Addition of Hydroxyurea to Transfusion Programme to Treat Progressive Cerebral Vasculopathy

Abstract 4813

Cerebro-vascular accidents (CVA) amongst paediatric patients with sickle cell disease (SCD) cause significant morbidity and mortality. Regular blood transfusions are used to prevent progressive cerebral vasculopathy. In primary stroke prevention, transcranial Doppler (TCD) studies are used to identify children at high risk of developing CVA and maintaining regular transfusion to keep HaemoglobinS (HbS) below 30% has shown to reduce this risk by 90%. However, about 10% children maintained on regular blood transfusions continue to have progressive vasculopathy despite maintaining HbS% below 30. There are few established options to try and prevent progressive vasculopathy despite adequate transfusion; possible approaches include intensifying the transfusion regime to maintain an even lower HbS%, revascularization surgery and correction of other thrombogenic risk factors. Hydroxyurea (HU) has been used in SCD to reduce the frequency of painful crises and acute chest syndrome. Its primary mode of action is thought to be to increase HbF levels but other mechanisms of action which may be beneficial include the reduction in white cell count, endothelium stabilization, improved expression profile of adhesion molecules, and nitric oxide donation. Herein we present our experience of combining treatment with HU to a transfusion programme in paediatric sickle cell patients with evidence of progressive cerebral vasculopathy whilst optimally transfused.

4 paediatric patients with SCD were transfused as secondary stroke prevention, but had progressive cerebrovascular disease on magnetic resonance imaging (MRI/MRA). Following detailed discussions with the parents, HU was started in addition to the transfusion to try and arrest the progression. The dose of HU was gradually increased whilst monitoring counts, assessing tolerability with a view to achieving doses of at least 25mg/kg. All patients had regular clinical review, full blood counts, HbF and HbS percentages monitored baseline pre and post transfusion. All patients had annual TCD to assess cerebral circulation flow velocities and MRI/MRA. Iron chelation was commenced or continued as appropriate to their clinical circumstances for secondary iron overload.

In this cohort, there were 2 females and 2 males, all of African descent. The mean age at diagnosis of first CVA was 5years (Range3-5yrs) with a mean steady state Hb of 7g/dl, mean HbF of 2.8% and mean HbS of 82.1%. MRI/MRA showed middle cerebral artery (MCA) cortical infarction in all patients at diagnosis but in addition showed varying degrees of areas of watershed infarction, small vessel disease with deep white matter ischemic change and moya-moya formation with small haemorrhages. The cohort remained on transfusions for a mean period of 55 months (Range 25–108) and received transfusions at a mean of 4 weekly intervals (Range 2–6 weeks). Mean Hb values post transfusion were 10.8g/dl with a mean HbF of 2% and HbS of 24.2%. TCD velocities in non-stenosed vessels showed a mean decrease in MCA by 26cm/sec (-11.8%), and in Internal carotid artery (ICA) by 14cm/sec (-8%). All 4 patients had evidence of clinical symptoms with new neurological deficits, and MRI/MRA scans showed a worsening picture of cerebral vasculopathy with increasing stenosis and new vessel formation. The mean duration of treatment with HU and transfusion was 18 months (Range 12–32months) with a mean Hb value of 11.4g/dl with a mean HbF of 5.8% and HbS of 14.6%. TCD on treatment with HU and transfusion showed a further mean reduction in flow velocity in MCA by 8cm/sec (-4.1%) in the non-stenosed vessels, and in ICA by 4cm/sec (-2.5%). MRI/MRA showed no evidence of progression. One patient had clinical symptoms of TIAs without further infarction and underwent neuro-revascularization.

Our study shows that a carefully selected cohort of paediatric patients with advancing cerebral vasculopathy, may benefit from HU in addition to transfusion with modest but clinically significant improvement in HbF% and TCD profile over and above the substantial improvement seen after transfusions. It is possible that this added benefit is by way of HU reducing vascular endothelial damage, mild increases in HbF% and as yet, undefined mechanism. Further, larger studies are needed to assess the value of combining HU and transfusion, although our experience suggests that it is safe, well tolerated and potentially beneficial.