HbSC disease is it different and how should we manage it? David Rees Department of Paediatric Haematology, King s College Hospital, London

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1 HbSC disease is it different and how should we manage it? David Rees Department of Paediatric Haematology, King s College Hospital, London

2 Different types of sickle cell disesease Severe sickle cell disease HbSS HbS/β 0 thalassaemia Severe HbS/β + thalassaemia HbSO Arab Moderate sickle cell disease HbSC Moderate HbS/β + thalassaemia HbSD Punjab Mild sickle cell disease Mild HbS/β ++ thalassaemia HbSE HbS/HPFH

3 HbSC HbS Codon 6 GAG-GTG glutamic acid - valine HbC Codon 6 GAG-AAG glutamic acid - lysine

4 HbSC Population genetics HbC polymorphic in West Africa Reduced risk of P falciparummalaria with HbAC and HbCC 25% population in some areas of West Africa have HbSC 25-30% cases of SCD in UK, USA people with HbSC in UK

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6 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

7 Is HbSC different different to HbSS? Yes

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9 HbSS HbSC P N=300 N=84 age Hb <0.001 LDH <0.001 MCH <0.001 Wbc <0.001 Vitamin D reticulocyte <0.001 bilirubin <0.001 creatinine <0.001 HbF 10.6% 3.0% <0.001 Peak TCD 128 cm/s 95 cm/s <0.001 Internal carotid blood flow 166 cm/s 125 cm/s <0.001

10 Pathophysiology Typical red cell contains 47% HbC, 47%HbS, 4%HbF, 2%HbA 2 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

11 Leaky red blood cells & disease progression 3. Gardos channel Swollen lighter Cl - K + Normal Shrunken denser 1. KCl cotransport Deoxy Hb 2. P sickle Ca 2+ Red blood cell shrinkage increases the concentration of HbS inside which greatly encourages polymerisation

12 KCC Transport in SCD

13 Increased KCC activity in HbSC disease

14 Clinical Features of HbSC Disease Mortality Life expectancy 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

15 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

16 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

17 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

18 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

19 Clinical Features of HbSC Disease Cerebrovascular disease Stroke risk 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

20 TCD in HbSC Disease

21 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

22 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

23 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

24 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

25 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

26 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

27 Hydroxyurea and HbSC disease No randomised controlled studies Study of 15 patients from North America Yates et al, Paediatr Blood Cancer 2013;60: HU dose: median maximum 24mg/kg No change in total Hb: 10.5 vs1.8g/dl Increased MCV 72.5 vs91.7fl Increased HbF: 2.2% vs7.3% Reduced episodes of pain: 1.18 vs 0.44/year Reduced ACS: 0.24 vs0 /year Recurrent thrombocytopenia main side-effect

28 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

29 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