hbsc disease –is it different and how should we manage it?
TRANSCRIPT
HbSC disease – is it different and
how should we manage it?
David Rees
Department of Paediatric Haematology,
King’s College Hospital, London
Different types of sickle cell disesease
• Severe sickle cell disease– HbSS
– HbS/β0thalassaemia
– Severe HbS/β+thalassaemia
– HbSOArab
• Moderate sickle cell disease– HbSC
– Moderate HbS/β+thalassaemia
– HbSDPunjab
• Mild sickle cell disease– Mild HbS/β++thalassaemia
– HbSE
– HbS/HPFH
HbSC
• Population genetics
– HbC polymorphic in West Africa
– Reduced risk of P falciparum malaria with HbAC
and HbCC
– 25% population in some areas of West Africa have
HbSC
– 25-30% cases of SCD in UK, USA
• 3000 – 5000 people with HbSC in UK
Diagnosis of HbSC disease
• Straightforward
• Suggested by blood film
• Haemoglobin analysis
• DNA analysis not usually necessary
– Unless unexpectedly severe phenotype
• Detected by neonatal screening
• Prenatal diagnosis offered in UK
HbSS HbSC P
N=300 N=84
age 9.9 9.9 0.95
Hb 8.3 11.0 <0.001
LDH 553 306 <0.001
MCH 27.8 24.8 <0.001
Wbc 11.7 7.9 <0.001
Vitamin D 13.7 14.3 0.65
reticulocyte 337 131 <0.001
bilirubin 57 22 <0.001
creatinine 50 57 <0.001
HbF 10.6% 3.0% <0.001
Peak TCD 128 cm/s 95 cm/s <0.001Internal carotid
blood flow166 cm/s 125 cm/s <0.001
Pathophysiology
• Typical red cell contains– 47% HbC, 47%HbS, 4%HbF, 2%HbA2
• Red cell dehydration occurs– HbC binds to red cell membrane
– Abnormal cation transport• Red cell dehydration
– Increased intracellular HbS concentration
– Deoxygenation worsens dehydration and causes HbS polymerization
• HbC crystals form in oxygenated state
K+
2. Psickle
3. Gardos channel
Cl-
DeoxyHb
Ca2+
1. KCl cotransport
Leaky red blood cells & disease progression
Normal
Swollenlighter
Shrunkendenser
Red blood cell shrinkage increases the concentration of HbS inside which greatly encourages polymerisation
Clinical Features of HbSC Disease
• Mortality
– Life expectancy 10-20 years greater than for HbSS
– Increased mortality evident only after the age of 20 years
– Median survival in USA
• 60 years for men
• 68 years for women
• Growth
– Normal height, weight
– Puberty at normal time
Stevens et al 1986
Clinical Features of HbSC Disease
• Acute pain
– Pain rate approximately half that of HbSS patients
– 0.4 episodes of acute pain per year
– 40% adults never experienced acute pain
• Acute chest syndrome
– Incidence similar to that in HbSS
– 30% patients affected
– Later onset than in HbSS and less likely to progress to
chronic lung disease
– Potentially more difficult to treat with higher haemoglobin
giving less scope for simple transfusion
Vichinsky at al 1997
Proliferative Retinopathy in HbSC Disease
• More common than in HbSS– Possible effect of increased blood viscosity
– Possible reduced damage to peripheral vessels results in more abnormal vessels
• 30% adults with HbSC have proliferative retinopathy (3% HbSS)– Clinically significant retinopathy in 8%
• Retinopathy rare before 14 years age
• 6% eyes of HbSC adults have significant visual impairment
Clarkson 1992, Condon et al 1972
Clinical Features of HbSC Disease
• Splenic function
– In children
• Splenic function preserved for longer
– normal at 4 years
• 6% children had splenic complications
– painful infarction, acute sequestration, haemorrhage
– In adults, on ultrasonography
• 50% have splenomegaly
• 40% asplenic
• 10% normal spleens
• 10% adults may benefit from splenectomy
Zimmerman et al 2000, Aquino et al 1997, Subbannan et al 2009
Clinical Features of HbSC Disease
• Renal complications
– Similar prevalence of papillary necrosis to HbSS
– 2.2% have chronic renal failure (half rate of HbSS)
– Median onset of chronic renal failure 25 years
later than in HbSS
Lesorbe et al, 1978
Clinical Features of HbSC Disease
• Cerebrovascular disease
– Stroke risk 50-100 fold greater than in general
population
– 2-3% patients have stroke
– Transcranial Doppler readings lower in HbSC than
HbSS
• Role of TCD not defined
Deane et al 2008
Clinical Features of HbSC Disease
• Pregnancy
– Pregnancy complications higher than controls
– HbSC sometimes first presents in pregnancy
– Pain, transfusion and UTI less common than in
HbSS
– ACS, hypertension, VTE similar incidence to HbSS
• Pulmonary hypertension
– Less common that HbSS but does occur
How should HbSC disease be
managed?
• No evidence interventions
• Management largely based on studies on
patients with HbSS
– Sometimes management inferred from studies of
HbSS
– Sometimes smaller numbers of HbSC incuded in
larger study
Pain in HbSC disease
• Precipitants not identified– Preliminary evidence suggests that environmental
factors may be different
• Intravenous fluids– Value unknown
• Oxygen– Unknown but theoretically harmful
• Increased cation red cell loss
• Formation of HbC crystals
• Transfusion rarely appropriate– Possible role for venesection
Infection in HbSC Disease
• Infection– Increased risk of infection but less than for HbSS
– Gram-negative bacteremia more prominent than pyogenic infections in HbSS
– Risk of septicaemia possibly greater in older children and teenagers
• Penicillin V
– PROPS study did not include children with HbSC disease
– usually prescribed for HbSC in UK as for HbSS
– In UK recommended life-long
– Increasing tendency to stop aged 5 years
– possible arguments for starting in later childhood
Lane et al 1994, Milner et al 1991
Management of HbSC Disease
• Primary Stroke Prevention
– Value of transcranial Doppler scanning undefined
– Possible role for children to have TCD at some point – eg at
5 and 10 years
– Different criteria needed for interpretation
– Abnormal > 130cm/s
• Silent cerebral infarctions
– Frequency and significance unknown
– MRI/MRA as clinically indicated
Miller et al 2001
Management of HbSC Disease
• Blood transfusion
– More likely to require exchange transfusion because of higher haemoglobin
– Transfusion targets based on keeping %HbS+%HbC below a certain level
• Perioperative management
– Not included in TAPS study
– 18% overall complication rate post-operatively
– In intra-abdominal surgery
• 35% incidence of ACS or acute pain in untransfused
• 0% incidence in transfused patients
Hydroxyurea and HbSC disease
• No randomised controlled studies
• Study of 15 patients from North America
– Yates et al, Paediatr Blood Cancer 2013;60:323-325
– HU dose: median maximum 24mg/kg
– No change in total Hb: 10.5 vs 1.8g/dl
– Increased MCV 72.5 vs 91.7fl
– Increased HbF: 2.2% vs 7.3%
– Reduced episodes of pain: 1.18 vs 0.44/year
– Reduced ACS: 0.24 vs 0 /year
– Recurrent thrombocytopenia main side-effect
Magnesium and hydroxyurea
• Randomised controlled trial in HbSC disese
– 5 – 53 years old
– Endpoint: reduction in hyperdense cells
• HU + placebo
• Mg + placebo
• Hu + Mg
• Placebo + placebo
– Stopped early because of slow recruitment
– Mg had no effects, but no effective inhibition of HbSC achieved
Conclusions
• HbSC is significantly different to HbSS– less severe– Much less evidence on management
• Need specific patient/parent information for children with HbSC– Currently not available
• Need to say different things to parents of neonates with HbSC– No evidence that splenic palpation is useful– 40% chance of being asymptomatic– Risk of life and organ threatening complications low
• Need research specifically on HbSC disease