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. 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. There are five other major sickle genotypes:¹

• HbSS disease or sickle cell anaemia: homozygote for the beta S globin with usually a severe or moderately severe phenotype
• HbS/beta0 thalassaemia: severe double heterozygote for HbS and beta0 thalassaemia, and almost clinically indistinguishable from sickle cell anaemia
• HbSC disease: double heterozygote for HbS and HbC with intermediate clinical severity
• HbS/beta+ thalassaemia: mild to moderate severity, but variable in different ethnic groups
• HbS/hereditary persistence of fetal Hb (S/HPHP): very mild phenotype or symptom-free
• HbS/HbE syndrome: very rare and generally very mild clinical course
• Rare combinations of HbS with HbD Los Angeles, HbO Arab, G-Philadelphia, among others

• Heterozygotes; there is typically 60% HbA and 40% HbS.
• No clinical problems but hypoxia may occur in certain circumstances, e.g. anaesthesia or flying in non-pressurised aircrafts.
• Blood count and film are normal; diagnosis is made by a positive sickle test or Hb electrophoresis.
• Sickle cell trait protects against malaria.
• Screening all those of african descent is essential before general anaesthesia.

• The number of patients in the United Kingdom was estimated at 5000 in 1993 with the number being estimated as more than 10,000 by 2000.¹
• The sickle beta globin gene is spread widely throughout Africa, the Middle East, Mediterranean and India. It 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 usually begin in the second six months of life when HbF levels are falling.

• Anaemia, jaundice, pallor, lethargy, growth retardation and general weakness
• Increased susceptibility to infections
• Hyperplasia of bone marrow leads to frontal bossing of the skull
• Splenomegaly may be present in infancy and early childhood but recurrent splenic infarcts then cause autosplenectomy
• Delayed puberty

• Vaso-occlusive crises:
  • The most common type of crisis. May be precipitated by cold, infection, dehydration, exertion or ischaemia. Often no specific cause can be found.
  • Very painful with occlusion of small vessels by sickled erythrocytes. 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, retinal haemorrhage and retinal detachment.
  • Large vessels may also be involved, causing thrombotic cerebrovascular accidents, acute sickle chest syndrome and placental infarction.
  • Brain syndrome:
    • 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:
  • Usually precipitated by infection with parvovirus
  • Causes sudden lethargy and pallor
  • Require urgent transfusion
  • With the severe anaemia associated with an aplastic crisis, patients may present with high-output congestive heart failure
• Sequestration crisis:
  • Occurs mainly in babies and young children. Trapped red cells cause rapid enlargement of liver and spleen. Hepatic sequestration may occur in adults.
  • A large proportion of the total red cell mass may be trapped in the spleen or liver. Death may occur due to severe anaemia.
  • The chest syndrome:
    • Due to sequestration of sickle cells in the pulmonary circulation. Rare before puberty but is then the most common cause of death in Britain in patients with sickle-cell disease.
    • Presents with acute dyspnoea and pleuritic pain. Onset can be insidious or rapid, leading to death in untreated patients within hours.
    • Infiltrates are seen on the chest x-ray.
    • Treatment: inspired oxygen, continuous positive airways pressure and exchange transfusion. Occasionally ventilation may be necessary.
• 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.

• Sickle cell trait: diagnosed by the finding of a positive sickling test together with haemoglobins A and S on electrophoresis.
• Sickle cell anaemia: anaemia (typically 6-8 g/dl), increased reticulocyte count, sickled erythrocytes on the peripheral blood film, positive sickling test; haemoglobin electrophoresis shows an absence of haemoglobin A and mostly haemoglobin S with a variable amount of haemoglobin F.
• Sickling tests: include mixing drop of blood with 2% sodium metabisulphite.
• Prenatal diagnosis: pre-implantation genetic diagnosis as well as genetic diagnosis from amniocentesis, chorionic villus sampling and fetal blood sampling is now available.²

• 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.
• Family members and partners should be offered screening as well as prenatal diagnosis discussed.

• Parental and patient education:
  • Avoiding situations that can precipitate crises, e.g. cold, dehydration, exhaustion and early recognition and treatment of infection.
  • How to palpate 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.
• 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.
  • Infection and dehydration should be treated promptly and aggressively if necessary.
• 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.
• 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 transfusions may be required to reduce the proportion of HbS if the haemoglobin level is relatively high, such as 9 g/dl or greater.
• Bone marrow transplantation:
  • Offers the opportunity for cure.
  • Overall survival is 90-95%, with graft rejection of around 10-15%.
• 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 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.

Painful crises

• Pain experienced in a vaso-occlusive crisis results from oxygen deprivation of tissues and avascular necrosis of the bone marrow.
• 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.
• The optimum clinical management of painful crises is still not resolved. Most episodes coped with at home respond to simple oral analgesia, increased fluid intake, warmth, rest, and, for some patients, massage of the affected area.
• A simple analgesic ladder is appropriate, starting with paracetamol. If this is ineffective, a non-steroidal anti-inflammatory drug can be added, followed by codeine phosphate. Any further treatment will involve opiate analgesia and possibly admission to hospital.

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.
• Chronic pulmonary disease usually develops in patients older than 30 years. Cor pulmonale may develop.
• Gallstones caused by chronic haemolytic anaemia.
• Eye: retinopathy, retinal infarcts and retinal detachment.
• Transfusion complications: alloimmunization, exposure to possible infections, risk of iron overload and haemosiderosis.
• Chronic leg ulcers: may become infected.
• Avascular necrosis: often in the femoral head.
• Chronic renal failure:³
  • Occurs in up to 5% of patients with sickle cell anaemia
  • Causes a worsening anaemia
  • Patients may require treatment with high doses of erythropoietin
• Pregnancy:
  • May be associated with an increased incidence of painful crises.
  • Maternal mortality is slightly increased and there is an increase in the rate of fetal loss.
• Learning difficulties:
  • Subtle, but important and widespread, neuropsychological defects result from sickle-cell disease and may be present even in the absence of 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.

• Since 1973, the average life span of a patient with sickle-cell disease has increased from 14 years to 50 years.³
• The most common causes of death are pulmonary complications, cerebrovascular accidents, causes related to infection, acute splenic sequestration, and chronic organ damage and failure.
• Frequent episodes of severe pain correlates with early death in patients with sickle-cell disease.
• Continued production of high concentrations of fetal haemoglobin is associated with a longer life expectancy.