This week our case involved the care of a 10 year old girl with SCD who had transfered her care to the UK. She presented in outpatient clinic for the first time and we had to determine her management. During subsequent screening she went on to have elevated transcranial Doppler results that lead to exchange transfusions. She then was changed to hydroxycarbamide therapy at her request after 2 years and full counselling.
An approach to a new SCD patient in clinic:
- Current symptoms: pain, infections?
- Previous admissions particularly focussed questions on any previous chest crisis/sequestration events.
- Previous transfusion history.
- Development and puberty – refer to endocrine if no signs after 14 years females and 14.5yrs males.
- Neurological issues?
- Drug history – Penicillin v and folic acid?
- Knowledge of local service and who to call for advice if concerns
- Family history – ? Any other family members at risk
- ? Registered on to National haemoglobinopathy database – leaflet available if patient not already registered.
- Growth and development. Pubertal features if of appropriate age.
- Check for murmur, jaundice, pallor and spleen size.
- BP – if elevated this is a risk factor for CVA in children.
- Urinalysis – only needed annually
- FBC, Retics
- Film (only indicated at first visit unless concerns)
- U&E and LFTs (baselines to compare if unwell) – interestingly 50% of SCD children will have gallstones by age 10 years.
- Blood group and extended phenotyping including ABO,RhDCcEe, Duffy type, S s including U typing if indicted, Kidd and Kell. Genotype may also be indicated looking for variety RHCE genes that are commoner in SCD population. Genotype will be required if had transfusion in last 3 months as serology won’t work.
- HPLC and a confirmatory test using another technique required if first presentation.
- Echo if murmur or low o2 sats.
- TCD screening indicated 2-16 years annually.
- MRI Brain indicated if headaches, developmental concerns or elevated TCD.
- MRI hip/shoulder if persisting pains in these areas as at risk of AVN.
- Penicillin V should be Rx from 3 months old as it has been shown that as Hb F falls there is a risk of hyposplenism.
- Folic acid.
- If travelling needs Men ACWY vaccines and malaria prophylaxis.
- Ensure had all childhood vaccinations including pneumococcal vaccine and the pneumococcal vaccine should be repeated 5 yearly.
- Annual flu vaccination
- Hep B vaccination
- Consider annual blood borne viral screening in regularly transfused patients.
Reviews should be 3 monthly up to age 2 years then minimum 6 monthly to 5 years and can be extended depending on clinical picture.
TCD screening indicated 2-16 years annually.
If TCD results 170-199 cm/sec warrants at repeat in 1-4 months maybe sooner if less than 10 years.
If > 200cm/sec may be a role in quick repeat scan prior to Rx depending on individual circumstances. If persistently abnormal to commence regular transfusions. Can review Tx after minimum of 1 year and consider transferring to hydroxycarbamide. If changing to HC needs slow taper of Tx after reaching HC max tolerated dose.
MRI/MRA Brain important if abnormal TCD to detect any subclinical infarcts (39% by 18 years will have evidence of silent infarcts) and assess for vasculopathy. As any evidence of this will lead to a regular transfusion plan for secondary stroke prevention.
Risk factors for CVA in children:
- TCD >200cm/sec
- Previous infrarcts
- Cerebral vasculopathy
- Recurrent Sepsis
- Rapid rise in Hb level
- Renal disease, Diabetes and Blood pressure
Evidence base that influenced the above:
- SIT trial 2014 (1) : Established TX as effective in secondary CVA prevention. RCT ,29 centres internationally with children 5-15 years with at least one infarcts on screening MRI scan. 196 children in total.Arms were std care (observe. no HC) Vs Tx >90g/l with aim HbS <30%. Results: 58% Relative risk reduction in recurrent infarcts in Tx group. Also improvements in QOL, priapism, AVN, Acute chest crisis and painful crisis (all stat significant) . NNT to prevent 1 CVA was 13. Though infarcts were still seen in Tx group suggesting in secondary CVA prevention transfusion not always effective.
- STOP trial 1998 (2) : Established role of Tx in primary stroke prevention. RCT with children SCD 2-16 years no previous CVA and Doppler USS abnormal >200cm/sec in MCA or ICA. High doppler pt randomised to std care Vs Tx with Hb S <30 and target Hb <120. Exchange or top up could be used. Once reached targets above transfused 3-4 weekly. Results:Trial stopped early as 92% RRR in Tx arm of CVA. NNT in treatment group 7 to prevent 1 CVA.
- STOP 2 2005 (3): stopping Tx in patients for primary prevention not safe. Extension of STOP study where children with high TCD who had normal dopplers after 30 or more months on Tx were recruited and any other children fulfilling same criteria. Must have normal TCD x2 and have had Tx for at least 24 times in the 30 month period and had HbS <30% on at least 20 out of 30 months. Assigned to a stop Tx group vs ongoing Tx. Results: trial stopped early as more CVA or abnormal Doppler results in STOP group (16 events: 14 abnormal doppler and 2 CVA in Stopped group vs none in ongoing Tx group) stat significant finding P< 0.001
- SWiTCH 2012(4): No excess CVA in secondary prevention CVA patients changed to HC but stopped early as liver iron loading between two arms equivalent. RCT recruited 134 patients non- inferiority trial looking at SCD patients with prev CVA and iron overload on transfusion for at least 18 months. Arms compared HC and venesection to Tx and chelation. Results: There were 7 CVA out of 67 pt in HC arm Vs none in Tx arm with CVA – still non inferior when trial stopped early due to evidence of equivalent iron loading.
- TWiTCH 2015 (5): confirms non inferior to transfer to HC after at least 1 year of regular Tx in patients with previously abormal TCD and no vasculopathy. Multicentre trial in USA and Canada, 121 patients age 4-16 years with abnormal TCD and non severe vasculopathy. Hydroxycarbamide arm patients started at 20mg /kg/ day and titrated to max tolerated dose with overlap median of 6 months with transfusion. Results: primary endpoint of similar TCD measurements at 2 years, P value 0.023. Some criticism that primary endpoint too short to establish if difference in groups.
Regular Tx: exchange Vs top up?
BSH guidance advises that either exchange or top up may be indicated for primary stroke prevention.
Points to consider:
- In this case the patients baseline Hb was on the higher side possibly increasing the risk of hyperviscosity if simple top ups used. This would also make reducing HbS to <30% challenging without getting Hb higher than advised 100-110 target.
- Iron overload: should have 3 monthly ferritin and liver scans 1-2 years to quantify overload if concern.Worsened overload in top up compared to exchange.
- Access problems- need line for exchange.
- Alloimmunisation rates similar for both techniques even though often more blood used in exchange.
If exchange used ideally blood should be ABO,Rh and Kell matched, Hb S neg, allo ab neg and less than 7 days old.
Patients on regular Tx should have HepB vaccines and annual blood borne viral monitoring.
Hydroxycarbamide initiation after primary stroke prevention:
TWiTCH supports changing from regular transfusion to Hydroxycarbamide after a minimum of 1 year of regular transfusion. Discussions regarding when and if this should occur need to be made on an individual basis.
Transfer to HC therapy should be gradual with initiation at 20mg/kg/day and slow titration to max tolerated dose with weaning blood transfusion volumes once MTD reached.
Patients should be counselled regarding need to stop Hydroxycarbamide 3 months prior to conception and that it has no effects on fertility.
Excellent overview of SCD in CNS disease:
DeBaun and Kirkham. Central nervous system complications and management in sickle cell disease. Blood 2016;127(7):829-838.
Useful UK guidelines:
Davis et al. Guidelines on red cell transfusion in sickle cell disease. Part I principles and laboratory aspects. BJH 2017 176 (2) 179-191.
Davis et al. Guidelines on red cell transfusion in sickle cell disease. Part II indications for transfusion. BJH 2017 176 (2) 192-209.
NHS screening programme. Sickle cell disease in childhood. Standards and guidelines for clinical care. 2nd edition October 2010.
1) DeBaun et al. Controlled trial of transfusions for silent cerebral infarcts in sickle cell anaemia. NEJM 2014;371:699-710.
2) Adams et al. Prevention of first stroke by transfusions in children with sickle cell anaemia and abnormal results in transcranial Doppler ultrasonography.
3) Adams et al.Discontinuing prophylactic transfusions to prevent stroke in sickle cell disease. NEJM 2005;353:2769-2778.
4) Ware et al. Stroke with transfusions changing to hydroxyurea (SWiTCH). Blood 2012;119(17) 3925-3932.
5) Ware et al. Hydroxycarbamide versus chronic transfusion for maintenance of transcranial flow velocities in children with sickle cell anaemia – TCD with transfusions changing to Hydroxyurea. (TWiTCH): a multicentre open label phase 3 non-inferiority trial. Lancet 2016 387; 10019 661-670.