Haemoglobinopathy Screening

“Haemoglobinopathies” are disorders of globin chain synthesis, and include the thalassaemias and haemoglobin variants, such as sickle haemoglobin. Although there is a national antenatal and newborn screening programme (see sections below), the need for opportunistic testing may arise in the primary care setting. Indications for testing include:

1) Explanation of haematological abnormalities such as anaemia or microcytosis

2) To give or confirm a diagnosis e.g. sickle cell disease or B thalassaemia major

3) Identification of sickle cell disease or trait pre-operatively

When to consider testing

• Family history of previous alpha/beta thalassaemia or haemoglobin variant
• Haematological abnormalities: if anaemic or microcytic, with family origin from appropriate area AND iron deficiency is excluded as cause for microcytic anaemia
• Red cell indices (MCH <27 pg, MCV <80fL) or morphological appearances are suggestive of a haemoglobinopathy
• Pre-operative testing for at risk groups for HbS
• HbA1c uninterpretable due to presence of variant Hb (as suggested by biochemistry report)
• New arrival in UK with history of sickle cell/ beta thalassemia, or from “at risk” ethnic group
• ONE retest only, in teenage years (when the individual is able to understand the genetic implications) for those identified as having a variant Hb, b thalassaemia trait or a⁰ thalassaemia trait in childhood

At risk groups:

When testing:

• Informed consent must be taken from the patient. A diagnosis of a haemoglobinopathy has implications not only for them, but potentially for relatives of the patient and partners if they are considering conceiving in the future.
• If a patient has anaemia or microcytosis, other causes should be considered, such as severe iron deficiency. In patients who are not iron replete, the testing for haemoglobinopathy can be difficult to interpret.
• However, in patients with an unexplained microcytosis, haemoglobinopathy should be considered as a cause.
• Consider whether the patient has had a recent blood transfusion. If so, the test should wait until at least 3 months after the transfusion.

On the request:

• Please include the reason for testing, and the patient’s family origins. Family origins are vital for accurate reporting.
• If testing for thalassaemia trait because of microcytosis, please first send a FBC and test for iron status. Treat a low ferritin for iron deficiency anaemia and recheck the FBC in 3 months. If the results are still indicative of a possible haemoglobinopathy despite correcting ferritin to >30, then haemoglobinopathy screening is indicated

On receiving results:

The haemoglobinopathy test reports contain both the diagnosis (or probable diagnosis in the case of a thalassaemia traits) and details of actions needed or recommended. Please read the whole report.

• If testing has been done as part of the antenatal or neonatal screening programmes, please document the result in patient’s notes, but follow-up should happen as detailed in the sections below.
• A result, even a negative one, should be communicated to the patient and documented in the patient’s medical record. This helps to avoid unnecessary repeat testing in the future.
• Once a haemoglobinopathy has been excluded, there is no indication for repeat testing. If one has been diagnosed, repeat testing should only happen in the context of a specialist clinic, or antenatal care in future pregnancies.
• Patients with a positive result should be informed by the requestor. In addition:

1) Adults identified as having a significant haemoglobinopathy should be referred to the haematology clinic (as detailed on the report)

2) Children identified as having a significant haemoglobinopathy should be referred to the paediatric clinic (as detailed on the report)

3) Adults, resident in Coventry, identified as carriers are sent a letter with their results and information and a telephone number to call to make an appointment should they so wish (appointments are not routinely sent due to historic high DNA rates for these). Those living outside Coventry are not routinely followed up, but may be referred by their GP to either the Birmingham Genetic Counselling service or to Dr Nicolle (Consultant Haematologist) for counselling and further information.

4) Children, resident in Coventry, identified as carriers, are sent an appointment with the Haemoglobinopathy Specialist Nurse along with their results and information. Those living outside Coventry may be referred by their GP to the Birmingham Genetic Counselling service.

Interpretation of results and reports

What is a “significant haemoglobinopathy”?

This refers to a haemoglobin disorder which has clinical implications for the patient themselves. It includes HbSS sickle cell disease and sickling disorders caused by compound heterozygous states (HbSS, HbSC, HbSDPunjab, HbSbthalassaemia, HbSdbthalassaemia, HbSOArab, HbSE, HbSLepore and HbSHPFH); b thalassaemia major and intermedia; HbH disease; HbEbthalassaemia.  If a patient is identified as having one of these conditions, they should be referred to a haemoglobinopathy specialist (either paediatrician or haematologist) for ongoing care, even if they are apparently asymptomatic, as they may have silent chronic complications which can have an impact on their health in the future and will need advice on maintaining good health (e.g. through vaccinations/ penicillin V/ eye checks).

What carrier states are significant?

• Being a carrier for HbS has genetic implications when considering having children, but may also have implications for the patient themselves, as sickling may occur in extremis.
• Carriers of HbC have microcytosis, but no other implications. HbDPunjab, HbOArab carriers will be asymptomatic. All these carrier states have genetic implications, because of their interaction with HbS.
• HbE or HbLepore carriers may have similar indices and haemoglobins to those with b thalassaemia trait, and it is important not to try and correct these with iron supplement unless iron deficiency has been proven. Both are genetically significant because of their potential interactions with HbS and b
• b and db thalassaemia carriers will have microcytosis and mild anaemia. It is important not to try and correct these with iron supplement unless iron deficiency has been proven. Both are genetically significant because of their potential interactions with HbS, HbE, HbLepore and other b There are many different genotypic and phenotypic variants causing b thalassaemia and “normal” haemoglobin will vary from carrier to carrier.
• a⁰ thalassaemia: the diagnosis of “probable” or “possible” a⁰ thalassaemia is based on MCV, MCH and ethnic origin; the definitive diagnosis requires DNA testing, which will be done in appropriate clinical circumstances, for example if a partner may also be a carrier of a⁰

What carrier states are not significant?

This will generally be stated on the report, for example:

• a⁺ thalassaemia trait: this cannot interact with anything to produce a significant haemoglobinopathy, but may explain a low MCV in the absence of iron deficiency. Family/ partner screening is not indicated.
• “Fast- running” haemoglobins: these are generally of not clinical or genetic significance, but may interfere with HbA1c testing, so the comment “Variant Hb identified. HbA1c cannot therefore be used for the monitoring of diabetic control; please request fructosamine as an alternative” will be on the report.

Screening Programmes

Antenatal screening programme

Coventry is a high prevalence area and as such, there is universal screening of pregnant women booked to deliver at UHCW.  Women booked in the rest of Warwickshire are screened based on their Family Origin Questionnaire.  The national standards recommend screening by 10/40 gestation, but bloods should be taken at booking, regardless of the stage of the pregnancy.

• Women should be screened in each pregnancy (one of the few indications for repeat testing), to enable positive results to be flagged to genetic counselling services and timely partner testing, and/or referral for prenatal diagnosis and decisions regarding the pregnancy if a couple are at risk of having a baby with significant haemoglobinopathy.
• Significant haemoglobinopathies include sickle cell disease (HbSS, SC and other compound heterozygotes), beta thalassaemia major or intermedia and possible Hb Barts.
• Carriers living in Coventry have their results phoned directly to the Haemoglobinopathy Specialist nurses and are offered an appointment for counselling within 2 weeks.
• Carriers living outside Coventry have their results phoned to the Birmingham Genetic Counsellors, who will arrange to see the women for counselling.
• Partner tests will be followed up by the appropriate counselling services and “at risk” pregnancies flagged to Birmingham Children’s Hospital laboratory and/or referred for prenatal diagnosis (and counselling regarding this and termination of pregnancy if that is the couple’s choice)
• If a couple is known to be expecting a baby with a significant haemoglobinopathy, they may also meet with the paediatric team during the pregnancy to help them prepare.

Neonatal screening programme

Newborn sickle cell screening is offered to all babies in England, as part of the newborn dried blood spot screening programme.  The objective is to identify infants at risk of sickle cell disease within the neonatal period.

• Infants identified as having sickle cell disease from Coventry are reported by Birmingham Children’s Hospital laboratory directly to the Haemoglobinopathy Specialist nurse and paediatrician and are seen within two weeks.
• Other possible significant haemoglobinopathies which may be identified and directly reported to the Haemoglobinopathy Specialist nurse include b thalassaemia major and Ebthalassaemia, although these are not always reliably diagnosed, but may be informed by known parental Hb status.
• Infants identified as having significant haemoglobinopathies living outside Coventry are reported to the Birmingham Genetic Counsellors and Birmingham Children’s Hospital clinicians and followed up by them (or, if they feel appropriate, the Coventry team may take over their care).
• The parents of infants identified as being a carrier for a Hb variant are sent a letter with their results and an appointment with the Haemoglobinopathy Specialist Nurse if they live in Coventry.
• Newborn screening does not identify thalassaemia traits, as HbF is the predominant Hb present at birth.  If there is a family history, testing later in life (if blood tests are being done for another reason, or when the child is old enough to understand implications) may be appropriate, but this does NOT need to be done routinely.