Information and resources

Haemoglobin is a protein that is carried by red blood cells. Its main function is to pick up oxygen in the lungs and deliver it to the peripheral tissues to maintain the viability of cells. Haemoglobin is made from two similar proteins, usually referred to as subunits, which “stick together”. Both subunits must be present for the haemoglobin to function normally. One of the subunits is called alpha, and the other is beta. Inside each subunit, there is a small iron-containing molecule called heme, to which oxygen is bound. Before birth, the beta protein is not expressed. Instead, a chain called gamma is produced.

Like all proteins, the “instructions” to synthesise haemoglobin are found in DNA (the material that makes up genes). Normally, an individual has four genes that code for the alpha protein, or alpha chain. Two other genes code for the beta chain. The alpha chain and the beta chain are made in precisely equal amounts, despite the differing number of genes. The protein chains join in developing red blood cells, and remain together for the life of the red cell.

The composition of haemoglobin is the same in all people. The genes that code for haemoglobin are identical throughout the world. Occasionally, however, one of the genes has a change or variant. Although the changes that produce abnormal haemoglobins are rare, several hundred haemoglobins variants exist. Most variant haemoglobins function normally, and are only found through specialized research techniques. Some haemoglobin variants, however, do not function normally and can produce clinical disorders, such as sickle cell disease.

Usual types of haemoglobin

Haemoglobin A: This is the designation for the most common haemoglobin variant that exists after birth. Haemoglobin A is a tetramer with two alpha chains and two beta chains (a₂b₂).

Haemoglobin A2: This is a minor component of haemoglobin found in red cells and consists of two alpha chains and two delta chains (a₂d₂). Haemoglobin A2 generally comprises less that 3% of the total red cell haemoglobin.

Haemoglobin F: Haemoglobin F is the predominant haemoglobin during foetal development. The molecule is a tetramer of two alpha chains and two gamma chains (a₂g₂).

Clinically significant haemoglobin variants

Haemoglobin S: This is the predominant variant in people with sickle cell disease. The disease-causing gene change is found in the beta chain. The highest frequency of sickle cell disease is found in tropical regions, particularly sub-Saharan Africa, tribal regions of India and the Middle-East. The carrier frequency ranges between 10% and 25% across equatorial Africa.

Haemoglobin C: Haemoglobin C results from a gene change in beta globin. It can cause sickle cell disease when it is inherited with haemoglobin S. It can also cause haemoglobin C disease when two haemoglobin C variants are inherited. Haemoglobin C is most prevalent in Western Africa, especially in Nigeria and Benin.

Haemoglobin E: This variant results from a gene change in the haemoglobin beta chain. It can cause thalassaemia major or intermedia hen coinherited with beta thalassaemia. Haemoglobin E is extremely common in Southeastern Asia (Thailand, Myanmar, Cambodia, Laos, Vietnam, and India) where its prevalence can reach 30-40%.

Haemoglobin D: There are different types of haemoglobin D variants, but the most vlinically significant is haemoglobin D^Punjab (also called D^{Los Angeles}). It results from a gene change in the beta globin chain. It can cause sickle cell disease if coinherited with haemoglobin S. As the name indicated, it is most frequent in the Punjab Area (Northwestern India), where the carrier frequency can be around 2%.

Haemoglobin O^Arab: This variant results from a gene change in the beta globin chain. It can cause sickle cell disease when it is inherited with haemoglobin S. It is more frequent in North Africa, Middle East and Eastern Europe.

Haemoglobin Lepore: Haemoglobin Lepore is an unusual variant that is th product of the fusion of the beta and delta globin genes. It can cause thalassaemia major/intermedia when a person inherits two copies of haemoglobin Lepore, or when it is inherited with beta thalassaemia. It can also cause sickle cell disease when inherited with haemoglobin S. It occurs most frequently in patients originating from the Mediterranean region.

Sickle cell disease is the name for a group of inherited conditions that affect the red blood cells. The most serious type is called sickle cell anaemia. Sickle cell disease mainly affects people of African, Caribbean, Middle Eastern, Eastern Mediterranean and Asian origin. In the UK, it’s particularly common in people with an African or Caribbean family background. People with sickle cell disease produce unusually shaped red blood cells that can cause problem because they don’t live as long as healthy blood cells and they can become stuck in blood vessels. Sickle cell disease is a serious and lifelong condition, although long-term treatment can help manage many of the problems associated with it.

Sickle Cell Anaemia (HbSS)

Sickle cell disease is an inherited blood condition. Babies with sickle cell disease are usually well at birth but may start to develop symptoms from around 4 months of age. The symptoms of SCD are:

• Chronic anaemia: long term decreased number of red blood cells and/or the amount of haemoglobin they carry.
• Infections: people with SCD, especially infants and children, are more likely to experience infections such a flu, meningitis, and hepatitis.
• Sudden pain crisis: this happens when the sickle blood cells obstruct a blood vessel. This can be triggered by different situations, such as intense exercise, stress, infections, sudden temperature changes and not drinking enough water.
• Hand-Foot Syndrome: swelling in the hands and feet, often along with a fever, is caused by the sickle cells getting stuck in the blood vessels and blocking the blood from flowing freely through the hands and feet.
• Acute Chest Syndrome (ACS): blockage of the flow of blood to the lungs can cause acute chest syndrome. ACS is similar to pneumonia; symptoms include chest pain, coughing, difficult breathing, and fever.

Because of the sickling, the patients suffer a chronic haemolytic anaemia and the usual 120 half life of erythrocytes falls to 20 days for patients with sickle disease. The chronic haemolysis results in a rapid production of erythrocytes and a FBC that contains reticulocytes, occasional nucleated erythrocytes, target cells and sickle cells. As the spleen becomes compromised with repeated infarctions, Howell-Jolly bodies are also seen.

Several factors can lead to crises in sickle cell disease: hypoxia, dehydration, vascular stasis, fever, cold and acidosis. Anything that leads to hypoxia will promote sickling. Therefore, patients with respiratory compromise due to infection or chronic respiratory diseases are prone to develop sickle crisis.

There is no single best treatment for all people with SCD. Treatment options are different for each person depending on the symptoms. Treatments can include receiving blood transfusions, maintaining a high fluid intake (drinking 8 to 10 glasses of water each day), receiving intravenous therapy (fluids given into a vein) and medications to help with pain. Nowadays, with the proper treatment, most people affected with SCD live normal long lives.

Other types of sickle cell disease

The different forms of sickle cell disease are:

Severe sickle cell disease: symptoms and management similar to that in sickle cell anaemia.

• HbS/ß thalassaemia
• HbS/O^ArabModerate sickle cell disease:

• HbS/C
• HbS/D^Punjab
• HbS/LeporeMild sickle cell disease: clinically non relevant

• HbS/E
• Hbs/HPFH

Beta Thalassaemia is generally caused by point mutations or chromosome 11, following a recessive inheritance pattern (meaning that a mutation in each allele is needed to develop the disease). The symptoms of beta thalassaemia differ greatly from one patient to another, depending mostly on the severity of the mutation. Beta thalassaemia includes:

• Thalassaemia minor: this usually occurs in patients who are heterozygous for one beta thalassaemia mutation (beta thalassamia carriers or bête thalassaemia trait). Individuals will suffer from mild microcytic hypochromic anaemia, whih is usually asymptomatic and it is not expected to cause any health issue.
• Thalassaemia intermedia: Patients with symptoms that range from those observed in thalassaemia minor and those in thalassaemia major. Patient’s require frequent medical check ups and usually require sporadic blood transfusions.
• Thalassaemia major: also called Mediterranean anemia or Cooley anemia. It is caused by severe mutations in both alleles. No functional ß chains are produced, and thus no haemoglobin A can be assembled. This is he most severe form of ß-thalassemia: those with thalassaemia major need to have regular blood transfusions from infancy onwards in order to survive. Long term transfusions can lead to iron overload, so this patients also need iron chelating therapy.

Alpha globin is made by four genes, two on each strand of chromosome 16. Alpha thalassaemia usually occurs by deletion of some of these four genes. Depending on the total number of alpha genes that a patient has, there are different outcomes:

Alpha globin genes:

4 alpha globin genes: most common scenario, person is not a carrier.

3 alpha globin genes: silent alpha thalassaemia carrier. There is overlap between the red blood cell indices of these individuals and those with 4 gene copies, although the MCV may be slightly lower.

2 alpha globin genes: alpha thalassaemia carrier (also called alpha thalassaemia trait). Individuals who have alpha thalassaemia trait are identified by microcytosis, erythrocytosis, hypochromia and mild anaemia. Individuals with a thalassaemia trait will experience no significant health problems except a possible slight anaemia which cannot be treated with iron, with consequent mild fatigue symptoms.

• When the two copies are in different alleles (also called in trans), the person is an alpha + carrier. It is most commonly detected in people with African ancestry.
• When the two copies are in the same allele (also called in cis), the person is alpha 0 carrier. It is most commonly detected in people with Southeast Asian ancestry.

1 alpha globin gene: the person will be affected with haemoglobin H disease. Haemoglobin H disease is characterized by mild to moderate anaemia, hypochromia and microcytosis. Individuals who have haemoglobin H disease generally have a persistent stable state of anemia, which may be accentuated by increased haemolysis during viral infections and by exposure to oxidant medications, chemicals and foods such as sulfa drugs, benzene, and fava beans (similar to individuals who have G6PD deficiency).

As the red cells mature they lose their ability to withstand oxidant stress and haemoglobin H precipitates, leading to haemolysis. Therapy for individuals who have haemoglobin H disease includes folate, avoidance of oxidant drugs and foods and frequent medical check ups.

No alpha globin genes: the absence of alfa chains causes severe anaemia and leads to hydrops foetalis. This diagnosis is frequently made in the last months of pregnancy when fetal ultrasound indicates a hydropic fetus. The mother frequently exhibits toxemia and can develop severe postpartum hemorrhage. These infants are usually stillborn. There can be other congenital anomalies, though none are pathognomonic for alpha thalassaemia major. If the diagnosis is made early, intrauterine transfusions can be performed.

More uncommonly, alpha thalassaemia can also be caused by point mutations in any of the four alfa globin genes. Some examples of these haemoglobin variants are: Constant-Spring, Icaria, Seal Rock, Pakse, Quong Sze, Sun-Praire and Adana.

Information Leaflets

• Sickle Cell carrier information leaflet: Sickle cell carrier: description in brief – GOV.UK (www.gov.uk)       
• Haemoglobin E carrier information leaflet: Haemoglobin E carrier: description in brief – GOV.UK (www.gov.uk)
• Haemoglobin Lepore carrier information leaflet: Your antenatal blood test result: you are a haemoglobin Lepore carrier – GOV.UK (www.gov.uk)
• Haemoglobin C carrier information leaflet: Newborn screening: Your baby carries a gene for Haemoglobin C – GOV.UK (www.gov.uk)
• Haemoglobin O^arab information leaflet: Haemoglobin O Arab carrier: description in brief – GOV.UK (www.gov.uk)
• Haemoglobin D carrier information leaflet: Newborn screening: Your baby carries a gene for Haemoglobin D – GOV.UK (www.gov.uk)
• Delta Beta Thalassaemia information leaflet: Delta beta thalassaemia carrier: description in brief – GOV.UK (www.gov.uk)

Patient associations and information sources

• Sickle Cell Society
• UK Thalassaemia Society
• Scottish Paedriatic & Adult Haemoglobinopathy Managed Clinical Network (www.spah.scot.nhs.uk): offers useful information sources and support groups for parents and patients.
• NHS Choice (http://www.nhs.uk/Conditions/Sickle-cell-anaemia/Pages/Introduction.aspx)

• NICE – Clinical Knowledge Summaries (http://cks.nice.org.uk/sickle-cell-disease#!topicsummary): this website offers some information on sickle cell disease, diagnosis and, more importantly, the clinical management of both affected patients and carriers.
• NHS Sickle Cell and Thalassaemia e-learning New sickle cell and thalassaemia screening e-learning resource – PHE Screening (blog.gov.uk): education and training to support the NHS Screening Programme for Sickle Cell and Thalassaemia.
• Sickle Cell and Thalassaemia Handbook for Laboratories 
• Haemoglobinopathy network for children and adults in Scotland