A study into the effectiveness of Hydroxycarbamide (Hydroxyurea) in treating the complications caused by Sickle Cell Anaemia and side effects caused by taking the drug:

by f1sam (student)

Sam Williams

Sickle Cell Anaemia is a disease that affects the haemoglobin in the red blood cells. The haemoglobin is what the oxygen binds to so changing this means less oxygen is carried around the body. The blood cells also change shape in a sickle shape and become fragile which means that they can break up and clog up blood vessels which leads to blood clots. These episodes are called crises’. Crisies’ can cause many problems such as strokes and heart attacks. Sickle Cell Anaemia can also cause acute chest syndrome a life-threatening infection in the lungs which can cause problems with the air circulating in the lungs. All of these conditions need urgent medical attention due to the severe risk they cause to a person’s health.

The most common treatment for Sickle Cell Anaemia is with the drug hydroxycarbamide, also known as hydroxyurea. The drug, which is given if a person has recurring episodes of a sickle cell crisis which require treatment in hospital, was found to stimulate the production of a type of haemoglobin called foetal haemoglobin. Foetal haemoglobin (HbF) is found in unborn babies and is gradually replaced by adult haemoglobin as the child gets older. As foetal haemoglobin is not affected by the sickle cell mutation, it is able to partly take over the role of adult haemoglobin, helping to reduce the risk of someone with the condition experiencing a sickle cell crisis. Replacing the affected adult haemoglobin with foetal haemoglobin by treatment with Hyrdoxyurea which stimulates production of HbF means that blood cells are able to carry more oxygen around the body. Having fewer red blood cells that are affected by Sickle Cell Anaemia also means that they won’t become fragile so blood clots are less likely. This reduces the threat of Crisies’ to an affected person.

Red blood cells are the body’s principal means of transporting oxygen around the body. Sickle cell anaemia is a genetic blood disorder where red blood cells develop abnormally. These cells are rich in iron containing haemoglobin which bind to oxygen and are responsible for the blood's red colour. In humans, red blood cells are flexible biconcave disks. Sickle cell anaemia however, contains an abnormal type of haemoglobin called ‘haemoglobin S’. This protein changes the shape of the red blood cells into a sticky, rigid, sickle shape, especially at low oxygen levels. These sickle shaped cells are more fragile and carry less oxygen. They can also die prematurely which results in a shortage of red blood cells. Due to the fragile nature of the sickle red blood cells, they can break up and clog up blood vessels, causing nearby tissue to become starved of oxygen in episodes known as a ‘sickle cell crises. These crises’ can cause moderate pain and in severe cases, caused by lack of a regular oxygen supply, can lead to strokes and heart attacks. The frequency of these crises differs from person to person so the exact frequency cannot be stated. They can occur several times in one year or not at all for several years, however it is known that they last between 5-7 days.

Sickle cell anaemia is the most common genetic condition in England affecting, around 12,500 people and every one in 2,000 babies. The disease is much more common in people of African and Mediterranean descent and is also seen in people from South and Central America, the Caribbean, and the Middle East.

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Detection and Diagnosis:

Haemoglobin electrophoresis - Haemoglobin electrophoresis is a test that measures the different types of the oxygen-carrying protein haemoglobin in the blood.

Blood is taken from a vein, in an airtight vial or tube attached to the needle and taken away to be analysed.

Many different types of haemoglobin (Hb) exist. The most common ones are HbA, HbA2, HbF, HbS, HbC, Hb H, and Hb M. Healthy adults only have significant levels of HbA and HbA2.

Some people may also have small amounts of HbF (which is the main type of haemoglobin in an unborn baby's body). Certain diseases are associated with high HbF levels (when HbF is more than 2% of the total haemoglobin).

HbS is an abnormal form of haemoglobin associated with sickle cell anaemia.

HbC is an abnormal form of haemoglobin associated with haemolytic anaemia. The symptoms are much milder than they are in sickle cell anaemia.

Normal Values

In adults, these haemoglobin molecules make up the following percentages of total haemoglobin:

Hb A: 95% to 98%
Hb A2: 2% to 3%
Hb F: 0.8% to 2%
Hb S: 0%
Hb C: 0%

In infants and children, these haemoglobin molecules make up the following percentages of total haemoglobin:

Hb F (newborn): 50% to 80%
Hb F (6 months): ...

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HbS is an abnormal form of haemoglobin associated with sickle cell anaemia.

HbC is an abnormal form of haemoglobin associated with haemolytic anaemia. The symptoms are much milder than they are in sickle cell anaemia.

Normal Values

In adults, these haemoglobin molecules make up the following percentages of total haemoglobin:

Hb A: 95% to 98%
Hb A2: 2% to 3%
Hb F: 0.8% to 2%
Hb S: 0%
Hb C: 0%

In infants and children, these haemoglobin molecules make up the following percentages of total haemoglobin:

Hb F (newborn): 50% to 80%
Hb F (6 months): 8%
Hb F (over 6 months): 1% to 2%

Sickle cell test:

A chemical is added to the patient's blood sample that reduces the amount of oxygen it carries. In those who carry the sickle cell gene, the reduced amount of oxygen will cause crystals to form. These crystals alter the shape of the RBC, resulting in the characteristic sickle shape. To confirm and identify the amount of HbS present a test is used that separates out the different types of haemoglobin. Each type of haemoglobin will form a unique 'pattern' so that HbS can be identified and a diagnosis of sickle-cell disease made.

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In unaffected individuals HbS is not present. In those who have sickle cell trait, 20% to 40% of the haemoglobin is HbS. In sickle cell disease, as much as 80% to 100% of the haemoglobin may be HbS

A study was done in 1995 in America and Canada by Harvard university into the use of Hydroxyurea in Sickle Cell Anaemia, to answer the question of whether hydroxyurea was clinically useful to patients with sickle cell disease. The study included over 290 patients in the in the placebo-controlled, double-blind investigation. The initial results were reported in the New England Journal of Medicine, May 18, 1995.

In order to have a meaningful study that was relevant to Sickle Cell Anaemia sufferers and produced valid data, strict entry criteria were established:

Inclusion Criteria

Age 18 years or older.
Homozygous Hb SS disease.
At least three painful crises reported to the physician in the year before the study.

Exclusion Criteria

Pregnancy.
Patients with known drug addiction or who regularly consumed 30 or more oxycodone tablets (or equivalent other narcotic) in two weeks.
Concurrent use of other potentially anti-sickling agents.
History of stroke in the preceding six years.
Prior treatment with hydroxyurea.
Antibody to the HIV virus.
Pre-existing depression of blood counts that would obscure bone marrow suppression by the hydroxyurea.

A total of 299 patients were included in the study. The initial hydroxyurea dose used was 15 mg/kg/day, and was increased by 5 mg/kg every 12 weeks to the maximum tolerated does.

The primary variable that was measured was pain. A painful crisis was defined as a “visit to a medical facility that lasted longer than four hours and required parentally administered narcotics for pain control.” Other variables that were evaluated were acute chest syndrome.

Results:

The median number of crises experienced by patients on hydroxyurea was approximately half that of the control group. Also, hydroxyurea treatment reduced, by more than half, the number of hospitalizations caused by sickle cell crises. Further supporting the effectiveness of hydroxyurea in preventing sickle cell crises, the median time to the first crisis was 3.0 months in the hydroxyurea group compared to 1.5 months in the placebo controls. The median time to the second crisis was also greater in the patients on hydroxyurea relative to the controls (8.8 in patients being treated with Hydroxyurea and 4.6 months in the control group.

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Acute chest syndrome is a leading cause of death of patients with sickle cell disease. The patients on hydroxyurea had 25 episodes of acute chest syndrome, while the placebo control patients experienced 51 episodes.

A second study, carried out at The Johns Hopkins University Evidence-based Practice Centre, Baltimore, Maryland, America published in February 2008, further looked into the effects of Hyrdoxyurea on sickle cell anaemia, but this time on children. In one small, randomized trial of HU in children with SCD; the yearly hospitalization rate was lower with Hyrdoxyurea than placebo with 1.1 compared to 2.8. The increase in foetal haemoglobin (Hb F%) was 10.7 percent. Twenty observational studies of HU in children reported similar increases in Hb F%, while haemoglobin concentration increased by roughly 1 g/dl.

One large randomized trial tested the effectiveness of Hyrdoxyurea in adults with sickle cell anaemia and found that after 2 years of treatment, Hb F% increased by 3.2 percent and haemoglobin increased by 0.6 g/dl, The average number of painful crises was 44 percent lower among patients treated with Hyrdoxyurea.

Ethical Issues:

There are issues surrounding the side effects of the drug hydroxyurea. It has been recorded that the drug can negatively affect young children taking it to treat sickle cell anaemia as it can reduce growth rates and there is a lack of significant data to contradict this as yet.
Another issue with this study is the exclusion criteria for people able to take the drug. People that fall outside these criteria are unable to take the drug which they feel they should be allowed to take in an attempt to treat their sickle cell anaemia which is potentially life threatening.
Issue also surround the use of the drug over a prolonged period of time. There is also little data this subject so it is unknown whether patients treated with Hyrdoxyurea will get any serious side effects later in life that have not yet been discovered.

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Social Issues:

There are issues involved in the research into the use of Hydroxyurea in treating Sickle Cell Anaemia. In carrying out the research, a control group of sufferers were given a placebo, rather than the Hydroxyurea, thus allowing researchers to compare the effects with and without the drug. The subjects were unaware that they weren’t taking the drug so weren’t getting any of the benefits of it. In not taking the drug, the subjects had a greater chance of having a Crisis and of having Acute Chest Syndrome. This would result in greater pain for the subject and a greater chance of being hospitalised.

There are some definite benefits of the use of Hydroxyurea in humans. This drug can halve the risk of a person having a Crisis or of having Acute Chest Syndrome. This will not only reduce the pain, which a sufferer has a result of the disease but it can improve the quality of life and also leads to them living longer with the disease as these complications are strongly linked with death. Also, as a person is having less of these complications due to taking the drug, they are likely to have to spend less time in hospital being treated which is a benefit for the person and for the healthcare system. This drug also has the benefit of working in all age groups to prevent acute events and chronic organ dysfunction and is sustainable as the benefits continue over time without medication resistance or tolerance.

There are disadvantages associated with taking Hydroxyurea, as well as advantages. For example, there are concerns over the possible effects of the drug on growth and development, especially in children, as the drug can block cell division. This means that the drug cannot be taken by children so another treatment has to be found. The primary side-effect of hydroxyurea is suppression of blood counts, particularly the white blood cells and platelets; this puts patients at risk of infection and bleeding. Other reported adverse reactions are bone marrow depression, anorexia, nausea, vomiting, diarrhea, constipation, and dermatological reactions such as rashes, skin ulceration and hyper pigmentation. Skin cancer has also been reported. Large doses may produce moderate drowsiness, headache, dizziness, disorientation, hallucinations, and convulsion.

There are several other treatments available for Sickle Cell Disease:

The only current cure for sickle cell anaemia is a bone marrow transplant. This involves replacing the affected bone marrow with bone marrow donated from someone who does not have sickle cell anaemia. During the process of a bone marrow transplant the bone marrow is removed from a large bone of the donor, such as the pelvis, through a large needle that reaches the centre of the bone. Stem cells contained in the bone marrow are harvested or filtered out and, after receiving high doses of chemotherapy or radiation to eliminate whatever bone marrow they have left, the new stem cells are put into the person intravenously, in a similar way to a blood transfusion. The stem cells will then find their way to the bone and start to grow and produce more cells. After a bone marrow transplant, the new bone marrow will begin to produce healthy blood cells. However, there are some significant risks involved in having a bone marrow transplant. In patients who do not receive a bone marrow donation from a matched sibling, the transplanted cells from a donor may attack the patient's own tissues, a potentially fatal condition called graft-versus-host disease (GVHD). Drugs that destroy bone marrow and suppress immunity must be administered before the procedure so that the body's immune system does not attack the transplanted tissue. Still, this does not always prevent the problem.

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As a result of these risks, it is estimated that 1 in 10 people who receive bone marrow will die due to complications that arise from the procedure

Due to the risk, a bone marrow transplant is only usually recommended if:

A child is under 17 years of age (children often have less organ damage from sickle cell disease than adults, which improves their chances of survival).
A child has a brother or sister with healthy bone marrow.
A child’s symptoms are severe enough to be life threatening, for example if they have had one or more episodes of acute chest syndrome.

Although not available at the moment, gene therapy could be used to cure Sickle Cell Disease. Sickle cell anaemia is caused by a defective gene in the haemoglobin gene that causes red blood cells to become crescent or sickle-shaped and sticky. Inheriting two bad copies of the gene—one from each parent—leads to fragile, sticky red blood cells that clump together and can block blood vessels leading to strokes and damaging organs. A person with one mutated copy sickle cell gene does not show any symptoms of the disease and does not require treatment. Researchers are exploring whether inserting a normal gene into the bone marrow of people with sickle cell anaemia will result in the production of normal haemoglobin. Scientists are also exploring the possibility of turning off the defective gene while reactivating another gene responsible for the production of foetal haemoglobin.

Researchers have however successfully used gene therapy to treat sickle cell disease in mice. Researchers, led by Philippe Leboulch, of Harvard Medical School and the Massachusetts Institute of Technology, designed a new gene that can counter the effects of the sickle cell gene. The process involves removing the bone marrow from mice with a sickle cell disease, isolating the stem cells—which give rise to red blood cells—and inserting the new anti-sickling gene. When the genetically modified stem cells were transplanted back into the mice, they produced healthy round red blood cells and although the mutant gene is still present in the stem cells, the new gene is able to counteract its ill-effects and produce healthy cells. Ten months after receiving the modified stem cells, about 99 percent of the red blood cells in the mice contain the anti-sickling gene and appear healthy.

Treatment:

There are several treatments available to treat sickle cell anaemia.

Bone marrow transplants – bone marrow transplants are sometimes used to cure sickle cell anaemia. Bone marrow is taken from a brother or sister who doesn’t have the disease and has the same marrow type.

The goal of treatment is to manage and control symptoms, and to limit the number of crises.

Patients with sickle cell disease need ongoing treatment.

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Treatment for a sickle cell crisis includes:

Blood transfusions (may also be given regularly to prevent stroke)
Pain medicines
Plenty of fluids

Other treatments for sickle cell anaemia may include:

Hydroxyurea , a medicine that may help reduce the number of pain episodes (including chest pain and difficulty breathing) in some people
Antibiotics to prevent bacterial infections, which are common in children with sickle cell disease

An article published in the British Medical Journal (BMJ), appears to support the fact that Hydroxyurea is beneficial in treating Sickle Cell Anaemia. This test for Hydroxyurea in this report were done on 101 children in France and looked into the effects on growth and toxicity, unlike in the report above which was done on adults. Although the subjects are of a different age, the results are likely to be similar. The report states that: “Hydroxyurea is the first drug that specifically decreases the frequency and severity of painful crises in sickle cell disease in children.” And” A decrease in the severity of painful crises was reported by all but six of the 101 children with sickle cell disease studied, after an initial improvement in five of these six. No significant difference in growth velocity had been reported in the initial group of 35 children and adolescents” This report supports the data given by the earlier report in America and Canada as it shows that after taking the drug the subjects reported positive effects and experienced less Crises’ and even describes that it had little negative effect on growth as was feared in America.

This article from the BMJ is likely to be very reliable as it is entirely on evidence taken from medical professionals in France, and is written on behalf of the French Study Group on Sickle Cell Disease. The Journal is aimed at and written by British Medical professionals and as a result is detailed and accurate in its articles, and unlike some sites which are aimed at the general public, it doesn’t need to simplify the language used. The article specifically gives several references from other professional sources that back up the information given. The only downfall in this source is its age, as it was written in and uses data from 1999 and earlier and as a result may be out of data today. Overall there is little doubt that over the reliability of this source as it is taken from a professional, well respected medical journal.

The two studies discussed earlier both appear to show the same results for the use of Hyrdoxyurea to treat sickle cell anaemia. They both shown a decrease in the number of hospitalisations of a person, due to them having a crisis, in the group taking the drug compared to the group not taking the drug or taking a placebo. The fact that these studies, and that printed in the British Medical Journal all come up with correlating evidence is enough to suggest that Hyrdoxyurea can be used to effectively treat sickle cell anaemia.

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One downside of comparing the two studies is in the age range of the members in the study. While the first, carried out by Harvard University, focuses only on those aged over 17 the second, by The Johns Hopkins University Evidence-based Practice Centre, looks at the affect of Hyrdoxyurea on children alone. This difference in ages could produce differing results that cannot be reliably compared. Also, both of the studies were only carried out over a short period of time and the lack of long-term studies limits conclusions about side effects such as toxicity and possible mortality. However, the reliability of the actual data is unlikely to be called into question as all the studies have been carried out by professional, reputable institutes and the data published on official websites.

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