Sickle Cell Disease and Sickle Cell Anaemia

Sickle cell haemoglobin (HbS) results from an autosomal recessively inherited mutation in which the amino-acid glutamine is replaced by valine at position 6 in the beta globin chain of haemoglobin. Sickle cells have a reduced deformability and are easily destroyed, causing occlusion of the microcirculation and a chronic haemolytic anaemia with a median haemoglobin concentration level of about 9 g/dl.¹

Sickling disorders include heterozygous (AS) sickle cell trait, homozygous (SS) sickle cell disease, compound heterozygous states for HbS with haemoglobins C, D, E, or other structural variants and the combination of the sickle cell gene with different forms of thalassaemia.

• Heterozygotes; there is typically 60% HbA and 40% HbS. Sickle cell trait protects against malaria.
• People with sickle cell trait are generally asymptomatic and have no abnormal physical findings.³
• Laboratory tests are normal with no anaemia, no evidence of haemolysis, and no laboratory abnormalities other than the presence of haemoglobin AS on haemoglobin electrophoresis. However many people with sickle cell trait will have decreased ability to concentrate their urine.³
• There may be an increased incidence of urinary tract infection during pregnancy.³
• Painless haematuria occurs in 1 to 4 % of people with sickle cell trait (a minority may have significant problems with recurrent haematuria requiring medical intervention, transfusion, and iron therapy).³
• Complications such as splenic infarction, pain episodes, and sudden death may be induced by severe hypoxia (including flying in unpressurised aircraft, visiting very high altitudes or problems during general anaesthesia), severe dehydration and severe physical exertion.³
• Screening all those of African descent is essential before general anaesthesia.
• Management:³
  • Adequate hydration, avoidance of excessive fluid loss and avoiding severe heat are very important to help prevent complications such as exertional heat injury, splenic infarction, pain episodes and sudden death.
  • Those people with sickle cell trait who participate in sports activities should be advised to build up slowly in training with paced progressions, allowing longer periods of rest and recovery between repetitions. Preseason strength and sports-specific conditioning programmes should be encouraged.⁴
  • Those with haematuria should actively hydrate themselves before during and after physical exertion. If there is frequent, severe or persistent haematuria, the person may need to avoid activities that regularly cause episodes. Hydration and bed rest may abort episodes if done immediately.

• About 10,000 people in the United Kingdom have sickle cell disease.¹
• The sickle beta globin gene is spread widely throughout Africa, the Middle East, Mediterranean and India (e.g. sickle genes are present in 1 in every 50 Asians and 1 in every 100 Northern Greeks). The gene has spread through population movement to the Caribbean, North America and Northern Europe.
• The frequency of sickle cell carriers is up to 1 in 4 in West Africans and 1 in 10 in Afro-Caribbeans. It has reached high levels in these populations because the carrier state protects against malaria.

The symptoms of sickle cell anaemia can begin between 3 months and 6 months of age when HbF levels are falling.

• Anaemia, jaundice, pallor, lethargy, growth retardation and general weakness; the most common causes of anaemia are acute splenic sequestration, transient red cell aplasia, and hyperhaemolysis in patients with severe infection.¹
• Increased susceptibility to infections by encapsulated bacteria such as pneumococcus; the risk of overwhelming infection is highest before the age of 3 years.¹
• Splenomegaly may be present in infancy and childhood but recurrent splenic infarcts then cause autosplenectomy.
• Delayed puberty.

• Vaso-occlusive crises (obstruction of the microcirculation by sickled red blood cells causing ischaemia):
  • This is the most common type of crisis. May be precipitated by cold, infection, dehydration, exertion or ischaemia. Often no specific cause can be found.
  • Occlusion of small vessels by sickled erythrocytes causes pain which is variable from mild to severe. May present with swollen painful joints, tachypnoea or other signs of lung involvement, neurological signs, acute abdominal distension and pain (mesenteric sickling and bowel ischaemia), loin pain (renal papillary necrosis may cause renal colic or severe haematuria), priapism, hyphaema and retinal occlusion.
  • Large vessels may also be involved, causing thrombotic strokes, acute sickle chest syndrome and placental infarction.
  • Stroke:
    • Variable presentation, including fits and focal neurological signs.
    • Cerebral infarction is commoner in children.
    • Haemorrhage from microaneurysms which develop around infarctions ('moya moya') is more common in adults.
• Aplastic crisis (temporary cessation of erythropoiesis causing severe anaemia):⁵
  • Usually precipitated by infection with parvovirus B19 virus.
  • There is usually a drop in haemoglobin over about 1 week.
  • Recovery may be spontaneous but a transfusion is usually required.
  • With the severe anaemia associated with an aplastic crisis, patients may present with high-output congestive heart failure.
• Sequestration crisis (sudden enlargement of the spleen causing a decrease in haemoglobin concentration, circulatory collapse and hypovolaemic shock):
  • Occurs mainly in babies and young children. The severity is variable but can present with shock and anaemia.²
  • Acute splenic sequestration has been defined as an acute fall of haemoglobin and markedly elevated reticulocyte count, together with an acute increase in spleen size.⁵
  • If unrecognised, sequestration causes significant mortality. Mortality rates can be reduced substantially by parental education, regular palpation of the abdomen at home to detect early signs of splenic enlargement, and prompt transfusion.⁵
  • Recurrent splenic sequestration is an indication for splenectomy.⁵
• Acute chest syndrome (vaso-occlusive crisis affecting the lungs):
  • Defined as a new pulmonary infiltrate on the chest radiograph combined with one or more manifestations such as fever, cough, sputum production, tachypnoea, dyspnoea, or new onset hypoxia.
  • Lung infections tend to predominate in children, and infarcts predominate in adults.
• Hyper-haemolytic crisis (excessive haemolysis): uncommon; during painful crises there may be a marked increase in the rate of haemolysis with a fall in the haemoglobin level.

Other causes of haemolytic anaemia.

• Full blood count and blood film: the haemoglobin level is in the range 6-8 g/dL with a high reticulocyte count of 10-20%; the blood films may show sickled erythrocytes ad features of hyposplenism.
• Sickling of red cells on a blood film with 2% sodium metabisulphite.
• Sickle solubility test: a mixture of HbS in a reducing solution such as sodium dithionite gives a turbid appearance because of precipitation of HbS, whereas normal haemoglobin gives a clear solution.
• Haemoglobin analysis, e.g. by electrophoresis, is always needed to confirm the diagnosis. There is no HbA, 80-95% HbSS, and 2-20% HbF.
• Sickle cell trait is diagnosed by the finding of a positive sickling test together with haemoglobins A and S on electrophoresis.

• Neonatal screening for sickle cell disease using the heel prick test is universal in the United Kingdom.¹
• Screening and appropriate counselling should be available and offered to all people who are not of North European origin before general anaesthesia, before conception of a baby or at diagnosis of pregnancy, and neonatally.
• Women are now offered screening for sickle cell disease as an integral part of early antenatal care. In high prevalence areas, all women will be offered a blood test for sickle cell disorders; in low prevalence areas, a family origin questionnaire is used to determine who is offered the sickle cell blood test.
• Prenatal diagnosis: sickle cell disease can also be diagnosed in a fetus through prenatal diagnosis (following genetic counselling) from amniocentesis, chorionic villus sampling and fetal blood sampling.^1,6

It is very important that people with sickle cell disease should be reviewed regularly at a specialist centre; non-specialist hospitals should contact the nearest specialist centre when treating patients with sickle cell disease.⁵ Patients should be monitored regularly in specialist clinics for their growth, development and organ function so that active management may be considered before organ failure develops. Referral for specialist assessment should be made if puberty is delayed beyond 14 years in girls or 14.5 years in boys.⁵

• Parental and patient education:
  • Avoiding situations that can precipitate crises, e.g. cold, dehydration, exhaustion and early recognition and treatment of infection.
  • Palpation for splenic size to ensure early presentation of splenic sequestration can significantly reduce deaths.
  • All patients should be advised to avoid alcohol because of its dehydrating effects and smoking because it may cause the acute sickle chest syndrome.
• Folic acid supplementation may be required. Zinc supplementation should also be considered if growth is retarded. Vitamin D deficiency is very prevalent in non-white children in the UK and may co-exist with sickle cell disease, so advice should be given regarding vitamin supplementation.⁵
• Psychological:
  • Good support of patients, families and other carers is essential.
  • Cognitive behavioural therapy may be indicated.
• Infection:
  • Oral penicillin prophylaxis is started at diagnosis. The risk of pneumoccocal infection remains high but decreases with age. There is a steady rise in prevalence of penicillin resistant pneumococci.
  • Immunisation with pneumococcal, meningococcal and haemophilus vaccines.
  • Yearly influenza vaccination is also recommended.¹
  • Hepatitis A and B immunisations are recommended for those receiving regular transfusions.⁵
  • Infection and dehydration should be treated promptly and aggressively if necessary.
• Blood transfusions:
  • Transfusion may be required for severe anaemia or to reduce the proportion of HbS if there are lung or central nervous system complications.
  • Partial exchange transfusion (rather than top up transfusion) is indicated when it is necessary to reduce the percentage of haemoglobin S quickly in acute life threatening complications, such as severe acute chest syndrome, acute stroke, multi-organ failure or urgent preparation for major surgery.⁵
  • Iron overload is a possible complication of regular transfusions and iron chelation should be started in all children receiving regular blood transfusions.⁵
• Stroke:¹
  • Stroke prevention: it is recommended that transcranial Doppler ultrasonography is performed annually in children aged 2-16 years with sickle cell disease and that regular blood transfusions should be considered in those with abnormal findings on transcranial Doppler ultrasonography.
  • Assessment and prevention of nocturnal hypoxia (obstructive sleep apnoea) when relevant may be important in preventing strokes.
  • Exchange transfusion should be performed when a stroke occurs. Stroke is considered an indication for bone marrow transplantation in children and adolescents who have siblings with identical HLA.
• Treatment of acute chest syndrome:¹
  • Treatment includes inspired oxygen, incentive spirometry (also used for pain crises with back or chest pain), continuous positive airways pressure and exchange transfusion. Occasionally ventilation may be necessary.
  • Antibiotics are given using a combination of a macrolide with intravenous cephalosporin.
  • Transfusion or exchange transfusion produced improvements in several uncontrolled studies.
  • Hydroxycarbamide decreased the episodes of acute chest syndrome in one multicentre study.
  • Periodic transfusion is also effective in preventing recurrences.
• Treatment of priapism:⁵
  • Priapism is an emergency requiring hydration and analgesia.
  • In minor episodes bladder emptying, exercise such as jogging, warm baths and analgesia may help abort an attack.
  • Oral etilefrine may reduce the frequency of stuttering priapism.
  • In a prolonged episode, aspiration and irrigation of the corpora cavernosa with epinephrine or etilefrine is now the treatment of choice.
  • Children and their carers should be advised to seek treatment early and should attend hospital as an emergency if priapism persists for more than 2 hours.
• Bone marrow transplantation:
  • Offers the opportunity for cure.
  • Overall survival is 90-95%, with graft rejection of around 10-15%.
• Hydroxycarbamide (hydroxyurea):
  • The mechanism of action of hydroxyurea has not been fully elucidated.
  • Concerns remain about its myelosuppressive and teratogenic effects and its possible long term toxicity.
  • Hydroxyurea can reduce the frequency of crises in sickle cell disease, can reduce the episodes of acute chest syndrome,⁵ and reduce the need for blood transfusions. It is not yet licensed for use in sickle cell disease. It should still be used only on a named patient basis with close haematological supervision.
• Contraception:
  • Hormone and barrier methods are all acceptable choices but intrauterine devices are not recommended as they may be associated with uterine bleeding and infection.
  • Depot contraceptive (depo-provera) is safe and has been found to improve blood picture and reduce pain crises.⁷

Painful crises

• Pain experienced in a vaso-occlusive crisis results from oxygen deprivation of tissues and avascular necrosis of the bone marrow.
• Dactylitis is a common early manifestation that may occur before the age of 6 months.¹
• The risk of vaso-occlusive episodes is increased by exposure to cold, fever, and dehydration.
• Over 90% of hospital admissions for patients with sickle cell disease are for painful crisis, but nearly all sickle pain is coped with in the community.
• Pain has been reported to occur on up to 30% of days with a loss of 10% of schooldays in children.
• Hydroxycarbamide can reduce the frequency of painful crises in sickle cell disease (unlicensed indication in the UK).¹
• Management:
  • Avoid exposure to cold, fever, dehydration and stress.
  • Most episodes coped with at home respond to simple oral analgesia, increased fluid intake, warmth and rest.
  • A simple analgesic ladder is appropriate, starting with paracetamol and/or ibuprofen.⁵ If necessary use weak opioids, e.g. codeine or dextropropoxyphene, for patients with mild pain.¹
  • Always look for a cause, e.g. infection.¹
  • Admit patients if pain does not subside promptly, if there is a need for strong opioid treatment, or if there is fever, pallor or signs of respiratory compromise.¹
  • Benzodiazepines may be helpful to reduce anxiety.¹

Travel advice

• Increased fluid intake, abstinence from alcohol, and physical movement during travel, including flights, are helpful.
• Appropriate antimalarial prophylaxis is essential for patients travelling to areas at risk of malaria.
• Emphasis on a bacteriologically clean drinking water supply. Patients should increase their oral fluid intake above the standard 3 l/day for adults when they are in hot climates to compensate for the increased insensible losses.

• Sickle cell disease is very variable in its manifestations. The pattern of organ involvement alters with age.
• Infection: patients are prone to infection, especially pneumococcus, typhoid osteomyelitis and haemophilus because of hyposplenism resulting from sickling and consequent autosplenectomy.
• Stroke: clinical evidence of stroke occurs by age 20 years in 11% of patients with sickle cell disease.¹
• Priapism: males with sickle cell disease may experience painful erections, which may be brief but recurrent or may last six hours or more and can lead to impotence.¹
• Chronic pulmonary disease usually develops in patients older than 30 years. Cor pulmonale may develop. Pulmonary hypertension occurs in about 30% of adults with sickle cell disease and is associated with high rates of leg ulcer, priapism, and renal dysfunction.¹
• Gallstones caused by chronic haemolytic anaemia.
• Eye: retinopathy, retinal infarcts, retinal haemorrhage and retinal detachment.
• Transfusion complications: alloimmunisation, exposure to possible infections, risk of iron overload and consequent organ damage.
• Chronic leg ulcers: may become infected.
• Avascular necrosis: often in the femoral head and humeral head.
• Chronic organ damage: vaso-occlusion, hyperhaemolysis, and increased blood viscosity are major causes of chronic organ damage (osteonecrosis, liver failure, renal failure, leg ulcer, retinopathy), which is very variable in severity.¹
• Chronic renal failure:⁸
  • Occurs in up to 5% of patients with sickle cell anaemia.
  • Causes a worsening anaemia.
  • Patients may require treatment with high doses of erythropoietin.
• Learning difficulties:
  • Subtle, but important and widespread, neuropsychological defects result from sickle cell disease and may be present even in the absence of overt neurological complications.
  • This damage is probably responsible for the decreased intellectual ability of about five points in IQ in patients with sickle cell disease compared with controls.
  • This reduction indicates a twofold risk for significant learning difficulties and the need for remedial education compared with their peers.

• Patients with sickle cell disease are at high risk of perioperative complications, especially acute chest syndrome and pain.
• Preoperative transfusion may decrease the risk of postoperative complications.

• Worsening anaemia, vaso-occlusive crises, and acute chest syndrome may occur during pregnancy.
• Fetuses are at increased risk of prematurity, low birth weight or even death.
• Pregnant women with sickle cell disease must be monitored by an obstetrician and a specialist in the disease working closely together.
• Although controversial, prophylactic transfusion aiming to maintain a haemoglobin concentration above 90 g/l is recommended by most specialists for women with a history of severe clinical manifestations of sickle cell disease.

• Clinical severity and prognosis are very variable, ranging from survival into the 60s and 70s to a severe disease with substantial organ damage and early death.¹
• Since 1973, the average life span of a patient with sickle cell disease has increased from 14 years to 50 years.⁸
• The most common causes of death are pulmonary complications, cerebrovascular accidents, causes related to infection, acute splenic sequestration, and chronic organ damage and failure.

1. de Montalembert M; Management of sickle cell disease. BMJ. 2008 Sep 8;337:a1397. doi: 10.1136/bmj.a1397.
2. Stuart MJ, Nagel RL; Sickle-cell disease. Lancet. 2004 Oct 9-15;364(9442):1343-60. [abstract]
3. Eckman J, Platt A. Sickle cell trait. The Sickle Cell Information Center, Sickle Cell Foundation of Georgia, 1997.
4. National Athletic Trainers' Association, USA. Consensus statement: sickle cell trait and the athlete.
5. Sickle cell disease in childhood : various standards and guidelines for clinical care, NHS Sickle Cell & Thalassaemia Screening Programme (various dates)
6. OMIM; Sickle cell anemia
7. Manchikanti A, Grimes DA, Lopez LM, et al; Steroid hormones for contraception in women with sickle cell disease. Cochrane Database Syst Rev. 2007 Apr 18;(2):CD006261. [abstract]
8. Claster S, Vichinsky EP; Managing sickle cell disease BMJ 2003;327:1151-1155

• Sickle Cell Society
• UK National Screening Committee information; Sickle Cell & Thalassaemia
• Tahar A, Inati A, Kazzi Z; Sickle cell anemia. eMedicine, December 2008.
• Significant haemoglobinopathies: guidelines for screening and diagnosis, British Committee for Standards in Haematology (September 2009)