SICKLE CELL ANAEMIA

SICKLE CELL ANAEMIA

"Large number of thin, elongated, sickle-shaped and crescent-shaped forms"

Sickle cell anaemia is an abnormality of haemoglobin structure. Instead of the usual HbA, sufferers have HbS, which becomes sickle-shaped when deoxygenated.

1. SICKLE CELL ANAEMIA IS AN INHERITED CONDITION.

· Sickle cell sufferers are homozygous for an abnormal gene located on an autosomal chromosome (i.e. it is not sex-linked). They have no HbA, just HbS and 50% of their red blood cells are sickled.

· Sickle cell trait patients have inherited 1 abnormal gene, and 1 normal gene - i.e. they are heterozygous. Such people are usually unsymptomatic with 50% HbA, 50%HbS and just 1% of their red blood cells sickled.

2. HOW SICKLING OCCURS.

· A fibrous precipitate forms when there is a high concentration of deoxygenated HbS. This precipitate deforms the red blood cells giving them their sickle shape.

· HbS differs from HbA in that it contains valine, not glutamate at position 6 of the beta-chain:

               HbA : val - his - leu - thr - pro - glu - glu

               HbS : val - his - leu - thr - pro - val - glu
 
        beta-chain :  1     2     3     4     5     6     7

· Valine is nonpolar, glutamate is polar. The substitution of valine in HbS reduces the solubility of deoxygenated HbS, but has little effect on the solubility of oxygenated HbS.

· The valine creates a "sticky patch" on all HbS chains. The corners of the HbS chains have a complementary site which can bind to a "sticky patch" thus forming these long cell-distorting fibres.

· In oxygenated HbS the oxygen masks this complementary site, so it is only in deoxygenated HbS when the complementary site is exposed that sticking and hence sickling occurs.

3. THE CONSEQUENCES OF SICKLED CELLS.

· Sickled RBC are more fragile than normal RBC and haemolyze (break-down) more readily. Hence they have a shorter life-span which leads to anaemia. However, HbS releases oxygen to tissues more readily than HbA, so patients can feel well under normal conditions despite being anaemic.

· Sickled RBC become trapped in the small blood vessels, impairing the circulation and leading to damage of the organs.This also creates a viscious cycle as blockage of the blood vessel leads to a local region of low oxygen concentration and hence more HbS is deoxygenated so more sickling occurs.

· The sickling process is normally reversible but repeated sickling may produce "permanent sickles".

4. CAUSES AND SYMPTOMS.

· Sickling is precipitated by other factors along with hypoxia:

Infection
Dehydration
Cold
Acidosis

- In many cases the cause of a so-called "crisis" is unknown.

· Typical symptoms of oxygen starvation to areas:

Bone pain (most common)
Chest - pleuritic pain
Cerebral - heamiparesis and fits
Spleen - painful
Penis - persistent painful erection
Liver - pain with abnormal biochemistry
Kidney - papillary necrosis causing haematuria and renal tubular defects causing lack of concentration of urine

· Long term problems:

Susceptibility to infection - especially streptococcus pneumoniae which can cause a fatal meningitis or pneumonia.
Chronic leg ulcers - due to ischaemia i.e. inadequate blood flow caused by sickle blockage.
Gallstones - pigment stones from persistent haemolysis.
Chronic renal failure.
Aseptic necrosis of bone - especially femoral heads.
Blindness - due to retinal detachment and proliferative retinopathy.

5. MANAGEMENT.

· Avoidance of precipitative factors (see above).
· Prophylaxis to prevent pneumococcal infection.
· Folic acid given to those with severe haemolysis.
· Regular transfusions are given only if there is severe anaemia or frequent crises.

6. GEOGRAPHICAL DISTRIBUTION.

· In parts of Africa where malaria is a major cause of death the frequency of the sickle gene is as high as 40%.
· Those with heterozygous sickle genotypes i.e. Sickle-Cell Trait, are protected against the most lethal form of malaria - hence the geographical distribution.
· This is an example of BALANCED POLYMORPHISM.

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