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strokes in sickle cell disease: prevention and treatment 2nd pan-european conference on haemoglobinopathies berlin, 13

Incidence of stroke decreased after the STOP trial. Fullerton HJ, et al. Blood. 2004;104:336-9.. Since the publication of the STOP trial in 1998, the annual rates of stroke for children in California have declined. Agenda. The incidence and risk factors for stroke Why do children with SCD have strokes?Prevention of strokeSTOP I and STOP II trialsimpact of hydroxyureathe role of HSCT.

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strokes in sickle cell disease: prevention and treatment 2nd pan-european conference on haemoglobinopathies berlin, 13

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    3. Agenda The incidence and risk factors for stroke Why do children with SCD have strokes? Prevention of stroke STOP I and STOP II trials impact of hydroxyurea the role of HSCT

    4. Correlation of CVA type to age of patients with SCD Ohene-Frempong K, et al. Blood. 1998;91:288-94. CVA = cerebrovascular accident.

    5. Age at first CVA is linked to SCD genotypes Ohene-Frempong K, et al. Blood. 1998;91:288-94.

    6. Stroke statistics Incidence of stroke is 1.02% per year between 2 and 5 years of age Clinical evidence of stroke occurs by 20 years of age in 11% of patients with SCD More than half the patients who have had a first stroke experience a recurrence Ohene-Frempong K, et al. Blood. 1998;91:288-94. Fullerton HJ, et al. Blood. 2004;104:336-9.

    7. Location of cerebral vasculopathy in SCD Overt strokes distal internal carotid artery and anterior and middle cerebral arteries can be affected Silent infarcts affect 20–35% of children with SCD usually occur in the deep white matter of the frontal and parietal lobes and to a lesser extent in the basal ganglia or thalamus 70% of cases are bilateral are associated with cognitive defects and risk of overt stroke Switzer JA, et al. Lancet Neurol. 2006;5:501-12.

    8. Risk factors for cerebrovascular accidents in SCD Infarctive stroke1 prior transient ischaemic attack (RR: 56; IC95%: 12–285) low steady-state haemoglobin concentration rate of and recent episode of acute chest syndrome elevated systolic blood pressure Genetic factors2 Silent infart3 Haemorrhagic stroke1 low steady-state haemoglobin high leucocyte count Others past history of bacterial meningitis is significantly more frequent in SCD patients with CVA4 nocturnal hypoxemia; mean overnight Sa02 was independently associated with time to CNS event5 Ohene-Frempong K, et al. Blood. 1998;91:288-94. Hoppe C, et al. Blood 2003;101:2865-9. Hoppe C, et al. Br J Haematol 2005; 128: 751-66.4. De Montalembert M, et al. Eur J Pediatr. 1993;152:201-4.5. Kirkham FJ, et al. Lancet. 2001;357:1656-9.

    9. Agenda The incidence and risk factors for stroke Why do children with SCD have strokes? Prevention of stroke STOP I and STOP II trials impact of hydroxyurea the role of HSCT

    10. Cerebral vasculopathy in SCD Switzer JA, et al. Lancet Neurol. 2006;5:501-12.

    11. Classic example of cerebral vasculopathy in SCD Merkel KH, et al. Stroke. 1978;9:45-52.

    12. Platt OS. N Engl J Med. 2005;353:2743-5.

    14. Agenda The incidence and risk factors for stroke Why do children with SCD have strokes? Prevention of stroke STOP I and STOP II trials impact of hydroxyurea the role of HSCT

    15. Stroke risk increases with TCD flow rate Adams RJ. Control Clin Trials. 1998;19:110-29.

    16. Most patients with abnormal TCD had normal MRA, except those with >>200 cm/sec TCD often detects flow abnormalities indicative of stroke risk before MRA lesion become evident MRA substudy of the STOP study

    17. The probability of remaining stroke-free is greater with long-term transfusions in children with SCD Adams RJ, et al. N Engl J Med. 1998;339:5-11.

    18. Chronic transfusion may be required for high-stroke risk patients 79 subjects having normalized TCD under transfusion were randomized 38 to continue cRCT therapy 41 to discontinue cRCT therapy No neurological events in the cCRT group 1. Adams RJ, et al. N Engl J Med. 2005;353:2769-78. cRCT = chronic red cell transfusion.

    19. Stroke-prevention strategies Prevention of a first stroke annual TCD from 2 years of age on1,2 monthly transfusion in children with abnormal TCD velocities (> 2 m/s in internal carotid or middle cerebral artery on 2 occasions)1 Prevention of secondary stroke chronic transfusions to maintain ~30% HbS1 hydroxyurea and phlebotomy (Phase III Stroke With Transfusions Changing to Hydroxyurea [SWiTCH trial])3 1. National Institutes of Health. The management of sickle cell disease. 4th ed. 2002. (NIH publication No 02-2117) www.nhlbi.nih.gov/health/prof/blood/sickle/index.htm; 2. Roberts L, et al. Ann Hematol. [Epub ahead of print 2009 May 20]. 3. Aygun B, et al. Br J Haematol. 2009;145:524-8.

    20. Experience of the Hôpital Necker in the prevention of cerebral vasculopathy AbnlTIA = abnormal transient ischaemic attack; BMT = bone marrow transplantation.

    22. Chronic transfusion practices in the SWiTCH trial Ongoing: the SWiTCH study randomizes children with previous stroke to standard therapy (transfusion and chelation) or alternative therapy (HU and phlebotomy) – 295 American SCD children with previous stroke receiving chronic transfusions were identified at 23 institutions Mean age at initial stroke: 6.0 ± 2.9 years Mean duration of transfusion therapy: 6.1 ± 3.8 years Overall average pre-transfusion HbS: 35 ± 11% Aygun B, et al. Br J Haematol. 2009;145:524-8. HU = hydroxyurea.

    23. Consequence of stroke prevention with blood transfusions Adams RJ, et al. N Engl J Med. 1998;339:5-11.

    24. Hydroxyurea for cerebral vasculopathy:what are the pros and cons? Stroke recurrence rate was 10% for those who discontinued blood transfusions and were treated with HU after an overlap period1 No strokes were observed in 34 patients at risk of first strokeby TCD after HU treatment and follow-up of 96 patient-years2 HU treatment decreased TCD velocities in 21 patients with conditional and abnormal velocities; 1 neurological event occurred during the study3 Several reports of CVA, some of them fatal, in patients treated with HU 1. Ware RE, et al. J Pediatr. 2004;145:346-52.2. Gulbis B, et al. Blood. 2005;105:2685-90.3. Zimmerman SA, et al. Blood. 2007;110:1043-7.

    25. The role of HSCT in stroke prevention: the French experience Bernaudin F, et al. Blood. 2007;110:2749-56. EFS = event-free survival; GVHD = graft-versus-host disease;OS = overall survival; RM = transplantation-related mortality.

    26. Summary Sickling of red cells, intimal thickening of the large intracranial vessels, superimposed thrombosis, increased adhesiveness of sickle cells to the vascular endothelium, procoagulant state, and nitric oxide depletion related to haemolysis may contribute to the development of stroke in patients with SCD The incidence of stroke is high in children with SCD Chronic blood transfusion therapy can decrease the risk of primary and secondary stroke Early intervention is needed to prevent worsening of cerebral vessel damage Repeat blood transfusions can lead to iron overload Stroke is considered an indication for BMT in children and adolescents who have siblings with identical HLA HU therapy to prevent strokes in SCD is debated

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