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KirsiJahnukainen
UllaWartiovaara-Kautto

Sickle Cell Disease

Essentials

  • Sickle cell anaemia is a recessively inherited, serious haemolytic disease.
  • Heterozygous carriers (with the proportion of HbS in haemoglobin fractions below 40% and no other globin gene mutations) are asymptomatic.
  • All patients with sickle cell disease should be referred to specialized care.
  • Patients with sickle cell disease and carriers of the gene mutation who are of fertile age need genetic counselling if the spouse also has a haemoglobinopathy or is a carrier.

Aetiology

  • Sickle cell disease is caused by a beta globin gene mutation inherited from both parents, making the structure of the haemoglobin beta chain abnormal and leading to the production of sickle haemoglobin (HbS).
  • The abnormal haemoglobin makes erythrocytes sickle shaped. Such cells are easily haemolyzed, irritate blood vessel walls and activate inflammatory reactions and coagulation.
  • There are various types of sickle cell disease (HbSS, HbSC, HbS-beta, HbSD); see table T1. The most common type causing the most significant health issues is HbSS is caused by a homozygotic HbS mutation in the beta globin gene.

Epidemiology

  • Sickle cell anaemia is most common in Africa but also occurs in Asia, the Far East, North, Central and South America, the Mediterranean countries and, due to immigration, even further north in Europe.

Symptoms

  • Sickling of red blood cells produces the large spectrum of findings associated with sickle cell disease.
  • The most central features are
    • Chronic haemolysis appearing during the first year of life, not necessarily involving severe anaemia
    • Impaired circulation due to small vessel obstruction and inflammation that leads to chronic oxygen deficiency in parenchymal organs
    • Organ damage appearing later in adulthood in organs such as the spleen, kidneys, ocular fundi, heart, lungs and brain
  • Without treatment, sickle cell disease will lead to premature death.
  • Sickle cell crises are due to acutely increased sickling tendency of red blood cells, haemolysis, circulatory disorder and oxygen deficiency in tissues. Such crises may be fatal and require active, rapid treatment.
  • Infections, fever, dehydration, pregnancy and changes in partial oxygen pressure and temperature make patients susceptible to sickle cell crises.
  • Crisis symptoms include one or more of the following:
    • Severe pain in any part of the body - most commonly the skeleton, sometimes the abdomen, chest or head.
    • Impaired oxygenation
    • Priapism
    • Fever
    • Cerebrovascular disorder (infarction or haemorrhage)
    • Sudden loss of vision or hearing
    • In small children, dactylitis
    • In small children, splenic or hepatic sequestration, where most (or all) of the blood volume is trapped in the spleen or in the liver
  • Due to their underlying disease, patients are hyposplenic and, consequently, susceptible to infections.

Laboratory findings

  • Most patients have haemolytic anaemia Haemolytic Anaemia (elevated lactate dehydrogenase (LD) and 3-20% reticulocytes). The severity of anaemia may vary from mild to severe enough to require red blood cell transfusion (table T1).
  • HbSC- or HbS-beta disease is also associated with microcytosis (table T1). HbSS is a normocytic disease unless the patient has also inherited an alpha globin gene mutation.
  • Diagnostic tests: blood haemoglobin fraction test (table T1), plasma ferritin test (within range or elevated) and blood count (table T1)
  • The haemoglobin fraction test usually detects both carriers and those with the symptomatic form of disease.
  • Genetic tests are performed in specialized care.

Clinical and haematological findings in patients over 5 years of age with sickle cell anomalies, and in sickle cell carriers

Sickle cell anomalyClinical severityHbS (%)HbF (%)HbA2 (%)Hb (g/l)Reticulocytes (%)MCV (fl)
SSSevere> 90< 10< 3.560-1103-20> 80
Sß°Severe to moderately severe> 80< 20> 3.560-1003-20< 80
Sß+Moderately severe> 60< 20> 3.590-1203-10< 75
SCSevere to moderately severe50< 5< 3.5 (50 % HbC)100-1503-1075-95
SA (carrier)Asymptomatic< 40< 1< 3.5Within rangeWithin rangeWithin range
Lyhenteet:
  • SS = homozygous for the mutation causing sickle cell disease (HbS)
  • Sß° = heterozygous for sickle cell disease and ß-thalassaemia mutations (no ß-globin production)
  • Sß+ = heterozygous for sickle cell disease and ß-thalassaemia mutations (partial ß-globin production)
  • SC = heterozygous for sickle cell disease and HbC mutations
Treatment and follow-up
  • Patients diagnosed with sickle cell anaemia should be referred without delay to a paediatric or adult haematology unit at a tertiary care centre for investigations and for planning treatment.
  • As soon as the diagnosis and lines of treatment have been confirmed, an agreement can be made on follow-up in other specialized care units according to instructions provided by the tertiary care centre. However, the patient should be assessed at least annually at a unit specializing in the treatment of sickle cell disease.
  • The patients need folic acid and calcium/vitamin D supplementation (1-5 mg of folic acid and 20-50 µg vitamin D daily).
  • Hydroxyurea treatment is started in specialized care.
  • If the patient has symptoms of cerebrovascular disorder, if a child patient shows changes in transcranial Doppler examination or if significant organ damage is detected, red blood cell exchange transfusion or other special treatment is started.
  • Due to hyposplenism, all patients should be given so-called splenectomy vaccination (meningococcal, Haemophilus influenzae type B [Hib] and 13-valent pneumococcal vaccines) and children from 3 months to 5 years of age penicillin prophylaxis (3 months to 3 years: 200 000 IU [125 mg] twice daily; 3-5 years: 400 000 IU [250 mg] twice daily); for those allergic to penicillin, a macrolide. In addition, annual influenza vaccinations should be given.
  • In paediatric patients, temporary cessation of erythropoiesis due to a parvovirus infection may lead to an aplastic crisis, and red blood cell transfusion may be needed.

Treatment of sickle cell crises

  • Patients who, based on acute symptoms, are suspected of having a sickle cell crisis should be referred to emergency services for internal diseases or paediatrics.
  • Effective analgesic medication.
    • Opioids are often needed for the treatment of infarction pain due to lack of oxygen in tissues.
  • Rest, fluid administration, ensuring sufficient oxygenation
  • Active search for and treatment of infections
  • If the pain crisis is particularly severe or prolonged, or if the patient has problems with oxygenation, for example, or disorders of cerebrovascular circulation, a haematologist should be consulted urgently. Without red blood cell exchange transfusion, the situation will become worse and may rapidly lead to multiple organ dysfunction.
  • N.B.! Red blood cell transfusion must always be done using phenotyped erythrocytes, as far as possible Blood Transfusion: Indications, Administration and Adverse Reactions. The erythrocyte phenotype should be defined as soon as the diagnosis has been confirmed.
  • In splenic or hepatic sequestration, a child will need immediate red blood cell transfusion, and splenectomy must be considered later.

Genetic counselling

  • In fertile age, carriers of gene mutations causing sickle cell disease and patients with sickle cell disease need genetic counselling if their spouses also carry a gene mutation causing a haemoglobinopathy.
    • Basic investigations (blood count, ferritin and haemoglobin fractions) for the spouse should always be done in primary health care. In countries where sickle cell disease is rare, and the spouse is of local descent (all grandparents from the same country) performing blood count may suffice, provided that its result is normal. Consult local recommendations for further guidance and details.
    • If, based on the basic investigations, the spouse may have a haemoglobinopathy or may be a carrier, the couple should be referred to a clinical genetics unit.
    • The investigations should be done and genetic counselling provided as early as the pregnancy planning stage, if possible.
  • It is important to identify couples with a risk of having a child with symptomatic sickle cell disease.
    • If both parents carry a gene mutation causing sickle cell disease, in each pregnancy they will have a 25% risk of having a child with symptomatic sickle cell anaemia. Carrying of beta thalassaemia, HbD or HbC in one parent combined with carrying of HbS in the other parent will produce a similar 25% risk of disease for each child.

    References

    • Kavanagh PL, Fasipe TA, Wun T. Sickle Cell Disease: A Review. JAMA 2022;328(1):57-68 [PubMed]
    • Piel FB, Steinberg MH, Rees DC. Sickle Cell Disease. N Engl J Med 2017;376(16):1561-1573 [PubMed]