and not enough research has been carried out into the long term effects.