23rd May 2023

Haemoglobinopathies

Thalassaemia

Overview of thalassaemia

Haemoglobin consists of four polypeptide subunits that contain two alpha chains and two beta chains. Thalassaemias are inherited autosomal recessive genetic disorders that cause reduced synthesis of alpha or beta chains in haemoglobin. This impairs formation of red blood cells, reducing their oxygen-carrying capacity, resulting in microcytic hypochromic anaemia. The defects are caused by genetic point mutations or deletions of key gene fragments. There are two main groups of thalassaemia based on the polypeptide chain that is affected: alpha and beta thalassaemia.

The haemoglobin alpha chain is coded by 4 alleles, leading to a range of severity of alpha thalassaemia, depending on the number of alleles affected. The beta chain is coded by 2 alleles, resulting in only two possible variants of beta thalassaemia.

Alpha thalassaemia predominantly affects those of Asian or African descent, while beta thalassaemia is prevalent in the Mediterranean and Southeast Asian population.

Patients present with a range of phenotypes depending on their inherited thalassaemia trait. These include symptoms of anaemia i.e. fatigue and pallor, slow growth rates in children, jaundice, hepatosplenomegaly, or death in-utero.

Treatment is mainly supportive and includes blood transfusion, oral iron chelating agents to prevent overload, and patient education.

Alpha thalassaemia

Alpha thalassaemia is due to reduced or absent alpha chain production and accumulation of beta-like chains. There are two alpha chain genes (HBA1 and HBA2) on each copy of chromosome 16, thus four alleles exist. The number of deleted alpha-globin alleles determines which of the four different traits seen in alpha thalassaemia results.

Alpha thalassaemia minima (silent carrier)

• One affected alpha chain
• Asymptomatic
• No anaemia
• Normal haemoglobin analysis

Alpha thalassaemia minor (alpha thalassaemia trait)

• Loss of two alpha chains
• Homozygous if one alpha chain on each chromosome affected
• Heterozygous if both alpha chains on one chromosome affected
• Mild asymptomatic microcytic hypochromic anaemia
• Homozygous patients are more affected – mild anaemia, low MCV, splenomegaly

Haemoglobin H disease

• Three alpha chains affected
• Variable clinical severity
• Symptomatic from birth but typically do not require regular blood transfusion
• Periods of increased haemolysis and aplastic crises e.g. during infection, may require blood transfusion
• Risk of iron overload even in absence of regular blood transfusion

Haemoglobin Bart’s Hydrops Foetalis (Homozygous alpha thalassaemia)

• Deletion of all alpha chains
• Severe anaemia during foetal development causing foetal hydrops
• Often in-utero death occurs

Management of alpha thalassaemia

• Patient education and counselling, particularly around family planning is important.
• Avoid iron supplementation unless proven to be iron deficient, due to risk of iron overload.
• Blood transfusion, depending on the clinical severity and symptoms of anaemia.
• Iron chelating therapy, as these patients are at risk of iron overload from repeated blood transfusions or from increased absorption from the gastrointestinal tract. Careful monitoring of cardiac, endocrine, and hepatic function is required.
• Splenectomy may be considered in patients with painful splenomegaly, hypersplenism with pancytopenia, increased transfusion requirement, and worsening anaemia.
• Haematopoietic stem cell transplant is the only curative treatment and should be considered in severe transfusion dependent patients.

Beta thalassaemia

Beta thalassaemia is a result of defective beta chain synthesis due to point mutation in the HBB gene on chromosome 11. Two alleles may therefore be affected; the mutated alleles can create either partially functioning, non-functioning, or reduced quantities of beta-globin, resulting in the variations of beta thalassaemia.

Beta thalassaemia can be classified as major, intermedia or minor. However, there has been a shift recently to classify beta thalassaemia as transfusion dependent or non-transfusion dependent.

Beta thalassaemia major (Cooley’s anaemia, transfusion dependent)

• Both beta chain alleles affected resulting in no functional beta chain production.
• Severe haemolytic anaemia requiring regular blood transfusions.
• Symptoms manifest between 6 to 12 months of life during the transition from foetal to adult haemoglobin production, when gamma-chain production ceases and beta-chains fail to form.
• Present with pallor, abdominal distension secondary to hepatosplenomegaly, fatigue, and poor feeding.
• Bony abnormalities may also be present such as frontal and parietal bossing and chipmunk facies due to increased extramedullary haematopoiesis.

Beta thalassaemia intermedia

• Both beta chains affected but variable quantity and function of beta chains.
• Range of signs e.g. pallor, jaundice, splenomegaly. Can present as a less severe phenotype, as some adult haemoglobin (HbA – α2β2) is produced.
• For some, blood transfusions are only required later in life in 30s or 40s, however, each case is unique.

Beta thalassaemia minor (beta thalassaemia trait)

• Only one beta chain affected
• Heterozygous carrier
• Asymptomatic or mild anaemia that is often mistaken as iron deficiency due to microcytosis.

Sickle Cell Disease

Overview of sickle cell disease

Sickle cell disease is one of the most common monogenic, hereditary haemoglobinopathies. It is inherited in an autosomal recessive manner, where individuals with both alleles develop sickle cell anaemia (HbSS), and those who carry one allele acquire the sickle cell trait (HbSA).

Mutation in the beta globin gene results in substitution of glutamic acid with valine at the sixth amino acid of the beta globin chain. This alters the structure and properties of haemoglobin and causes red blood cells to sickle. This results in polymerisation of the abnormal haemoglobin within the red blood cell and the formation of haemoglobin tetramers.

Sickle cells on peripheral blood film.

Image Source: Wikimedia Commons (2012). Sickle cells, Licensed under a creative commons licence. Available for free at: https://commons.wikimedia.org/wiki/File:Sickle_cells.jpg (Accessed on: 10 January 2023).

Acidosis, hypoxia, infection, dehydration, cold temperatures, pregnancy, and stress can all trigger polymerisation of abnormal haemoglobin and hence, sickling of red blood cells. These sickle cells adhere to the vascular endothelium, resulting in vaso-occlusion. The abnormal structure of the sickle cell makes them prone to haemolysis, which contributes to anaemia. Patients with sickle cell disease are subjected to acute and chronic complications of this disease.

There is a high prevalence of sickle cell in countries where malaria is endemic; sickle cell has protective properties against severe malaria. These include Sub-Saharan Africa, India, Eastern Mediterranean, and the Middle East.

The only cure for sickle cell disease is bone marrow transplantation. Management of sickle cell focuses on the following:

• Infection prevention – immunisation, lifelong prophylactic penicillin
• Symptom control – analgesia, hydroxycarbamide (reduces frequency of acute pain, blood transfusion and chest syndrome), crizanlizumab (reduces vaso-occlusive crises), blood transfusions
• Management of clinical complications

Foetal haemoglobin (HbF) and sickle cell

HbF is composed of two alpha chains and two gamma chains. Unlike HbS, HbF does not enter the polymerization phase when sickling occurs and helps to slow this process. This explains why patients are asymptomatic in the first few months of life, when HbF is the predominant haemoglobin type. Hydroxycarbamide is a treatment used in sickle cell disease which increases the production of gamma globin chains, resulting in increased levels of HbF.

Some individuals have hereditary persistence of foetal haemoglobin, where high levels of HbF are due to beta-globin gene deletions or point mutations in the promoters of the HbF genes.

Clinical syndromes in sickle cell disease

Sickle cell crisis

This describes several acute conditions seen in sickle cell, although typically refers to painful episodes secondary to vaso-occlusion. These episodes can be precipitated by cold environments, dehydration, infection, and exercise.

Management of these crises focuses on managing pain while minimising the adverse effects of vaso-occlusion. Patients may require opioid analgesia, intravenous fluids, supplemental oxygen, and antibiotics if suspected infection. Blood transfusions are only indicated in patients experiencing anaemia with life-threatening vaso-occlusive events, symptomatic anaemia, organ dysfunction and during high-risk procedures e.g. surgery.

Acute chest syndrome

This can follow a vaso-occlusive crisis and accounts for 25% of deaths in sickle cell disease. Hypoxia secondary to hypoventilation causes sickling of red blood cells and occlusion of the pulmonary microvasculature. This in turn results in localised hypoxia in the lung tissue which contributes to the vicious cycle of more sickling red blood cells.
Patients present with shortness of breath, hypoxia, chest pain, cough, and tachypnoea. Severe cases can present as respiratory distress or even failure. Patients may also have a fever.

The aim of management in acute chest syndrome is to prevent progression to respiratory failure. Patients are treated with blood transfusion, optimal analgesia to improve respiratory effort which prevents atelectasis, and intravenous antibiotics as bacterial pneumonia cannot be ruled out. Incentive spirometry is also used to prevent further atelectasis.

Splenic sequestration crisis

This is a life-threatening crisis that causes a significant haemoglobin drop secondary to trapping and pooling of red blood cells in the spleen. Consequently, patients can present with hypovolemic shock with a rapidly enlarging spleen. Splenic sequestration crises mainly present in childhood where patients have yet to develop fibrotic spleens from repeated splenic infarcts.

Treatment is with blood transfusion and splenectomy.

Aplastic crisis

Aplastic crisis is characterised by an acute drop in haemoglobin with transient cessation of erythropoiesis and hence, reduced reticulocytes in the peripheral bloodstream. This commonly lasts between 7 to 10 days. It is most commonly precipitated by infection e.g. Parvovirus B19, Epstein-Barr virus, and streptococcus pneumoniae.

Management is with blood transfusion in severe cases.

Other complications

The complications of sickle cell disease are extensive due to the multi-organ impact of vaso-occlusion from sickled cells.

Complications of sickle cell disease