Sickle cell disease is an inherited genetic condition that involves defects in the shape and function of haemoglobin in the blood. This increases the likelihood of blockages in the blood vessels and disrupted blood flow, which can result in serious complications.
The Role of Haemoglobin
Haemoglobin is an essential cellular component of the red blood cells that play the role of transporting oxygen in the blood to the bodily tissues where it is required.
Sickle haemoglobin differs in physical shape from the normal haemoglobin, with a curved sickle-shaped rather than flat-disc shaped cells. The shape alters the properties of the cells, causing then to become more rigid and less flexible. As a result of this, the cells are more likely to hemolyse and cause blockages in the blood vessels that disrupt the flow of blood.
The specific gene mutation that results in sickle haemoglobin involves a substitution of thymine for adenine (from GAG to GTG) on the sixth codon of the genetic sequence. This leads to the coding of valine rather than glutamate on the sixth position of the haemoglobin beta chain.
This genetic alteration changes the physical properties of the haemoglobin cells, changing their shape to the characteristic sickle shape and the physical properties, such as solubility and stability. It is these properties that account for changes in function and the common complications of the disease.
Genetic Inheritance Pattern
Sickle cell disease is an inherited condition that follows an autosomal recessive pattern. This means that males and females are affected equally and both parents must carry a gene mutation, even if they are asymptomatic, for the child to be affected.
When both parents carry a single gene mutation, known as sickle cell trait, there is a 25% chance that the disease will develop, 25% chance that the child will be unaffected and a 50% that they will possess a gene mutation as an asymptomatic carrier.
When there is insufficient oxygen in the vascular system, sickle haemoglobin becomes considerably more insoluble, increasing the polymer formation in the blood and the overall viscosity. This leads to the formation of tactoids, a gel-like form of haemoglobin that exists in equilibrium with its ordinary soluble state. The proportion of each type depends on:
- Oxygen presence: more oxygen supports prevalence of the liquid state
- Sickle haemoglobin concentration: more HbS supports gel-like state
- Other haemoglobins: Normal adult and fetal Hb support liquid state
Over time, the membrane of the cells become permanently damaged, leading to cells permanently staying in the bi-concave sickle shape, even when the blood is exposed to sufficient levels of oxygen once again.
Initial symptoms of sickle cell disease tend to present in young children approximately six months to one year old, as the high concentration of foetal haemoglobin plays a protective role before this time. There are three main complications that can arise: sickle cell crisis, anaemia and multiple organ damage
Sickle cell crises may result due to the increased viscosity of the blood and the formation of blockages in the blood vessels. When the rigid cells group together, they can disrupt the flow of oxygen and restrict the supply to tissues that require oxygenation. This results in sudden and severe pain, known as sickle cell crisis, that usually require medical management.
Anemia can present due to hemolysis of the red blood cells with sickle haemoglobin in the spleen. As a result, the red blood cells have a shorter lifespan than normal and hemolytic anaemia can present.
Main organ damage can occur to patients with sickle haemoglobin over an extended period of time. This may affect the heart, skeleton, spleen, brain, eyes, lungs, kidneys, penis and skin.