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Sickle cell disease

Sickle cell disease is a group of inherited RBC disorders, and the most common intrinsic haemolytic anaemia, i.e. the most common cause of haemolytic anaemia due to intrinsic defects of the RBCs. It’s most common in African and Mediterranean populations.

It’s caused by a point mutation in the beta globin gene causes haemoglobin to precipitate into a sickle-shape when deoxygenized, which gives the name. This leads to microvascular occlusion and haemolysis. There are multiple types with varying severity. The most severe form of sickle cell disease (HbSS) is called sickle cell anaemia.

Sickle cell anaemia causes moderately severe anaemia with clinically detectable jaundice due to haemolysis. It also causes hyposplenism, which leads to increased susceptibility to severe infections by encapsulated bacteria, like osteomyelitis and sepsis.

Pathophysiology

Sickle cell anaemia is caused by a point mutation in the β-globin gene, causing a glutamate to be replaced by a valine. The mutated β-globin gene causes an abnormal form of haemoglobin called haemoglobin S (HbS) to form. The normal, healthy form of haemoglobin is called haemoglobin A.

People who inherit the mutated β-globin from both parents (and therefore are homozygotes) have sickle cell anaemia, the most severe form, called HbSS. These people have 75 – 95% haemoglobin S, the remaining being foetal haemoglobin (HbF).

People who only have the mutation on one allele are heterozygotes and is said to have sickle cell trait or HbAS. In these people haemoglobin S accounts for only 40% on all haemoglobin, which is often not enough to be symptomatic.

The problem with HbS is that, when deoxygenated, the HbS molecules polymerize and form a gelatinous network inside the RBC. This causes the RBC to change shape to the characteristic sickle-shape, forming a stiff, viscous sickle cell. Several factors can induce this sickling, like:

  • Hypoxia
  • Low pH
  • Fever
  • Infection
  • Exercise
  • Dehydration
  • Abrupt temperature changes
  • Stress

The sickle cells cause two problems. Because they are stiff, they can’t circulate properly through capillaries, causing capillary occlusion with microinfarctions and ischaemia, especially of the spleen, which may cause hyposplenism. Second, they’re more prone to haemolysis in the spleen. The increased RBC turnover that occurs with the haemolysis may increase the demand for folate, causing macrocytic anaemia.

Clinical features

People with sickle cell anaemia have continuous anaemia, sometimes with jaundice. Most people with sickle cell anaemia experience symptoms within the first years of life.

Acute complications can also occur. Acute splenic sequestration crises can occur, where a large number of sickled cells accumulate in the spleen, causing sudden drop in blood volume and splenomegaly. Acute aplastic crisis occurs in case of parvovirus B19 infection, in which the virus causes complete but temporary cessation of RBC production. Vaso-occlusive crises is a consequence of sudden vaso-occlusion, leading to episodes of severe bone pain and dactylitis, as well as priapism.

Due to chronic microinfarctions of the spleen these patients lose splenic function early (hyposplenism). This makes them more susceptible to infections by encapsulated bacteria, like S. pneumoniae, H. influenzae and salmonella. Chronic microinfarctions also cause chronic pain and can cause infarction of virtually any organ.

Diagnosis and evaluation

Treatment

  • Avoiding painful crises
    • Avoid triggers
    • Pneumococcal and H. flu vaccines
    • Antibiotic prophylaxis during invasive procedures
    • Vigorous oral hydration during or in anticipation of periods of exercise, stress
    • Treatment with hydroxyurea – increases the amount of foetal haemoglobin which reduces the proportion of HbS
  • Management of acute crises
    • Vigorous hydration
    • Treatment of underlying cause
    • Analgesia
    • Blood transfusion
    • Bone marrow transplant