The unstable haemoglobins.

The unstable haemoglobin haemolytic anaemias result from the presence in the red cell of a structurally abnormal haemoglobin variant. There are many mutations producing unstable haemoglobins; most are single amino acid replacements that affect a few key areas of the haemoglobin structure. A wide range of haemoglobin instability is evident from in vitro studies, extending from mutants with a subclinical degree of instability to those associated with severe haemolytic disease. The characteristic feature of variants associated with haemolysis is a markedly decreased stability which is readily detectable by simple screening tests. The in vivo consequence is the precipitation of the unstable haemoglobin to give Heinz bodies which are associated with the red cell membrane and lead to premature cell destruction. The unstable haemoglobins have a greater tendency to spontaneously oxidise to methaemoglobin with subsequent formation of haemichromes and precipitation. This process is significantly accelerated by external factors such as exposure to oxidative substances and increased temperature; thus haemolytic crises are frequently associated with infections in otherwise asymptomatic carriers of unstable haemoglobins. The clinical expression of the unstable haemoglobin mutation may also be modified by proteolysis of the unstable globin chain in the bone marrow. This proteolytic mechanism can predominate in the case of extremely unstable globin chains to produce primarily a thalassaemic phenotype with little if any circulating unstable haemoglobin or evidence of haemolysis.