All haemoglobins (Hb) consist of a haem (iron-containing) molecule bound to four globin chains (2 alpha and 2 non-alpha chains). The haem component is responsible for carrying oxygen, and the globin chains are essential for the stability, oxygen affinity and many other properties of the molecule. Inherited disorders of haemoglobin fall into two main categories. In the thalassaemias there is decreased or absent production of normal alpha or beta globin chains leading to reduced production of the main adult haemoglobin, Hb-A. These are very diverse disorders at the genetic and clinical levels. The structural Hb disorders result from mutations in the alpha or beta globin genes that alter the stability or function of the Hb molecule and are characterised by the presence of an abnormal Hb, such as sickle Hb (HbS). Haemoglobinopathies usually show autosomal recessive inheritance. Carriers of the abnormal gene (heterozygotes) are often asymptomatic, whereas those who inherit an abnormal gene from both parents (homozygotes) express the disease. Red cell transfusion is a common form of treatment in β-thalassaemia major and sickle-cell disease.
β-thalassaemia major
There are around 800 patients with this condition in the UK. Patients with this severe form of thalassaemia usually present with severe, life-threatening, anaemia before the age of one year as synthesis of fetal Hb (α and γ globin chains) switches to adult HbA (α and β globin chains). They are then transfusion-dependent for life. The only cure for β-thalassaemia major is haemopoietic stem cell transplantation from a compatible donor. The cure rate is high in young children who have not yet developed severe iron overload from frequent red cell transfusions, but less than 30% of patients have an HLA-compatible family donor. Transplant-related mortality and morbidity is much higher in adults. Recently, the use of haemopoietic stem cells from the umbilical cord blood of HLA-compatible siblings or unrelated donors has shown very promising results. However, for the majority of patients, regular transfusions of red cells are the mainstay of treatment. Transfusions are given at two to four weekly intervals to maintain a mean Hb around 120 g/l. The aim is to fully relieve the symptoms of anaemia and suppress the patient's own increased abnormal red cell production in the marrow (ineffective erythropoiesis) which causes the skeletal abnormalities and spleen enlargement seen in under-treated patients. All patients need iron chelation therapy (see above) to prevent progressive and ultimately fatal organ damage.
Sickle-cell disease
There are 12,000−15,000 individuals with sickle-cell disease in the UK. It is an autosomal recessive condition and only homozygotes have the full clinical picture (HbSS) which is the most severe form. The sickle gene may also be found in combination with other abnormal haemoglobin genes common in the same populations, such as sickle-β-thalassaemia, which is variable in its severity, and SC disease (HbSC), which is usually milder. The characteristic features of all forms of sickle-cell disease are:
- chronic haemolytic anaemia
- recurrent acute sickle cell crises mainly affecting the long bones
- hyposplenism (due to splenic infarction) with an increased susceptibility to infection
- chronic organ damage due to recurrent sickling affecting particularly the CNS, liver, kidneys, bones/joints and lungs.
For most patients the mainstay of management is supportive with pain relief, fluids and antibiotics, and long-term folic acid supplements. Patients with severe disease causing stroke, acute chest syndrome or frequent painful sickling crises may be treated with hydroxyurea or, if age ≤ 16 years, allogeneic bone marrow transplantation from a related donor. Most patients require red cell transfusion intermittently and only to treat specific severe complications of the disease or in preparation for surgery.
The majority of patients with sickle-cell disease in the UK will receive red cell transfusion on several occasions during their life. Red cell transfusion is not usually indicated for acute sickle crisis, but exchange transfusion may be required for acute chest syndrome, intractable priapism, to prevent recurrence of stroke, for red cell aplasia (due to parvovirus infection) and to treat splenic or hepatic sequestration.
Exchange transfusion may be needed in acute stroke. The aim of exchange transfusion is to reduce the percentage of HbS to < 30% whilst keeping the haemoglobin below about 100 g/l. In adults who have adequate venous access, exchange transfusion by cell separator may be performed by staff experienced in its use. Manual exchange transfusion is more often used for children. For major surgery and in some obstetric cases, prophylactic exchange transfusion is required. In aplastic or sequestration crises, top-up transfusion may be necessary.
Before transfusing any patient with sickle-cell disease, discuss with haematologist, as most patients are adapted to a Hb level around 60−80 g/l, and raising the haemoglobin during an acute episode may worsen the crisis, causing microvascular damage.
Haemoglobinopathy trait
Patients who are carriers for haemoglobinopathies (thalassaemia or sickle-cell trait) are asymptomatic and never require transfusion on account of their haemoglobinopathy status.