Sickle cell syndromes

Published on 03/04/2015 by admin

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Sickle cell syndromes

The sickle cell syndromes are a group of haemoglobinopathies which primarily affect the Afro-Caribbean population. The common feature of these diseases is inheritance of an abnormal haemoglobin β-chain gene – the gene is designated β^S. Inheritance of two β^S genes leads to a serious disorder termed sickle cell anaemia. A similar syndrome can result from inheritance of the β^S gene with another abnormal β gene such as the haemoglobin C gene or β-thalassaemia gene. Inheritance of the β^S gene with a normal β-chain gene (β^A) causes the innocuous sickle cell trait (Fig 17.1).

Fig 17.1 Inheritance of sickle cell syndromes.
Two pedigrees showing inheritance of sickle cell syndromes. In the first family one child is unaffected, one has sickle cell trait and one has sickle cell anaemia. In the second family one child has inherited the abnormal sickle gene and the HbC gene; this double heterozygosity leads to haemoglobin SC disease.

Pathophysiology

The abnormal β^S gene has a high incidence in tropical and subtropical regions as the abnormal haemoglobin produced (HbS) gives some protection against falciparum malaria. HbS differs from normal haemoglobin (HbA) in that glutamic acid has been replaced by valine at the sixth amino acid from the N-terminus of the β-globin chain. The clinical features of sickle cell anaemia arise from the propensity of red cells containing haemoglobin S to undergo ‘sickling’. In the deoxygenated state HbS undergoes a conformational change leading to the creation of haemoglobin tetramers which aggregate to produce large polymers. The red cell loses its normal deformability and becomes characteristically sickle-shaped (Fig 17.2). Damage to the membrane leads to increased rigidity and the ultimate sequestration of the red cell in the reticuloendothelial system causing haemolytic anaemia. The inflexible sickle cells also become lodged in the microcirculation causing stasis and obstruction.

Fig 17.2 Blood film in sickle cell anaemia.

Clinical syndromes

Sickle cell anaemia (HbSS)

This classic form of sickle cell syndrome is enormously variable in severity.

Haemolytic anaemia

The haemoglobin is generally in the range 60–100 g/L. Because HbS releases oxygen more readily than HbA, the symptoms of anaemia are often surprisingly mild. Intercurrent infection with parvovirus or folate deficiency can block erythropoiesis and cause a sudden fall in haemoglobin – the ‘aplastic crisis’.

Vascular-occlusive crises

Acute, episodic, painful crises are a potentially disabling feature of sickle cell anaemia. They may be triggered by infection or cold. Patients complain of musculoskeletal pain which may be severe and require hospital admission. Hips, shoulders and vertebrae are most affected. Attacks are generally self-limiting but infarction of bone can occur and must be distinguished from salmonella osteomyelitis. Avascular necrosis of the femoral head is a crippling complication. Other organs are vulnerable to infarction; most serious is neurological damage which may manifest as seizures, transient ischaemic attacks (TIAs) and strokes. Vaso-occlusion in infancy is responsible for the ‘hand–foot syndrome’, a type of dactylitis damaging the small bones of hands and feet (Fig 17.3).

Fig 17.3 Dactylitis in sickle cell anaemia. (Reproduced with permission from Linch D C, Yates A P 1996 Colour Guide Haematology Churchill Livingstone, Edinburgh.)

Sequestration crises

These arise from sickling and infarction within particular organs. Specific syndromes include ‘acute chest syndrome’ with occlusion of the pulmonary vasculature, ‘girdle sequestration’ caused by occlusion of the mesenteric blood supply, and hepatic and splenic sequestration.

Other complications

These are multiple, usually caused by vascular stasis and local ischaemia.

Genitourinary. Papillary necrosis with haematuria; loss of ability to concentrate urine; nephrotic syndrome; priapism.

Skin. Lower limb ulceration.

Eyes. Proliferative retinopathy; glaucoma.

Hepatobiliary. Liver damage; pigment gallstones.

Diagnosis

Diagnosis depends on the following:

Blood film appearance (see Fig 17.2).

Screening tests for sickling. The blood sample is deoxygenated (e.g. with sodium metabisulphate) to induce sickling.

Haemoglobin electrophoresis. In sickle cell anaemia (HbSS) there is no HbA detectable (Fig 17.4).

Fig 17.4 Cellulose acetate electrophoresis to separate haemoglobins A, F, S and C.
Lane 4, control sample; Lanes 2, 3, 6, 7, normal; Lane 1, sickle cell anaemia; Lane 5, sickle cell trait.

Management

General. Patients need support in the community and easy access to centres experienced in the management of sickle cell anaemia. Prophylaxis is important. Patients should avoid factors known to precipitate crises, take folate supplements (because of chronic haemolysis) and be prescribed penicillin and pneumococcal vaccine (because of hyposplenism caused by infarction). Infections require prompt treatment. Transcranial Doppler ultrasonography can identify children at high risk of stroke. Annual retinal screening is recommended.

Painful vascular-occlusive crises. First-line treatment is rest, increased fluids and adequate oral analgesia. Constitutional upset or pain not relieved by oral analgesia necessitates hospital admission with continued rest, warmth, intravenous fluids and opiate analgesia. Psychological support is vital.

Blood transfusion. Acute or chronic simple red cell transfusion may be given to relieve severe anaemia and to reduce the amount of circulating sickle haemoglobin. Chronic transfusions are the most effective intervention to prevent recurrent cerebrovascular events. Other indications for transfusion include complications such as chest syndrome and priapism. Blood transfusion is not usually required for episodes of pain. Exchange transfusion is preferred to simple transfusion for rapid reduction of HbS levels or where simple transfusion would cause hyperviscosity or circulatory overload. Blood is phenotypically matched to reduce the chance of alloimmunisation. Iron chelation may be required.

Pregnancy and surgery. Transfusion is not routinely indicated in an uncomplicated pregnancy but may be needed for severe anaemia or other sickle-cell-related complications. During surgery it is important to avoid hypoxia and dehydration. Preoperative simple transfusion or even exchange transfusion may be appropriate for high-risk procedures.

Hydroxycarbamide. Increasing the level of fetal haemoglobin in red cells with the antimetabolite hydroxycarbamide can reduce the severity of the disease. Clinical trials have been encouraging with significant reductions in painful crises, major complications, blood transfusion, hospital admissions and mortality rates. It is important to ensure compliance as clinical benefit may not be immediate. There are concerns regarding the leukaemogenic and teratogenic effects of hydroxycarbamide but with cautious use and patient education (e.g. appropriate contraception) the risks appear to be low.

Stem cell transplantation. Allogeneic stem cell transplantation offers the possibility of a cure in selected high risk patients but it will not be more widely applicable until the toxicity is reduced (see p. 56).

Gene therapy. Gene therapy has the potential to provide a cure without the risks of allogeneic stem cell transplantation (see p. 103).

Prognosis

The risk of early death is inversely related to fetal haemoglobin levels. The most common causes of death are infection in infancy, cerebrovascular accidents in childhood and adolescence and respiratory complications in adult life.

Doubly heterozygous sickling disorders

Here patients inherit the β^S gene and another abnormal β gene – usually HbC or β-thalassaemia. HbSC disease is similar to HbSS but there is a tendency for fewer painful crises and a higher incidence of proliferative retinopathy and avascular necrosis. The severity of sickle cell/β-thalassaemia depends on whether patients have the β⁺ or β⁰ genotype. The less common HbS/β⁰ form has a similar clinical picture to HbSS.

Sickle cell trait (HbAS)

Sickle cell trait normally causes no clinical problems as there is enough HbA in red cells (approximately 60%) to prevent sickling. However, haematuria occasionally occurs as a result of renal papillary necrosis and additional care is required during pregnancy and anaesthesia. Diagnosis is by a sickling test and Hb electrophoresis (see Fig 17.4). Life expectancy is normal although there may be a slightly increased risk of sudden death during intense exercise in young adults.

Counselling and prenatal diagnosis

Genetic counselling is needed by those affected with either the homozygous disease, compound heterozygosity or the trait. Prenatal diagnosis is possible using mutation analysis on PCR-amplified DNA from chorionic villi (see p. 100).

Screening strategies

Screening of all newborn babies for sickle cell syndromes is recommended to reduce the risk of early death from infection. Preconception testing and antenatal testing of pregnant women is performed depending on individual risk and the local prevalence of sickle cell disease. A similar approach is adopted prior to surgery.

Sickle cell syndromes

The sickle cell syndromes are a group of haemoglobinopathies which primarily affect people of African origin.

Inheritance of two β^S genes leads to the serious clinical disorder sickle cell anaemia (HbSS).

Clinical problems in sickle cell anaemia include chronic haemolytic anaemia, vascular-occlusive crises, sequestration crises and susceptibility to infection.

Routine management of sickle cell anaemia entails prophylactic measures, supportive care during vascular-occlusive crises and the selective use of blood transfusion and hydroxycarbamide.

Sickle cell trait (HbAS) is an innocuous clinical disorder but genetic counselling is often needed.

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