Date of publication: 2005-11-29
Version: 1.0
Sickle cell anaemia is a hereditary disorder affecting haemoglobin (Hb), which is the pigment protein in the red blood cells that makes the blood red and delivers oxygen to the different parts of the body. In sickle cell anaemia, certain situations such as stress cause abnormal haemoglobin to alter the shape of the red blood cells. Instead of being disc-shaped, the cells become sickle (crescent) shaped. The curved sickle cells have difficulty passing through the smallest blood vessels, and they obstruct the blood flow. Another problem is that the life span of sickle cells is shorter than that of normal red blood cells.
The disease may have several serious complications. For example, severe pain episodes are common when the blood flow is restricted and the body’s tissues and organs are deprived of oxygen. Anaemia, infections, leg ulcers, kidney damage, thrombosis and stroke are other serious complications associated with the disorder.
The trait for sickle cell anaemia is often carried by people from areas of the world with a history of malaria epidemics. This means that the disease mostly affects people from Africa, the Middle East, India, and the Mediterranean region. Carriers of the genetic trait for sickle cell anaemia have increased resistance to severe malaria (falciparum type).
Almost 2 per cent of the world’s population have the sickle cell trait, and almost 3 per cent of all newborns are carriers. In Africa, over 10 per cent of the population are carriers, while in Europe the prevalence is estimated to 0.1 per cent. More than 225,000 babies per year are born with sickle cell anaemia. Of these, 200,000 are born in Africa and over 20,000 in Asia, while in Europe the number is only 200. There is no study of the incidence in Sweden, but less than 100 individuals are affected ─ all originating from countries where the disorder is common.
Sickle cell anaemia is caused by a mutation in a gene on chromosome 11. The gene, known as the beta globin gene, provides the blueprint for the production of haemoglobin protein. When the gene is defective, the resulting protein is abnormal.
The mutated gene causes an amino acid substitution in the haemoglobin beta protein chain, and as a result the characteristics of the haemoglobin molecules are altered. The abnormal molecules tend to clump together, particularly under deoxygenated conditions. This process is known as “sickling”. When the haemoglobin molecules cluster together, they form long strands (polymers), which distort the cells. The altered cells, known as sickle cells, are shaped like a crescent or a sickle. They do not flow well through the blood vessels and their life span is reduced.
The abnormal haemoglobin also produces substances (particularly oxidants) that damage the membranes of the red blood cells. The transport channels in the cell membrane are over-activated, which results in blood-cell dehydration. The sickle cells also become “sticky” and adhere to the inside walls of the blood vessels. This increases the risk of blood clotting and subsequent tissue damage inside the blood vessels.
These abnormal red blood cells are the cause of sickle cell anaemia. The characteristic symptoms of this disorder are:
1. Anaemia (haemolytic anaemia) owing to shortage of red blood cells. The reduced lifespan of the sickle cells causes the condition.
2. Episodes of blocked blood vessels and poor blood circulation (vasoocclusive crises).
Sickle cell anaemia is an autosomal recessive disorder. This means that both the parents of a child with the disorder are usually asymptomatic carriers of a mutated gene. In each pregnancy where both parents are carriers there is a 25 per cent risk that the child will inherit two mutant genes, and thus the disease. In 25 per cent of the cases the child will neither inherit the disease nor be a carrier. In 50 per cent of the cases the child will inherit one recessive mutant gene, and will thus, like the parents, be a healthy carrier.
Individuals with sickle cell anaemia usually have a double set of the recessive mutant gene for the disease, but it is also possible to develop the condition if an individual has inherited one trait for sickle cell anaemia and one for another haemoglobin disorder (for example haemoglobin C or certain beta thalassemias). Separate information on thalassemia is available in the rare disease database of the Swedish Board of Health and Welfare.
A carrier of one sickle cell trait is usually symptom-free, although the ability to concentrate urine may be impaired. Under extreme conditions a carrier of one mutant gene may display mild symptoms.
If one parent is not a carrier, but the other has inherited sickle cell anaemia (and thus has two abnormal genes), the children will all be carriers of the defective gene but the condition will not affect them. If an individual with an inherited autosomal recessive disorder has a child with someone who has one copy of the defective gene, there is a 50 per cent risk that the child will develop the condition, while in 50 per cent of the cases the child will be a healthy carrier.
The severity of the disease is determined by the inherited ability to produce alternative haemoglobin molecules, especially foetal haemoglobin (HbF). Foetal haemoglobin is an effective oxygen carrier that all people have in their blood before birth. If further production of HbF can be promoted, and the high concentration of HbF in the red blood cells is thereby retained, the symptoms of sickle cell anaemia are less pronounced.
Tissue damage associated with sickle cell anaemia is mainly a result of oxygen deprivation. Although most body tissues may be affected, the organs that normally have slow blood flow and low oxygen levels, such as bone marrow and spleen, are most severely damaged, as well as organs with limited blood flow in the microcirculation, such as the retina, parts of the kidney, and the femur (thigh) and humerus (upper arm) bone. An early sign of kidney damage is an increase in urine volume, caused by malfunctioning urine concentration. Individuals with sickle cell anaemia are also at increased risk of damage to the retina (retinopathy).
Sickle cell anaemia may have acute complications (see below). The symptoms are usually caused either by blood vessel blockages preventing oxygen from reaching peripheral tissues (vasoocclusive crises), or by temporarily decreased production of red blood cells in the blood marrow, leading to acute anaemia (aplastic crisis). Individuals with the disorder are also at increased risk of developing severe bacterial infections, mainly because damage to the spleen has a negative effect on the immune system.
The symptoms of sickle cell anaemia change with age. Although the severity of the condition varies, all individuals from the age of 3-4 months are affected by red blood cell deficiency (anaemia). To compensate for the deficiency, the bone marrow produces abnormal amounts of cells, resulting in bone expansion and deformation (bone marrow hyperplasia). Neonates are sensitive to infection, and they may develop spleen sequestration, which is a life-threatening condition resulting from increased blood volume in the spleen.
Painful inflammations of the fingers and toes (dactylitis), caused by oxygen deprivation, are also common in early life.
From the age of one, additional symptoms include pain in the long bones, acute respiratory problems caused by sickling in the lungs, and pulmonary infection. There is also a risk of blood clots and stroke.
From the age of four there is also a heightened risk of acute chest syndrome (see below), and priapism, which is a painful condition caused by blood collecting in the penis. In adults, the dominant symptoms include heart, lung, liver and spleen damage, and small ulcers (skin sores) may also present.
Acute complications
Pain episodes
The most common symptom of sickle cell anaemia is the occurrence of pain episodes owing to sickling. The pain is usually localized to the bones and is caused by reduced blood flow and oxygen deprivation affecting the bone marrow. In young children, oxygen deprivation in the bone marrow causes reddening and painful swelling in the hands and feet. Older people are more likely to experience pain in the long bones, the back and the hips. However, pain episodes can present in any part of the body and the symptoms are easily misdiagnosed.
Acute chest syndrome
Acute chest syndrome is a life-threatening condition in which the patients experience chest pain, often combined with fever and breathing difficulties. A chest x-ray will usually reveal characteristic anomalies. The aetiology of the condition is unknown, but it is likely that a pulmonary infarction has been caused by sickling in the blood vessels of the lungs. In young individuals, an infection may cause enough stress to trigger acute chest syndrome.
Infection
People with sickle cell anaemia are vulnerable to bacterial infections in the bloodstream (sepsis), and pneumonia. In many cases, infections that are normally considered rare may present, for example in the bones or in the peritoneum (the membrane that lines the abdominal cavity). It is recommended that all individuals with sickle cell anaemia who have fever with a temperature exceeding 38.5° C (101.3 F) should see a physician for assessment and possible treatment.
Aplastic crisis
Individuals with sickle cell anaemia normally have relatively stable haemoglobin values. However, for the values to remain stable, the production of red blood cells in the bone marrow has to increase to compensate for their reduced life span. Certain virus infections significantly lower the production, resulting in acute anaemia. The symptoms include pallor, fatigue, increased heart rate and shortage of breath. Such aplastic crises usually improve spontaneously within days.
Stroke
Abnormal cell proliferation in the blood vessel walls may block the passage of oxygenated blood to the brain. The anterior and middle brain artery (arteria cerebri anterior, arteria cerebri media) are particularly affected, but the arteries supplying the brain stem and the cerebellum with oxygen (arteria basialis and arteria vertebralis) may also be obstructed. Around 6-12 per cent of all individuals with sickle cell anaemia will suffer a stroke. In children under the age of ten the stroke is usually caused by cerebral infarction (blood clots that block blood flow to the brain). The incidence of hemorrhagic strokes (bleeding in the brain) and transient ischemic attacks (TIA), in which part of the brain is temporarily deoxygenized, increases with rising age.
The most common symptoms of stroke are neurological, for example paralysis or muscle atrophy, often limited to one side of the body. The symptoms of cerebral haemorrhage include severe headaches, vomiting and sometimes loss of consciousness. The risk of stroke may be predicted with some accuracy by measuring the blood flow in cerebral arteries, or through the simpler procedure of measuring the individual’s habitual sickle cell count in the blood stream. If the patient always has more than 10-15 per cent sickle cells in the blood, there is a higher risk of stroke. The risk of stroke is an important factor to be considered when decisions are made about treatment and preventive measures.
Acute splenic sequestration
This is an acute, life-threatening condition in which sickle cells pool in the spleen, stopping blood from passing through it. Children under the age of three are at particular risk, but the condition may affect anyone with an enlarged spleen. Splenic sequestration is a major cause of death in children with sickle cell anaemia. The condition results from trapped sickle cells in the blood vessels that obstruct circulation in the spleen. Within hours, blood accumulates in the spleen, forcing it to enlarge. As a result, the haemoglobin level drops dramatically and induces a condition of shock, caused by the limited amount of oxygen in the bloodstream. The condition may be fatal within hours. Early symptoms include fatigue, pallor, elevated heartbeat, increased breathing rate and early satiety. Splenic sequestration requires immediate intervention and it is therefore important that parents and other caregivers recognise the symptoms.
Priapism
Priapism is a painful, persistent erection. The triggering factors of priapism are not known, but the episodes often commence during dream sleep, sometimes after sexual activity or when the bladder is full.
Chronic problems in sickle cell anaemia
Growth
Children with sickle cell anaemia tend to grow more slowly than normal and their puberty is delayed. However, over time they almost always catch up with their peers.
Kidney damage
Repeated episodes of oxygen deprivation often cause vital organ damage. Individuals with sickle cell disease always have an impaired ability to concentrate urine. Kidney damage can lead to progressive kidney disease and, finally, organ failure.
Impotence
Recurrent priapism episodes may cause impotence.
Femur and humerus head necrosis
When blood does not flow freely to a bone, the cells in the bone begin to die, causing the bone and its surrounding cartilage to wither and die (necrosis). This is a condition which leads to chronic pain and functional disability, particularly affecting people between the ages of 25 and 30.
Leg ulcers
With increasing age, leg ulcers may become a problem, especially about the ankles. Around the age of 10, 12-20 per cent of all individuals with sickle cell anaemia develop leg ulcers. Men are more frequently affected than women. Several ulcers may develop simultaneously, and they may be very painful and difficult to treat. The ulcers are often surrounded by subcutaneous inflammations (reactive cellulitis), and local lymph nodes may be swollen. Once healed, the risk that the ulcers will reappear is high, and they also tend to develop more frequently with age.
Gallstones
When the blood cells break down more rapidly, the production of gall pigment (bilirubin) increases. When there is too much bilirubin in the bile, gallstones are formed. By the age of 10, around 14 per cent of all individuals with sickle cell anaemia have gallstones, and by the age of 30, 75 per cent are affected. In most cases, these pigment stones produce no symptoms at all, but occasionally they cause chronic gastrointestinal problems or acute inflammations in the gall bladder or the pancreas.
Psychological and social effects
Like all people affected by a chronic disease, individuals with sickle cell anaemia may feel different from their peers. The teenage years are a particularly sensitive time and feelings of insecurity and low self-esteem are common. In addition, the teenager may be very concerned about pain episodes and organ damage. Under these circumstances, depression or anxiety disorders may also develop.
In suspected cases of sickle cell anaemia, the diagnosis can be confirmed by measuring the level of normal and abnormal haemoglobin molecules in a blood test, a procedure known as haemoglobin fractioning. This test can be carried out from the age of two months. The presence of sickle cells can also be determined in a molecular genetic test, by investigating a blood sample for the mutated haemoglobin gene.
Prenatal diagnosis can be performed by genetic analysis (causative mutation) of a chorionic villi sample (placenta specimen). Newborns can also be tested.
The treatment strategies for sickle cell anaemia can be subdivided into four different categories: preventive measures, symptom relief, stimulation of foetal haemoglobin production, and gene replacement therapy.
Preventive measures
Measures should be taken to prevent sickle cells from blocking blood vessels, causing oxygen depletion and potential organ damage. It is also important that preventive measures are taken to allow the child to develop and live life as normally as possible.
Children under the age of five are particularly vulnerable to infections should, depending on the symptoms, be treated with antibiotics. In some cases, preventive antibiotics should be administered. Vaccination against pneumococcal infections and hepatitis are also recommended.
Hydroxyurea treatment with the aim of increasing foetal haemoglobin (HbF) should be considered for patients who have had several sickle crises, who have severe chronic pain, or who are at a high risk of stroke. Another treatment option is regular blood transfusions in order to reduce the proportion of sickle cells in the bloodstream. There are, however, a number of complications associated with blood transfusions, such as iron overload, which requires medical treatment. Blood stem cell transplantation (haematopoietic stem cell transplantation) may also be considered in some cases (in lay language this procedure is often referred to as “bone marrow transplantation”).
It is important that individuals with sickle cell anaemia and people who are close to them are well informed about the disorder and how to treat and manage it. Information should be given on repeated occasions and should be adapted to age. All parents should learn how to assess their children with regard to breathing difficulties, pallor and spleen size. It is also important that both the parents and the affected individual learn to use pain relief medication correctly.
Individuals with sickle cell anaemia should take care not to become dehydrated or cold, and should therefore drink plenty of fluids, wear sufficiently warm clothing in cold temperatures, and avoid swimming in cold water. Activities at high altitudes (over 3000 m), where the oxygen level is low, should also be avoided. Air travel in pressurised cabins poses no problems.
Psychological and social support are important, as sickle cell anaemia is physically and mentally trying for the affected individual, who has to go through repeated pain crises resulting in long absences from school. Under these circumstances, low self-esteem and negative feelings are common. Having someone to share thoughts with is one way of alleviating the problems, and establishing contact with a psychologist or a counsellor may be helpful. It is important that the family is in regular contact with a care provider who has a good knowledge of the disorder. The family should also have access to a network of professionals knowledgeable about the condition. The paediatric care provider, daycare and school staff should all be a part of this network.
Treatment of symptoms
Acute symptoms and complications caused by the disorder (vasoocclusive crises, acute chest syndrome, aplastic crises, acute spleen sequestration) need to be relieved and treated. The treatment consists of providing sufficient hydration, antibiotics, pain relief and sometimes oxygen therapy or blood transfusions. As the pain is often severe, it is important to plan for regular effective pain control. The patient should be well informed about self-administered treatment at home, but should also learn to recognise conditions for which hospital care is required.
Stimulation of foetal haemoglobin (HbF) production
A high proportion of HbF in the blood lowers the risk that sickling will occur. Several chemical agents elevate the HbF level, but currently hydroxyurea is the drug of choice for treatment of sickle cell anaemia. Hydroxyurea is a cytotoxic substance used for treating malignancies, and long-term usage increases the risk of leukaemia and foetal harm in pregnancy. For this reason, hydroxyurea is only administered in severe cases of sickle cell anaemia. There are no established guidelines for determining who should be treated with this drug. However, the positive effects can be seen in both children and adults, and as hydroxyurea reduces the risk of vasoocclusive crises and recurring stroke, its usage is likely to increase.
Replacement of the defective gene
If a child with sickle cell anaemia has a sibling with the identical tissue type, a blood stem cell transplant can be performed. All blood cells are produced by stem cells in the bone marrow, which is a spongy tissue in the cavities of the bone. In a transplantation of blood stem cells (a haematopoietic stem cell transplant, popularly known as a bone marrow transplant), the affected child’s blood stem cells can be replaced with new ones taken from the healthy donor. Tissue types are inherited from both parents, and each child has a 25 per cent chance of having the same tissue type as a sibling. If the transplant is successful, the child is fully cured. However, the procedure is highly demanding and involves major risks, including an elevated fatality rate. Furthermore, the recipient of the new stem cells is often affected by permanent organ damage, which may lead to infertility. Owing to the risks involved, there are no general recommendations that determine who should be transplanted, and every case needs to be assessed individually.
Individuals with sickle cell anaemia should obtain a letter from their physician containing information about the disorder. The letter should be brought along when visiting any care facility, including the dentist.
It is important to drink plenty of water to avoid dehydration, especially during the warm seasons of the year or in conjunction with physical exercise.
Physicians at the regional hospital paediatric clinics have competence in treating sickle cell anaemia.
Resource personnel for children:
Senior physician Jonas Abrahamsson, Queen Silvia Children’s Hospital, SE-416 85 Göteborg, Sweden. Tel +46 (0)31-343 40 00, email: jonas.abrahamsson@vgregion.se.
Professor Rolf Ljung, Paediatric Clinic, Malmö University Hospital, SE-205 02 Malmö, Sweden. Tel +46 (0)40-33 10 00, email: rolf.ljung@skane.se.
Professor Ildiko Marky, Queen Silvia Children’s Hospital, SE-416 85 Göteborg, Sweden. Tel +46 (0)31-343 40 00, email: ildiko.marky@pediat.gu.se.
Resource personnel for adults:
Professor Robert Hast, Haematological Clinic, Karolinska University Hospital, Solna, SE-171 76 Stockholm, Sweden. Tel +46 (0)8-517 726 02, email: robert.hast@ki.se.
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The Swedish Paediatric Haematology Health Care Planning Group (Vårdplaneringsgruppen för pediatrisk hematologi, VPH), arranges training in the field of paediatric haematology. Information is found at: http://www.orebroll.se/vph
Education is usually provided by the university hospitals in each region.
Extensive research is currently being carried out to learn more about the various manifestations of sickle cell anaemia. Researchers are also interested in substances that increase the foetal haemoglobin level, and several clinical trials of hydroxyurea are currently ongoing. New methods for haematopoietic stem cell transplantation are being developed that may be beneficial for people with sickle cell anaemia. Gene therapy may be a future approach.
An information booklet on sickle cell anaemia which summarises the information in this database text is available free of charge from the customer service department of the Swedish National Board of Health and Welfare (in Swedish only, article number 2001-12-145). Address: SE-120 88 Stockholm, Sweden. Tel: +46 75 247 38 80, fax: +46 35 19 75 29, email: publikationsservice@socialstyrelsen.se. Postage will be charged for bulk orders.
The Swedish Paediatric Haematology Health Care Planning Group (Vårdplaneringsgruppen för pediatrisk hematologi, VPH), have a “mini care programme” (written by Jonas Abrahamsson, who is listed under “Resource personnel”). The programme (in Swedish) is available at the VPH website: www.blf.net/onko/page4/page29/page29.html.
There are several excellent websites providing information about sickle cell anaemia to individuals with the disorder, as well as to their families and health care providers:
Sickle Cell Information Center, Atlanta, GA, USA
Internet: www.scinfo.org.
The Sickle Cell Society, London, United Kingdom
Internet: www.sicklecellsociety.org.
Atkins RC, Walters MC. Haematopoietic cell transplantation in the treatment of sickle cell disease. Expert Opin Biol Ther 2003; 3: 1215-1224.
Claster S, Vichinsky EP. Managing sickle cell disease. BMJ. 2003; 15: 1151-1155.
Henthorn JS, Almeida AM, Davies SC. Neonatal screening for sickle cell disorders. Br J Haematol 2004; 124: 259-263.
Management and therapy of sickle cell disease. NIH publication 1996-2117 (third edition). Editors: Reid CD, Charache S and Lubin B.
Maples BL, Hagemann TM. Treatment of priapism in pediatric patients with sickle cell disease. Am J Health Syst Pharm 2004; 15;61(4):355-363.
Park KW. Sickle cell disease and other hemoglobinopathies. Int Anesthesiol Clin 2004; 42: 77-93.
Rappaport VJ, Velazquez M, Williams K. Hemoglobinopathies in pregnancy. Obstet Gynecol Clin North Am 2004; 31: 287-317.
Sickle Cell Disease. Basic Principles and Clinical Practice. Raven Press 1994. Ed Embury SH, Hebbel RP, Mohandas N, Steinberg MH.
Walters MC, Storb R, Patience M, Leisenring W et al. Impact of bone marrow transplantation for symptomatic sickle cell disease: an interim report. Blood 2000 Mar 15; 95(6): 1918-1924.
Ware RE, Zimmerman SA, Schultz WH. Hydroxyurea as an alternative to bloodtransfusions for the prevention of recurrent stroke in children with sickle cell disease. Blood 1999; 94: 3022-3026.
Westerdale N, Jegede T. Managing the problem of pain in adolescents with sickle cell disease. Prof Nurse 2004; 19: 402-425.
OMIM (Online Mendelian Inheritance in Man).
Internet: www.ncbi.nlm.nih.gov/omim
Search word: sickle cell anemia
The Swedish Information Centre for Rare Diseases, produced and edited this information material.
The medical expert who wrote the draft of this information material is Senior Physician Jonas Abrahamsson, Queen Silvia Children’s Hospital, Göteborg, Sweden.
The revision of the material was assisted by Professor Rolf Ljung, MAS University Hospital, Malmö, Sweden.
The relevant organisations for the disabled/patient associations have been given the opportunity to comment on the content of the text.
The expert group on rare diseases of the Swedish National Board of Health and Welfare approved the material prior to publication.
Date of publication: 2005-11-29
Version: 1.0
Publication date of the original Swedish version:
2004-06-22
For enquiries contact The Swedish Information Centre for Rare Diseases, The Sahlgrenska Academy at the University of Gothenburg, Box 400, SE-405 30 Gothenburg, Sweden, tel: +46 31 786 55 90, email: ovanligadiagnoser@gu.se.