Thalassaemia - Children with Thalassaemia in Leeds Children's Hospital - Guidelines For Management of

Publication: 01/05/2012  
Next review: 27/01/2025  
Clinical Guideline
CURRENT 
ID: 2930 
Approved By: Trust Clinical Guidelines Group 
Copyright© Leeds Teaching Hospitals NHS Trust 2022  

 

This Clinical Guideline is intended for use by healthcare professionals within Leeds unless otherwise stated.
For healthcare professionals in other trusts, please ensure that you consult relevant local and national guidance.

Guidelines For Management of Children with Thalassaemia in Leeds Children’s Hospital

Mechanism for referral

Urgent concern regarding child or young person <18 years old with possible new diagnosis or complications of thalassaemia including those presenting to the Emergency Department?

Ring :  
0900-1700 Monday to Friday 0113 3927179
All other times and Bank Holidays 0113 3927431
If no answer to the above numbers 0113 2432799 (Leeds Teaching Hospitals switchboard)

Ask for specialist registrar covering paediatric haematology or consultant on call for paediatric haematology/oncology.

Unless there is a specific contraindication, all such patients should be cared for on the paediatric haematology wards.

All new patients who may have sickle cell disease or thalassaemia who are <18 years old who are not presenting unwell and need outpatient referral should be discussed with/referred to the Paediatric Haematology Department, Martin Wing, Leeds General Infirmary, LS1 3EX. This includes infants identified through the neonatal haemoglobinopathy screening programme.

Tel 0113 3928776
Fax 0113 3928488

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When to refer from the community

Previously undiagnosed patient

Emergency referral

Clinically, the presentation of a child with thalassaemia major or intermedia may be insidious, with poor feeding, faltering growth, pallor, and increased susceptibility to infection. If untreated, progressive anaemia and metabolic stress eventually cause heart failure and death. There is enlargement of the liver and spleen. The ineffective expansion of the erythropoietic marrow results in bone thinning and deformity. Untreated, children with β thalassaemia major die from heart failure or infection before the age of five. It is from four to six months of age onwards that infants with thalassaemia major can become symptomatic.

If a patient with such a presentation is identified in the community make contact with the haemoglobinopathy team as described above.

Outpatient referral

Possible new case of thalassaemia presenting through neonatal screening, new presentation at an older age or following movement of a family to the Leeds area. Make contact with the haemoglobinopathy team as described above

Essential longer term management in the community

Guidance for management in the community will be described in clinic letters/discharge summaries but ongoing interventions in partnership with the thalassaemia clinic will include:

  • Ensuring adherence to the immunisation programme.
  • Provision of support for the family at home and in school to disseminate appropriate advice in the community and school and facilitation of regular review or emergency presentation at Leeds Children’s Hospital or the local paediatric unit.
  • Supporting the thalassaemia centre in providing ongoing treatment with adjunctive treatment.  

Treatment with iron chelation or more complex therapy will be managed by the thalassaemia centre.

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Acute Clinical Presentation in the Treated Thalassaemia Patient

Key questions

  • What is the transfusion history?
    Is the patient on a regular transfusion programme, intermittently transfused or not transfused? When was the last transfusion? Are the symptoms compatible with a transfusion reaction? What was the Baseline Hb/pre transfusion Hb? Are alloantibodies present?

Consider

Transfusion reactions including: delayed transfusion reaction, hyperhaemolysis syndrome, transfusion transmitted bacterial infection, transfusion-transmitted acute lung injury, fluid overload, anaphylactic reactions.

  • Is there an indwelling venous device – e.g. Portacath, Hickman line?
    Check when line last accessed.
    Any anticoagulation – is this therapeutic?
    Consider
    Sepsis – local or systemic
    Venous thromboembolism

  • Any features of sepsis?

    Note: Sepsis Six; consider as immunocompromised
    Does the patient have an indwelling line?
    Has the patient undergone splenectomy, and if so, has appropriate post-splenectomy infection prophylaxis been continued?
    Is the patient chelating with deferiprone, and if so, has neutrophil count been checked to exclude agranulocytosis?
    Is the patient chelating with desferrioxamine and if so, are the clinical features compatible with Yersinia or Klebsiella sepsis?

    Consider
    Gallstones, CNS sepsis, UTI, endocarditis
    Klebsiella and Yersinia sepsis more common in iron loaded patient, may include meningitis, cerebral abscess, UTI.
    Yersinia enterocolitica may mimic appendicitis.
    Malaria if relevant travel

Despite splenectomy, and perhaps because of successful pneumococcal prophylaxis, the majority of bacteraemia is now with gram negative organisms: Klebsiella, E Coli and sometimes salmonella species. Presentation is with high fever and sometimes associated circulatory collapse, there may be evidence of pneumonia, biliary tract infection, meningitis or cerebral abscess.

If suspicion of infection treatment with broad spectrum antibiotics such as intravenous tobramycin and piptazobactam after blood cultures have been taken. Where individuals have central venous catheters consider vancomycin or teicoplanin.

Yersinia enterocolitica causes infection in this patient group far in excess of others, as it thrives in high iron conditions. It can cause localised infection in the tonsil or bowel, or can cause septicaemia. There is usually high fever and abdominal pain, sometimes vomiting and diarrhoea. It can be mistaken for appendicitis or other acute surgical abdomen. The organism can be cultured from blood or stool specimens. If it is suspected, all chelation treatment should be stopped until the infection is treated, or - if not confirmed - until abdominal symptoms resolve. Treatment for Yersinia is usually with ciprofloxacin, initially intravenously in an acutely ill patient; septrin and co-amoxiclav are also reported to be effective. Antibiotic treatment should be commenced on clinical suspicion of Yersinia infection, in a chelated patient with fever and abdominal pain, pending a diagnosis. If Yersinia enterocolitica infection is suspected, desferrioxamine treatment must be stopped and not restarted until the infection is fully resolved.

Uncommonly, other specific transfusion transmitted infections such as hepatitis B (although not likely in vaccinated individuals), hepatitis C or rarely HIV cause the patient to present acutely and should be borne in mind. The risk of neutropenia or agranulocytosis in patients receiving deferiprone should be borne in mind, so in such patients presenting with fever or other features of infection, an urgent FBC should be requested. Suitable broad spectrum intravenous antibiotics (as per local febrile neutropenia protocol) should be started immediately if the neutrophil count is significantly low.

  • Has the patient undergone splenectomy?
    Consider
    Sepsis
    VTE – especially in nontransfusion-dependent thalassaemia
    Pneumococcal, meningococcal and haemophilus infection risk

  • What drugs are used for iron chelation?
    Consider drug side effects
    Deferiprone: neutropenia and agranulocytosis
    Deferasirox: renal and liver toxicity, upper gastrointestinal ulceration and haemorrhage, acquired Fanconi’s syndrome (acute renal tubular damage)
    Desferrioxamine: Sepsis with Yersinia, Klebsiella, mucormycosis.

  • What is the degree of iron overload – is this patient at risk of cardiac iron?
    Is there a history of palpitations?
    Is there increasing iron loading as suggested by ferritins, recent MRI results - cardiac T2*, liver iron
    Cardiac drugs - ACE inhibitor, amiodarone, digoxin
    89% patients in cardiac failure seen when Cardiac T2* < 10ms
    Those with previous cardiac iron may still develop arrhythmias.
    T wave abnormalities are common in thalassaemia patients and are nonspecific.
    Other symptoms and signs should be used to support a diagnosis of ischaemic cardiac complications.

  • What history of liver disease?
    Recent liver iron concentration measurements, viral hepatitis, B or C
    Liver disease may be advanced if the patient also has hepatitis, or a history of poor iron chelation over a prolonged period or alcohol excess.

  • Is the patient diabetic? What is their control like?
    Hypo-/hyperglycaemia?
    Review fructosamine to consider control. If this is not available the HbA1c can be used but this is diluted with blood transfusion and may mask poor control.

  • Is there any other endocrine complication, treated or undiagnosed?
    Hypocalcaemia, hypothyroidism, hypoparathyroidism, adrenal insufficiency, undiagnosed diabetes
    May impair cardiac function/rhythm
    Adrenal function presentation may be subacute, only manifesting at times of acute illness

  • Could thalassaemia explain acute pain?
    Wide range of complications including gallstones, renal stones, fracture, pancreatitis, PE.

    Use wider history to focus on underlying cause

Key symptoms

  • Acute breathlessness?
    Assess for pneumonia, PE, sepsis, acidosis, severe anaemia
    BP may be low normally in these patients – check previous records

  • Acute abdominal pain?
    Gallstones, biliary tract sepsis
    Renal stones (hypercalciuria)
    Hepatic congestion from cardiac failure?
    Yersinia infection
    Non transfusion dependent thalassaemia post splenectomy – VTE?
    Portal vein thrombosis, mesenteric infarction

    NB Review medical pathologies prior to any surgical intervention
    Pancreatitis ± gallstones
    NB: Measure splenomegaly – compare to baseline, consider splenic infarcts

  • Acute back pain?
    On treatment for osteoporosis?  Recent DXA results - risk osteoporotic fracture?
    Confirm any history of trauma
    Assess for spinal cord compression – e.g. weakness, paraesthesia, bladder control.
    At risk of extramedullary haematopoeisis? e.g. non transfusion dependent thalassaemia, under transfused although can occur in any patient
    Urgent MRI spine should be undertaken if suspected

  • Acute neurological presentation?
    Any features of sepsis consider specific infections above.
    Leg weakness, bladder or bowel dysfunction
    Extramedullary haematopoiesis with spinal cord compression
    Imaging, blood and CSF cultures where indicated
    Urgent MRI spine if any possibility

  • Acute anaemia?
    Baseline Hb, transfusion history?
    Any intercurrent illness, fevers, diet issues?
    Parvovirus (and if considered possible, any other family members with thalassaemia should have review/Hb check)
    Folate deficiency

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General advice

For most presentations, desferrioxamine treatment should be continued. The exception is suspected Yersinia enterocolitica infection, where it must be stopped and not restarted until the infection is fully resolved.

When acutely unwell, patients may not tolerate any degree of anaemia and should be transfused to a haemoglobin of >12 g/dl.

Recommended assessment for the acutely presenting patient should include the following (those starred * depending on clinical presentation):

  • FBC, group and antibody screen, direct antiglobulin test, U+E, LFT, Calcium and Phosphate, Glucose, thyroid function.
  • Blood cultures, urine culture, culture of stool*, CSF*
  • ECG CXR*
  • Echocardiogram*
  • Ultrasound of abdomen

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Outpatient management

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New diagnosis

Learning that their infant has a serious blood condition inevitably comes as a shock to the parents. Parents should be aware of their risk of having an affected child through counselling during pregnancy. This counselling should have included information about inheritance, the option of pre-natal diagnosis and other choices, and the effects of thalassaemia and its treatment on the child and the family. It should be backed up by suitable written information. Additionally, if the risk was not identified during the pregnancy, affected infants may be identified through the newborn screening programme. Whenever the diagnosis is made, the way in which it is conveyed to the parents, and the initial conversations they have with professionals, will colour their expectations and attitudes. The first discussions must therefore be accurate, unhurried, considered and sensitive.

The baby and parents should be seen as soon as possible and preferably within two weeks after birth or diagnosis, for babies identified by the screening programme, an initial home visit is preferred. The neonatal heel prick test is a screening, not diagnostic, test and early confirmation is required.

If the presentation is a clinical one, then assessment may be urgent, within one to two days.

A professional interpreter is essential at this consultation if the family are not primary English speakers.

If only one parent is present, it is advisable that a friend or relative is also present

Strenuous efforts should be made to involve both parents from the start.

The first discussions must be accurate, unhurried, considered and sensitive.

Information regarding the key contacts for advice and queries should be provided.

Appropriate written information should be made available. The family should additionally be given the contact details for the UK Thalassaemia Society and any local branches/support organisations.

A management plan tailored to the individual child must be agreed and implemented. The family will meet their ‘key contact’ within the clinical team, and given contact numbers for subsequent use.

Investigations at first visit

  • Full blood count and blood film examination
  • Haemoglobin analysis by electrophoresis or high performance liquid chromatography (HPLC)
  • Genetic analysis for β thalassaemia mutations, α thalassaemia genotype and Xmn1 C-> T polymorphism. Family studies may be informative.

For diagnosis confirmation ensure two test results are available confirming the diagnosis including one after the age of 6 months. It should be emphasised that the clinical phenotype cannot be predicted accurately in the early stages, and that the child will be monitored carefully for clinical signs indicative of the need to commence transfusion.

Organise the testing of parents and siblings unless already available.

Send information regarding diagnosis and management plan to the general practitioner and shared care paediatrician as appropriate.

A copy should also be sent to the parents / patient as appropriate.

If patients move a referral letter and copy letters will be sent to the new consultant.

Every person with thalassaemia will have the opportunity for their care and condition to be reviewed at least annually with a team of health care professionals who have particular experience in caring for thalassaemia disorders. This can take place during a visit to the Specialist Centre, or at an outreach clinic where members of the Specialist Team visit the local centre at which the person receives their routine care.

The assessment should cover all aspects of care including educational and lifestyle factors that may affect health or influence adherence to treatment. See proforma used for clinic review.

Discussion of treatment options should include any new information which has become available, and an individual treatment plan for the next 12 months will be agreed.

A copy of the annual review consultation including the care plan will be copied to the patient or, for children, their parents as well as health professionals involved in their care.

Data should be entered into the annual review screens of the NHR for consented patients.

People in families affected by thalassaemia should be able to meet and gain support from other affected families at the Centre or in the community.

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Initial Review of Patients Previously Treated Outside the UK

Immediate investigations

FBC, blood film, haemoglobin HPLC (although may not be informative if recently transfused; family study may help)

Serum or plasma ferritin assay

ABO and full red cell phenotype and antibody screen. (If recently transfused, DNA studies for red cell antigens, via Reference Laboratory of National Blood Service)

Hepatitis B & C serology to include Hep B surface antibody titre

HIV serology preceded by pre-test counselling

Full renal, liver, bone, sex hormone profiles, random glucose, TFTs, fructosamine if diabetic,PTH, vitamin D, G6PD level

Sample to Regional Transfusion Centre to define molecular variants (α and β globin genotype, -158 GγXmn1 C>T polymorphism). Parental samples may be informative.

Semi urgent investigation

Glucose tolerance test if not established diabetes mellitus

Abdominal and pelvic ultrasound to assess for gallstones, liver fibrosis or cirrhosis, spleen size and renal tract pathology (renal stones) and uterine/ovarian tissue in females

Cardiac T2*

Liver iron quantification using T2* or R2

DEXA scan

Other specialist assessments

Audiology

Ophthalmology

Bone densitometry

Cardiac review

If diabetic, specialist diabetic clinic - arrange GTT if glucose tolerance uncertain

If other endocrinopathies, endocrine clinic

If hepatitis B antigen or C antibody positive, hepatology clinic

Patient and family should be offered genetic counselling, as appropriate

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Review before initiation of transfusion and decision to start transfusions

Follow up clinics leading up to initiation of transfusion programme

During the early clinic visits, treatment options for the child in future should be discussed including the different options for iron chelation and the availability of stem cell transplantation.  Families should be made aware of the need for frequent monitoring of growth, development, and blood test results. Where possible, the family should be given the opportunity to meet with other families who have children with thalassaemia.

After diagnosis, monitor regularly from the age of 4 months at least monthly until the clinical phenotype is established.
History: feeding difficulties, infections, ill health, developmental delay
Examination: assess bone expansion (including head circumference), growth curves and hepatosplenomegaly.

Investigation:

Haemoglobin level should be checked at least monthly

Consent should be sought from all patients for entry of their details on the National Haemoglobinopathy Registry (NIHR), and data entered in a timely fashion to assist audit and assessment of good quality outcome information.

If from neighbouring clinic will need annual review in Leeds.

Stem cell transplantation

Refer for consideration of stem cell transplantation at around age of 12 - 18 months. It is paramount in all discussions of this treatment option to stress the usually excellent results of conventional transfusion and chelation therapy.

If the mother of a child with thalassaemia becomes pregnant, referral to the specialist transplant centre should be made for discussion of possible cord blood stem cell harvesting as a source for donor material for the affected child. If not already tested, the HLA type of the affected child should be established.

Current list of indications for stem cell transplantation can be found at bsbmt.org/indications-table.

Prevention Using Prenatal Diagnosis and Preimplantation Genetic Diagnosis 

All couples at risk of having children with a thalassaemia disorder should be referred to specialist genetic counselling as soon as the risk is recognised. Counselling is provided by a genetic specialist with specific experience in both prenatal diagnosis and preimplantation genetic diagnosis for haemoglobin disorders. DNA analysis is provided for all at risk couples.

All at risk couples should be informed of prenatal diagnosis (PND) and preimplantation genetic diagnosis (PGD) as options to achieve a healthy family. If the woman has a thalassaemia disorder, her treating haematologist should be involved in the management plan prior to PGD.

Decision re transfusion:

A decision to commence transfusion will be made by the designated consultant for the service. It should be based on the presence of anaemia (usually below 70 g/l) which is accompanied by inappropriate fatigue, poor feeding, developmental delay or regression, faltering growth, or any symptoms or signs of cardiac failure.

Exclude correctable problems such as iron deficiency or intercurrent infection, or compounding factors such as G6PD deficiency.

An ‘acute’ case of anaemia, eg. due to a viral infection, does not necessarily indicate a regular transfusion programme. Where possible, the decision to start regular transfusions should not be delayed until after the 3rd year, as the risk of developing multiple red cell antibodies increases, with subsequent difficulty in finding suitable units for transfusion.

Once it is decided that transfusion is probable start course of hepatitis B vaccinations aiming to complete before first vaccination

Further investigations

Before the first transfusion, the following investigations should be carried out:

Speciality Investigations

 

Haematology

Serial Hb measurements

G6PD screen + assay if low

Transfusion

Full red cell phenoptype [C, c, D, E, e, K, k, Jka, Jkb, Fya, Fyb, Kpa, Kpb, MNS, Lewis]

Biochemistry

LFT and baseline ferritin assay

Microbiology

Hepatitis B surface antigen,

Hepatitis C antibody

HIV antibody

Where transfusion is started because of fall in height velocity or bony changes (often intermedia) it should not be assumed that lifelong transfusion will then be necessary. After maximum height is achieved, and bones are fused, in some cases it is possible to 'wean off' and then stop regular transfusions entirely, although the patient still needs to be carefully monitored for other complications.

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Protocol for transfusion

Consent for transfusion should be recorded using the organisations policy for consenting long term multi-transfused patients.

Pre-transfusion haemoglobin level should be between 90 - 105 g/L.

Transfusion interval is usually between 3 and 4 weeks.

Raise Hb to 15g/dl

Formula: Volume of blood (ml) = patient weight (kg) x Hb increment (g/dl) x 3.5*

*This may change - refer to paediatric haematology transfusion policy

Matched red cells for Rh (D, C, c, E, e) and Kell (K) blood group antigens

Large volume units should be chosen, preferably greater than 300 mls (for adults and children when one or more full unit is required), and wherever possible units should be less than 2 weeks old. No more than 2 attempts to site a cannula should be made by any one individual

To reduce donor exposure, transfusions are not normally given to the nearest ml, so for example if the calculated volume is 330 ml and one matched unit is identified containing 305 ml, part of a second unit would not be necessary.

Record dates of transfusion, the patient weight, the volume of blood transfused at each episode and the estimated haematocrit of the transfused blood (available from the blood transfusion laboratory) 

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Monitoring recommendations for patients at risk of iron overload (those on regular top-up transfusions every three months or less, SCD on regular top-up transfusion, manual exchange or on automated apheresis with progressive rise in serum ferritin, non-transfusion-dependent thalassaemia and non-transfused rare inherited anaemia)

Frequency of review

Haematology clinic - clinical

Haematology clinic - investigations

Referral - clinical

Referral -investigations

Every three months

General clinical overview
Adequacy of iron chelation?
Adherence issues?

Serum ferritin

Liver function tests

Cardiac review if T2*< 10 ms and any evidence of cardiac impairment

8 years@
If T2*< 10 ms and any evidence of cardiac impairment
- Cardiac T2* MRI

Every six months

Weight and height (standing and sitting)

Random glucose

12 yrs calcium and phosphate

 

8 years@
If T2*< 10 ms - Cardiac T2* MRI
Ferriscan if >15mg/g dry weight

Annual

≥ 10 years pubertal staging.

Calculate annual transfusion intensity
ml/kg/year pure red cells

Calculate average daily transfusion iron loading  expressed as mg/ kg/day **

Anti-HCV, HbsAg, anti HB core Ab
Soluble transferrin receptors (low levels relative to blood loading may indicate high cardiac risk)
Vitamin D
From puberty  or 10 yrs if family Hx Glucose tolerance tests
10 yrs
Thyroid function
10 yrs
Morning testosterone and cortisol

Age >5yrs
Ophthalmology and audiometry assessment for chelation toxicity

Cardiac review if aged 16-25 years or if T2* 10-20 ms

Community dental review

 

8 years @
Ferriscan  
every year

8 years @
if T2* 10-20 ms
- Cardiac T2* MRI

Refer to endocrinology if no pubertal changes girl aged 13yrs or boy aged 14yrs

Every 2 years

 

 

Cardiac review from aged 7-16 years
12yrs comprehensive dental assessment

8 years @ - Cardiac T2* MRI
if T2* >20 ms (ie normal)

DEXA scan
From puberty

@ ≥ 8 years Ferriscan or if not available T2* MRI of liver every year, and additionally if significant changes to therapy occur.

Cardiac T2* MRI every 2 years if T2* >20 ms, every year if T2* 10-20 ms, 6 monthly if T2*<10 ms, 3 monthly if T2*< 10 ms and any evidence of cardiac impairment. MRI monitoring should start from age 8 years but earlier if initiation of chelation therapy has been delayed, or adherence is very poor.

** assume 1 ml of pure red cells contains 1.08 mg of iron. Patients whose transfusion iron loading is more than 0.3 mg/kg/day, require higher doses of chelating agents to achieve negative iron balance.

Non transfusion dependent thalassaemia

NTDT patients should have liver MRI assessment if ferritin is above 800 μg/l at baseline. NTDT patients with previous iron overload or who are receiving iron chelation therapy should have regular liver MRI assessment as the ferritin is unreliable.

Non-transfused rare inherited anaemia

NTRIA patients should have a baseline liver and cardiac MRI assessment if ferritin is >1 000 μg/l. NTRIA patients with defects in the iron metabolism or haem pathway should be considered for MRI assessment if the ferritin is >500 μg/l or sooner if there are features to suggest iron overload on clinical examination.

Poor compliance with chelation therapy should prompt earlier scans if needed.

Rate of iron loading (ROIL) from transfusion

Rate of iron loading

The ROIL in mg/kg/day can be calculated from the number of units given over a measured time period. Patients with average ROIL (0.3–0.5 mg/kg/day) are likely to require average doses, whereas those with ROIL less than 0.2 mg/kg/day or greater than 0.5 mg/kg/day are likely to require dose adjustment accordingly.

Rate of iron loading mg/kg/day   =
units of blood transfused x 200
Weight x days over which the blood was administered

 

Rate of iron loading mg/kg/day    =

  ml of blood transfused x 1:08
Weight x days over which the blood was administered

Prognostic indicators

Ferritin

Long-term control of ferritin with desferrioxamine therapy has prognostic significance and maintenance of the ferritin below 2500 μg/l is associated with a lower risk of cardiac disease and death. Maintenance of ferritin below 1000 μg/l may be associated with additional advantages in transfusion dependent thalassaemia.  If possible primary aim would be to keep ferritin levels between 500-1000ug/L but from 8yrs more emphasis should be placed on the Ferriscan and T2* MRI results.

Liver iron concentration (LIC)

Long term liver iron concentrations above 7 mg/g dry weight have been associated with increased risk of fibrosis and above 15 mg/g dry weight with increased risk of myocardial iron overload.  Liver biopsies have procedure-associated risks and the distribution of iron in the liver may be inhomogeneous. Liver biopsies are now undertaken only where histology will contribute to management.

Cardiac T2*

Cardiac T2* values less than 20 ms are associated with increased myocardial iron and T2* less than 10 ms is associated with an increased risk of developing cardiac failure.

Iron loading kinetics

For the majority of transfusion dependent thalassaemia patients, iron is stored in the liver first  before extrahepatic iron loading occurs so liver iron concentrationwill reflect total body iron.  When iron is removed via chelation, it is removed from the liver first before the heart, so cardiac T2* values are slow to change relative to LIC.  Patients who have undergone a splenectomy will experience iron shunting to the heart more quickly even with a relatively low liver iron concentration. The spleen acts as a buffer as part of the macrophage system and stores and regulates iron

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Iron chelation treatment

The most important long-term problem associated with regular transfusions in thalassaemia is iron overload. Blood contains iron which cannot be excreted from the body, and a typical thalassaemia patient on a regular transfusion programme will accumulate 0.3-0.5mg/kg of iron per day. Excessive iron is toxic, the most vulnerable organs being the heart, liver and endocrine glands. Once the body has accumulated 12-24 g of iron significant clinical manifestations of iron toxicity can be expected. Without treatment to remove the iron, the majority of patients develop cardiac problems and died of heart failure by the age of 20. Therapy to remove or 'chelate' excess iron is therefore essential and this must be started within a year or so of starting regular transfusions.

The aim of therapy with all chelation regimes is to attain and maintain annual average serum ferritin at 1000 ±500 μg/l , liver iron 3-7 mg/ g dry weight, and cardiac T2* >20 ms. Persistently high ferritin levels (>2500μg/l) are associated with an increased risk of cardiac disease and death

Treatment

Initiation of chelation treatment

Transfusion dependent thalassaemia patients should be commenced on iron chelation therapy after 10 transfusions or when the serum ferritin >1 000 μg/l on two occasions.

Non transfusion dependent thalassaemia patients should be offered iron chelation therapy if ferritin is above 800 μg/l or liver iron is above 5 mg/g/dry weight.

Non-transfused rare inherited anaemia patients should be assessed on a disease and individual basis and chelation therapy or venesection (if Hb is adequate) considered if there is evidence of iron overload (ferritin > 500 μg/l or LIC > 5mg/g/dry weight).

Sickle Cell Disease patients receiving top-up transfusions should be commenced on iron chelation as per transfusion dependent thalassaemia patients. SCD patients on exchange transfusion programmes should be offered iron chelation therapy on an individualised basis according to the type of exchange and the severity of the existing iron overload as measured by liver iron MRI assessment.

Chelation regimens

Under 6 yrs of age

First line : Desferrioxamine

Start at 20 mg/kg/day 3 nights a week for 2 weeks then introduce 5 nights a week. Review dose every 3 months to see if dose escalation/decrease needed. The lowest effective dose should be used. The average daily dose will probably lie between 20 and 40 mg/kg/day. Doses in excess of 40mg/kg/day should only be prescribed following discussion with the consultant Haematologist and only if benefit for the patient outweighs the risk of unwanted effects. Patients with serum ferritin levels of < 2000 mcg/L should require about 25 mg/kg/day, and those with levels between 2000 and 3000 nanogram/mL about 35 mg/kg/day.

Therapeutic index. Mean daily dose (mg/kg)/ferritin (μg/l). Aim to keep <0.025 at all times  to reduce the risk of toxicity especially to eyes and ears.

After one month of treatment prescribe ascorbic acid orally on days of Desferrioxamine chelation. The recommended dose is 200mg for adults and 100 mg for children.

Second line : Add deferiprone 

If maximum dose Desferrioxamine achieved, after 6 months, if inadequate chelation and adequate adherence and tolerant of desferrioxamine add deferiprone. Deferiprone to start at at 25mg/kg/ od, then increasing to bd after 2 weeks and then tds after 2 weeks. Dose increases based on side effects and severity of iron overload to maximum of but should not exceed 100 mg/kg/day.

Third line: Substitute deferiprone with deferasirox-FCT

After maximum dose of deferiprone achieved, after a further 6 months, if inadequate chelation and if adequate adherence and tolerant of desferrioxamine stop deferiprone and substitute with Deferasirox-FCT; start at 7 mg/kg/day for 2 weeks then increase to 14mg/kg if no significant side effects.  Dose escalation of Deferasirox at 3 months based on side effects and tolerability.

6yrs or over or if 2 yrs or over and intolerant to Desferrioxamine

First line : Deferasirox-FCT

Film-coated tablets/granules. Start at 7 mg/kg/day for 2 weeks then increase to 14mg/kg if no significant side effects. Review dose every 3 months to see if dose escalation/decrease needed based on assessment of iron loading. If needed, every 3-6 months increase by 3.5 - 7 mg/kg/day up to 21 mg/kg/day. Usual maximum 21mg/kg/day so consider adherence and if combination therapy needed if ineffective. Maximum quoted dose is 28mg/kg/day.

Second line : Add deferiprone

When maximum dose of deferasirox achieved, after 6 months if inadequate chelation and adequate adherence and tolerant of deferasirox add deferiprone. Deferiprone to start at at 25mg/kg/ od, then increasing to bd after 2 weeks and then tds after 2 weeks . Dose increases based on side effects and severity of iron overload to maximum of but should not exceed 100 mg/kg/day.

Third line : Substitute deferiprone with desferrioxamine

When maximum dose of deferiprone achieved, after 6 months, if inadequate chelation and if adequate adherence and tolerant of Deferasirox, substitute deferiprone with desferrioxamine. Initiate at appropriate dose of Desferrioxamine for age and Deferasirox-FCT at 14 mg/kg/day.

Monitoring for complications of iron chelation

 

Deferasirox

Deferiprone

Desferrioxamine

Prior to starting

Creatinine, ALT, urinalysis

FBC

Creatinine, ALT

FBC

Creatinine, ALT

Weeks 1 to 4 inclusive

Weekly creatinine and urinalysis

ALT fortnightly

Weekly neutrophils for 4 weeks then monthly

 

Week 5 onwards

 

 

 

Monthly

ALT

Creatinine

Urinalysis

ALT

Creatinine

ALT

Creatinine

Every 3 months

 

 

Height and weight

Annual from age 5 years

Audiometry

Ophthalmology (specifically electroretinogram)

Transfusional rate of iron loading

Audiometry if receiving combination therapy

Ophthalmology if receiving combination therapy

Zinc level

Audiometry

Ophthalmology (specifically electroretinogram)

Transfusional rate of iron loading

Zinc level

Calculate therapeutic index

Mean daily dose (mg/kg)/ferritin (μg/l.)

Aim to keep <0.025 at all times.

Adjustments to chelation regime – dose decreases with low iron stores

The risk of chelator toxicity is likely to be higher when body iron stores are either low (Ferritin persistently < 1000 μg/dl and/or desferrioxamine mg/kg to serum ferritin ratio > 0.025, or when LIC is < 3 mg/g dw) or when ferritin is decreasing rapidly. The association of chelator toxicity and low iron stores is less clear in the case of deferiprone and deferasirox but the same precautions should nevertheless be taken, particularly in ferritin < 500 μg/L). Deferiprone is probably the least toxic chelator in this scenario.

Chelator dose should be reduced and may need to be maintained in a very low range (e.g. desferrioxamine 10 – 20mg/kg per infusion 5 per week; deferasirox 5 – 10mg/kg/day, deferiprone 50 – 75 mg/kg/day) in these patients. Licensing of deferasirox recommends considering an interruption of chelation when ferritin is <500. This may not be the best strategy in regularly transfused patients as they will continue to load iron at a rate of 0.3 – 0.5 mg/kg/day. An alternative approach is to continue chelation at very low dosage (e.g. deferasirox 5 – 10 mg/kg/day) with monthly monitoring of adverse symptoms, increment in ferritin, creatinine, ALT and urinalysis. Chelator dose should be reduced if there is a rapid decline in ferritin (> 500 over a three month period), and ferritin is persistently < 1000 μg/dl, and when LIC is <3 mg/g dw, cardiac T2* is > 20ms. Desferrioxamine dose per infusion should be reduced rather than the frequency of infusion. Conversion from desferrioxamine to oral chelation should be considered if ferritin is consistently in the range 500 – 750 μg/l or LIC < 3 mg/g dw.

Adjustments to chelation regime with severe myocardial iron loading

(Myocardial T2* < 10 ms) not clinically in Heart Failure

If iron stores are low (Ferritin < 1000 μg/l, LIC < 7 mg/g dw), deferiprone monotherapy should be considered first line therapy. The dose should be escalated to 100 mg/kg/day.

If iron stores are high (Ferritin > 1000 μg/l, LIC > 7 mg/g dw), desferrioxamine / deferiprone combination is recommended.

Deferiprone should be given at 85-100 mg/kg/day and combined with desferrioxamine infusions (40 – 60mg/kg/day), either continuous i.v., continuous s.c., or intermittent s.c. infusions over 12 hours, 5 – 7 times per week depending on iron levels.

If deferiprone therapy is not tolerated, the alternative options are continuous i.v. desferrioxamine (40-60mg/kg/day, 7 days per week) or high dose deferasirox (30-40 mg/kg/day) with careful monitoring for adverse effects.

Chelator doses should be adjusted based on ferritin and LIC for avoiding chelator toxicity.

Adjustments to chelation regime with severe myocardial iron loading

(Myocardial T2* < 10 ms), clinically in Heart Failure

Desferrioxamine at a dose 50-60 mg/kg should be started immediately via a peripheral line and given as a continuous 24 hour i.v. infusion. A long-term intravenous line should be inserted to facilitate long-term therapy. Simultaneous deferiprone (75-100mg/kg/day) should be combined with the desferrioxamine infusions as soon as possible.

Notes on cardiac iron loading

Myocardial iron appears to clear more quickly with continuous i.v. desferrioxamine (Anderson, Westwood et al. 2004) or desferrioxamine / deferiprone combination (Tanner, Galanello et al. 2007) compared to deferasirox regimes. This may result from differing chelator efficacy, but could also relate to the degree of iron loading. It has been shown that cardiac iron decreases only after liver iron is controlled, and it is noteworthy that patients in the deferasirox trials had higher LIC than in the deferiprone trials. Despite these reservations it is advisable for patients with the severest degrees of myocardial iron loading to be chelated with continuous intravenous desferrioxamine or desferrioxamine / deferiprone combination. Deferasirox monotherapy (at a dose around 40mg/kg/day) should only be used in patients unwilling or unable to sustain treatment with continuous desferrioxamine or desferrioxamine / deferiprone combination. In all patients careful review of compliance and trends in ferritin, and echocardiographic parameters should be undertaken regularly to ensure that the patient continues to engage with treatment.

Notes on chelators 

Desferrioxamine

Desferrioxamine doses of 40 mg/kg five days a week have been used, but these are often insufficient to promote a negative iron balance. Thus at an average rate of iron loading in transfusion dependent thalassaemia (0.3–0.5 mg/ kg/day) only 65% of patients will be in negative iron balance, whereas at 50–60 mg/kg five days a week this rises to 86% of patients. Due to potential desferrioxamine toxicities (growth and audiometry) children should not receive a mean daily dose exceeding 40 mg/kg. Adults generally tolerate 50 mg/kg well.
Mean daily doses should be adjusted downwards as ferritin values fall in line with the therapeutic index.

Parents and patients should be taught how to administer subcutaneous desferrioxamine infusions. The training and performance should be documented in the patient's records. Their technique should be assessed regularly. Children should be encouraged to participate in setting up and administering the desferrioxamine infusions at an early age. Initiation of desferrioxamine infusions in very young children (age <5) is best done starting with 2- 3 infusions per week and gradually increasing to 5 infusions over a 3 month period. Means of facilitating the delivery of desferrioxamine such as Thalaset® needles, anaesthetic cream, disposable elastomeric pre-filled infuser pumps (not in very young children as the infused volumes are too large) should be offered to all children and adults. Ascorbic acid should be taken approximately 30 minutes after starting each desferrioxamine infusion. Monitoring for adverse effects should include 3 monthly sitting and standing height, annual audiometry, and radiological investigation of any bony symptoms. Desferrioxamine should be stopped if there are symptoms of gastrointestinal disturbance (abdominal pain, severe diarrhoea) or high fever. Patients should be aware of the risk of overwhelming infection due to Yersinia and Klebsiella, and seek medical attention as soon as possible if they have symptoms or signs of severe infection.

Deferasirox

Dosing is also critical to response with deferasirox: thus while over 80% of transfusion dependent thalassaemia patients with average ROIL respond to daily deferasirox-FCT at 21 mg/kg/day, this falls to just over half of patients at 14 mg/kg). Adjustment in doses should be in line with ferritin trends and LIC values as well as the presence of any derangement in serum creatinine and transaminase levels.

Deferiprone

The relationship of dosing to iron balance with deferiprone is less clear as long-term LIC trends show considerable interstudy variation, reflecting the heterogeneity of dosing schedules, ROIL, baseline LIC values, and follow-up periods. Unlike desferrioxamine, the response to deferiprone depends on baseline LIC; thus at 75 mg/kg/day, a negative iron balance was achieved in less than a third of patients overall but in 50% of patients where baseline LIC exceeded 9 mg/g dry weight. Note risk of agranulocytosis and need for urgent FBC if any infection symptoms.

Ascorbic acid

Use in conjunction with Desferrioxamine. Ascorbic acid orally on days of chelation may increase urinary iron excretion. The recommended dose is 200mg for adults and 100 mg for children. There is a potential risk of increasing toxic iron levels and precipitating cardiac toxicity in patients who are heavily iron loaded and at risk of cardiomyopathy. Ascorbic acid should not be used on non-Desferrioxamine days in all patients and in the early stages of intensive chelation therapy for patients with cardiac failure or with myocardial T2* <10msec. 

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Management of thalassaemia intermedia, including haemoglobin E/β thalassaemia

Patients should receive regular folic acid supplementation.

After transfusion for an episode of acute anaemia, for example after infection, the patient should be observed carefully for several months to determine steady-state symptomatology and haemoglobin level.

The decision for regular transfusions should be made by the lead consultant.  Indications for long-term transfusions include symptomatic anaemia, falling growth velocity, delayed puberty, bone problems (facial deformities, recurrent fractures, premature epiphyseal fusion), pulmonary hypertension, symptomatic extramedullary haematopoietic masses, chronic ankle ulceration.

The rationale for transfusion should be carefully discussed with the patient and/or parents and family, perhaps over the course of several clinic visits. This will entail accepting the reality of a chronic condition in an older child, and preparing for the problems association with regular transfusion.

Where transfusion is started because of fall in height velocity or bony changes (often intermedia) it should not be assumed that lifelong transfusion will then be necessary. After maximum height is achieved, and bones are fused, in some cases it is possible to 'wean off' and then stop regular transfusions entirely, although the patient still needs to be carefully monitored for other complications.

Red cell units transfused must be phenotype compatible, and matched for ABO, Rhesus (C/c,D,E/e) and Kell.

Assessment of iron stores should take into account the severity of the anaemia, number of transfusions received, and clinical evidence of iron-related toxicity (heart, liver and endocrine disease).

As the serum ferritin is unreliable in thalassaemia intermedia, an additional measure of iron stores should be undertaken; this will usually be by a non-invasive MRI technique.

Liver iron concentration is the most important parameter for assessing iron overload in NTDT and should be assessed using Ferriscan or T2* MRI. Assessments should start from age 8 and repeated every 2-5 years.

Ferritin should be measured at least once per year, and correlated with LIC. Increasing ferritin levels (particularly > 800μg/l) should prompt a repeat LIC assessment.

Myocardial T2* should be considered for assessment of myocardial iron loading in older patients and those who require more frequent transfusions (3-6 per year).

Non transfusion dependent thalassaemia patients should be offered iron chelation therapy if ferritin is above 800 μg/l or liver iron is above 5 mg/g/dry weight.

Careful consideration should be given to the risks/benefits of splenectomy in these patients. The decision must be made after consultation with the lead consultant, and requires careful counselling and discussion.

Patients with thalassaemia intermedia should be transfused for several months prior to splenectomy to reduce spleen size, suppress marrow activity, and reduce the numbers of circulating, pro-thrombotic thalassaemic red cells.

Prior to the procedure, an abdominal ultrasound scan should be done to detect gall stones. If present, a cholecystectomy should also be considered. A wedge liver biopsy should be taken at the time of laparotomy, for histological assessment and analysis of liver iron content.

Thalassaemia intermedia patients should have regular echocardiography from age 15 years. Where echocardiography proves inconclusive in regard to pulmonary pressures, further investigation with cardiac MRI and right heart catheter studies should be considered to confirm the diagnosis.

If pulmonary hypertension is found, treatment with regular transfusion should be strongly considered. Regular transfusion is normally recommended for these patients.

Growth and pubertal development should be monitored regularly from the age of 10, and referral to the designated endocrinologist made if abnormalities are documented.

A period of regular transfusion during the years of peak potential growth and puberty should be considered.

Symptoms due to extra-medullary haematopoietic masses should be investigated, usually with MRI imaging, and treated. Radiotherapy can be considered if there is urgent need to reduce the mass; hyper transfusion and hydroxycarbamide act more slowly. Asymptomatic masses may require therapy depending on their position (eg if impinging on the spinal cord), but if not threatening vital structures, may simply be monitored.

Hydroxycarbamide therapy should be instituted only after careful definition of the expected benefits. The decision should be made with the Centre consultant. The patient should be made fully aware of possible adverse effects of the drug, and supplied with written information. It should be started at a dose of 10-15 mg/kg/day, and the full blood count monitored frequently. The maximal dose is not known, but it is unlikely that patients will tolerate doses in excess of 20-25 mg/kg/day.

(See LHP Sickle cell guidelines for more details).

Referral to the lead consultant for stem cell transplantation should be offered to families, for detailed discussion of transplant as an option.

Patients with moderate/severe thalassaemia intermedia should be reviewed at least annually at the specialist Centre.  

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Transition to adult services

Transition is ‘the purposeful planned movement of adolescents and young adults with chronic physical and medical conditions from child-centred to adult-oriented health care systems.’

The importance of transitional care has been highlighted in the Children’s National Service Framework Hospital Standards , Improving the transition of young children with long term conditions to adult health services and the intercollegiate report, Bridging the gaps: health care for adolescents. This includes a requirement for children and adult services to take the needs of this group of patients into consideration when planning and developing services.

Here at Leeds we follow the “Ready, Steady, Go” programme developed by Southampton University Hospital. This is a generic programme, as many of the problems faced by each sub-speciality group during transition are similar. Through this program we ensure the medical, psychosocial and vocational needs of the young person are being addressed by following a structured, but adaptable, transition plan. A key principle throughout the process is ‘empowering’ the young person to take control of their lives and equipping them with the necessary skills to be able to function independently and confidently in adult services.

The transition programme starts with a “Moving to Adults” information leaflet and a questionnaire which, through a series of structured questions, is designed to establish when the patient is likely to be ready to move to adult services and what needs to be done to get “Ready” for the move to adult services. In due course this is followed up by a questionnaire to assess progress and keep them “Steady” and ensure that they have all the skills to “Go” to adult services at a time which has been mutually agreed by the patient, medical professionals and where appropriate parents.

The programme is facilitated through our Annual Review Clinic. The idea of transition and the gradual switch of focus from parent to young person, should be introduced at the first Annual review visit, as part of an overview of what parents can expect from annual review sessions. 

The Moving to Adults Leaflet should be given to the young person when they move from primary to secondary education. Progress should then be assessed at each visit until the patient is ready to move to adult services.

At the point of transition to adult services, the annual review session will be attended by both Adult and paediatric Haematologists together with the Adult specialist nurse for red cell disorders and Charge Nurse for Paediatric Haematology.

Before the first appointment with adult services, the patient will attend a “Welcome to adult services” session. This session will include, a tour of the unit (outpatient clinic, day unit, in patients wards); information about how to book or rearrange an appointment and who to contact in an emergency.

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Clinic organisation

  • All regions in England should be covered by a clinical network incorporating local thalassaemia Clinics and one or more Specialised Thalassaemia Centres.
  • Procedures within the network should ensure that all patients have access to a specialist Centre, either for their regular care if living nearby or for regular review at least once a year, and for additional specific consultations as needed, if living more distantly.
  • A ‘Key Contact’ health professional will be designated for each patient.
  • Local Clinics and specialised Centres within the network, should record and exchange information relating to clinical events monitoring investigations, and changes in treatment.
  • Patients and carers should have access to peer support groups.

Patient-held records can be an effective way of transmitting information between clinical staff in different clinics, and also provide an opportunity for the patient to gain a better understanding and become more involved in their own care and monitoring.

Expectations of local Clinics

  • provide regular transfusions at times convenient to the patient and family, and prescriptions for chelation and any other necessary therapy
  • undertake regular blood tests and provision of compatible red cell units
  • monitor growth, and general health and wellbeing
  • organise some, or all, of the regular assessment tests
  • offer support to the patient and family.

Expectations of a thalassaemia Centre (in addition to the above) should:

  • offer consultation at specific key 'milestones' (at diagnosis, at initiation of regular transfusion, at initiation of regular chelation therapy, at transfer to adult clinic)
  • offer annual review for all the patients in the network, for overview of transfusion
  • chelation efficacy and side effects, and review of monitoring investigations
  • supervise complex management (eg switching chelation regime, problems with adherence to chelation, decisions about splenectomy , management of endocrine, bone/joint, cardiac, liver complications and fertility treatment, bone marrow transplantation, psychosocial issues)
  • guide management of acute clinical events, or take over care of such events by transfer of patient
  • supervise moderate to high intensity surgery
  • manage pregnancy
  • offer education and training for staff at local Clinics and the Centre
  • audit performance and outcomes
  • be involved in clinical research studies

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Provenance

Record: 2930
Objective:

Summary:
Guidance on the in patient and out patient management of children with thalassaemia and related disorders

Aims:
To improve the in patient and out patient management of children with thalassaemia and related disorders 

Objectives
To provide evidence-based recommendations for appropriate diagnosis, investigation and management of thalassaemia and related disorders

Clinical condition:

Thalassaemia

Target patient group: Thalassaemia, child
Target professional group(s): Secondary Care Doctors
Secondary Care Nurses
Allied Health Professionals
Adapted from:

Evidence base

References:

  1. Society for Adolescent Health and Medicine, 1993. www.adolescenthealth.org
  2. Getting the right start: National Service Framework for Children, Young People and Maternity Services: Standard for hospital services, 2003 Department of Health (Gateway reference 2003, product number 31352) (accessed 6 August 2010) http://www.dh.gov.uk/prod_consum_dh/groups/dh_digitalassets/@dh/@en/documents/digitalasset/dh_4067251.pdf
  3. Improving the transition of young children with long-term conditions to adult health services, 2006 Department of Health (Gateway reference 5914, product number 271588) (accessed 6 August 2010) http://www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/Browsable/DH_4132944
  4. Royal College of Paediatrics and Child Health. Bridging the gaps: health care for adolescents. London: RCPCH; 2003.
  5. Southampton University Hospital trust. Ready steady go programme. www.uht.nhs.uk/ OurServices/Childhealth/TransitiontoadultcareReadySteadyGo/Transitiontoadultcare.aspx

Approved By

Trust Clinical Guidelines Group

Document history

LHP version 5.1

Related information

Appendices

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Clinical features of thalassaemia

Beta (β) thalassaemia is a genetic disorder of haemoglobin production. It is inherited in an autosomal recessive pattern (apart from in vary rare 'dominant thalassaemia' mutations), and is common in people originating from the Mediterranean, the Middle East, South Asia, South East Asia and the 'Far East'. In the UK, β thalassaemia major is more or less restricted to ethnic minority populations, the largest groups being Cypriot, Indian, Pakistani and Bangladeshi. The disorder is due to a range of mutations associated with the beta globin gene, resulting in reduced or absent production of β globin, one of the constituents of the adult haemoglobin molecule (HbA). Reduced β globin production, leading to excess free α globin chains, damages red cell precursors in the bone marrow. This results in ineffective erythropoiesis, severe anaemia and compensatory erythroid marrow hyperplasia.

• β thalassaemia major

Haemoglobin production is so reduced that normal growth, development and quality of life can only be achieved by regular red cell transfusions from infancy. Death at an early age is inevitable if no transfusions are given. Where the term 'thalassaemia' is used without qualification, it usually refers to β thalassaemia major.

• β thalassaemia intermedia

A reduced amount of haemoglobin is produced, sufficient for growth and development without the absolute requirement for regular transfusions. Growth may fail, and other complications may develop, in later childhood and adulthood, requiring regular transfusions to start. The compound heterozygous states of β thalassaemia with a thalassaemic haemoglobin variant (Including HbE, Lepore, Knossos) or an alternative thalassaemic mutation (e.g. δβ thalassaemia) often result in a thalassaemia intermedia phenotype, but can cause thalassaemia major.

However, there is a continuum or ‘grey-scale’ of clinical severity, with no absolute cut-off between thalassaemia major and intermedia. The term ‘non-transfusion-dependent thalassaemia’ NTDT is now commonly used to describe those who may require occasional, but not regular transfusion, in contrast to those whose haematology, symptoms and signs have required them to be treated with regular transfusions - ‘transfusion-dependent thalassaemia’ or TDT.

• Haemoglobin H disease and Alpha (α) thalassaemia major

A result of deletion of three or four of the four globin genes or from non-deletional mutations which inactivate them. If all 4 α globin genes are affected, the result is typically intrauterine anaemia and usually the early stillbirth of a hydropic infant (Bart's Hydrops foetalis) as α globin chains are required to form foetal haemoglobin. The next most severe form of α thalassaemia, when 3 of 4 α genes are affected, is known as Haemoglobin H disease and is usually a mild condition with features typical of a chronic haemolytic anaemia, although a few individuals develop more severe problems, including transfusion dependency.

Babies with homozygous β thalassaemia are initially asymptomatic, as the major haemoglobin at birth is foetal haemoglobin (HbF). As a result of the physiological switch from HbF to HbA, the latter becomes predominant by about four to six months of age, and it is from this stage onwards that infants with thalassaemia major can become symptomatic. Clinically, the presentation is insidious, with poor feeding, faltering growth, pallor, and increased susceptibility to infection. If untreated, progressive anaemia and metabolic stress eventually cause heart failure and death. There is enlargement of the liver and spleen. The ineffective expansion of the erythropoietic marrow results in bone thinning and deformity. Untreated, children with β thalassaemia major die from heart failure or infection before the age of five.

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Haemoglobinopathy screening

Population and antenatal screening to identify carriers of β thalassaemia is technically easy and cheap. Identification of a carrier parent, usually the mother, followed by testing of the partner allows identification of couples at risk of having an affected child.

Newborn screening is primarily aimed at detecting babies with sickle cell disease, in whom early interventions can prevent fatal complications before clinical presentation. However, most babies with β thalassaemia major will be identified by the same screening test, and early diagnosis can reduce morbidity associated with late presentation, and anxiety for affected families.

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Iron Loading

Background

Iron overload in thalassaemia major, if untreated, is usually fatal in the 2nd or 3rd decade of life. Toxic effects are thought to be due to the appearance of non-transferrin bound iron (NTBI) in the plasma and toxic unbound iron in intracellular compartments. The majority of deaths, even when effective iron chelation therapy is available, are due to iron related cardiomyopathy, presenting as cardiac arrhythmias and cardiac failure. Iron toxicity also causes hypothalamic and pituitary damage resulting in growth hormone and gonadotrophin deficiency, presenting as short stature, delayed or absent puberty, and infertility. Other endocrine problems include glucose intolerance, diabetes mellitus, hypothyroidism and hypoparathyroidism. The liver is also an important site of iron toxicity: hepatic fibrosis can occur early in childhood eventually leading to cirrhosis, liver failure and hepatocellular carcinoma. Chronic hepatic complications are accelerated in the presence of chronic hepatitis C virus infection

Assessment and monitoring

It is important to record dates of transfusion, the patient's weight, the volume of blood transfused at each episode and the estimated haematocrit of the transfused blood (available from the blood transfusion laboratory). These data can be used to calculate annual transfusion intensity, expressed in ml/kg/yr of pure red cells, and average daily transfusional iron loading (expressed as mg/ kg/day), assuming 1 ml of pure red cells contains 1.08 mg of iron. Patients whose transfusion iron loading is more than 0.3 mg/kg/day, require higher doses of chelating agents to achieve negative iron balance.

Serum ferritin levels (monitored serially at least every three months) are simple to do, and are a helpful guide for monitoring chelation therapy. (Persistently high levels (>2500μg/l) are associated with an increased risk of cardiac disease and death and levels maintained in the range 500-1500 μg/l over the long term carry a relatively low risk. Ferritin levels are elevated during intercurrent acute infections, chronic inflammatory conditions and chronic viral hepatitis, and this leads to an overestimate of the degree of iron loading. Conversely, low levels may give a false reassurance.

Liver iron

Direct measurement of liver iron, Liver iron concentration (LIC), following needle or intra-operative wedge biopsy, provides an accurate measure of body iron stores however the method is invasive, iron deposition is patchy, and results show poor reproducibility, particularly if the biopsy is small or cirrhotic. The MRI T2* technique has the advantage that it can be done at the same time as the T2* cardiac scan but is probably less accurate in measuring liver iron levels, the normal level is about 0.2-1.6 mg/g dry weight (dw). The use of MRI scanning now enables safe, sequential assessment of liver iron, and with the current available data, it seems reasonable to aim for a level of 3-7 mg/ g dw.

Cardiac MRI

There is a relationship between low T2* and impaired LV function in patients on long term desferrioxamine chelation, LV impairment becomes increasingly likely when T2* falls below 20 milliseconds (ms). The authors recommend 20 ms as a cut-off for early detection of cardiac iron overload. One consistent finding in cross-sectional studies of patients on long-term desferrioxamine is a lack of correlation between myocardial T2* and serum ferritin or liver iron. Nearly all patients with clinical evidence of heart failure have a very low T2* (<10 ms).

It can be recommended for routine monitoring in children from 8 years of age and adults with thalassaemia.

Patients in the adult centre are monitored by ‘Ferriscan’, this option is being considered in the paediatric centre. One 2014 study compared a modification of T2* MRI with ‘Ferriscan’.  Although both methods showed a good linear relationship between LIC and MR parameter, the agreement of results between the two methods was inadequate over the range of clinically relevant values. This suggests that T2* MRI and ‘Ferriscan’ have different sensitivities to different forms of storage iron in the liver, and that the methods cannot be used interchangeably.

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Iron Chelation

Pregnancy

There are reports of serious adverse outcomes during pregnancy, including heart failure and dysrhythmias.

Renal impairment

Managing iron overload in patients with renal impairment or renal failure is challenging, and there are relatively few published data to guide recommendations. There are potential problems with all three licensed chelators.

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Referral for Consideration of Bone Marrow Transplantation Surgery, including Splenectomy

Current list of indications for stem cell transplantation can be found at bsbmt.org/indications-table.

Referral to unit stem cell transplant consultant lead for discussion about blood and marrow transplantation should be offered to parents when the child is 1 – 2 years of age. This is regardless of the availability of a matched sibling donor as subsequent children born to the parents may prove to be an HLA match and alternative donor transplantation could be considered.

It is especially important to discuss with families the major risks of transplantation including transplant related mortality and infertility. Fertility cryopreservation should be considered for all patients if applicable. The child should be included in the discussions in an age appropriate manner and this requires adequate provision of play specialists, psychology and clinical nurse specialists experienced in the procedure for thalassaemia.

There is a systematic ‘work up’ of the child pre-transplant, including assessment of renal and hepatic function, echocardiogram, lung function, dental assessment, and most important evaluation of iron load and optimisation of chelation pre-transplantation.

The evaluation of iron load and end-organ damage must include MR liver iron quantitation, also T2* of the heart if possible, under sedation if required in young children. A liver biopsy for the assessment of fibrosis is may be undertaken (Ishak staging).

Post-transplant follow up in the early months is at the transplant centre, with regular communication to the referring team.

In order to achieve the full benefits of a transplant, the patient’s iron load needs to be re-evaluated post-transplantation and interventions undertaken to normalise it. This involves as a minimum measurement of ferritin and MR liver iron quantitation. Usually iron load has increased due to the transfusion requirements of transplantation on top of the existing load at transplantation. Depending on the stability of the graft and venous access, reduction of the iron load is achieved either with venesections or chelation for a few months. It is usual to evaluate this around 6 months post-transplantation. The aim should be to normalise the iron load (ferritin ≤ 300 μg/l and MR liver iron quantitation showing < 3 mg/g dw)

Patients who have had a transplant should be followed up in a long-term effects clinic for transplanted patients. During follow up, pubertal development and fertility function should be assessed, and discussed with the patient and family, and genetic counselling offered.

Families should be aware that the child, when s/he grows up, needs to be advised that their partner needs early testing for thalassaemia or other haemoglobin disorders. The transplanted individual will still pass on the thalassaemic mutation to their offspring despite a successful transplant, so there would be a risk of significant haemoglobin disorder in their children if the partner was a carrier for thalassaemia, sickle cell, or other relevant variants.

If the mother of a child with thalassaemia becomes pregnant, prenatal diagnosis should be offered and if accepted HLA typing of the foetus can be undertaken. Cord blood stem cell harvesting should be offered to all families whether or not prenatal diagnosis has been undertaken.

Surgery including Splenectomy

Acute surgical presentations may include appendicitis, cholecystitis and fractures, particularly of the hip. Yersinia enterocolitica infection can mimic acute appendicitis, and it is extremely important to consider this diagnosis before undertaking unnecessary appendicectomy.

Any patient undergoing laparotomy should be considered for intra-operative open wedge biopsy of the liver. It is important not to miss this opportunity to stage liver disease and to assess body iron stores safely. Patients with thalassaemia major and intermedia are at increased risk of thrombosis, therefore perioperative thrombo-prophylaxis should generally be given to cover major procedures.

All patients undergoing planned surgery should have a clear management plan drawn up by the surgical, anaesthetic and Haemoglobinopathy Centre teams documenting their fitness for surgery for the patient with regard to cardiac, endocrine, hepatic and metabolic factors, and the timing of surgery should be planned and agreed.

All patients should have an individualised risk assessment for thrombosis and be appropriately managed to reduce the risk. Preparation for planned procedures should generally include a period of optimal chelation therapy, and a detailed cardiac assessment. Patients should also have a dental check. Endocrine or metabolic disturbance should be excluded or corrected, with particular attention to management of hypocalcaemia, diabetes, and hypothyroidism.

Surgery in thalassaemia major patients should be undertaken with optimal haemoglobin level (10-12 g/dl). In patients with thalassaemia intermedia, consideration should be given to a period of regular transfusion of several months before and after certain types of surgery, for example joint replacement, in order to suppress bone marrow and extra-medullary haematopoietic activity.

Transfusion requirements could be significantly decreased by splenectomy if requirements are more than 200-220 ml red cells/kg/year assuming haematocrit of packed cells 75% (Rebulla and Modell 1991). This equates to 250-275 ml/ kg/year of SAG-M, Buffy Coat Depleted Red Cells with a haematocrit of about 60%, currently supplied by the National Blood Service.

The risks of splenectomy include post-splenectomy sepsis, thrombocytosis and thrombotic complications particularly in thalassaemia intermedia patients who are not regularly transfused.

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Cardiac Complications

Cardiac monitoring for children under the age of 15 years should be supervised by the service paediatric cardiologist, and transfer to adult cardiac care should be planned in advance.

All patients should have access to T2* MRI scanning. Scans should be repeated every 2 years if T2* >20 ms, every year if T2* 10-20 ms, 6 monthly if T2*<10 ms, 3 monthly if T2*< 10 ms and any evidence of cardiac impairment. MRI monitoring should start from age 8 or earlier if initiation of chelation therapy has been delayed, or adherence is very poor.

Patients should have a regular Cardiology assessment, to include cardiac imaging and functional assessment. The frequency will depend largely on degree of iron overload, and we recommend that this is the same frequency as suggested for MRI scanning.

Any symptoms or signs suggestive of cardiac disease should be addressed immediately. Urgent referral to the Centre Cardiologist should be made, and if cardiac disease is thought likely, chelation therapy should be intensified. The findings, implications for prognosis, and treatment plan must be discussed in detail with the patient and the family. Support from the psychologist may be helpful in exploring treatment adherence issues.

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Endocrine Complications

Regular assessments of growth, including weight and height (standing and sitting), should be recorded every six months from diagnosis until final adult height is attained with referral to the service paediatric Endocrinologist if there is any concern.

Puberty should be systematically assessed annually from the age of 10, with referral to the service paediatric Endocrinologist if there is any suspicion of delay (no pubertal changes in girls by age 13 and boys by age 14) or arrested puberty (puberty starts but then does not proceed).

Appropriate investigations, replacement therapy, and planned management of problems are best achieved by joint consultation between the Endocrinologist, and the thalassaemia clinician, optimally in joint clinics.

Evidence of faltering growth (declining centiles for height and height velocity) is often apparent around the age 8-12. This should be investigated thoroughly with consideration given to desferrioxamine toxicity, and growth hormone deficiency. A growth hormone stimulation test should be administered, and if positive, growth hormone therapy instituted (Grade B).

Delayed puberty should be fully investigated. Adolescents with evidence of hypogonadism should be treated with hormone replacement therapy, under guidance from the paediatric Endocrinologist.

Surveillance needs to continue into adult life too for patients who have no pubertal problems in their teens, in case of secondary gonadal failure, impotence or infertility.

Glucose intolerance should be watched for, with random glucose levels every 3-6 months, and oral glucose tolerance tests annually from puberty or from age 10 if there is a positive family history. Calcium and phosphate levels should be checked every 3-6 months from age 12 and parathyroid hormone levels measured if low. Thyroid function should be assessed at least annually from age 12. Endocrine deficiencies should be treated with standard therapy.

Patients with diabetes should be managed according to standard recommendations for Type 2 Diabetes (Diabetes NSF) and in conjunction with the specialist diabetes clinic. Patients with impaired glucose tolerance (Fasting glucose <7mmol/l, 140 min glucose 7-11.5 mmol/l) should be monitored for diabetic complications, receive advice concerning diet and exercise, and should intensify chelation. Although oral hypoglycaemic agents can be sufficient, some patients will need treatment with insulin. HBA1C is unreliable after transfusion, and monitoring fructosamine levels can give an indication of glucose control.

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Liver Complications

Liver function tests and serum ferritin should be monitored every 3 months, and hepatitis virology every year. Adequate protection from hepatitis B virus should be ensured by a full course of vaccination initiated before the first transfusion, and then by serial monitoring of anti-HBs titre and 'booster' vaccination as needed.

Liver iron level should be maintained below 7mg/g dry weight. Assessments of liver iron should be made by MRI (R2 or T2*) rather than liver biopsy.

Patients with active hepatitis C infection (HCV RNA positive) should be referred to the designated Hepatologist for further virological studies (genotype, quantitation of viral load), histological staging and decisions about management. Anti-viral therapy should be considered even if liver disease is relatively mild, in view of the interaction between hepatic iron loading and hepatitis C infection.

Unexplained abnormalities of liver function tests should be investigated promptly. Liver biopsy remains the only modality able to provide a histopathological diagnosis.

Patients with established cirrhosis should be reviewed regularly, at least annually, by the designated Hepatologist. Surveillance for hepatocellular carcinoma (alpha fetoprotein, liver ultrasound or abdominal CT) is necessary, at least once each year, together with oesophagoscopy to examine for varices. Liver iron levels should be kept as low as possible in these patients, and anti-viral treatment should be considered if infected with hepatitis C.

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Bone Complications

Children with thalassaemia major should receive optimal transfusion to prevent excessive bone expansion

Dietary intake should be assessed and advice given to maintain an adequate intake of calcium and Vitamin D.

Children and adults should be encouraged to exercise regularly.

The recommended desferrioxamine dose in childhood should not be exceeded  

Regular assessment of sitting height, and in the case of bone or joint pains, radiological investigations should be undertaken to rule out desferrioxamine-related bone disease

Hormone replacement therapy should be initiated after discussion with the service paediatric Endocrinologist, usually by the age of 16yrs if hypogonadism is present, and other endocrine derangements have been sought and corrected

Bone mineral density in the hip and spine should be measured every 18 - 24 months, more frequently if there is concern, by dual energy x-ray absorptiometry (DEXA) in all patients over 10 years of age.

Established osteoporosis (Z score < - 2.5 in either hip or spine) should be managed with advice about diet, exercise, hormone replacement therapy, and bisphosphonate therapy in those over 16 years of age.

Patients with severe back pain should be carefully evaluated with MRI scanning. They should be referred promptly for orthopaedic advice and pain management.

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Dental care

Individuals with thalassaemia should have access to early, regular and preventive dental care. This will help reduce the impact of any associated oral features and allow dental development to be monitored. This should include preventive oral care, including fluoride application / prescription, fissure sealants, and dietary advice.  

Comprehensive oral assessment age 12-13yrs will enable planning for/prevention of difficulties from overcrowding/misplaced teeth.

Dental care should be delivered as a coordinated team approach. This will help to identify and manage the risk factors associated with thalassaemia and the potential associated co-morbidities. The appropriate setting for any given dental treatment, namely primary or secondary (hospital-based) care can then be determined.

Where dental infection is present, it should be managed early and aggressively.

Patients, especially those who have had the spleen removed, are at increased risk of infection following any dental procedures associated with bacteraemia, including extractions or scaling but oral co-amoxiclav, a dose before the procedure and continuing at 625 mg three times daily for 48 hours after, is usually given but advice form the dental team is needed.

If sedation or GA is planned, close liaison with the haematology team is required – this will allow transfusion to be arranged and the haemoglobin to be optimised. Inhalation sedation is preferable to intravenous sedation but may not be sufficient to enable the delivery of a longer/more complex treatment, particularly when the patient is very anxious.

Anaesthetists should also be made aware of any additional cardiac, liver and/or renal complications.

All patients should have a comprehensive dental assessment with their local dentist prior to starting bisphosphonate therapy to ensure that they are as dentally fit as feasible. To minimise the risk of osteonecrosis of the jaw, emphasis is on reduction of mucosal trauma and avoiding dental extraction where possible. Preventive dental advice should be given, emphasising the importance of reporting any symptoms such as loose teeth, pain, or swelling, as soon as possible.

For all patients with thalassaemia receiving regular transfusions, invasive dental care should be delivered as soon as possible after a planned transfusion, as the patient’s haemoglobin will be optimal.

Although there is a theoretical risk associated with local anaesthetic containing adrenaline (may lead to impairment of local circulation), this is used routinely for patients with thalassaemia without reported problems.

If maxillofacial surgery is planned for managing severe facial deformity associated with bone marrow expansion due to thalassaemia, careful consideration should be given to the medical and surgical risks, including the risk of more extensive bleeding from the hyper-vascular bone.

If a patient has spontaneous or chronic bone exposure, referral to an oral surgery/oral and maxillofacial surgery specialist should be considered. When a patient is already on bisphosphonates and a dental extraction is unavoidable, straightforward extractions can be undertaken in primary care, although a second opinion can be sought when necessary. Surgical extractions should be undertaken by a specialist in oral surgery/maxillofacial surgeon.

All patients should be advised of the risk of osteonecrosis of the bone pre-operatively and closely monitored post-operatively.

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Fertility and Management of Pregnancy

Iron chelation should be optimised from childhood, to reduce the risk of developing hypogonadotrophic hypogonadism and other endocrine disorders.

Where there is clinical or biochemical evidence of pubertal delay, including delayed pubertal growth, or other hormone disturbance, management by the service  Endocrinologist is required.

Early referral for discussion of fertility issues should be offered, even if not specifically requested, as some patients may hesitate to bring up the subject. This should be to a clinic experienced in treating patients with thalassaemia so that an informed and realistic discussion can take place. Input from other members of the multidisciplinary team may be helpful in this regard.

It is imperative that the couple is given the opportunity to discuss the risk of having a child with thalassaemia or other major haemoglobin disorder, for example sickle cell disease if the partner carries sickle cell trait. The partner must be offered a test and, if he or she carries thalassaemia or a variant haemoglobin, they should be counselled together about their options, and pre-natal diagnosis arranged if they wish. In discussing pre-natal diagnosis, the issue of incidental chromosomal disorders or other genetic conditions should also be considered. This may be particularly relevant if the marriage is consanguineous.

If there is any clinical or biochemical evidence of delayed puberty, referral to a specialist paediatric endocrinologist will be made promptly for appropriate management.

At a time of their choosing, patients with thalassaemia who are wishing to conceive will be referred to an endocrine/andrology clinic (men) or assisted conception clinic (women) with specific experience in managing people with thalassaemia. Both the thalassaemia patient and their partner will need to complete fertility investigations.

A woman must be fully pre-assessed as to her fitness for pregnancy before conception, spontaneous or assisted. This needs to be by an obstetrician experienced in the area, and there needs to be a discussion about possible risks.

These assessments should be up-dated no more than 12 months before conception

 

–A cardiology review including myocardial iron quantification by T2*, ejection fraction assessment, and an assessment for arrhythmias if there is a history of palpitations.

–Assessment for diabetes by a glucose tolerance test in non-diabetic patients and assessment of fructosamine for effectiveness of diabetic control in known diabetics. A target preconception fructosamine of < 300 nmol/l is desirable for optimal outcomes.

–Thyroid function should be normal before pregnancy, with or without thyroxine replacement.

–Patients who have been splenectomised need to be up to date with immunisations including pneumococcus, and all women should be fully hepatitis B virus immune.

–Bone density assessment, with treatment to improve this prior to pregnancy, if required.

–Women who are alloimmunised should be assessed for risk of risk of haemolytic disease of the foetus and newborn, including red cell phenotype/genotype of the father.

 

Medication review is required in a woman pre- and during pregnancy

–Folic acid 5 mg/day should be started 3 months prior to conception.

–Prophylactic penicillin V 250 mg twice daily should continue if splenectomised.

–Oral iron chelation drugs should be stopped 12 weeks prior to any planned fertility treatment or attempting natural conception.

–Desferrioxamine can be continued up to the day of ovulation for assisted conception or as soon as a period is missed and pregnancy test is positive in natural conception. –Most other medication should cease – particularly bisphosphonates and ACE inhibitors.

–If ACE inhibitors are required to improve arrhythmia, or intensive iron chelation necessary to reduce cardiac iron, conception should be postponed until these can be safely stopped or converted to alternative drugs that are safe in pregnancy.

–Vitamin D levels should be optimal pre conception and during pregnancy.

–Women with thalassaemia who have undergone splenectomy and / or have a platelet count greater than 600 x 109/l should commence or continue taking low-dose aspirin (75 mg/day) and they should be offered low-molecular-weight heparin thromboprophylaxis.

–Women with thalassaemia who are not already using prophylactic low-molecular-weight heparin should be advised to use it during antenatal hospital admissions.

 

General pre-pregnancy issues need to be considered, as for any other woman:

  • folic acid supplements (starting at least 3 months before conception)
  • red cell antibodies
  • rubella immune status
  • HIV
  • hepatitis C
  • smoking cessation/limitation of alcohol intake
  • review of any other relevant immunisations e.g. for hepatitis B, pneumovax, seasonal influenza.

It should be remembered that couples may be infertile for reasons unrelated to thalassaemia, and a range of investigations may be necessary to establish the nature of the problem.

Induction of ovulation or spermatogenesis may be required for patients who have hypogonadism, and treatment in a centre with experience of such patients will minimise the risk of hyper stimulation syndromes and multiple births.

Fertility treatment will be managed jointly between the endocrine / assisted fertility clinicians and the specialist haematologist.

Management of women in pregnancy and during delivery will be by an obstetrician with experience of women with thalassaemia, jointly with the specialist haematologist.

Women should be reviewed by the specialist cardiologist at 28 weeks gestation to assess cardiac function and help advise on plan for delivery

Mode of delivery will be discussed and planned in advance, taking account of any cardiac concerns and possible cephalo-pelvic disproportion.

If there has been operative delivery, or the woman has had splenectomy, is a smoker, or has any additional risk factors, VTE prophylaxis with low molecular weight heparin should be given for up to 6 weeks post-partum.

There should be an early review by the specialist haematologist, ideally before the woman leaves hospital, to discuss which medications usually including desferrioxamine iron chelation can be restarted immediately, and which need to be with-held until after breast feeding stops.

Although optimally managed men with thalassaemia may be spontaneously fertile, there should be planning for pregnancy as they need to stop oral iron chelators at least 3 months before conception, switching to desferrioxamine for that period. Other complications such as diabetes mellitus and hypothyroidism should be optimally managed before attempted conception.

Men who have hypogonadotrophic hypogonadism need to be referred to a specialist reproductive endocrinology clinic with experience in the management of men with thalassaemia. There should be realistic discussion about the likelihood of spermatogenesis induction, as treatment is long and may not be successful.

Patients who have undergone successful bone marrow transplantation for thalassaemia will still pass on thalassaemic globin genes to their children, so partner testing and counselling is required before any fertility treatment starts.

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Prenatal Diagnosis and Preimplantation Genetic Diagnosis

All couples at risk of having children with a thalassaemia disorder should be referred to specialist genetic counselling as soon as the risk is recognised.

Counselling is provided by a genetic specialist with specific experience in both prenatal diagnosis and preimplantation genetic diagnosis for haemoglobin disorders.

DNA analysis is provided for all at risk couples.

All at risk couples are informed of prenatal diagnosis (PND) and preimplantation genetic diagnosis (PGD) as options to achieve a healthy family.

A couple at risk of having a child with a thalassaemia disorder should be offered PGD if the female partner is under 40 years of age at the time of treatment, and there is no living unaffected child from the current relationship.

If the woman has a thalassaemia disorder, her treating haematologist should be involved in the management plan prior to PGD.

All at risk couples should be referred to a genetic specialist or genetic counsellor, with expertise in the genetic aspects of the haemoglobin disorders and prevention, to ensure the couple fully understand the risk of having an affected child and the benefits and limitations of available options for preimplantation genetic diagnosis and prenatal diagnosis.

DNA studies should be carried out on both partners.

The couple should be referred for PGD if they choose

Couples opting for PND should be given the contact details of the PND centre so they can self-refer as soon as a pregnancy is recognised, or the genetic counsellor should refer immediately on their behalf.

If the woman chooses to terminate an affected pregnancy following PND, this should be carried out as soon as possible and preferably within five days of the woman receiving the results.

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Equity and Diversity

The Leeds Teaching Hospitals NHS Trust is committed to ensuring that the way that we provide services and the way we recruit and treat staff reflects individual needs, promotes equality and does not discriminate unfairly against any particular individual or group.