Sickle cell anaemia is an abnormality of haemoglobin structure. Instead of the usual HbA, sufferers have HbS, which becomes sickle-shaped when deoxygenated.
· 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.
· 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 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.
· 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".
· Sickling is precipitated by other factors along with hypoxia:
- In many cases the cause of a so-called "crisis" is unknown.
· Typical symptoms of oxygen starvation to areas:
· Long term problems:
· 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.
· 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.
© 1997 Hannah Cole
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