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Sickle cell disease

SCD is caused by a haemoglobin defect, known as Haemoglobin S. In SCD, the bone marrow cannot produce enough healthy red cells. The red cells produced look like sickles, are not flexible and can stick on vessels’ walls causing blood clots and preventing oxygen from reaching the body tissues.

About HbS carriers

Carriers of HbS do not have a disease. They have no physical or mental symptoms and do not require a special diet, medical advice or treatment. Their red blood cells are usually similar in size to those of non-carriers, since the quantity of haemoglobin is not reduced. Smaller red cells (microcytic) are sometimes seen in those carriers of HbS who have coinherited α-thalassaemia, a combination common in many populations. Otherwise, the red cells examined under the microscope may be indistinguishable from red cells of non-carriers.

Sometimes, altered shapes (poikilocytosis) and cells with pointed ends are seen, but the typical sickle-shaped cells, characteristic of this disorder in the homozygote state (i.e. in full blown disease), are not often seen in HbS carriers.

The carrier status cannot become a disease over time. Indeed, most individuals will be unaware that they are carriers unless specifically tested.

Carrying haemoglobin S has no effect on health, length or the quality of life. The rare exception to this occurs when a carrier is in a situation of severe lack of oxygen, in which case, pain and blood vessel blockage may be experienced.

Other names describing an individual who carries the HbS variant include:

  • Carrier of the sickle cell trait
  • Individual heterozygous for HbS
  • Sickle cell carrier

HbS/HbS

If both parents are carriers of HbS, there is at each pregnancy

  1. a one-in-two (50%) chance that the child will also be a carrier of HbS;
  2. a one-in-four (25%) chance that the child will be completely unaffected;
  3. a one-in-four (25%) chance that the child could inherit HbS from both parents (HbS/HbS) and have the full-blown disease known as sickle cell disease (SCD) or sickle cell disorder or sickle cell anaemia or homozygous sickle cell disease (as shown below)


HbS/HbSS

If one parent is a carrier of haemoglobin S (HbS) and the other is a patient with sickle cell disease (HbS/HbS), at every pregnancy there is a one-in-two chance (50%) that the child will be an HbS carrier, and a one-in-two chance (50%) that the child could inherit sickle cell disease (SCD) – (HbS/HbS).

Combination of HbS with β-thalassaemia and other abnormal haemoglobins

HbS/β-thalassaemia

If one parent is a carrier of HbS and the other parent is a carrier of β-thalassaemia, at each pregnancy there is a one-in-four chance (25%) that their child could inherit fully functional genes; a one-in-four chance (25%) that the child will be a carrier of HbS; a one-in-four chance (25%) that the child could be a carrier of β-thalassaemia; and a one-in-four chance (25%) that the child could inherit the compound haemoglobin disorder referred to as sickle cell/β-thalassaemia (HbS/β-thal) as shown below.

 

Combinations can occur with other haemoglobin variants such as HbC, HbPunjab, HbE and HbO Arab.

HbS/HbC disease

If one parent is a carrier of HbS and the other parent is a carrier of another abnormal haemoglobin, haemoglobin C (HbC), at each pregnancy there is a one-in-four chance (25%) that the child could inherit fully functional β-globin genes, a one-in-four chance (25%) that the child will be a carrier of haemoglobin C (HbC), a one-in-four chance (25%) that the child will be a carrier of HbS, and a one-in-four chance (25%) that the child could inherit a compound haemoglobin disorder called haemoglobin S/haemoglobin C (HbS/C).

HbS/HbD Punjab

If one parent is a carrier of HbS and the other parent is a carrier of the variant haemoglobin D Punjab, at each pregnancy there is a one-in-four chance (25%) that the child could inherit fully functional β-globin genes; a one-in-four chance (25%) that the child will be a carrier of haemoglobin D Punjab; a one-in-four chance (25%) that the child will be a carrier of HbS; and a one-in-four chance (25%) that the child may inherit the compound haemoglobin disorder referred to as haemoglobin D Punjab/haemoglobin S (HbS/HbD Punjab).

HbS/HbE

If one parent is a carrier of HbS and the other is a carrier of HbE, at each pregnancy there is a one in four chance (25%) that the child will inherit fully functional genes; a one-in-four chance (25%) that the child will be a carrier of HbE; a one-in-four chance (25%) that the child will be a carrier of

HbS; and a one-in-four chance (25%) that the child may inherit the compound haemoglobin disorder called Haemoglobin S/Haemoglobin E (HbS/HbE).

HbS/HbO Arab

If one parent is a carrier of haemoglobin S and the other of haemoglobin O Arab, at each pregnancy there is a one-in-four (25%) chance that the child will inherit fully functional genes; a one-in-four (25%) chance that the child will be a carrier of haemoglobin O Arab; a one-in-four chance (25%) that the child will be a carrier of sickle cell; and a one-in-four (25%) chance that the child may inherit the compound haemoglobin disorder called Haemoglobin S/Haemoglobin O Arab (HbS/HbO Arab).

It is believed that the sickle cell abnormal haemoglobin originated in Africa, where it is most commonly encountered, while India is considered as an additional place of origin. HbS is prevalent in the indigenous population of some Middle East and Mediterranean countries, while population migration has taken the gene to almost all regions of the world, including Western and Northern Europe. According to current epidemiological data, about 7% of the global population carries an non-functional haemoglobin gene, with more than 500,000 affected children born annually. More than 80% of these are born and live in the developing part of the world. More than 70% of them have a sickle disorder, and the rest have thalassaemia syndromes. A significant number of affected children born in developing countries even today die undiagnosed or misdiagnosed, receiving sub-optimal treatment, or left untreated altogether.

What is sickle cell disease?In this condition, almost all of the haemoglobin in the patient’s blood is HbS. The red cells which contain this variant will change in shape from a biconcave disc to a crescent, or sickle shape, but will also lose flexibility, becoming considerably more rigid. This means that they cannot change their shape easily, as normal red cells with common Hb (HbA) do. As a consequence, passage through small blood vessels is difficult. Loss of flexibility can become serious in conditions of lack of oxygen or in the case of an infection with fever, or when patients with SCD become dehydrated.

In these situations, the sickle red cells greatly increase in number and can block the passage of blood (sickling Sickle cell crisis). As a result, the patient feels pain in the area of the body which is not receiving blood. Such events can be severe enough to damage tissues in joints, spleen, kidneys and even the brain. In addition, as these altered red cells (sickle cells) do not survive in the circulation for as long as normal cells do, and are continuously destroyed, the patients experience a degree of anaemia, which may become severe under certain circumstances, leading to a need for blood transfusion.

As a chronic disorder, sickle cell disease requires treatment in specialized centres aimed at both preventing and managing complications, including the prevention of infections by means of immunizations and the management of pain, which may be severe enough to require hospitalization. In order to prevent some of the complications effectively, it is necessary to have the patient under continuous observation from early childhood, and in this context a policy of newborn screening is recommended, so that affected children may be identified and followed up from birth.

Readings

What is sickle cell disease? A child born with sickle cell disease will show no visible signs of the disease. The baby may be diagnosed if a neonatal screening programme is available in the country where the family lives. Early diagnosis is particularly important to prevent complications. Screening of newborns is the best way to achieve this, if the parents have not been tested, no prenatal tests were carried out, and there is no other affected child in the family. It is possible to diagnose sickle cell disease at this very early age by means of simple but specific laboratory tests, such as those described earlier in this booklet for the diagnosis of the sickle cell carrier state. Special features seen in the laboratory diagnosis of SCD include the presence of sickle-shaped red cells, which constitute around 10% of all the cells, and the presence of HbS reaching levels of around 90-95% in one of the laboratory analyses. When more specific information is needed to clarify or confirm diagnosis, genetic tests are used (as described earlier for confirming the α- carrier state, and sometimes the β-carrier state).

Readings

Sickle cell disease affects people in different ways and with variable severity. Some people are mildly affected, whilst others are severely affected, variability occurring even amongst members of the same family. The reasons for this are not always clear but several contributing factors have been linked with the severity of sickle cell disease. For example, the level of foetal haemoglobin (HbF), which some people continue to produce well into adulthood, is important. Normally, the level of haemoglobin F falls to about 1% by the end of the first year of life and stays at this level right through adulthood.

haemoglobin F for a longer time. Levels of HbF above 7% appear to be related to fewer sickling crises and fewer complications of sickle cell disease. The level of HbF may be boosted by the use of certain drugs, and this is currently considered as the most promising method for reducing sickling of the blood cells. The advantage of foetal haemoglobin is that it does not have the capacity to sickle and its presence prevents red blood cells from sickling.

Hydroxyurea

Several drugs have been shown to increase the production of foetal haemoglobin. Of these, Hydroxyurea is the most promising and the one that is currently being prescribed. There is good evidence now that Hydroxyurea reduces sickling crises and the need for blood transfusions, although it may not be suitable for all patients. Hydroxyurea has the potential to reduce bone marrow activity, and this as a consequence increases the risk of infection. It should not be used for patients who are likely to become pregnant, or for those who have difficulty following or adhering to the instructions given for their treatment.

Careful follow-up is needed, with regular visits to the clinic. Hydroxyurea is not a cure for sickle cell disease, but it is an effective treatment for preventing or reducing sickling crises.

Its effect will only last for as long as the person is taking the drug.