The Progression and Development of Silent Infarcts in Children with Sickle Cell Anemia Is Prevented by Chronic Transfusions and Is Unrelated to Level of Hemolysis

Abstract

The risk for arterial strokes in children sickle cell disease can be predicted by measurement of cerebral blood velocity by transcranial dopppler ultrasonography (TCD) and decreased by institution of chronic transfusions. In the STOP II study, children with homozygous HbSS or HbSβ° with initial abnormal TCD who had been on chronic transfusion for at least 30 months and had normal TCD, while on transfusion, were randomized to either discontinue or remain on transfusions aimed at maintaining HbS levels below 30%. The patients were then followed for reversal back to abnormal TCD or the development of strokes. The study was stopped after 79 of a planned 100 patients were randomized as there were 16 events in patients randomized to discontinue transfusions as opposed to no events in patients randomized to the continue transfusion arm. Magnetic resonance imaging (MRI) was performed at base line before randomization, at the end of the study or at the time of suspected neurologic events, according to a standardized protocol. All images were reviewed for the presence size and location of ischemic lesions by experts unaware of the treatment assignment. Patients were stratified at randomization according to the presence or absence of ischemic lesions on MRI. We have analyzed data from the study to determine whether transfusion were effective in preventing the development and/or progression of silent ischemic lesions detected by MRI. Among the 79 patients in the study 21 (26.6%) had lesions while 58 (73.4%) had no MRI lesions at base line. At baseline there were no significant differences in age, hemoglobin, lactate dehydrogenase (LDH) levels and reticulocyte counts between patients with and without MRI lesions. Of the 58 patients with negative MRI 28 were randomized to the continue transfusion while 30 to the discontinue transfusions arms, reflecting the initial stratification. Their mean age was 12.6 and 11.6 years respectively. After a mean follow up time of 463.9 days 0/28 patients in the continue transfusion group as opposed to 6/30 patients, followed for a mean of 522 days, in the discontinue transfusion group developed new lesions (p=0.024). There were no significant differences in age, levels of hemoglobin, levels of fetal hemoglobin, LDH levels, reticulocyte count or bilirubin levels between the 6 patients who developed new lesions and the 24 who did not. Two of the six patients who developed new lesions also experienced a study end point and 4 did not. There was no correlation between the development of new lesions and initial abnormal TCD velocity in these 6 patients. When patients who either developed new lesions or had on increase in the total number of lesions were studied a total of 77 patients could be analyzed as 2 did not have follow up MRI. Fourteen patients were worse when compared to base line, 3/37 in the continue transfusion arm as opposed to 11/40 in the discontinue transfusion arm (p=0.03). There was no significant difference in age, hemoglobin level, LDH levels, reticulocyte count or fetal hemoglobin levels between the 11 patients who were worse compared to the 29 patients whose MRI remained unchanged while off transfusions. As expected, the majority of all ischemic lesions were distributed to the frontral and parietal white matter areas. We conclude that transfusions were protective against the development of silent infarcts in our selected subpopulation of sickle cell patients with abnormal cereberal blood velocity measured by TCD. Furthermore markers of increased hemolysis such as LDH, biluribin and reticulocyte counts were not associated with risk for the development of silent infarcts in our patients.