Haemoglobin is the protein in red blood cells that transports oxygen. Fetal haemoglobin (HbF) is usually replaced by haemoglobin A (HbA) at around 6 weeks of age. Patients with sickle-cell disease have an abnormal variant called haemoglobin S (HbS). HbS causes red blood cells to be an abnormal “sickle” shape.

Sickle cell anaemia is an autosomal recessive condition where there is an abnormal gene for beta-globin on chromosome 11. One copy of the gene results in sickle-cell trait. Patients with sickle-cell trait are usually asymptomatic. Two abnormal copies are required for sickle-cell disease.

As the synthesis of HbF is normal, the disease usually does not manifest itself until the HbF decreases to adult levels at about 6 months of age.

Pathophysiology

• in the deoxygenated state the HbS molecules polymerise and cause RBCs to sickle
  • HbAS patients sickle at p02 2.5 - 4 kPa
  • HbSS patients at p02 5 - 6 kPa
• This process is initially reversible but, with repeated sickling, the cells eventually lose their membrane flexibility and become irreversibly sickled.
• This is due to dehydration, partly caused by potassium leaving the red cells via a calcium-activated potassium channel called the Gardos channel. These irreversibly sickled cells are dehydrated and dense, and will not return to normal when oxygenated.
• Sickling can produce:
  • shortened red cell survival
  • impaired passage of cells through the microcirculation, leading to obstruction of small vessels and tissue infarction
• HbS releases its oxygen to the tissues more easily than does normal haemoglobin, and patients therefore feel well despite being anaemic (except, of course, during crises or complications).

Risk factors:

• The sickle gene is most common in Africans (up to 25% gene frequency in some populations) but is also found in India, the Middle East and Southern Europe. Its distribution mirrors that of malaria infestation.
• Around 10% of UK Afro-Caribbean's are carriers of HbS (i.e. heterozygous). Such people are only symptomatic if severely hypoxic.

Relation to malaria:

It is more common in people of African descent as the heterozygous condition offers some protection against malaria. Having one copy of the gene (sickle-cell trait) reduces the severity of malaria. As a result, patients with sickle-cell trait are more likely to survive malaria and pass on their genes. Therefore, there is a selective advantage to having the sickle cell gene in areas of malaria.

Precipitating factors:

• infection
• dehydration
• cold