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Haemoglobin is the protein in red blood cells (erythrocytes) which transport oxygen in the bloodstream. Each consists of four haem groups, each surrounded by a globin chain. Haemoglobin A (HbA, Î±2Î²2) is the most abundant normal haemoglobin found in adults (95~98%) while the rest are HbA2 (Î±2Î´2) and HbF (Î±2Î³2). Abnormal haemoglobin maybe produced when genetic mutation happens, causing alteration in the amino acids chain making up the globin chain. Sickle haemoglobin (HbS), is the most common Hb variants, caused by a point mutation on the beta(Î²)-chain gene.2,3,4
Sickle cell anaemia (SCA or SCD-SS) is the most common and severest form of sickle cell disease (SCD, haemoglobinopathy caused when one inherits two abnormal genes for the production of HbA), at which one is homozygous for the HbS gene.7 Erythrocytes in SCA patients contains mainly HbS which tends to polymerize into long rods when deoxygenated and deform the erythrocytes to become sticky, stiff, more fragile and having a curved, sickle shape. Compare to sickle cells, normal erythrocytes will constantly having a biconcave-disc shape and is soft and flexible.8,9,10
Figure 1: Peripheral blood smear with sickle cell at 1000X magnification. Photograph by Dr Ulrich Woermann
(281 words)The formation of sickle cells due to the high level of HbS causes anaemia in the patients.11 First, the cells lost elasticity when deoxygenated, causing vascular obstruction (blockage of blood vessels) and ischaemia (situation when supply of blood to a certain body part is less than needed). Second, sickle cells have a shorter life span (10~20 days) compared to normal erythrocytes (120 days), resulting in chronic haemolysis. The body will have insufficient erythrocytes as the bone marrow cannot make new erythrocytes quick enough to replace the dying ones. Lastly, the damaged erythrocytes have surface with increased adherence to vascular endothelium, promoting acute vaso-occlusion and proliferative lesion. These situations lead to symptoms such as severe pain episode, acute chest pain and hand-foot syndrome, permanent damage to vital organ, infections, lung disease or stroke.12,13,14 However, symptoms rarely manifest before the age of six months, because only at that time the level of the HbF in the infants will fall to the adult level and being replaced by HbS.15
Figure 2: Sickling of red blood cells causing vascular obstruction.
A Possible Solution - Hydroxyurea / Hydroxycarbamide Treatment
The only available cure for SCA is bone marrow/stem cells transplant but this carry a high risk and is only available for few patients only (mostly children). However, Hydroxycarbamide (British Approval Name) or Hydroxyurea (HU) has shown promising results and is the first drug approved by U.S Food and Drug Administration (FDA) in 1998 for treatment in adults with SCA.12 Although do not cure the disease, HU therapy can directly modify the disease process.16
SCA patients have two types of erythrocytes: F cells (contain HbS and about 20~25% HbF) and non-F cells (mostly HbS and virtually no HbF). However, the amount of HbF differs in each F cells. F cells typically survive for six weeks while non-F cells mostly survive for two weeks.17,18,19 Hence, an approach in treating SCA is to shift Hb production from HbS to HbF. HU, a cytotoxic drug, was first experimented on SCA patients in 1984, with result showing a rapid increase in F cells within 72 hours after therapy. 6,20
11Hydroxyurea can only be prescribed by physicians. Before initiating treatment, complete blood counts should be obtained. An initial dose of 15 mg/kg of body mass/day is administered if the blood counts are acceptable. Change in dose is also based on the change in blood counts (refer Table 1). Hydroxyurea is readily absorbed and will not accumulate in the body. So if adverse effect is shown after taking the medicine, the therapy can be stopped and continue with a smaller dose after the symptoms subdue.28 The process is done until the maximum dose that can be tolerated by the patients without toxicity reaction is found or the maximum tolerable dose of 35 mg/kg/day is reached.11
A Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH) was conducted from 1992 to 1995 to study the effect of HU. The result clearly showed that HU reduced the number and severity of pain episodes. The frequency of pain episodes was lowered from a median of 4.5 to 2.5 per year with significant decrease in rates of acute chest syndrome and blood transfusion. HU arms also have lower mean number of occurrence of pain episodes and chest pain than placebo arms (Graph 1 & 2).21
Graph 1: Difference in the number of occurrence of pain crisis/pain episodes between patients taking hydroxyurea and placebo in MSH
Graph 2: Number of occurrence of acute pain and transfusion in patients taking hydroxyurea and the control group in MSH
Follow-up studies up to nine years for the 233 patients from the original subjects was being carried out after the MSH was ended and also showed promising result.
Besides, data from treatment series on children also show that HU do not affect growth of the children and may instead improve it.23,24
HU belongs to a group called hydroxamic acids. Its carbonyl group can bind to the iron molecules of the ribonucleotide reductase and inhibits the enzyme. This causes less non-F cells to be produced from the mature erythroid precursor in the marrow and increase the production of F cells from the immature progenitors. The precursor mostly produced HbS while the progenitors produce more HbF.25,26 Besides, metabolism of HU produces nitric oxide that can stimulate guanylate cyclase, an enzyme containing haem iron, and results in the production of HbF.27
Figure 3: Chemical Structure of Hydroxyurea11
Figure 4: Effect of Hydroxyurea
Social and Economic Implication
Patients with SCA may have some issues such as depression, low self-esteem, poor family relationship and social isolation. Their activities are restricted because of the anaemia and pain crisis. They can also be hospitalised for the complications of SCA such as stroke, chronic lung disease, infections and ulcers. As a result, they have limited life and always out of reach with people. Infections and lung disease are also responsible for most death in SCA patients.6
Other than that, SCA also cause the patients to have a low quality of life, as with patients with arthritis and myocardial infarction.29 The disease is also linked with decreased lifespan, with the average life expectancy only in the 40s in era before hydroxyurea.30 Thus, careful medical monitoring and good family, friends and group support are important to help the patients dealing with the disorder and improve the patients' quality of life and to lead normal life.
Besides, environments that are cold and have low oxygen tension tend to induce pain crisis. Thus, some occupations such as commercial divers and aircrews are deemed unsuitable for SCA patients. The potential of an employee to be absent from job due to treatment or complications of SCA is also an issue. SCA patients are usually discriminated as the employers will prefer employee with no serious health issue. Prejudice and lack of tolerance of the colleagues are also some of the problems that will be encountered at the work place.
The patients can also be hospitalised because of acute pain crisis, anaemia, stroke, acute chest syndrome and infections. This can happen quite often if the patients do not get good medical support. This can cause huge economical impact to the nation. For example, in 2004, United States spent about $488 million in hospital cost for the 113,000 hospitalisations for the sickle cell disease patients.11 As the disease is life long, the patients need to undergo life-long treatments, causing the patients and their family to bear heavy financial burden.5
Benefits and Risks
Treating SCA using HU has being associated with less incidence of severe pain episodes and acute chest pain, and ultimately mortality.21,22 As HU can reduce sickling of erythrocytes, there is less occurrences of vaso-occlusive and thus its complications. This can also help to prevent organ damage. There is also a reduction in haemolysis, from 34% of red cells survival before treatment to 84% during the treatment.31 This leads to less number of blood transfusion needed, number of hospital visits and days being hospitalised due to SCD-related complications. By this, the quality of life of the patients can be improved considerably. They can wander more into the society, instead of being isolated like before.
Financial benefit can also be gained from HU treatment. Moore et al. (2002) projected that if all patients are made available to HU treatment, there will be an almost 50% reduction in the hospitalisation, at the same time saving about $26 million annually. During MSH, the average annual cost of HU was about $1,000 per year, with $400 per year for visits and tests. However, this cost can be offset by reduced costs for hospitalizations, emergency room visits, opiates, and transfusion, resulting in net savings of about $5,000 per patient per year. 32
There are certain risks associated with use of HU. Bone marrow suppression is expected as that is the therapeutic effect of HU. Thus, if the leukocyte and platelet counts are too low, the drug is stopped temporary. The count usually return to normal after two weeks.11 Other possible side effects included decreased sperm count, hyperpigmentation (darkening of skins and nails), skin dryness. There are also concerns that the drug will cause birth defects in children of adults, growth relay in children and leukaemia in those on therapy.6,16
However, a report by The Center for the Evaluation of Risks to Human Reproduction, USA (CERHR) in 2007 has stated that although there is development toxicity in foetus and reproductive toxicity based on the evidence from experimental animal (rat and mice), its effects are unclear in human. Nevertheless, couple planning to have babies should discontinue the drug and the drug is normally not prescribed to pregnant women. On the other hand, the panel concluded that HU treatment does not cause growth relay in children aged five to fifteen years.6,16
In the follow up studies of MSH, the authors also commented that:
In the National Institutes of Health USA State-of-the-Science Conference statement in 2008, the panel commented that:
Figure 5: Blood Transfusion
(1812 words)Blood transfusion is a safe and usual procedure in which blood is given through an intravenous line to the patient.33 Blood transfusions can lower the amount of non-F cells in the body and hence sickle cells, thus lowering the chances that they will adhere to the vessels and block them. Besides, the number of normal erythrocytes is also increased, increasing oxygen supply to the body. Blood transfusion is used in treating sudden SCD-related complications, lowering the risk of stroke and preventing pneumonia.34 So, it is helpful for patients suffering pain crisis or chest syndrome. However, unlike HU, it does not change the physiological pathway of the body and have limited effects. The donated blood must be screened to detect contamination and analysed to ensure that the donor's blood match the recipient's. Blood is transfused over a period of one to four hours through a vein on arm (except in emergency when blood is transfused more quickly).35
Stem Cell Transplant
Figure 6: Stem Cell Transplant
(2085 words)Stem cell transplant is currently the only available cure for the sickle cell disease.7,14 Haematopoietic stem cells are immature cells that can differentiate into blood cells and can be found in bone marrow, bloodstream or umbilical cord blood.37 Stem cell transplant replaces the abnormal stem cells in the recipient with the normal ones from donor. Before the transplant, the recipient own marrow is completely destroyed. The recipient then receives the stem cells through an intravenous line. After transplant, the healthy stems cells will travel to bone marrow and start producing healthy blood cells with normal haemoglobin, hence the patient is cured.36
A few years ago, stem cells transplant are only done in children with SCD. It is too harsh for the adults because the procedure to remove their marrow is too toxic for them, after suffered from accumulate organ damages. But in 2009, this treatment has been performed successfully in ten adults and nine were cured. This is achieved by using a smaller dose of radiation and immune suppressant, leaving some patient's bone marrow to remain and co-exist with the donor's morrow.37,38,39 This success shows possibility of wider application of stem cells transplant in SCA patients. Yet, it is still much more restricted, economically and practically, than HU treatment.
Questions about efficacy, effectiveness and harms of HU treatment and barriers to its use and future research needed were addressed in the report (Hydroxyurea for the Treatment of Sickle Cell Disease) to Agency of Healthcare Research and Quality, USA in February, 2008. The evidence report was prepared by a team from John Hopkins University Evidence-based Practice Center. The team searched for English articles, cited in MEDLlNEÂ®, EMBASE, TOXLine, and CINAHL, addressing the questions, electronically and manually, through 30 June, 2007. Relevant articles were reviewed and graded according to their quality with regard to reporting data. The data from randomised controlled trials is considered the best, followed by non-randomised controlled trials and observational studies. Conclusions are only drawn if there are plenty of high-grade evidences that support the conclusion, ensuring validity of the conclusions and thus the information provided by the report should be reliable. Besides, the report was presented as evidence in NIH Consensus Development Conference in 2008 for Hydroxyurea treatment for SCA.6 However, one drawback of the report is that only English articles are reviewed. So, articles published in other languages are left out.
MSH was a randomised, doubled-blinded controlled trial involving 299 SCD-SS patients with at least three pain episodes a year. It was carried out to study the effect of HU in reducing the pain episodes. The trial was stopped earlier with a mean follow-up of 21 months due to the beneficial effect shown. The trial showed that HU works effectively in reducing the rate of occurrences of pain episodes. No important adverse effect was reported during the trials, so it is safe to say that HU is at least safe in short-term. After that, follow-up is conducted on the subjects for 9 years to study the long-term effects. The results also show promising effect in using HU for treatment of SCA. The data are convincing and should be valid as the number of subjects is fairly large and are carried out in double-blind at which both doctor and patients have no knowledge whether the patients receive HU or placebo. Nevertheless, MSH only involved adults and hence the effect of HU in children is not investigated.