Pathophysiology of cardiovascular disease in haemoglobinopathies and rare anaemias
Introduction to Haemoglobinopathies
Transcript of Introduction to Haemoglobinopathies
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Professors Baba Inusa
Guy’s and St Thomas’ NHS Foundation Trust
Introduction to Haemoglobinopathies
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Case Scenarios slides and group comments
Common Disorders of haemoglobin
Common sickle cell types
Management strategy
Summary
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Haemoglobin
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Baby – Hb F - 2 alpha/2 gamma
Adult - Hb A – 2 alpha/2 beta
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Human Hemoglobin Genes and Products
-globin gene
family
b-globin gene
family
“Embryonic”
“Fetal”
“Minor adult”
“Major adult”
Chromosome 16 Globin proteins Chromosome 11
Gower 1: z2 e2
Gower 2: 2 e2
Portland: z2 g2
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F: 2 g2
A2: 2 d2
A: 2 b2
Sickle Cell Foundation of Ghana
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The thalassemia continue to be an evolving global burden due to migration
1. Taher AT et al. Lancet 2018;391:155-167; 2. Weatherall DJ. Blood 2010;115:4331-4336; 3. Weatherall DJ. Blood Rev 2012;26S:S3-S6.
Predominance in low- or middle-income countries stretching from sub-Saharan Africa,
through the Mediterranean region and the Middle East, to South and Southeast Asia
Recent global population movements have also led to increasing incidences in areas of
the world previously relatively unaffected by these conditions such as Europe and the US
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14 month old immigrant to the UK
1. Born at term, no consanguineous parents
2. At 6 months sitting without support and crawling at 8 months
3. At 10 months less vigorous feeding and sleepy with periods of irritability
4. Blood test- Hb 70gm/L
5. No HbS/ or Hb C on electrophoresis
6. HbF%- 70%
• What additional information?
• Any more blood test?
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I am not the father
1. 2 months old baby diagnosed with sickle cell disease, the father is upset because premarital counselling testing did not find him to be carrier of either HbS or HbC? The mother of the baby insists he is the biological father.
2. A repeat tests confirms Sickle cell disease
• what are the possible explanations?
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Gladwin and Vichinsky NEJM 359:2254-2265, 2008
Hypothetical Mechanisms of SCD Clinical Subphenotypes
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SCD-SS SevereSFA2
SCD-Sbo thal SevereSFA2
SCD-S(db)o thal very mildSFA2
Variant Hbs in RBC Clinical Course
FS
FS
FS
Newborn > 6 mo.
SCD-S/HPFH AsymptomaticSFA2FS
Variants of Sickle Cell Disease
with Hb Phenotype Similar to SCD-SS
Hb level, MCV, A2 %, parental studies, helpful in diagnosis.
DNA-based mutation analysis essential for genotype establishment
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Alkaline Gel
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SCD Management in Early Childhood
• Even with limited evidence, maybe it works:
1979
2006
Hassell, Am J Prev Med 38:S512, 2010
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Survival in Pediatrics
Dallas Cohort2000-2007
Blood , 2010 Apr 29;115(17):3447-52
All patients: 94% HbSC: 98.4%
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Progressive Vascular Damage Results in Chronic Complications
Images with permission from Pr. P. Bartolucci.
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Normal spleen
Splenic sequestration
Splenic infarction
The Spleen inHbSS/Sβothal
Pneumococcal infection
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UK standards- 2019
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SCD Management in Early Childhood
• Even with limited evidence, maybe it works:
1979
2006
Hassell, Am J Prev Med 38:S512, 2010
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Antibiotic Prophylaxis – Childhood SCD
1. Prophylactic penicillin beginning age 2-3 months of life until the age of 5 (SS/Sβothal)
2. Evidence: Benefit early (PROPS I)
No clear benefit later (PROPS II)
NEJM 314:1593, 1986
Group Number of episodes
RR (CI)
Placebo 4 (2%)
Penicillin 2 (1%) 0.5 (0.1-2.7)
J Peds127:685, 1995
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Prophylactic Antibiotics
• Twice daily penicillin prophylaxis or alternative should be prescribed by 3 months of age and continued throughout childhood (A)
• Text specifies: Penicillin V should be offered to all children according to the following dosage schedule
• 62.5 mg po bid <1 yr
• 125 mg po bid 1-5 yr
• 250 mg po bid >5 yr
Erythromycin is a suitable alternative if penicillin allergy is documented
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Quality Indicators/Audit Standards
• US (Wang, et al)1. All children with FS on initial newborn screen should receive antibiotic
(eg, penicillin) prophylaxis by 2 mo
2. Children with sickle cell anemia who are younger than 5 yrs should receive antibiotic (eg, penicillin) prophylaxis
• UK (NHS 2010)
1. 90% of infants should have been offered and prescribed Penicillin V (or alternative) by 3 months
2. 99% of infants should have been offered and prescribed Penicillin V (or alternative) by 6 months
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Quality Indicators/Audit Standards
• US (Wang, et al)1. All children with FS on initial newborn screen should receive antibiotic
(eg, penicillin) prophylaxis by 2 mo
2. Children with sickle cell anemia who are younger than 5 yrs should receive antibiotic (eg, penicillin) prophylaxis
• UK (NHS 2010)
1. 90% of infants should have been offered and prescribed Penicillin V (or alternative) by 3 months
2. 99% of infants should have been offered and prescribed Penicillin V (or alternative) by 6 months
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NHLBI ER – Immunizations
• Assure that people of all ages with SCD have been vaccinated against Streptpneumoniae
(Strong Recommendation, Moderate-Quality Evidence)
• All individuals with SCD should receive immunizations according to the ACIP harmonized immunization schedule unless they have a personal contraindication
(Consensus–Adapted)
• All infants with SCD should receive the complete series of the 13-valent conjugate pneumococcal vaccine series beginning shortly after birth and the 23-valent pneumococcal polysaccharide vaccine at age 2 years, with a second dose at age 5 years.
(Consensus–Adapted)
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Immunisations
1. Immunisation against pneumococcal infection should include PCV13 and Pneumovax according to national schedules (C)
2. If PCV13 is not given during the first year, two doses should be given 2 months apart in the second year.
3. Pneumovax (23 valent polysaccharide pneumococcal vaccine) should be given in addition at 2 years (and 5-yearly thereafter) at least 2 months after PCV13.
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Performance thresholds: what to aim for Acceptable: ≥ 90.0%; Achievable: ≥ 95.0%
1. Specific positive disorders HbSS, HbSC, HbS/β thalassaemia (S/β+, S/β°, HbS/dβ, HbS/γdβ, S/Lepore), HbS/DPunjab, HbS/E, HbS/OArab, HbS/HPFH, Hb S with any other variant and no Hb A,
2. Rationale: To optimise individual health outcomes, penicillin prophylaxis should start by 90 days of age in children with sickle cell disease. Parents of infants with insignificant results must be reassured as early as possible.
3. Proportion of newborn infants with a positive screening result who are seen at a paediatric clinic or discharged for insignificant results ≤ 90 days of age.
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Summary
Malaria prophylaxis- standard care; Long acting treated bed nets:
Nutrition and Vitamin D supplementation
Stroke prevention using TCD screening and blood transfusion
Hydroxyurea as primary and secondary stroke prevention
investigative- what is the most reliable chemoprophylaxis
Penicillin prophylaxis in children 0-5 reduces Mortality by 70%, coupled with
pneumococcal vaccination
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1. SCT screening pathways: https://www.gov.uk/government/publications/sickle-cell-and-thalassaemia-screening-care-pathway
2. SCT screening programme handbook: https://www.gov.uk/government/publications/handbook-for-sickle-cell-and-thalassaemia-screening
3. Parents information leaflets: https://www.gov.uk/government/collections/adult-carriers-sickle-cell-thalassaemia-unusual-haemoglobin
4. Education: https://www.gov.uk/guidance/sickle-cell-and-thalassaemia-screening-education-and-training
5. Standards: https://www.gov.uk/government/publications/sickle-cell-and-thalassaemia-screening-programme-standards
6. Population Screening Programmes: https://www.gov.uk/topic/population-screening-programmes
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14 month old immigrant to the UK
1. Born at term, no consanguineous parents
2. At 6 months sitting without support and crawling at 8 months
3. At 10 months less vigorous feeding and sleepy with periods of irritability
4. Blood test- Hb 70gm/L
5. No HbS/ or Hb C on electrophoresis
6. HbF%- 70%
• What additional information?
• Any more blood test?
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I am not the father
1. 2 months old baby diagnosed with sickle cell disease, the father is upset because premarital counselling testing did not find him to be carrier of either HbS or HbC? The mother of the baby insists he is the biological father.
2. A repeat tests confirms Sickle cell disease
• what are the possible explanations?