JPAC Joint United Kingdom (UK) Blood Transfusion and Tissue Transplantation Services Professional Advisory Committee

8.6: Haemoglobinopathies

Haemoglobin (Hb) molecules consist of four haem (iron-containing) complexes and four globin chains (two α and two non-α chains – Table 8.1). The haem component carries oxygen and the globin chains contribute to the stability and oxygen affinity of the Hb molecule.

Table 8.1 Normal adult haemoglobins

Haemoglobin

Globin chains

% of total Hb in adult

A

2α/2β

>95%

A2

2α/2δ

<3.5%

F

2α/2γ

<1%

 

Haemoglobinopathies are inherited disorders, usually autosomal recessive. Carriers (heterozygotes), with just one abnormal gene, are usually asymptomatic, whereas people who inherit an abnormal gene from both parents (homozygotes) express the disease. In most parts of the UK there is a programme of antenatal and neonatal screening for the most serious variants. Haemoglobinopathies fall into two main categories:

  • Thalassaemias Reduced or absent production of normal α or β-globin chains, leading to reduced levels of HbA, the main adult Hb. They are very diverse disorders at the genetic and clinical levels.
  • Abnormal haemoglobins A new Hb variant results from mutations in the genes for α or β globin chains that alter the stability or other functions of the Hb molecule (e.g. sickle Hb (HbS)).

8.6.1: β-thalassaemia major

By definition, β-thalassaemia major patients are transfusion dependent. Caused by impaired production of normal β-globin chains, this condition is most common in people whose ancestors originate from the Mediterranean, Middle East, South or Southeast Asia or the Far East. There are more than 1000 patients with this condition in the UK. Life-threatening anaemia develops in the first year of life as levels of fetal Hb (HbF) decline and adult HbA cannot be produced. Most patients are transfusion dependent for life, although some may be cured by haemopoietic stem cell transplantation in childhood. Undertreated anaemia leads to enlargement of the spleen, expansion of the bone marrow and skeletal abnormalities. The UK Thalassaemia Society has produced Standards for the Clinical Care of Children and Adults with Thalassaemia in the UK (http://www.hbpinfo.com/ukts-standards-2008.pdf) that includes recommendations on transfusion support.

Transfusions are usually given every 3 to 4 weeks to keep the pre-transfusion Hb concentration above 95–105 g/L (average Hb 120 g/L). This allows normal growth and development and prevents skeletal deformity due to bone marrow expansion. However, each transfused red cell unit contains up to 250 mg of iron and iron chelation therapy must be given from the age of 2 to 3 years to prevent organ damage, and eventual death, from iron deposition in the heart, liver, pancreas and endocrine glands. Chelation usually starts when the ferritin level exceeds 1000 ng/mL (after around ten transfusions). Options for reducing iron overload include subcutaneous desferrioxamine infusions on 5 to 7 nights a week and/or the newer oral chelating agents. The practice of infusing desferrioxamine only at the time of transfusion is of little benefit and it must not be added to the red cell transfusion pack. Before starting transfusion children should be given hepatitis B immunisation.

8.6.2: Red cell alloimmunisation in thalassaemia

Up to 30% of patients on long-term transfusion support develop blood group antibodies (alloimmunisation), most commonly to Rh and Kell antigens. There may be progressive difficulty in providing compatible blood. If possible, ‘extended phenotyping’ is carried out before the first transfusion and red cells matched for Rh (D, C, c, E, e) and K antigens should be routinely selected. This policy appears to reduce the risk of developing alloantibodies to other blood group systems. Donor exposure can be reduced by selecting larger volume red cell units from the blood bank, preferably less than 14 days old, and the transfusion of ‘double red cell donations’ taken from a single donor by apheresis.

8.6.3: Sickle cell disease

Sickle cell disease (SCD) is characterised by:

  • Vaso-occlusive episodes causing recurrent acute painful sickle cell crises and syndromes such as stroke or acute chest syndrome
  • Chronic haemolytic anaemia (Hb commonly 60 to 80 g/L in HbS/S)
  • Splenic atrophy and hyposplenism (due to splenic infarction) with increased susceptibility to sudden overwhelming infection by encapsulated bacteria such as Streptococcus pneumoniae and Streptococcus meningitidis
  • Chronic organ damage, such as chronic kidney disease and joint damage from avascular necrosis, caused by recurrent sickling episodes.

Patients with SCD are predominantly of Black African descent, although the sickle (HbS) gene also occurs in populations of Mediterranean, Arab and South Asian origin. Most patients with severe SCD are homozygous for the HbS gene (HbS/S) but combinations can occur with other haemoglobinopathies to produce sickling syndromes of variable severity such as sickle-β-thalassaemia, HbS/C or HbS/E. There are more than 12 500 patients with SCD in the UK.

8.6.4: Red cell transfusion in sickle cell disease

There are UK standards and guidelines for the clinical care of sickle cell disease in children (http://sct.screening.nhs.uk/cms.php?folder=2493) and adults (http://www.sicklecellsociety.org/app/webroot/files/files/CareBook.pdf) that include recommendations for transfusion.

Red cell transfusion in SCD is used in the treatment of acute sickle cell crises or to prevent certain long-term complications by reducing the proportion of HbS cells in the circulation (Tables 8.2 and 8.3). However, increasing the haematocrit above 30% increases the risk of hyperviscosity and vaso-occlusive events. Red cell exchange transfusion, automated or manual, can produce a significant reduction in HbS (target usually <30%) without the risk of hyperviscosity but venous access can be problematic in patients requiring regular or recurrent treatment. Indications for transfusion are developing quickly and the decision to transfuse should always be made in collaboration with the expert team at a comprehensive haemoglobinopathy centre.

Large, multicentre trials are exploring the benefits/risks of prophylactic transfusion in surgery. At present, exchange transfusion is usually only carried out in patients with severe SCD undergoing major surgical procedures. For ‘medium-risk’ surgery, ‘top-up’ transfusion (to 80–100 g/L) appears to be as effective as exchange transfusion and may be safer. Current evidence does not support the routine use of transfusion to prevent fetal complications in pregnancy but each patient requires careful multidisciplinary review. Following evidence from randomised controlled trials that prophylactic hypertransfusion (target HbS <25%, Hb 100–145 g/L) reduces the risk of stroke in children with abnormal flow in intracranial blood vessels, demonstrated by transcranial Doppler (TCD) screening, the numbers of SCD patients on long-term or lifelong transfusion regimens will increase significantly.

Table 8.2 Indications for red cell transfusion in acute complications of sickle cell disease

Top-up transfusion

Exchange transfusion

Transient red cell aplasia (usually parvovirus B19 infection)

Acute splenic or hepatic sequestration crisis

Acute stroke

Acute chest syndrome

Severe sepsis

Acute hepatic sequestration

Acute multi-organ failure

 

 

Table 8.3 Possible indications for elective red cell transfusion in severe sickle cell disease

Supported by high-grade evidence from clinical trials

High-grade evidence currently unavailable

Primary stroke prevention (abnormal TCD in childhood)

Secondary stroke prevention

Major elective surgery

Painful crises in pregnancy

Repeated severe painful crises

Pulmonary hypertension

Fetal complications in pregnancy

Leg ulceration

 

8.6.5: Red cell alloimmunisation in sickle cell disease

Alloimmunisation rates are high, exacerbated by differences in blood group distribution between patients with SCD and the predominantly white European blood donor population. Alloimmunisation rates of up to 57% have been reported after 200 transfusions. The majority of alloantibodies are to RhD, RhC and Kell. A significant proportion of SCD patients have the Ro phenotype (cDe) which is rare in donors of European origin. Serious Hazards of Transfusion (SHOT) reports show that transfusion reactions, especially acute or delayed haemolytic reactions, may be misinterpreted as sickle cell crises and treated inappropriately.

As with thalassaemic patients, preventing alloimmunisation to Rh and Kell appears to reduce the development of antibodies to other blood groups. Extended blood group phenotyping is ideally carried out before the first transfusion. If patients have already been transfused, molecular typing can be used. Donor red cells should be sickle Hb negative, and ideally less than 14 days old for top-up transfusions and 7 days old for exchange transfusions. At a minimum, transfused red cells should be matched for ABO, D, C, E, c, e and Kell.

It is often difficult to source fully compatible red cells in patients with multiple alloantibodies, especially when blood is required urgently. In that situation, the problem should be discussed with experts in transfusion medicine and blood group serology at the blood transfusion service, who will advise on the selection of the safest blood group combinations available in stock, taking into account the patient’s current and historical antibodies and the urgency of transfusion. They will also initiate a search for fully compatible donations and advise on the management of possible haemolytic reactions. Many non-ABO antibodies typically cause delayed extravascular red cell destruction, which is less severe than ABO haemolysis. If the transfusion of red cells with a clinically significant incompatibility is unavoidable the clinical team should ensure the patient is adequately hydrated, and careful monitoring for evidence of haemolysis, including delayed reactions, is essential (see Chapter 5). If severe haemolysis occurs, or if the patient has had previous haemolytic reactions, options for treatment or prophylaxis include high-dose corticosteroids and intravenous immunoglobulin.

8.6.6: Hyperhaemolytic transfusion reactions

Hyperhaemolytic transfusion reactions (HHTRs) are characterised by destruction of both donor and recipient red cells after transfusion, often with a rapid and life-threatening fall in Hb concentration. Laboratory tests for red cell antibody-mediated haemolysis are usually negative. Patients usually present several days after the last transfusion and it may, initially, be diagnosed as an acute sickle cell crisis. Further transfusion may worsen the haemolysis and should be avoided if possible. Treatment with high-dose intravenous immunoglobulin has been effective in some reported cases but the benefits of corticosteroids are uncertain.