Screening 8108 | Sickle Cell Disease | Stroke





Bio-Rad Variant NBS


Thal major
• Cannot justify screening programme • No early mortality • Most B Thal major picked up by absent A band

Sickle cell disease is the most common genetic condition in England, with higher prevalence than cystic fibrosis
Sickle Cell Disease1 Affects an estimated ~12,500 individuals Reported in more than 1 in 2,000 live births over 300 new births each year in England Highest prevalence occurring in people of African and AfroCaribbean origin, with birth prevalence as high as 1 in 300 in some areas (recessive) Cystic Fibrosis2 Affects an estimated ~8,400 individuals Reported in more than 1 in 2,500 live births Most common inherited disease of Caucasians (recessively


In the UK, sickle cell disease is as prevalent as cystic fibrosis – the only difference is in the ethnic group most likely to be impacted
1. Source: Development of transcranial Doppler screening services in England, Dianne Addei, Nov 2007 2. Source: Specialist Services National Definitions Set (2nd Edition)

Neonatal Screening for Sickle Cell Disease
• Heel-prick blood spot taken by midwife at 5-7 days • Blood spot sent to centralised neonatal screening laboratories – 12-13 in England • Spot analysed by HPLC or IEF • Hb variants confirmed by alternative method • Results sent out to Child Health, sickle cell counsellors, named paediatricians, depending on local arrangements

• • • • • • • • S/HPFH Post transfusion New mutations!! Thal intermedia Asylum seekers Family blame Other genetic disease Anger if don’t realise have been tested

4% 8% 6% 6% 8% 2% 45% 1% 7% 13% North East Yorkshire & The Humber West Midlands London SW NW E Mids East of Eng SE

Infection in sickle cell disease
• 600-700-fold increase in susceptibility to pneumococcal sepsis in first 2 years • 3 RCTs of penicillin prophylaxis show significant reduction in pneumococcal sepsis in under 5’s • Penicillin resistance increasing • Increased susceptibility to other encapsulated organisms - haemophilus, meningococcus • Seek advice if child febrile

Pneumococcal prophylaxis
Penicillin • Duration: lifelong throughout childhood Immunisation • Prevenar conjugate vaccine 7 valent covers 80% of serotypes causing disease • Pneumovax 23 valent vaccine covers 90% of serotypes

Severity of SCD
NEJM 2000 Dactylitis Hb <7g/dl Raised white cell count Early loss of splenic function HbF, βs globin gene haplotype nor presence of α thalassaemia not shown to be independent risk factors

Epidemiology • Childhood stroke in Baltimore Earley 1998
– overall incidence 1.3/100,000/y


285/100,000/y 0.61/100 pt yrs

• 250 times more common than other children • 25% of SS & 10% of SC stroke by 45

Rates of infarctive and haemorrhagic stroke in HbSS patients by age Ohene-Frempong 1998
Hazard Function



Ischaemic Stroke


Haemorrhagic Stroke Age years






TIAs, Stroke, Coma
9y girl HbSS, previously well, ‘Top of class’


Severe stenosis or occlusion of the terminal internal carotid artery / proximal middle cerebral artery with collateral vessels Yoon 2000

MRI findings

Effects of Iron Chelators on Liver Iron Concentration (LIC)
LIC: Good control with desferrioxamine or deferasirox; inconsistent effects with deferiprone
Deferasirox shown to maintain and reduce LIC in phase 2/3 clinical trials in adult and paediatric patients (12-month efficacy—LIC) 10 8 6 4 2 0 -2 -4 -6 -8 -10 Deferasirox Mean Change in LIC (mg Fe/g dw) β-thalassaemia SCD β-thalassaemia, MDS, other rare anaemias)


10 Doses (mg/kg/d)



Primary prevention?
Grade A evidence!

STOP trial
• Stroke Prevention Trial in Sickle Cell Anaemia • No previous history of stroke • Screened on 2 occasions for TCD velocity >200cm/s • 130 children randomly assigned to transfusion / supportive care • 10 cerebral infarctions in supportive care vs 1 in transfusion group (median FU 21 months) • Trial terminated early Adams, MD et al, NEJM 1998

• Problems • Chronic transfusion regime • Sensitisation 10% • 15% stopped transfusion unacceptable

UK childhood stroke guidelines
Primary prevention
• Children with haemoglobin SS or Sβo thalassaemia should be screened yearly from the age of 12 months for internal carotid artery or middle cerebral artery velocity >200cm/s using appropriately trained personnel and transcranial Doppler ultrasound (A) • Children with internal carotid artery/middle cerebral artery velocity >200cm/s should be offered long-term blood transfusion (A)

There are a number of sites particularly in London, where there are high numbers of children with sickle cell disease and no on-site TCD facility
North Middlesex


Newcastle Central Middlesex St Mary’s Leeds Manchester Sheffield Liverpool Nottingham Birmingham Leicester Northampton & Kettering Cambridge Milton Keynes Oxford Bristol Reading Southampton Plymouth Portsmouth Medway Maritime Hosp Luton London. University Hospital, Lewisham St George St Helier Ealing Hillingdon University College Guy’s & St. Thomas’s King’s College Whittington Royal Free Great Ormond St

Whipps Cross BHR Y

Royal London

River Thames
QE Hospital, Woolwich

Mayday University Hospital

Correlation between # children with sickle cell and lack of TCD provision Site with >100 children with sickle cell and no TCD facility Site with 50-100 children with sickle cell and no TCD facility

Source: Sickle Cell Anaemia Survey (May, 2008)

Therapy available/drivers
• • • • • • Improved symptomatic care Transfusion Hydroxyurea HSCT Improved psychologic and social care Drive from clients and health professionals to improve standards • Various NHS initiatives ,NSF etc

• Increasing emphasis on pro-active intervention • Identifying “ bad sickle “ looking for-• Abnormal TCD • Oxygen saturations • Early renal/lung disease • Falling school performance

UK Thalassaemia Register 1999: 807 patients / 164 doctors 71 only 1 attending 77 2 – 9 patients 8 10 – 30 4 > 50 11 doctors @ 9 sites saw 20 or more patients
? ? ? ?

The Process
• Define population at risk demographics, numbers and disease • what exists at present • what do we aspire to ,define standards • what is the gap • how to move from existing services to new clinical units • how to maintain /continually improve services

• Services best described as “patchy” • Little organisation about who does what • Particular concern is links or not of small units • Urgent need for standards and agreed networks of care

What existed in 2004
• No nationally organised network of care for patients with Haemoglobin disorders • Ad hoc arrangements around centres with interest and population • No data collection • No standards of care • Screening classic- chicken before egg !!

• • • • • Thalassaemia major completed 2006 sponsored by Thalassaemia society multidisciplinary group backing of DH main theme is promoting the development of a patient and family centred service .

Sickle Standards
• Again produced by multidisciplinary group including patient representative group Sickle cell society • Themes very similar to Thal • Define specialist units and relationship to smaller units • Defines good /best practice

Sickle (cont )
• • • • • Specifies penicillin prophylaxis Pneumococcal immunisation targets TCD targets Failsafe arrangements Again emphasis is on building on existing resources to ensure all have equitable access to both local and specialist care and that the role of each is defines

Clinical network arrangements:
1)Annual review of all affected infants by the specialist centre is recommended. 2)formalise existing informal networks is being developed with support from the DOH, BSH, the UK Forum Haemoglobin Disorders, the RCPCH 3)Support services for timely FU &Rx. 4)Experience from the USA shows that the main reason for the failure of the screening programme is the failure to ensure that identified infants are enrolled in a programme of treatment and care, or having been enrolled are subsequently lost to follow-up.

Specialist centres
• Local unit has designated centre • Annual review at specialist centre • Consideration of alternative treatment options such as hydroxyurea, transfusion programme, CBT, SCT • Links to specialist services

Specialist services
• • • • • • • • ENT Stroke screening, neurology Psychology - educational, clinical, CBT General surgery + anaesthetics Orthopaedics Endocrinology Ophthalmology HSCT

Local Inpatient management protocols
General • Pain relief • Hydration • Antibiotics • Oxygen saturations • Blood transfusion Specific • Acute chest syndrome • Stroke • Splenic sequestration + aplastic crises • Priapism

– need to move to a system of appraisal of networks – Quality standards defined – Pilot appraisal undertaken – proposed to undertake every 2 years – Who will be appraisers ? Must involve wide group of health professionals – Who will train ? – Who will pay ?

Cancer parallels
• In West Midlands 150 new cancers in children pa treatment lasts 1-3 years • 6-8 consultants with nursing , psychology and many other support services • Organised levels of care and Appraisal, high on public/managerial horizon • Haemoglobinopathy numbers on active treatment not that much less but huge gulf in resources available

There are a number of areas which require addressing in the shortterm in order to improve treatment of sickle cell disease
• Address gaps in TCD provision initially on Regional basis Enhance service provision • Address shortages in nursing (both hospital and community) and trained TCD ultrasonographers • Formulate a plan for direct access to medical advice/care Improve training & education • Improve education – particularly for non-haematologists:
(we GPs A&E doctors Anaesthetists are already addressing education of doctors, scientists and nurses)

• Ensure full involvement of key stakeholder groups: Raise the profile

- Royal Colleges - Royal College of Nursing - Royal College of Paediatricians Biannual then annual meetings of clinicians with key stakeholders ?advertising campaign

Capture key data

• Build a comprehensive, national database for capturing and analysing prevalence and treatment data and outcomes (NCEPOD)
(has been built but we need to encourage roll-out)

Provide better coordination

• Introduce regional and national roles for coordinating provision of services and best practice sharing
(initially using experience of DH (blood policy/clinical services) and then via exemplar sites)

• Involve the SC society who have done much in involving and informing patients

Outstanding issues
• Must move towards defining how an appraisal/audit of the clinical networks might work • Data collection probably should be inked to above ,live adverse event reporting • Must engage with local service planners and commissioners develop collaborative commissioning pathways .

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