Br J Haematol - 2023 - Bain - Significant haemoglobinopathies A guideline for screening and diagnosis

Significant Haemoglobinopathies: Guideline for Screening and Diagnosis (Br J Haematol 2023) EXECUTIVE SUMMARY • The British Society for Haematology (BSH) updated guideline outlines best‐practice screening, diagnostic, and laboratory standards for haemoglobinopathies in the United Kingdom. • It aligns clinical services with the National Health Service (NHS) Sickle Cell and Thalassaemia (SCT) Screening Programme and incorporates new technologies such as HPLC, capillary electrophoresis, mass spectrometry and DNA analysis. • Key objectives are: early identification of clinically significant sickle cell disease (SCD) and thalassaemia, provision of timely antenatal and neonatal results, appropriate partner testing, and robust quality assurance. KEY TOPICS & MAIN POINTS 1. Epidemiology & Pathophysiology – Globin-gene disorders constitute a major UK public-health issue; α-chain defects cause problems in utero, whereas β-chain disorders manifest after birth. 2. Indications for Testing – Pre-conceptual, premarital, antenatal, neonatal, pre-operative, opportunistic (GP/laboratory-triggered), microcytosis evaluation, monitoring of treated patients, and testing of recent UK arrivals. 3. NHS Screening Algorithms – High-prevalence areas (≥2 % screen-positive): universal laboratory testing + Family Origin Questionnaire (FOQ). – Low-prevalence areas (<1 % screen-positive): FOQ-led selective testing. – Provisional antenatal reports must be issued within 3 working days. 4. Laboratory Methodology – First-line: HPLC or capillary electrophoresis capable of quantifying Hb A₂ and Hb F and detecting Hb S, C, D-Punjab, E, O-Arab, Lepore. – Confirmation requires a complementary principle (e.g., CE after HPLC, DNA analysis, IEF, acid/alkaline electrophoresis). – Sickle solubility tests are for urgent/emergency use only and must always be confirmed. 5. Diagnostic Cut-off Values – β-thalassaemia trait: Hb A₂ ≥ 3.5 % plus MCH < 27 pg. – δβ-thalassaemia carrier: Hb F ≥ 5 % with MCH < 27 pg. – HPFH suspected when Hb F ≥ 10 % with normal MCH. – α⁰-thalassaemia suspicion: MCH < 25 pg in at-risk ethnicities. 6. Screening Timelines – Antenatal: initiate by 10 weeks, complete couple assessment by 12 weeks. – Neonatal: dried blood spot at day 5; follow-up before 90 days to start penicillin if SCD confirmed. – Infants <1 year entering the UK should be offered SCD screening. 7. Special Situations – Pre-operative detection of Hb S guides peri-operative management (cell-salvage, tourniquets). – Voxelotor therapy alters Hb patterns; labs must adjust reporting (combined “native + altered” percentages). – Hb H body staining is obsolete for α-trait discrimination but still useful in Hb H disease / ATR-X diagnosis. 8. Quality Assurance – ISO 15189 accreditation, participation in accredited External Quality Assessment (EQA) schemes, and compliance with NHS SCT Laboratory Handbooks are mandatory. IMPORTANT DETAILS & FINDINGS • High prevalence ethnic groups: African, African-Caribbean, Middle-Eastern, Indian, South-East Asian, Mediterranean (detailed in Table 1 of guideline). • Neonatal screen detects SCD genotypes, most β-thalassaemia major/TDT, many β-thal intermedia/NTDT, and some Hb H disease; it does NOT detect carriers of β-thal or Lepore, silent/near-silent mutations, or fully differentiate compound heterozygotes. • Laboratories must manage limitations due to recent transfusion, prematurity, and overlapping Hb variants. • Linkage between antenatal and newborn services via “At-Risk Pregnancy Alert” form is required to prevent missed or duplicated diagnoses. • Haemoglobinopathy cards and the National Haemoglobinopathy Registry facilitate patient identification and long-term care. ALL RECOMMENDATIONS Pre-conceptual / Premarital & Donor Screening 1. GPs should offer pre-conceptual haemoglobinopathy screening to people of child-bearing age in high-risk groups. 2. GPs should discuss and, where appropriate, offer premarital screening. 3. Assisted-conception clinics must screen both egg and sperm donors for relevant haemoglobinopathies. Antenatal Screening & Follow-up 4. All pregnant women must be screened following NHS SCT Programme guidance. 5. Significant Hb variants detected in antenatal samples must be confirmed by a different method. 6. β-thalassaemia carrier status should be diagnosed using MCH plus Hb A₂ percentage. 7. δβ-thalassaemia carrier status should be diagnosed using MCH plus Hb F percentage. 8. α⁰-thalassaemia carrier status should be suspected on MCH and ethnicity, and confirmed by DNA analysis in the mother (and father if also at risk). 9. Where the mother has β-thalassaemia or Hb E trait, the possibility of co-existing α⁰-thalassaemia should be assessed and, if relevant, confirmed by DNA testing. 10. A provisional antenatal report must be issued within 3 working days of sample receipt (process recommendation embedded in text). Neonatal & Infant Screening 11. Every newborn must be screened for SCD per National Screening Committee/PHE policy. 12. Babies showing only Hb F or very low Hb A must receive clinical follow-up and additional testing for β-thalassaemia major/TDT. 13. Any significant abnormality on newborn screen requires confirmatory testing to reach a definitive diagnosis. 14. All infants <1 year who newly enter the UK must be offered SCD screening. General / Opportunistic Testing 15. Clinicians should initiate haemoglobinopathy/thalassaemia testing when clinically indicated, with informed consent. 16. Laboratories should trigger further testing when routine results (including Hb A1c analysis) suggest a haemoglobinopathy. Pre-operative / Emergency Testing 17. Patients from ethnicities with appreciable Hb S prevalence must be screened for Hb S before anaesthesia. 18. If an emergency sickle solubility test is used, definitive confirmatory analysis is mandatory. Microcytosis & Diagnostic Work-up 19. Adults with unexplained microcytosis require clinical evaluation and testing for iron deficiency, anaemia of chronic disease, and thalassaemia according to indices and context. Monitoring & Special Therapies 20. Newly arrived patients with known or suspected SCD/thalassaemia must be fully investigated. 21. Patients with SCD on transfusion or hydroxycarbamide need appropriate laboratory monitoring (including Hb S and Hb F levels). 22. Patients with β-thalassaemia intermedia/NTDT on hydroxycarbamide or post-gene-therapy require Hb F monitoring. 23. Clinical and laboratory staff must remain vigilant for haemoglobinopathies whenever clinical/laboratory features suggest them. 24. Laboratories should recognise voxelotor-induced Hb alterations and, when needed, report combined (“native + altered”) Hb percentages. Laboratory Techniques & Interpretation 25. All abnormal screening results must be validated by a complementary method. 26. Antenatal laboratories must employ methods able to detect key variants and accurately quantify Hb A₂ and Hb F at programme action thresholds. 27. Hb A₂ should NOT be quantified by cellulose acetate electrophoresis with densitometry or by electrophoresis with elution. 28. Sickle solubility testing is generally unsuitable in infants <6 months; any solubility result (positive or negative) must be confirmed with definitive methods. 29. Iron-status assessment can aid interpretation but must not delay father testing in antenatal screening. 30. Examination for Hb H bodies is unreliable for α-trait screening and should not be used for that purpose. 31. Laboratories must understand disorders not picked up by current algorithms and the impact of transfusion on results. Service Integration & Communication 32. Each maternity service must have a written policy for linking antenatal and newborn screening, including use of the At-Risk Pregnancy Alert form. 33. Robust communication between antenatal and neonatal screening teams is essential to minimise anxiety, errors and missed diagnoses. Patient Identification 34. Haemoglobinopathy cards should be issued to individuals with major conditions. 35. Cards should also be given to carriers when a definitive diagnosis is established. 36. Cards should NOT be issued for presumptive α-trait unless DNA confirmation is available. Quality Assurance 37. Laboratories must participate in accredited EQA schemes and meet ISO 15189 and NHS SCT Laboratory Handbook standards. STATISTICS & DATA HIGHLIGHTS • High-prevalence threshold: ≥ 2 % antenatal booking samples screen-positive; low-prevalence < 1 %. • Foetal Hb F proportion: 90–95 % at 34–36 weeks’ gestation; falls to <2–3 % by 6 months post-natal. • Action limits: Hb A₂ ≥ 3.5 %; Hb F ≥ 5 % (δβ-trait) or ≥ 10 % (HPFH); MCH cut-offs 27 pg (β/δβ screener) and 25 pg (α⁰ suspicion). • Prophylactic penicillin in SCD: start by 90 days of age. • Screening timeline targets: antenatal couple completion ≤12 weeks; neonatal sampling at day 5; antenatal provisional report ≤3 working days. CONCLUSIONS The BSH guideline provides a comprehensive, evidence-graded framework for detecting and managing haemoglobinopathies across the UK. Uniform application of its recommendations—especially timely antenatal and newborn screening, confirmatory testing, modern laboratory methods, and stringent quality standards—should enhance early diagnosis, guide reproductive choices, reduce morbidity and mortality, and improve lifelong care for individuals with SCD, thalassaemia and related disorders.