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

HbC

Codon 6 GAG-AAG

glutamic acid - lysine

HbS

Codon 6 GAG-GTG

glutamic acid - valine

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

Is HbSC different different to HbSS?

• Yes

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

KCC Transport in SCD

Increased KCC activity in HbSC

disease

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

TCD in HbSC Disease

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