Transfusional iron overload in children with sickle cell anemia on chronic transfusion therapy for secondary stroke prevention

Abstract Background: Children and young adults with sickle cell disease (SCD) are at high risk of strokes and are frequently treated with red blood cell (RBC) transfusions. RBCs may be given by simple transfusion, manual exchange transfusion (ME), or erythrocytapheresis (ECP) with a goal of suppressing hemoglobin (Hb) S while minimizing transfusion-induced iron overload. There have been no formal comparisons of these modalities, and practices for transfusion management vary among institutions. We compared transfusion therapy outcomes among patients with SCD undergoing transfusion therapy for primary or secondary stroke prevention, hypothesizing that children would be more likely to achieve Hb S suppression and ferritin goals while receiving ECP. We also compared complications of transfusion therapy across transfusion modalities. Methods: This is a single-institution retrospective cohort study of 38 patients with SCD who received chronic transfusion therapy for primary or secondary stroke prevention from 1/1/2008 through 12/31/2012. Per institutional practice, younger patients receive ME for stroke prevention; they are offered ECP when their size is adequate for a large-bore double-lumen implantable port, but may choose to continue ME. The pre-transfusion Hb S goal is <30% for at least 2 years, then may be liberalized to <50% for subjects without either abnormal transcranial Doppler ultrasound or infarct recurrence. Hb S percentage and ferritin were measured prior to each transfusion. Patients on transfusion therapy for 6 or more months were included; one child who had a stroke after brain tumor biopsy was excluded. Subjects were censored at last date of follow-up or date of hematopoietic stem cell transplant. The following factors were evaluated: duration and mode of transfusion therapy, achievement of Hb S suppression goal, ferritin levels, and catheter complications. Categorical variables were compared with Fisher’s exact test and medians with the Mann-Whitney U-test in SPSS version 21 (IBM, Armonk, NY). Results: During the study period, 38 subjects (42% male) met all inclusion criteria. Of these, 5 received exclusively ECP, 17 received exclusively ME, and 16 received both modalities during the study period. For the most recent 12-month period of data for each participant, 13 received ECP and 25 received ME. There was no association between modality of transfusion and the proportion of visits during which subjects achieved their pre-transfusion Hb S goal during the 12-month period. The median proportion of visits achieving the Hb S goal was 0.80 for ECP (IQR 0.40-1.0) versus 0.50 for ME (IQR 0.28-0.90) (p=0.27). Furthermore, there was no significant difference in ferritin concentrations between transfusion modalities: median 875 ng/ml for ECP (IQR 578-2659) versus median 1527 ng/ml for ME (IQR 731-2568) (p=0.56). Children who had ever received ECP had a significantly longer total duration of transfusion therapy (median 97 months, IQR 51.5-134) than those receiving ME only (median 28 months, IQR 12.5-47) (p<0.001). Among 21 subjects who had ever received ECP, 15 (71.4%) experienced one or more catheter complications, including infection, thrombosis, catheter leakage, or venous stenosis, compared with 1/17 subjects (5.8%) who had never received ECP (OR for catheter complications 40 for subjects who had ever received ECP, 95% CI 4.29, 372.4, p <0.001). Five subjects switched from ECP to ME due to stenosis of the great vessels that precluded double-lumen port replacement. Conclusions: Children with SCD receiving ECP and ME for stroke prevention in this cohort had similar achievement of Hb S suppression goals and iron overload management. Additional patient-specific factors may be responsible for variations in pre-transfusion Hb S and ferritin concentrations. Catheter complications were significantly more common in children and adolescents receiving ECP compared with ME, likely due to the large-bore double-lumen port utilized for ECP at our center. Disclosures No relevant conflicts of interest to declare.

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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 ◽

10.1182/blood.v116.21.844.844 ◽

2010 ◽

Vol 116 (21) ◽

pp. 844-844 ◽

Cited By ~ 2

Author(s):

Russell E. Ware ◽

Ronald W Helms

Keyword(s):

Clinical Trial ◽

Iron Overload ◽

Recurrence Rate ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Stroke Prevention ◽

Recurrent Stroke ◽

Stroke Recurrence ◽

Secondary Stroke Prevention ◽

Study Enrollment

Abstract Abstract 844 Stroke occurs in 5–10% of children with sickle cell anemia (SCA) and has a very high (50-90%) risk of recurrence without therapy. Chronic monthly erythrocyte transfusions are administered to prevent recurrent stroke, but their long term use is limited by incomplete protection and serious side effects, including alloimmunization and iron overload. An alternative to transfusion for secondary stroke prevention in SCA is needed, ideally one that also improves the management of transfusional iron overload. Stroke With Transfusions Changing to Hydroxyurea (SWiTCH) was an NHLBI-sponsored Phase III multicenter randomized controlled clinical trial for children with SCA, stroke, and iron overload (NCT00122980). The primary goal of SWiTCH was to compare 30 months of alternative therapy (hydroxyurea and phlebotomy) with standard therapy (transfusions and chelation) for the prevention of secondary stroke and reduction of transfusional iron overload. SWiTCH had several distinctive study features with novel methodological and design components, including a composite primary endpoint containing both stroke recurrence rate and iron burden, a transfusion overlap period in the alternative arm to reduce the risk of recurrent stroke until a stable hydroxyurea dose was reached, and an inclusive independent stroke adjudication process for all suspected new neurological events. An increased number of recurrent stroke events were predicted to occur in the alternative arm compared to the standard arm, but this risk would be balanced by improved management of transfusional iron burden by repeated phlebotomy. A total of 161 pediatric subjects (83 male, 78 female) with SCA, documented stroke, and iron overload were enrolled in SWiTCH between October 2006 and April 2009; after screening 133 were randomized and received study treatment (67 participants in the alternative arm, 66 in the standard arm). The average age at enrollment was 12.9 ± 4.0 years with an average of 7.0 ± 3.7 years of chronic transfusions for secondary stroke prevention; 12% had already suffered a recurrent stroke before study enrollment. The average baseline liver iron concentration (LIC) by biopsy was 15.5 ± 10.1 mg Fe per gm dry weight liver and most subjects were receiving oral chelation treatment at the time of study enrollment. At study enrollment, 28% of subjects had previously known RBC alloantibodies (most within the CDE-Kell antigen systems) and 16% had previous RBC autoantibody formation. Baseline laboratory and clinical parameters were well-balanced between treatment arms, although a higher number of subjects with moya-moya were randomized to hydroxyurea/phlebotomy. A scheduled interim data analysis was performed after 1/3 of the subjects had completed all exit studies. This analysis (which occurred with ∼80% of all patient-years of study treatment completed) concluded that the LIC was not statistically different between the two treatment arms so no increased stroke risk was justified. Accordingly, following review by the Data and Safety Monitoring Board, the NHLBI terminated the SWiTCH trial in May 2010; at that time, the on-study stroke recurrence rate was 7 of 67 participants in the alternative arm compared to 0 of 66 participants in the standard arm. At the completion of all study treatment, the recurrent stroke events remained at 7 versus 0 (alternative versus standard arm), while TIA events occurred in 6 and 9 subjects respectively, and deaths were equivalent (1 and 1, both unrelated to treatment). SWiTCH primary and secondary endpoint analyses are currently in progress and details of the study results will be presented. Disclosures: Off Label Use: Hydroxyurea is used to reduce complications of sickle cell anemia.

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Hepatic Iron Overload in Children With Sickle Cell Anemia on Chronic Transfusion Therapy

Journal of Pediatric Hematology/Oncology ◽

10.1097/mph.0b013e3181a1c143 ◽

2009 ◽

Vol 31 (5) ◽

pp. 309-312 ◽

Cited By ~ 33

Author(s):

Kathy Brown ◽

Charu Subramony ◽

Warren May ◽

Gail Megason ◽

Hua Liu ◽

...

Keyword(s):

Iron Overload ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Hepatic Iron ◽

Transfusion Therapy ◽

Hepatic Iron Overload

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Family Perceptions of Barriers and Facilitators of Treatment Protocols for Secondary Stroke Prevention in Children with Sickle Cell Disease

Blood ◽

10.1182/blood.v116.21.4805.4805 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4805-4805

Author(s):

Eve S Puffer ◽

Melanie J Bonner ◽

Courtney D Thornburg

Keyword(s):

Iron Overload ◽

Sickle Cell ◽

Stroke Prevention ◽

Recurrent Stroke ◽

Iron Chelation ◽

Secondary Stroke Prevention ◽

Treatment Protocols ◽

History Of ◽

Family Perceptions

Abstract Abstract 4805 Children with sickle cell anemia (SCA) and a primary overt stroke are at high risk of recurrent (secondary) stroke. Chronic blood transfusion (CBT) dramatically reduces but does not eliminate this high risk, and results in transfusion-related hemosiderosis. We previously reported the use of hydroxyurea/phlebotomy as an alternative to CBT to reduce the risk of secondary stroke and improve management of iron overload (Ware et al. J Pediatr 2004). This study examines the caregiver and child experience with secondary stroke prevention. Individual semi-structured interviews were conducted with primary caregivers and children/adolescents (age > 5 years) recruited from the Duke Pediatric Sickle Cell Program. The interviewer (E.P.) asked about perceptions of risk of recurrent stroke and iron overload with and without therapy and facilitators and barriers of therapy. Interviews were coded and analyzed independently by two investigators (E.P and C.T.). The sample included 14 youth (10 males) with a median age of 12.5 years (range 3–17). All primary caregivers were female. Twelve children had a history of overt stroke and 2 had a history of silent stroke. All children had experience with CBT and 9 were receiving CBT at the time of the interview. Eleven children had experience taking hydroxyurea and 5 were taking hydroxyurea at the time of the interview. All caregivers agreed that their child was at risk of recurrent stroke, identified benefit of current treatment and reported high motivation to adhere to treatment protocols. They noted significant impact that stroke had on school functioning, attention, personality, participation in sports and overall quality of life. Caregiver-reported barriers to CBT and hydroxyurea fell into three main categories: (1) missed work and school and related consequences; (2) unexpected resource-related challenges; and (3) inconvenience of clinic appointments, all of which contributed to burden on the family and sometimes missed clinic appointments and treatments. There were higher levels of concern expressed by caregivers of children on CBT related to the higher frequency and longer length of medical appointments compared with those taking hydroxyurea. The primary child-reported barrier was dislike of needles or shots (although this decreased with age as expected); those taking hydroxyurea also noted that they sometimes forgot to take the medication if they were busy with other activities or fell asleep. Caregiver-reported facilitators of CBT and hydroxyurea included: (1) understanding importance of stroke prevention and connection to consistent treatment; (2) ancillary benefits of treatments in addition to stroke prevention; (3) link between treatment and long-term benefits. Caregivers were able to overcome treatment barriers via the following: (1) logistical supports including appointment and medication reminders; (2) shared responsibility with other family members including the child; (3) trust in medical staff; and (4) faith. Although children disliked needles and shots, many enjoyed the clinic visits due to fun activities in the clinic setting and rewards. In addition, iron overload was a significant concern for caregivers. For those with children on CBT, knowledge of the risks of iron overload motivated adherence with oral iron chelation. Automatic refills facilitated adherence with chelation therapy, but the taste of the medication was a major barrier to adequate iron chelation. Caregivers of children taking hydroxyurea noted the benefit of avoiding iron overload. Of those who had undergone phlebotomy, in-home phlebotomy was noted as a facilitator, though requirement for IV contributed to negative perception. In summary, as clinicians review options for secondary stroke prevention with families, they should discuss family perceptions and individual barriers and facilitators which may impact adherence with therapy and long-term outcome. Future research should also investigate whether these family perceptions predict actual adherence to protocols and treatment outcomes. Disclosures: Off Label Use: Hydroxyurea for secondary stroke prevention in sickle cell disease.

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Encephaloduroarteriosynangiosis and encephalomyoarteriosynangiosis for treatment of moyamoya syndrome in pediatric patients with sickle cell disease

Journal of Neurosurgery Pediatrics ◽

10.3171/2014.12.peds14522 ◽

2015 ◽

Vol 16 (1) ◽

pp. 64-73 ◽

Cited By ~ 23

Author(s):

Christoph J. Griessenauer ◽

Jeffrey D. Lebensburger ◽

Michelle H. Chua ◽

Winfield S. Fisher ◽

Lee Hilliard ◽

...

Keyword(s):

Sickle Cell ◽

Stroke Prevention ◽

Pediatric Patients ◽

Case Series ◽

Secondary Stroke Prevention ◽

Moyamoya Syndrome ◽

Cell Disease ◽

Transfusion Therapy ◽

The Mean

OBJECT Pediatric patients with sickle cell disease (SCD) and moyamoya syndrome (MMS) are at significant risk for cerebrovascular accidents despite chronic transfusion therapy. Encephaloduroarteriosynangiosis (EDAS) and encephalomyoarteriosynangiosis (EMAS) are additional therapeutic options for these patients. To date, the incidence of complications after and efficacy of EDAS and EMAS in stroke prevention in this population have been described in several institutional case series reports, but no randomized prospective trials have been reported. METHODS The authors retrospectively reviewed the cases of all pediatric patients at the University of Alabama at Birmingham with a history of homozygous hemoglobin S (HbS) and sickle cell/β-thalassemia (SB0 thalassemia) and on chronic transfusion therapy, including 14 patients with MMS who underwent EDAS or EMAS. RESULTS Sixty-two patients with SCD and on chronic transfusion therapy were identified. After exclusion of patients on chronic transfusion therapy for indications other than stroke prevention, 48 patients (77.4%) remained. Of those patients, 14 (29.1%) underwent EDAS or EMAS. Nine (18.8%) and 25 (52.1%) patients were on chronic transfusion therapy for primary or secondary stroke prevention, respectively, but did not undergo EDAS or EMAS. The 14 patients with SCD and radiological evidence of MMS and on chronic transfusion therapy for primary or secondary stroke prevention underwent 21 EDAS or EMAS procedures for progressive vascular disease (92.9% of patients), stroke (71.4%), and/or seizure (7.1%). The mean (± SD) time from initiation of chronic transfusion therapy to EDAS or EMAS was 76.8 ± 58.8 months. Complications included 1 perioperative stroke, 1 symptomatic subdural hygroma, 1 postoperative seizure, and 1 case of intraoperative cerebral edema that required subsequent cranioplasty. Before EDAS or EMAS, the stroke rate was calculated to be 1 stroke per 7.8 patient-years. One additional stroke occurred during the follow-up period (mean follow-up time 33.7 ± 19.6 months), resulting in a post-EDAS/EMAS stroke rate of 1 stroke per 39.3 patient-years, a 5-fold reduction compared with that in the pre-EDAS/EMAS period. The patients’ mean pre-EDAS/EMAS HbS level of 29.5% ± 6.4% was comparable to the mean post-EDAS/EMAS HbS level of 25.5% ± 6.1% (p = 0.104). CONCLUSIONS The results of this retrospective case series in a large cohort of pediatric patients with SCD and MMS suggest that EDAS/EMAS provides a stroke-prevention benefit with an acceptably low morbidity rate. Given the combined experience with EDAS and EMAS for this indication at this and other institutions, a prospective clinical trial to assess their efficacy compared with that of chronic transfusion therapy alone is warranted.

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Hydroxyurea Reduces Conversion From Conditional to Abnormal TCD Velocities In Children with Sickle Cell Anemia (SCA)

Blood ◽

10.1182/blood.v116.21.270.270 ◽

2010 ◽

Vol 116 (21) ◽

pp. 270-270 ◽

Cited By ~ 1

Author(s):

Jennifer Rothman ◽

Shelly Burgett ◽

Russell E. Ware ◽

Courtney Thornburg

Keyword(s):

Sickle Cell ◽

Sickle Cell Anemia ◽

Stroke Prevention ◽

Normal Range ◽

Original Cohort ◽

Transfusion Therapy ◽

Hydroxyurea Treatment ◽

The Mean ◽

Flow Velocities

Abstract Abstract 270 The use of transcranial Doppler ultrasound (TCD), a non-invasive imaging technique, is now clearly established for detecting high risk of stroke in children with sickle cell anemia (SCA). Children with TCD flow velocities ≥200 cm/s have a 10% risk of primary stroke per year. For these children, chronic blood transfusions (CBT) are recommended and have been shown to reduce the risk of primary stroke by up to 90%. The incidence of stroke has decreased to 0.06–0.17 per 100 patient-years since the institution of TCD screening (Fullerton et al. Blood 2004; Enningul-Egham et al., J Pediatr 2010). Although patients with conditional TCDs (flow velocities 170–199 cm/s) have an estimated stroke risk of 2–5% annually, and their rate of conversion from conditional to abnormal is 23% over an 18 month period (Hankins JS et al., BJH 2008), there are no clinical guidelines for primary stroke prevention in this group. We previously conducted a prospective cohort study of hydroxyurea in 37 children with SCA and TCD velocities >140 cm/sec, and demonstrated that TCD velocities decreased significantly after starting hydroxyurea (Zimmerman et al., Blood 2007; NCT00402480). In order to determine if hydroxyurea provided sustained reductions in TCD velocities, we conducted a retrospective review of these 37 children in this original cohort who had elevated TCD velocities and long-term hydroxyurea treatment. The following data were abstracted from the medical record between April 2000 and September 2009: treatment with hydroxyurea and CBT; adherence with treatments; stroke and non-stroke neurological events; and TCD time-averaged mean velocities (TAMV) immediately prior to initiation of hydroxyurea and at the end of extended follow-up. The primary outcome was comparison of pre and post TCD TAMV using a paired t-test. The mean age of enrollment on the original study was 6.8 years (1.8-14.8) and the mean age at follow-up was 12.9 years (5.3-18.5). The mean follow-up was 5.8 years (0.8-8.5) with an overall follow up of 215.1 patient years. Twenty males and 17 females were enrolled. The mean hydroxyurea dose was 25.2 ± 5.6 mg/kg/day, with one patient discontinuing therapy after 15 months. At follow-up, the mean hemoglobin was 8.9 ± 1.2 g/dL and mean HbF was 16 ± 7.2%. Sustained decreases were observed in both the right MCA (164.8 ± 25.5 cm/s to 124.9 ± 35 cm/s, p<0.001) and left MCA (167.9 ± 25.2 cm/s to 126.9 ± 30 cm/s, p<0.001) for all 37 patients. For the 15 patients with conditional TCD velocities at enrollment, 13 had maximal TAMV that reverted to and were sustained in the normal range (185.8 ± 10.0 cm/s to 132.9 ± 14.5 cm/s, p<0.001). Two converted to abnormal TCD velocities at 1.6 years and 4.5 years for a conversion rate of 13%; one was non-adherent but the other was adherent with hemoglobin of 10.8 g/dL and HbF of 23.5%. These two patients were started on CBT and remain stroke free. There were no primary stroke events observed in the 15 subjects with conditional TCD velocities over a total of 78.1 patient years. Of the 5 patients who had abnormal TCD velocities on enrollment and whose parents refused CBT, 1 patient had a stroke after 0.8 years of hydroxyurea therapy. This was the only patient who continued to have abnormal TCD velocities at MTD, 7 months after starting hydroxyurea. The remaining 4 patients continued to have TCD velocities in the normal range off transfusion therapy over 26.3 patient years. Overall, these data illustrate that treatment with hydroxyurea at MTD in children with SCA and elevated TCD velocities resulted in significantly lower and sustained improvements in TCD velocities. Additionally, for children with conditional TCD velocities, hydroxyurea resulted in a lower than expected conversion to abnormal values, thereby sparing many children from CBT without any noted increase risk of stroke. Hydroxyurea did not, however, protect fully against stroke in one patient who had persistently abnormal TCD velocities and therefore CBT remains the standard of care in this population until larger randomized trials are conducted. Further studies are required to evaluate hydroxyurea for primary stroke prevention in children prior to conversion to abnormal TCD and in children who already have abnormal TCD. The currently funded TCD With Transfusions Changing to Hydroxyurea (TWiTCH) clinical trial, which is scheduled to begin enrollment in late 2010, will help answer this important clinical question. Disclosures: Off Label Use: Hydroxyurea is used to reduce complications of sickle cell anemia.

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Silent cerebral infarcts occur despite regular blood transfusion therapy after first strokes in children with sickle cell disease

Blood ◽

10.1182/blood-2010-01-261123 ◽

2011 ◽

Vol 117 (3) ◽

pp. 772-779 ◽

Cited By ~ 154

Author(s):

Monica L. Hulbert ◽

Robert C. McKinstry ◽

JoAnne L. Lacey ◽

Christopher J. Moran ◽

Julie A. Panepinto ◽

...

Keyword(s):

Magnetic Resonance ◽

Sickle Cell Disease ◽

Blood Transfusion ◽

Sickle Cell ◽

Stroke Prevention ◽

Secondary Stroke Prevention ◽

Cell Disease ◽

Cerebral Infarcts ◽

Eligibility Criteria ◽

Transfusion Therapy

Abstract Children with sickle cell disease (SCD) and strokes receive blood transfusion therapy for secondary stroke prevention; despite this, approximately 20% experience second overt strokes. Given this rate of second overt strokes and the clinical significance of silent cerebral infarcts, we tested the hypothesis that silent cerebral infarcts occur among children with SCD being transfused for secondary stroke prevention. A prospective cohort enrolled children with SCD and overt strokes at 7 academic centers. Magnetic resonance imaging and magnetic resonance angiography of the brain were scheduled approximately every 1 to 2 years; studies were reviewed by a panel of neuroradiologists. Eligibility criteria included regularly scheduled blood transfusion therapy. Forty children were included; mean pretransfusion hemoglobin S concentration was 29%. Progressive cerebral infarcts occurred in 45% (18 of 40 children) while receiving chronic blood transfusion therapy; 7 had second overt strokes and 11 had new silent cerebral infarcts. Worsening cerebral vasculopathy was associated with new cerebral infarction (overt or silent; relative risk = 12.7; 95% confidence interval, 2.65-60.5, P = .001). Children with SCD and overt strokes receiving regular blood transfusion therapy experience silent cerebral infarcts at a higher rate than previously recognized. Additional therapies are needed for secondary stroke prevention in children with SCD.

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Characteristics of Children with Abnormal TCD in the Modern Era: Results from the Displace Consortium

Blood ◽

10.1182/blood-2019-129951 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2270-2270

Author(s):

Julie Kanter ◽

Mary Dooley ◽

Logan P Sirline ◽

Martina Mueller ◽

Shannon Phillips ◽

...

Keyword(s):

Board Of Directors ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Stroke Prevention ◽

High Risk Group ◽

Phase Iii ◽

Dissemination And Implementation ◽

Advisory Committees ◽

Transfusion Therapy ◽

The Mean

Background: Stroke is one of the most devastating complications of sickle cell anemia (SCA). In 1998, the Stroke Prevention Trial in Sickle Cell Anemia (STOP), demonstrated that a high-risk group of children with SCA could be identified using Transcranial Doppler ultrasound(TCD) and that chronic red cell transfusion therapy (CRCT) could reduce the risk of first ischemic stroke in this group by over 90% (Adams, et al NEJM 1998).At STOP studyenrollment, 9.7% of children with SCA were identified as having an abnormal TCD. Baby HUG, (NCT00006400), an NHLBI supported phase III trial showed that severe anemia in SCA was associated with elevated white blood cell (WBC) and higher TCD velocities (Lebensburger, et al Blood 2010 ). It is unclear if lower hemoglobin (Hb) and/or higher WBC are causative of elevated TCD velocities or correlative biomarkers. As new disease therapies become available, it is important to know the current rate of abnormal TCD and characteristics of those patients. The DISPLACE (Dissemination and Implementation Looking at the Care Environment) project is a multicenter, NHLBI-funded study whose primary purpose is to identify barriers to implementation of stroke screening in SCA and test novel methods for improving outcomes. DISPLACE is a 3-part study: retrospective assessment of current practice, qualitative review of barriers and facilitators to screening and a cluster-randomized intervention implementation project to improve stroke screening. Part 1 of the study showedthat TCD screening rates varied widely among institutions ranging from 30-75.2% (mean 48.4%, median 47%). We are now reporting on the rate of abnormal TCD and the characteristics and outcomes of patients with abnormal TCD. Methods: DISPLACE is a consortium of 28 US centers. Each site performed a rigorous retrospective chart review of children with SCA aged 2-16 years from 2012-2016. To be eligible for inclusion, children must have been seen at their institution at least 2x during the study period and have confirmation of SCA. A custom electronic data capture (EDC) system facilitated entry of de-identified data including demographics, TCD and MRI results, medications, transfusions, and laboratory values. For children with SCA who had TCD or central nervous system imaging prior to 2012, these results were also entered into the EDC. TCD results were recorded in the EDC as normal, conditional or abnormal based on their institutional interpretation. Labs and vitals were entered for each patient in closest proximity to each TCD. Confirmation and adjudication of each abnormal TCD and associated outcomes were performed. Stroke status was also recorded as well as presence or absence of CRCT. Results: In total, 5247 children with SCA are included in the database of whom 5225 should have received a TCD. Of this cohort, 4210 children (80.6%) had at least one TCD recorded in the database. Within this group, 207 (4.9%) of children had an abnormal TCD and 816 (19.4%) had a conditional TCD. For those children who underwent TCD during the study (2012-2016) period, there were 105 (2.9%) abnormal TCD and 501 (13.6%) conditional TCD (Table 1). The mean age of children at the time of abnormal TCD was 6.6 years (range 2-16 yr). The majority of children were <10 yr at first abnormal TCD. Over 30% of patients with an abnormal TCD were identified as receiving hydroxyurea.The mean Hb associated with an abnormal TCD was 7.8 +/- 1.1g/dl (range 5.7-10.6) and the mean WBC was 13 x109/L+/- 3.6 (range 3.9-23.4) (Table 2). Of the 105 patients with abn TCD during the study period, 18% had a stroke. Of the total 5247 patients in the database, 3093 (59%) had been prescribed hydroxyurea (HU) and 999 (19%) were prescribed CRCT. CRCT was prescribed most often for abnormal TCD (37%) or secondary stroke prevention (31%). Discussion: DISPLACE is the largest contemporary cohort of children with SCA. The incidence of abnormal TCD in the DISPLACE cohort is significantly lower than at randomization in the STOP study. The number of children receiving CRCT is higher than expected which may partly account for the decrease in frequency of abnormal TCD. Many patients with abnormal TCD were receiving HU when their TCD was abnormal and were started on CRCT. Additionally, while the outcomes of children with conditional TCD are still being evaluated, many of those children reverted to normal TCD without intervention. These data may also help us redefine the use and interventions needed for abnormal TCD. Disclosures Kanter: NHLBI: Membership on an entity's Board of Directors or advisory committees; bluebird bio, Inc.: Consultancy; SCDAA: Membership on an entity's Board of Directors or advisory committees; Guidepoint Global: Consultancy; GLG: Consultancy; Sangamo: Consultancy, Honoraria; Modus: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Imara: Consultancy; Cowen: Consultancy; Jeffries: Consultancy; Medscape: Honoraria; Rockpointe: Honoraria; Peerview: Honoraria. Adams:GBT: Consultancy, Other: consultancy to companies GBT and Blueburd Bio; Bluebird: Consultancy.

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A Single Institution Study of Chronic Erythrocytapheresis for Secondary Stroke Prevention in Children and Young Adults with Sickle Cell Disease

Blood ◽

10.1182/blood.v120.21.4754.4754 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4754-4754

Author(s):

Nadia L Cheek ◽

Robert L Saylors ◽

Raghu Ramakrishnaiah ◽

Suzanne Saccente ◽

Xinyu Tang ◽

...

Keyword(s):

Sickle Cell Disease ◽

Iron Overload ◽

Sickle Cell ◽

Stroke Prevention ◽

Organ Damage ◽

Secondary Stroke Prevention ◽

Cell Disease ◽

End Organ Damage ◽

Children And Young Adults ◽

The Mean

Abstract Abstract 4754 Introduction: The current standard of care for secondary stroke prevention in children and young adults with sickle cell disease and cerebral infarction is chronic simple transfusion (ST). Published data indicate that at least 18% of patients treated with chronic ST will experience a second overt infarct and at least 28% will experience additional silent infarcts. Since 1996, we have used chronic erythrocytapheresis (RCE) instead of chronic ST in our hospital to treat all patients with either overt infarction or abnormal transcranial doppler (TCD) with silent infarction. Here we present clinical, radiographic, and laboratory data from this group of patients treated with chronic RCE for secondary stroke prevention. Methods: This was a retrospective study of all patients treated with chronic RCE for either overt infarction or for an abnormal TCD with silent infarction at Arkansas Children's Hospital from 1996 through 2011. We reviewed clinical records and serial MRI/MRA scans and determined the time to progression from the time of the initial diagnosis of an overt or silent infarct to the time of the second overt or silent infarct. Events were classified as overt infarcts if the MRI demonstrated acute cerebral ischemia, based on increased signal intensity on T2-weighted images and restricted diffusion on diffusion-weighted images, and abnormal neurologic findings correlated with the abnormalities identified on MRI. Events were classified as silent infarcts if the MRI demonstrated new lesions 3 mm or greater in a single dimension with increased signal intensity on T2-weighted images and there were no corresponding abnormal neurologic findings. We also studied the pre-procedure hemoglobin S concentration (%S), pre-procedure ferritin levels, volume of blood transfused per kilogram, necessity for chelation medication, and presence of end-organ damage. Results: We identified 24 patients, ranging in age from 2 to 18 years at the initiation of chronic RCE, who were treated with 2539 RCE procedures during the study period. These patients were treated with RCE every two to six weeks with the goal of maintaining their pre-RCE %S at less than 30%. Progressive cerebral infarcts occurred in 42% (10 of 24) of the patients while receiving chronic RCE (Figure 1): 3 were overt (13%) and 7 were silent (29%). There were no additional infarcts observed after patients had been on chronic RCE for greater than 5 years. Eight patients (33%) experienced increased vasculopathy and 3 patients (13%) had an improvement in vasculopathy while on therapy. The mean pre-procedure %S concentration was 29%. The mean pre-procedure ferritin was 1188 ng/ml but approximately 60% of the patients had ferritin levels under 1000 ng/ml and only three patients required chelation. Patients received a mean of 45.5 ml/kg of packed red blood cells per procedure. There was no evidence of end-organ damage secondary to iron overload. Discussion: We determined that children with sickle cell disease and cerebral infarction experience additional silent and overt strokes despite intensive treatment with chronic RCE. The proportion of patients developing new overt infarcts in our study (13%) was slightly lower than that in a recent multi-institution study (18%; Hulbert et al, Blood 117:772, 2011) but the proportion of patients developing new silent infarcts in our study (29%) was no different (28%). Although patients receiving RCE have increased blood product utilization as compared with patients receiving ST, only three patients required chelation medication and none experienced end-organ damage secondary to iron overload. We conclude that chronic RCE is no more effective than chronic ST for secondary stroke prevention, that chronic RCE prevents the iron overload and need for chelation that is common with chronic ST, and that other forms of therapy are needed to prevent the progressive accumulation of cerebral infarcts in these patients. Disclosures: No relevant conflicts of interest to declare.

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Effectiveness of a top up transfusion programme in preventing cerebrovascular damage in a birth cohort of sickle cell disease

The Physician ◽

10.38192/1.6.2.24 ◽

2020 ◽

Vol 6 (2) ◽

pp. 1-8

Author(s):

Nadia Ibrahim ◽

Sabah Mahmood ◽

Sandra O'Driscoll ◽

Subarna Chakravorty

Keyword(s):

Sickle Cell Disease ◽

Iron Overload ◽

Sickle Cell ◽

Stroke Prevention ◽

Cerebrovascular Event ◽

Secondary Stroke Prevention ◽

Cell Disease ◽

Hepatic Iron Overload ◽

Significant Burden ◽

Haemoglobin S

Regular transfusions are effective in managing strokes in paediatric sickle cell patients. However, there are associated risks, including alloimmunisation and iron overload. This study evaluated the efficacy of top-up transfusions in primary and secondary stroke prevention in a single tertiary paediatric centre in Central London. Forty-seven children with sickle cell disease who received transfusions in the last decade were included. No patient on a primary stroke prevention transfusion programme had a cerebrovascular event during the study period but 9.5% on secondary stroke prevention programme did. Twenty-one per cent of patients in this cohort converted to exchange transfusions following transfer to adult services, of which 11% had subsequent strokes. Targeted pre-transfusion haemoglobin S % was not always met; 43% of HbS% readings in a 12- month period were above the set target of 30% and 37% were above the set target of 50%. About a third of patients had evidence of severe hepatic iron overload, but no significant cardiac iron. 25% of patients became alloimmunised, but not severe enough to warrant discontinuation of the transfusion programme. Although transfusions are effective for primary stroke prevention, iron overload remains a significant burden.

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