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2071.02_abboud_abstr

Cerebral Infarcts in Patients with Sickle Cell Disease
Patients with sickle cell disease are at risk of stroke, transient ischemic attacks (TIA), and silent infarcts. Stroke may be defined as an acute neurologic syndrome that results from either vascular occlusion or haemorrhage, resulting in ischemia and neurologic symptoms or signs lasting greater than 24 hours and shows positive findings on imaging. In contrast, TIA is an acute neurologic syndrome with deficits lasting less than 24 hours and no positive findings on imaging. Silent infarcts are small infarcts, typically less than 15 mm, that are evidenced by MRI as areas of increased signal on intermediate or T2-weighted pulse sequences, but produce no Stroke management includes treatment of stroke, prevention of stroke recurrence, and prevention of primary stroke. Stroke is usually treated by simple or partial exchange transfusion, although exchange transfusion has demonstrated superior efficacy in reducing stroke recurrence. After initial stroke management, patients remain at risk of recurrence if not placed on a regimen of chronic transfusions. In the first 2 to 3 years, 70% of patients will have recurrent stroke; in contrast, chronic transfusions reduce the Due to the adverse events associated with chronic transfusions, hydroxyurea plus phlebotomy has been proposed as an alternative approach for secondary stroke prevention. However, the SWiTCH trial (N = 133), a randomized placebo-controlled trial, showed that patients who received hydroxyurea + phlebotomy had a marked increase in stroke recurrence compared with patients who received transfusion + chelation therapy (ie, deferasirox). In addition, the hydroxyurea + phlebotomy regimen was not superior to transfusion plus chelation in reducing iron overload. Primary stroke prevention utilizes transcranial Doppler (TCD) ultrasonography, based on the work of Adams et al that showed that high cerebral blood velocity, as measured by TCD, is associated with higher risk of stroke. Data from the STOP trial demonstrated that TCD screening, combined with long-term transfusion in those patients with abnormal TCD, significantly reduced the risk of primary stroke. A recent study in the Créteil newborn sickle cell anaemia cohort (N = 217) concluded that early TCD screening and intensification therapy (including transfusion for patients with abnormal TCD and/or stenoses, hydroxyurea to symptomatic patients with no macrovasculopathy, and stem cell transplantation for those with HLA- genoidentical donor) reduced the cumulative risk of overt stroke by age 18 years from 11% to 1.9%. However, the 50% cumulative risk of all cerebral events highlights the need for additional preventive intervention. Specifically, the high cumulative risk attributed to silent infarcts (37%) underscores that TCD does not screen for the risk of silent infarcts. In fact, most patients who develop silent infarcts have normal TCD. The STOP II trial looked at the effect of discontinuing chronic transfusion on stroke prevention in patients with sickle cell disease and was terminated after 2 years due to the finding that it was unsafe to stop transfusions in patients who are at high risk of stroke. Recently, a subanalysis of STOP II looked at the effect of discontinuing transfusions on silent brain infarcts in the same patient population. This analysis found that transfusions help prevent the development of silent infarcts in patients with abnormal TCD: 8.1% of patients in the continued-transfusion group developed new MRI lesions compared with 27.5% of the transfusion-halted group. Iron overload is an inevitable consequence of chronic transfusions but may be effectively managed with chelating agents, including desferrioxamine, deferasirox, and deferiprone (not licensed for sickle cell disease in the United States or the European Union). A recent Cochrane review of randomized-controlled trials that compared deferasirox with desferrioxamine found no statistically significant difference in measures of iron overload, including reductions in serum ferritin or liver iron concentration. Significant differences were found, however, in measures of satisfaction and adherence, with a three-fold higher rate of patient satisfaction and a six-fold higher patient estimate of likeliness to continue therapy with deferasirox. Suggested Readings
Abboud MR, Yim E, Musallam KM, Adams RJ. Discontinuing prophylactic transfusions increases the risk of silent brain infarction in children with sickle cell disease: data from STOP II. Blood. 2011;118:894-898. Bernaudin F, Verlhac S, Arnaud C, et al. Impact of early transcranial Doppler screening and intensive therapy on cerebral vasculopathy outcome in a newborn sickle cell anemia cohort. Blood. 2011;117:1130-1140. Josephson CD, Su LL, Hillyer KL, Hillyer CD. Transfusion in the patient with sickle cell disease: a critical review of the literature and transfusion guidelines. Transfus Meerpohl JJ, Antes G, Rücker G, Fleeman N, Niemeyer C, Bassler D. Deferasirox for managing transfusional iron overload in people with sickle cell disease. Cochrane Database Syst Rev. 2010;(8):CD007477. Verduzco LA, Nathan DG. Sickle cell disease and stroke. Blood. 2009;114:5117- Vichinsky E, Butensky E, Fung E, et al. Comparison of organ dysfunction in transfused patients with SCD or beta thalassemia. Am J Hematol. 2005;80:70-74. Ware RE, Helms RW. Stroke with transfusions changing to hydroxyurea (SWiTCH): a phase 3 randomized clinical trial for treatment of children with sickle cell anemia, previous stroke, and iron overload. Blood. 2010;116:Abstract 844.

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