Chronic Red Cell Transfusion Therapy Research Articles

Successful Implementation Trial to Improve Stroke Risk (TCD) Screening in Children with Sickle Cell Anemia: A Roadmap to Care Enhancement

Stroke remains a devastating complication of sickle cell anemia (SCA). The STOP (Stroke Prevention Trial in Sickle Cell Anemia) protocol adopted in 2014 by the National Heart Lung and Blood Institute (NHLBI) guidelines includes stroke-risk screening using transcranial Doppler ultrasound (TCD) and prevention with chronic red cell transfusion therapy (CRCT). Theserecommendations were reinforced by the American Society of Hematology guidelines.However, despite the evidence supporting TCD screening in stroke prevention, the DISPLACE study (Dissemination and Implementation of Stroke Prevention Looking at the Care Environment) showed that real-world implementation was insufficient. To evaluate and improve sickle stroke screening, we conducted the NHLBI-funded multi-center DISPLACE study to identify barriers to TCD implementation and test novel methods for improving outcomes. DISPLACE is a 4-part study: 1) Retrospective calculation of TCD screening rates; 2) Assessment of barriers and facilitators; 3) Implementation trial to improve TCD screening and 4) Comparison of implementation sites to controls. Importantly, DISPLACE is the largest prospective study of children with SCA. This study employed a multi-level, multi-faceted cluster-randomized study of interventions to improve implementation rates of TCD. Methods: DISPLACE is a 28-center US consortium representing a range of: regions (urban vs rural), size (patient number), and institution type (academic vs community). In Part 1, sites performed a rigorous retrospective review of TCD screening from 2012-2016 to collect baseline rates. Part 2 included a barriers and facilitators assessment to TCD screening to inform the trial interventions: 1) Re-branding TCD as Sickle Stroke Screen, a meaningful name for SCD stakeholders; 2) Using a Single Coordinator (SC) for each site's TCD scheduling, and follow-up; 3) A custom designed provider-focused application, ProviderMinder TM (PM) created to remind providers to track TCD appointments and follow-up on results. When a TCD was due, PM alerted the provider to enter scan results or reason(s) missed. Once the TCD results (normal/conditional/abnormal) were entered in PM, providers were prompted to enter the next TCD date and/or intervention plan (if not normal). If a result was not entered, PM alerted the provider q3 days until the TCD was recorded as completed or rescheduled. The implementation trial (parts 3 and 4 of DISPLACE) included 16 sites that had the lowest TCD rates in part 1. The implementation trial included children with SCA aged 2-7 years (the group at highest risk for an abnormal TCD). Cluster randomization was used to allocate sites to PM alone (8 sites) or PM + SC (8 sites). The primary outcome was comparison of TCD rates between PM and PM+SC sites. Secondary outcomes included comparisons between 1) Part 3 sites' TCD rates and Part 1 baseline rates 2) Part 3 sites and control sites (to assess the impact of the educational rebranding of TCD). Results: Part 1 included 28 centers with 5246 children with SCA. Of the 16 intervention sites, 3 sites could not implement the interventions due to administrative issues but remained in the study and were re-designated as “control sites” and a 4th control site was added (they were not informed prospectively to avoid bias). Thus, there were 13 evaluable sites for the primary endpoint including 776 patients; 484 in sites using PM and 292 in sites using PM+SC. Control sites included 185 patients. The trial demonstrated superiority of the PM arm compared to the PM + SC arm (P<.0001 year 1 and p=0.002 year 2) in both years of implementation and in comparison, to the control sites (P<.0001 year 1, p=.009 year 2) with an overall improvement in mean TCD screening from part 1 by 25% (table 1). Conclusions: This was a highly successful implementation study in SCA. This study emphasizes the importance of performing barrier and facilitator assessments when introducing new guideline-recommended screenings into clinical practice. These findings also highlight the importance of ongoing quality assurance in SCA to ensure prevention practices are maintained. Despite the benefit of TCD (sickle stroke screening) in children with SCA, implementation was poor prior to these interventions. Results from this study will guide ongoing optimization of TCD screening and demonstrate the importance of adopting these interventions in the real world.

Dissemination and Implementation Looking at the Care Environment (DISPLACE) Study Evaluates Novel Interventions to Improve TCD (Sickle Stroke Screening) Implementation

Background: Stroke is a devastating complication of sickle cell anemia (SCA). The STOP (Stroke Prevention Trial in Sickle Cell Anemia) protocol was adopted in 2014 by the National Heart Lung and Blood Institute (NHLBI) guidelines for stroke-risk screening using transcranial Doppler ultrasound (TCD) and prevention with chronic red cell transfusion therapy (CRCT). These guidelines were upheld in the recent American Society of Hematology guidelines. Despite strong evidence supporting TCD screening (and CRCT initiation) in stroke prevention, wide scale implementation has not been achieved 4. DISPLACE (Dissemination and Implementation Looking at the Care Environment) is a multicenter, NHLBI-funded study conducted to identify barriers to TCD implementation and test novel methods for improving outcomes. DISPLACE is a 3-part study: 1) Retrospective assessment of current practice; 2) Assessment of barriers and facilitators; and 3) Implementation trial to improve TCD screening. This report focuses on Part 3. Methods: DISPLACE is a 28-center consortium across the US representing a range of: region (urban vs rural), size, and institution type (academic vs community). During Part 1, sites performed a rigorous retrospective chart review of children with SCA aged 2-16 years from 2012-2016 to collect baseline TCD rates. Part 2 included a rigorous mixed methods of the barriers and facilitators assessment to TCD screening was performed that resulted in 3 main interventions: 1.Re-branding TCD as Sickle Stroke Screen, a meaningful name selected by patients/families with SCD; 2. A Single Coordinator (SC) for each site's TCD screening, scheduling, and follow-up; 3. A newly designed application, Provider Minder (trademarked; PM). PMwas created to remind providers of patient appointments (versus reminders only sent to patients/families). Data entry in PM included birth date (to calculate age), city/state of residence, distance from SCD clinic and insurance. Date of last TCD was recorded to calculate date of next screen. When the TCD was due, the system alerted the provider to enter appointment completion or reason(s) why it was missed. TCD results were entered for PM to prompt for the next TCD date in a 10-14 month window (normal screens), 2-6 weeks (conditional screens), and intervention plan (abnormal screens): repeat scan in <2 weeks or other. If the provider failed to enter a patient's result, PM alerted the provider q3 days until the TCD was recorded as completed/rescheduled. Part 3 included 16 sites who successfully completed data entry in Part 1 and had the lowest TCD implementation rates. Part 3 inclusion criteria were the same as Part 1 except to specifically select children with SCA now aged 2-7 (the highest risk group to have an abnormal TCD in Part 1). All 28 sites received re-branding educational material (also disseminated to non-study sites). Cluster randomization was used to allocate sites to PM (8 sites) or PM + SC (8 sites). The primary outcome is which intervention results in the best TCD rates. Secondary outcomes include Part 3 sites’ improvement in TCD rates (compared to historical rates) and impact of the educational/rebranding of TCD to "Sickle Stroke Screen” in sites (4) that did not participate in Part 3. Stroke status, presence of CRCT after an abnormal TCD, missed TCD appointments, and medical decisions following TCD were also recorded. Results: Part 1 included 28 centers with 5223 individuals with SCA in the database. Of the 16 Part 3 sites, three could not implement the interventions due to a simultaneous change in hospital administration and site PI (1), inability to use PM due to institutional firewall (1) and inability to implement due to site specific issues (1). These 3 sites remained in the study as "control sites” and a fourth control site was added. Thus, 13 sites implemented the interventions with 877 patients; 520 were in sites using PM and 357 were in sites using PM+SC. Demographic data for the 877 children with SCA are in Table 1. The study ended on May 31, 2022. Calculations of TCD rates at all sites are in process and will be presented. Conclusions: Despite the benefit of TCD screening in children with SCA, guideline-based implementation remains poor. The range of barriers to screening has been previously reported by the DISPLACE study team and were used to design the study interventions. Results from this study will guide optimization of the intervention protocol proven to enhance TCD implementation. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Barriers and Facilitators to Chronic Red Cell Transfusion Therapy in Pediatric Sickle Cell Anemia.

Background: Chronic red cell transfusion (CRCT) therapy is one of a few effective disease-modifying therapies for children with sickle cell anemia (SCA). CRCT is recommended for primary and secondary stroke prevention for at-risk children with SCA and is sometimes used for other disease-related complications. However, CRCT can be resource- and time-intensive for patients/families, providers, and organizations. This study was conducted to provide a comprehensive, multilevel examination of barriers and facilitators to transfusion therapy in children with SCA from health care provider and caregiver perspectives. Methods: A qualitative descriptive approach was used to conduct key informant interviews in a sample of 26 caregivers and 25 providers across the United States. Interviews were analyzed using directed content analysis with the Multilevel Ecological Model of Health as an initial coding framework and the constant comparison method. Results: Ten barrier themes and 10 facilitator themes emerged across all ecological levels. Themes most commonly occurred on the patient and organizational levels. Key barriers themes included Logistical Challenges, Obtaining and Maintaining Venous Access, Alloantibodies/Alloimmunization and Reactions, and Iron Overload and Adherence to Chelation Therapy. Key facilitator themes included Nursing and Non-nursing Staff Support, Positive Child/Family Experiences, Logistical Help and Social Resources, Blood Bank and Access to Blood, and Transfusion-Specific Resources. Discussion: The comprehensive understanding of multilevel barriers and facilitators to transfusion therapy, including the role of nursing, in children with SCA can inform strategies to improve CRCT for patients/families and providers and can also be applied by organizations seeking to implement transfusion services for SCA.

Prevalence and Factors Associated with Echocardiographic Abnormalities in Children with Sickle Cell Disease; Results from the Displace Study

IntroductionCardiopulmonary complications remain a leading cause of morbidity and mortality in adults with sickle cell disease (SCD) particularly for people with sickle cell anemia (SCA) who have lower hemoglobin and higher baseline hemolysis. Many cardiovascular complications are not identified until adulthood when patients have developed irreversible pathology. Previous studies have suggested that SCD-specific therapies like hydroxyurea (HU) may be beneficial in reducing the hemolysis associated vascular dysfunction and reducing cardiopulmonary complications. This study describes the prevalence of and factors associated with left ventricular hypertrophy (LVH), left atrial dilation and high tricuspid regurgitant jet velocity (TRJV) in children with SCA. We also describe the association between patent foramen ovale (PFO) and ischemic stroke in children with SCA.MethodThis crossectional study used data collected as part of the Dissemination and Implementation Stroke Prevention Looking at the Care Environment (DISPLACE) study. American society of echocardiography (ASE) guidelines and cutoff values were used to define abnormalities in the echocardiographic variables.ResultsA total of 1414 children were included in the analysis. The median age was 9 years (range 5-12 years) and median hemoglobin of 8.6 g/dl. The most common abnormal findings on echocardiogram was left atrial dilatation (61% of the children), LVH (20% of children) and high TRJV (23% of children). Children with abnormal echocardiographic variables were more likely to have lower hemoglobin level. Children with LVH were more likely to have left atrial dilation, high TRJV and abnormal left ventricular end diastolic diameter (LVIDD). Multivariable analysis of LVH was conducted and included variables: age, sex, hemoglobin, reticulocyte count, treatment with chronic red cell transfusion therapy (CRCT) or hydroxyurea therapy (HU). Baseline hemoglobin levels were associated with the lower odds of having LVH (OR: 0.71, 95% CI: 0.60 - 0.84). The odds of LVH increases for every one-year increase in age (OR: 1.07, 95%CI: 1.02-1.13). Similarly, the odds of LVH was lower among males than females (OR:0.59, 95%CI: 0.38-0.93). The odds of LVH were higher among those on HU compared to no therapy (OR: 1.83, 95% CI: 1.41 - 2.37).Although not all children had a bubble, study, a total of 90(6.3%) had an identified PFO. We assessed the relationship between PFO and ischemic stroke. 102 (7.2%) of the 1414 children had an ischemic stroke. Out of this 5 (5.6%) had PFO. We also assessed the relationship between PFO and abnormal TCD. 142 (10.0%) of the 1414 had abnormal TCD and only 9 (10%) of the 142 had PFO. There is no evidence that the odds of having stroke was higher among those with PFO compared to those without (OR: 1.49, 95% CI: 0.20- 11.03, p = 0.6994). Similarly, no evidence that the odds of having abnormal TCD is higher among those with PFO compared to those without (OR: 0.85, 95% CI: 0.17- 4.25, p = 0.8463).ConclusionOverall results of the study showed echocardiographic abnormalities are common in and occur at an early age in children with SCA. The risk of LVH increases with increasing age and with lower hemoglobin. Further, we found higher use of HU among those with LVH, suggesting that possibly children with more severe disease requiring HU are also at increased risk of cardiopulmonary complications.Given the fact that high TRJV is an independent risk factor for death in adults with SCD and left atrial dilatation has been shown to be an independent predictor of cardiac events, our data support further investigation into identifying early biomarkers of cardiovascular morbidity in children with SCD. [Display omitted] DisclosuresKanter: Fulcrum Therapeutics, Inc.: Consultancy; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Forma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees; Beam: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Graphite Bio: Consultancy; GuidePoint Global: Honoraria; Fulcrum Tx: Consultancy.

Treatment-related Correlates of Growth in Children With Sickle Cell Disease in the DISPLACE Cohort.

Reduced growth and delayed maturation have been described in children with sickle cell disease (SCD). This study investigated growth and hemolysis in children with SCD in the DISPLACE (Dissemination and Implementation of Stroke Prevention Looking at the Care Environment) cohort. The database includes 5287 children, of which, 3305 had at least 2 growth measurements over a 5-year period. Body mass index was converted to z-scores (zBMI), and 19.8%, 66.1%, 14.2% of children were classified as underweight, normal, and overweight/obese, respectively. Multivariable analysis of growth was conducted and included variables: age, sex, blood pressure, hemoglobin, reticulocyte count, treatment with chronic red cell transfusion therapy (CRCT), or hydroxyurea therapy. Baseline hemoglobin levels were associated with the lower odds of being underweight (odds ratio [OR]=0.93, 95% confidence interval [CI]: 0.86-0.99), and higher odds of being overweight/obese (OR: 1.26, 95% CI: 1.17-1.36) compared with normal zBMI. CRCT was associated with being overweight/obese at baseline (OR: 1.85, 95% CI: 1.31-2.60). Overall, results showed that children who were underweight improved regardless of therapy over the 2-year time period. However, children on CRCT are at higher risk for being overweight and should be monitored closely.

Effect of Sickle Cell Related Therapies on Growth in Children with Sickle Cell Disease: Evidence from the Displace Study

Introduction Reduced growth and delayed maturation have been previously described in children with sickle cell disease (SCD) due to multifactorial causes including chronic anemia and increased hemolysis. Interventions that decrease anemia and inflammation may have a beneficial effect on growth in children with SCD. Previous studies have demonstrated that children with SCD treated with hydroxyurea (HU) and chronic red cell transfusion therapy (CRCT) experience linear growth and increase in body mass index (BMI) compared to their counterparts not on therapy. Unfortunately, most of these studies were limited due to small sample size, cross-sectional study design or were conducted from single or a few center(s). DISPLACE (Dissemination and Implementation of Stroke Prevention Looking at the Care Environment) is a large, NHLBI (National Heart, Lung, and Blood Institute) funded consortium to improve stroke prevention implementation in SCD. DISPLACE includes the largest database of children with SCD from 28 different centers in the US. These data allow for an optimal assessment of growth in children with SCD on different disease modifying therapies. Using the DISPLACE database, we conducted a cross-sectional sub-study to evaluate how HU and CRCT affect growth in children over time. Methods The DISPLACE study collected data on 5,247 children aged 2-19 years with SCD from 28 centers in the US between 2012-2016. The majority of children have data collected from at least five years of continuous care. At baseline and annually thereafter, all children had routine standard of care anthropometric measurements including height and weight, vital signs, laboratory tests including complete blood count and chemistries and SCD-related therapies including chronic blood transfusion therapy and hydroxyurea therapy. Body mass index was converted to z-scores (zBMI) based on the Centers for Disease Control guide for age and sex. Children were categorized based on the zBMI score as underweight, normal, and overweight/obese. Our inclusion criteria included children with documented results of weight, height, vital signs, clinical and laboratory tests at baseline. Children who do not have sufficient data for evaluation (at least one missing anthropometric measurement or laboratory value) were excluded. Results Of the 3,305 children included in the study, 19.8%, 66.1%, 14.2% were underweight, normal, and overweight/obese at their initial (baseline) visit respectively. Children who were overweight/obese had a significantly higher hemoglobin level (p&amp;lt;0.0001) and significantly lower reticulocyte count (p = 0.0334) at baseline than normal and underweight children. Children who are overweight/obese had a significantly higher systolic and diastolic blood pressure compared to those who are normal or underweight (p = 0.0079 and p = 0.0003 respectively). A higher proportion of children who were overweight/obese were on CRCT at baseline compared to children with normal or underweight zBMI (p = 0.0002). The proportion of children on HU therapy at baseline was similar across zBMI categories (p = 0.2412). The multivariable adjusted model showed that the baseline hemoglobin levels were associated with the odds of being underweight (OR 0.93, 95% CI: 0.86 - 0.99), or overweight/obese (OR: 1.26, 95% CI: 1.17 - 1.36) compared with normal zBMI. At baseline, blood transfusion was associated with being overweight/obese versus normal (OR: 1.85, 95% CI: 1.31 - 2.60). After two years of therapy, there was a statistically significant increase in median zBMI from baseline among children initiating blood transfusion versus controls, (p = 0.0481), but the zBMI difference in hydroxyurea therapy versus controls remain same. (p=0.3925). Conclusion In our US-based study, the majority of children with SCD (70%) had normal zBMI. As baseline hemoglobin is associated with zBMI, that may predict who is at risk for being underweight or overweight. In addition, patients treated with CRCT are more likely to be overweight and have higher blood pressure. These findings suggest that individuals on CRCT should be monitored and may need lower calories than those not on disease modifying therapies. Disclosures Kanter: bluebird bio, inc: Consultancy, Honoraria; Novartis: Consultancy; Sanofi: Consultancy; Medscape: Honoraria; Guidepoint Global: Honoraria; GLG: Honoraria; Jeffries: Honoraria; Cowen: Honoraria; Wells Fargo: Honoraria; NHLBI Sickle Cell Advisory Board: Membership on an entity's Board of Directors or advisory committees; SCDAA Medical and Research Advisory Board: Membership on an entity's Board of Directors or advisory committees; AGIOS: Membership on an entity's Board of Directors or advisory committees; BEAM: Membership on an entity's Board of Directors or advisory committees.

Catalytic Enantiodivergent Michael Addition by Subtle Adjustment of Achiral Amino Moiety of Dipeptide Phosphines.

SummaryOver the past decades, asymmetric catalysis has been intensely investigated as a powerful tool for the preparation of numerous chiral biologically active compounds. However, developing general and practical strategies for preparation of both enantiomers of a chiral molecule via asymmetric catalysis is still a challenge, particularly when the two enantiomers of a chiral catalyst are not easily prepared from natural chiral sources. Inspired by the biologic system, we report herein an unprecedented catalytic enantiodivergent Michael addition of pyridazinones to enones by subtle adjustment of achiral amino moiety of dipeptide phosphine catalysts. These two dipeptide phosphine catalysts, P5 and P8, could deliver both enantiomers of a series of N2-alkylpyridazinones in good yields (up to 99%) with high enantioselectivities (up to 99% ee) via the catalyst-controlled enantiodivergent addition of pyridazinones to enones.

Barriers and Facilitators to Chronic Red Cell Transfusion Therapy for Children with Sickle Cell Anemia: Results from the Displace Consortium

Introduction: Chronic red cell transfusion therapy (CRCT) is one of the only disease-modifying therapies for individuals with sickle cell anemia (SCA). CRCT plays a particularly critical role in stroke prevention for children with SCA who are at high risk (primary prevention) or who have had a previous stroke (secondary prevention). CRCT is also used to prevent other non-neurologic severe complications from SCA, such as recurrent splenic sequestration or severe acute chest syndrome. Only a few previous studies have focused on patient and provider experiences related to CRCT. This previous work has predominantly focused on patient/caregiver perceptions of children's quality of life while receiving CRCT and provider decision-making around CRCT for SCA. The present study sought to build on this previous work by examining barriers and facilitators to CRCT for stroke prevention as part of the aims of the Dissemination and Implementation Looking at the Care Environment (DISPLACE) study. DISPLACE is a multi-site study funded to evaluate and improve implementation of stroke prevention practices for SCA. The goal of this particular aim was to inform optimal strategies to enhance CRCT initiation for stroke prevention in SCA. Methods: A qualitative descriptive approach was used to obtain provider and patient/caregiver perspectives through key informant interviews with open-ended questions. Purposive sampling was used to identify patient/caregiver participants and purposive and snowball sampling were used to identify provider participants with the goal of enrolling participants until data saturation was reached. Interviews were digitally audio recorded and transcribed for analysis. Data were analyzed using inductive and deductive approaches. Deductive analysis followed the directed content analysis approach with the Multilevel Ecological Model of Health as an initial coding framework. Themes were developed around the barriers and facilitators to CRCT from an ecological perspective. Results: Fifty-two interviews were completed across patients/caregivers and providers (27 patient/caregivers and 25 providers) in order to reach data saturation. For patient/caregivers, 26 caregivers of children and adolescents with SCA (mean age = 39; 21 mothers, 4 fathers, and 1 aunt) and one young adult (age 18, female) completed interviews. For providers, 19 physicians, 2 nurse practitioners, 1 physician assistant, and 3 ancillary providers completed interviews (mean age = 50; 14 female; mean years of practice in SCA = 18.8). Patient/caregiver and provider themes were consistent with the multi-ecological framework and reflected barriers and facilitators at the patient, provider, organizational, and social-environmental/policy levels (Figure 1). Predominant (or high-frequency) themes with definitions and illustrative quotes are presented in Table 1. Predominant barriers reported by patients/caregivers and providers included: logistical challenges (patient level), obtaining and maintaining venous access (patient level), and alloantibodies/alloimmunization and transfusion reactions (patient level). A predominant barrier reported by providers was iron overload and adherence to chelation therapy (patient level). Predominant facilitators reported by patient/caregivers and providers included: nursing and non-nursing staff support (provider level), positive child/family experience (organizational level), and logistical help and social resources (social-environmental and policy level). Predominant facilitators reported by providers included transfusion-specific resources (organizational level) and proximity to a blood bank and access to blood (organizational level). Conclusions: Patient/caregivers and providers reported a range of barriers and facilitators to CRCT, though most occurred at the patient and organizational levels. Many of the barriers and facilitators also involved interactions across ecological levels. Results suggest interventions should address predominant and remediable barriers (e.g., logistical challenges and obtaining and maintaining venous access) and incorporate predominant facilitators (e.g., nursing and non-nursing staff support and positive child/family experience). Findings from this study may be used to guide interventions for improving CRCT initiation among children with SCA. Disclosures Adams: GBT: Consultancy, Other: consultancy to companies GBT and Blueburd Bio; Bluebird: Consultancy.

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

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 &lt;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.

S855 TCD IMPLEMENTATION RATES AND RESULTS IN THE MODERN ERA OF SICKLE CELL ANEMIA: RESULTS FROM THE DISPLACE STUDY

Background:Stroke is one of the most devastating complications of sickle cell anemia (SCA). The STOP (Stroke Prevention Trial in Sickle Cell Anemia) protocol was adopted in 2014 by the National Heart Lung and Blood Institute (NHLBI) guidelines for stroke‐risk screening using transcranial Doppler ultrasound (TCD) and prevention with chronic red cell transfusion therapy (CRCT) 1. Despite high‐level evidence supporting the use of TCD screening (and CRCT initiation) in stroke prevention2,3, wide scale implementation has not been achieved 4.Aims:The DISPLACE (Dissemination and Implementation Looking at the Care Environment) project is a multicenter, NHLBI‐funded study whose primary aim is to identify barriers to implementation of the STOP protocol 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 project using implementation science to improve TCD screening and CRCT implementation. We are reporting on part 1 of this project evaluating implementation rates of TCD screening and TCD outcomes (abnormal and conditional) in a large contemporary cohort.Methods:DISPLACE is a large multi‐site study consortium of 28 centers across the United States representing a range of characteristics: region (urban vs rural), size, and institution type (academic vs community). 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 had to have been seen at their institution at least 2x/calendar year (for 1 year) 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. The primary study outcome is to assess implementation of TCD screening (per center). TCD screening rates were calculated per center (TCD/child/year/center). TCD results were recorded in the EDC as normal, conditional or abnormal. Stroke status was also recorded as well as presence or absence of CRCT. Data included missed TCD appointments and medical decisions based on TCD results.Results:The study included 28 centers. In total, 5223 individuals with SCA (50.2% male, 93.7% HbSS) are included in the database (5187 of those eligible in the study period). This is the largest cohort of children with SCA ever studied. TCD screening rates varied widely among institutions ranging from 30–75.2% (mean 48.4%, median 47%). Of the total in the database, 3718 patients had a TCD during the study period (71.7%). Of those patients who had a TCD, 138 (3.7%) had an ABNORMAL TCD per STOP guidelines which is notably lower than the STOP study with a rate of abnormal TCD of 9.7% at study entry. Characteristics of patients with abnormal TCD (vs. those without) are forthcoming.Summary/Conclusion:Despite the benefit of TCD screening in children with SCA, guideline‐based implementation remains poor. The range of barriers to screening will help investigators optimize the intervention protocol to enhance TCD implementation. Notably, there are fewer children with abnormal screening rates in the modern era which may represent partial penetration of the STOP Protocol from prior screening and/or effect of disease‐modifying therapy. Data analysis is in process to further qualify these findings.

S856 ALTERATION OF IRON HOMEOSTASIS IN A MOUSE MODEL OF LIVER-STAGE PLASMODIUM INFECTION

Background: Stroke is one of the most devastating complications of sickle cell anemia (SCA). The STOP (Stroke Prevention Trial in Sickle Cell Anemia) protocol was adopted in 2014 by the National Heart Lung and Blood Institute (NHLBI) guidelines for stroke-risk screening using transcranial Doppler ultrasound (TCD) and prevention with chronic red cell transfusion therapy (CRCT) 1. Despite high-level evidence supporting the use of TCD screening (and CRCT initiation) in stroke prevention2,3, wide scale implementation has not been achieved 4. Aims: The DISPLACE (Dissemination and Implementation Looking at the Care Environment) project is a multicenter, NHLBI-funded study whose primary aim is to identify barriers to implementation of the STOP protocol 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 project using implementation science to improve TCD screening and CRCT implementation. We are reporting on part 1 of this project evaluating implementation rates of TCD screening and TCD outcomes (abnormal and conditional) in a large contemporary cohort. Methods: DISPLACE is a large multi-site study consortium of 28 centers across the United States representing a range of characteristics: region (urban vs rural), size, and institution type (academic vs community). 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 had to have been seen at their institution at least 2x/calendar year (for 1 year) 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. The primary study outcome is to assess implementation of TCD screening (per center). TCD screening rates were calculated per center (TCD/child/year/center). TCD results were recorded in the EDC as normal, conditional or abnormal. Stroke status was also recorded as well as presence or absence of CRCT. Data included missed TCD appointments and medical decisions based on TCD results. Results: The study included 28 centers. In total, 5223 individuals with SCA (50.2% male, 93.7% HbSS) are included in the database (5187 of those eligible in the study period). This is the largest cohort of children with SCA ever studied. TCD screening rates varied widely among institutions ranging from 30–75.2% (mean 48.4%, median 47%). Of the total in the database, 3718 patients had a TCD during the study period (71.7%). Of those patients who had a TCD, 138 (3.7%) had an ABNORMAL TCD per STOP guidelines which is notably lower than the STOP study with a rate of abnormal TCD of 9.7% at study entry. Characteristics of patients with abnormal TCD (vs. those without) are forthcoming. Summary/Conclusion: Despite the benefit of TCD screening in children with SCA, guideline-based implementation remains poor. The range of barriers to screening will help investigators optimize the intervention protocol to enhance TCD implementation. Notably, there are fewer children with abnormal screening rates in the modern era which may represent partial penetration of the STOP Protocol from prior screening and/or effect of disease-modifying therapy. Data analysis is in process to further qualify these findings.

Health-related Quality of Life in Children With Sickle Cell Disease Undergoing Chronic Red Cell Transfusion Therapy.

Chronic red cell transfusion (CRCT) therapy is one of few disease-modifying treatments for sickle cell disease (SCD). This study evaluated health-related quality of life (HRQL) in children receiving CRCT relative to 2 comparison groups: children with similar, severe SCD and children with milder disease risk defined by SCD genotype. For this study, 67 children with SCD between the ages of 8 and 18 completed the self-report Pediatric Quality of Life Sickle Cell Disease module (PedsQL SCD) as part of a pilot clinical program during routine hematologic visits. A medical chart review was also performed. Linear regression suggested that children in the CRCT group had significantly higher self-reported HRQL ratings for domains related to pain, F2,64=4.07 (P=0.022) and pain-related functioning, F2,64=4.32 (P=0.017), compared with children with similar and milder disease risk. Exploratory analyses implied that children in the CRCT group also had fewer worries about SCD-related complications, F3,63=9.68 (P<0.001). These patient-perceived benefits of CRCT may have important implications for treatment decisions and for providing ancillary support for children with SCD and their families.

Practice Patterns in the Use of MRI/MRA and Chronic Transfusion Therapy for Monitoring and Treatment of Stroke in Pediatric Patients with Sickle Cell Anemia

Introduction: Current stroke prevention guidelines in pediatric sickle cell anemia (SCA) specify the use of transcranial Doppler (TCD) and chronic red cell transfusion therapy (CRCT) for detection and prevention of stroke. Guidance on the use of MRI/MRA in the context of stroke prevention, screening, and monitoring is less clear. While overt stroke is able to be identified clinically, silent stroke can be more difficult to diagnose and screening guidelines have not been developed. The DISPLACE Consortium (Dissemination and Implementation Looking at the Care Environment) is a multi-center study funded to evaluate optimal implementation of stroke prevention guidelines. The purpose of the present study was to provide information on practice patterns across the DISPLACE Consortium as they relate to the use of MRI/MRA and CRCT for monitoring and treating stroke in pediatric patients with SCA.Methods: DISPLACE is a multi-site study in SCA including 28 centers across the United States. A practice patterns survey was sent to the principal investigator (PI) for each DISPLACE site through RedCap. All PIs are specialty care providers in hematology/oncology who provide care to pediatric patients with SCA. The sites were chosen to represent a range of characteristics, including both urban and rural regions, large and small academic institutions, and community-based institutions. The survey was developed by the study investigators and questions were provided predominantly in a multiple choice format. The following types of questions were asked about MRI/MRA: indication for pediatric patients with SCA in general and for those on CRCT for stroke prevention. The following types of questions were asked about CRCT: indication and frequency of CRCT and target hemoglobin S level.Results: All 28 providers completed the survey (100%). About half of providers were female (53.5%). Most providers identified as White (77.8%), followed by Asian (11.1%) and Black or African American (7.4%). Two identified as Hispanic or Latino (7.4%). MRI was used for the following indications: abnormal TCD (85.7%), conditional TCD (46.4%), recurrent headaches (78.6%), and behavior issues (53.6%). A few sites also reported obtaining an MRI if a child has had poor school performance (10.7%) or if there was concern for developmental delay (3.7%). Indications for MRA were similar. Notably, many sites reported the use of a screening or baseline MRI in the absence of other indications (25.0%). The most common indications for initiating CRCT were abnormal TCD (96.4%) and overt stroke (92.9%), followed by silent stroke (53.6%) and abnormal MRA (50.0%). The majority of sites reported scheduling CRCT at a frequency of every 4 weeks (63.0%), though many (37.0%) described other more frequent transfusions intended to either more rapidly reduce hemoglobin S levels or maintain a level under 30%. Most sites used a target of 30% hemoglobin S, though a few sites noted alternatives including 40% (3.7%) and 50% (3.7%). The frequency of MRI for patients receiving CRCT for stroke prevention was as follows: annually (44.4%), every 2 years (14.8%), and every 5 years (3.7%). Several sites reported obtaining MRIs only if there were new changes or concerns (14.8%) or reported alternative practices (14.8%) that depended on patient characteristics. Frequency for MRA was similar for patients on CRCT.Conclusions: The results of the DISPLACE practice patterns survey suggested nearly universal adoption of CRCT for children with abnormal TCD and prior overt stroke across sites. The use of MRI/MRA in detecting potential cerebrovascular abnormalities in the absence of clinical neurologic symptoms and for monitoring patients on CRCT was much more variable, which likely reflects the minimal amount of guidance for the use of MRI/MRA in SCA. Notably, a number of sites were using MRI/MRA to screen pediatric patients for cerebrovascular abnormalities and to monitor patients on CRCT. The variability in responses for MRI/MRA highlights the importance of future studies evaluating best neuroimaging practices for detecting cerebrovascular abnormalities (apart from TCD) and for using MRI/MRA to monitor patients on CRCT. DisclosuresSchlenz:NHLBI: Research Funding. Mueller:NHLBI: Research Funding. Phillips:NHLBI: Research Funding. Melvin:NHLBI: Research Funding. Adams:NHLBI: Research Funding. Kanter:bluebird bio: Membership on an entity's Board of Directors or advisory committees, Research Funding; NHLBI: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Apopharma: Research Funding; Sancilio: Research Funding; Global Blood Therapeutics: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; ASH: Membership on an entity's Board of Directors or advisory committees.

Results from the Displace Consortium: Practice Patterns on the Use of Transcranial Doppler Screening for Risk of Stroke in Children with Sickle Cell Anemia

Abstract Introduction: Stroke is one of the most devastating complications of sickle cell anemia (SCA). The STOP (Stroke Prevention Trial in Sickle Cell Anemia) protocol has been adopted by National Heart Lung and Blood Institute (NHLBI) as the guideline for stroke screening using transcranial Doppler ultrasound (TCD) and prevention with chronic red cell transfusion therapy (CRCT). Evidence from the STOP I/II studies indicates the protocol is highly effective, yet wide scale implementation has not been achieved. The DISPLACE (Dissemination and Implementation Looking at the Care Environment) project is a multicenter, NHLBI funded consortium of 28 sites across the United States whose purpose is to identify barriers to the implementation of the STOP protocol and test novel methods for overcoming barriers. The purpose of this study was to use data on practice patterns to evaluate current measurement and practice standards at DISPLACE consortia sites. This abstract presents reported TCD screening and CRCT practices. Methods: A practice patterns survey was sent to the principal investigator (PI) for each DISPLACE site via RedCap ©. PIs were hematology/oncology specialty care providers for children with SCA. Sites represent urban and rural regions, large and small academic institutions, and community-based institutions. The survey was developed by the study investigators; questions were predominantly in a multiple-choice format. Items pertaining to TCD screening included: screening technique (including type of TCD); screening frequency; follow-up for abnormal, conditional, and inadequate results; standard value ranges. Results: All 28 PIs completed the survey. About half of the respondents were female (53.5%). Most identified as White (77.8%), followed by Asian (11.1%) and Black or African American (7.4%). Two identified as Hispanic or Latino (7.4%). Slightly more sites reported using standard TCD (57.1%) versus imaging TCD (TCDi) (42.9%). To calculate the time-averaged mean of the maximum (TAMM) velocities and characterize TCD results, nearly all sites use the middle cerebral artery (96.4%); a majority also use the anterior cerebral artery and/or the terminal internal cerebral artery or distal internal cerebral artery (71.4%). Fewer sites use the posterior cerebral artery (35.7%) or the basilar artery (14.3%). In 7.1% of sites, the radiologist determines which vessels to use during the exam. TCD screening is ordered for children with SCA annually in 92.9% of sites and every 6 months in 7.1% of sites. When TCD screening indicates abnormal TAMM velocities, 85.7% of sites initiate CRCT, 7.1% initiate hydroxyurea (HU) therapy, and 3.6% initiate both HU and CRCT. For additional evaluation, an MRI/MRA is obtained at 64.3% of sites. For high conditional results, the most common action is to initiate HU (67.9%). Other responses include obtaining an MRI/MRA (46.4%) and/or repeating the TCD in 2-4 weeks (25.0%), 6-8 weeks (35.7%), or 12-16 weeks (7.1%). Results deemed inadequate led to repeating the TCD in 2-12 weeks (57.1%) or in one year (3.6%), obtaining an MRI/MRA (57.1%), beginning HU therapy (7.1%), or no repeat TCD or change in management (3.6%). Actions for low conditional results include repeating the TCD (71.4%), obtaining an MRI/MRA (32.3%), and/or initiating HU therapy (57.1%). Surprisingly, sites use different TAMM ranges to characterize the normal/abnormal findings (Table 1). Conclusions: Nearly all DISPLACE sites order TCD screening annually, as recommended in the guidelines, with some ordering screening more frequently. A few sites did not report initiation of CRCT per STOP protocol for abnormal TCD results; however, over half of the sites reported following up with an MRI/MRA, which may suggest evaluating for vasculopathy prior to CRCT. Some sites reported beginning HU therapy for abnormal results; this may reflect consideration of patients for whom CRCT is not possible, but data were not collected for confirmation. Interestingly, results suggest a reliance on MRI/MRA since sites commonly reported ordering neuroradiology studies for abnormal, conditional, and inadequate TCD results. This may suggest an unclear pathway for children with borderline TCD results, and an area for future study. While reported value ranges closely approximated those in the STOP protocol, results indicate sites conducting screening with TCDi may use more conservative values than the validated protocol. Disclosures Phillips: NHLBI: Research Funding. Mueller:NHLBI: Research Funding. Schlenz:NHLBI: Research Funding. Melvin:NHLBI: Research Funding. Adams:NHLBI: Research Funding. Kanter:AstraZeneca: Membership on an entity's Board of Directors or advisory committees; bluebird bio: Membership on an entity's Board of Directors or advisory committees, Research Funding; Global Blood Therapeutics: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sancilio: Research Funding; NHLBI: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Apopharma: Research Funding; ASH: Membership on an entity's Board of Directors or advisory committees.

Barriers to Implementation of Evidence-Based Stroke Prevention in Sickle Cell Disease: A Preliminary Study

Introduction: Evidence-based guidelines for stroke prevention in sickle cell disease (SCD) strongly recommend chronic red cell transfusion therapy (CRCT) for patients at high risk for stroke. Patients are defined as high risk if they have had an abnormal transcranial Doppler (TCD) screen or have already suffered an initial stroke. Despite these guidelines, CRCT is likely underutilized. The barriers to implementation for CRCT are poorly understood but are likely due to a combination of patient and health-care-access variables. This study was performed to assess the implementation of CRCT in patients with SCD at high risk for stroke treated at a large, Southeastern hospital. It was hypothesized that age, provider type, and distance from comprehensive care would be associated with CRCT status. Additional factors, including indication for CRCT and insurance status, were also examined as exploratory variables.Methods: A retrospective chart review was used to identify patients defined as high risk for stroke, their current CRCT status as well as additional demographics. High-risk patients were identified using current clinic rosters and previous stroke prevention trial databases from January 1, 2000 to December 31, 2014. Information collected included patient's current age, gender, indication for CRCT, last known zip code, insurance status, and provider type at last known encounter (SCD versus primary care or ED only). Demographics were compared between patients maintained on CRCT, patients still receiving care but not on CRCT, and patients who had been lost-to-follow-up (LTFU, treatment status unknown) using one-way ANOVA and Chi-square tests or Fisher's Exact tests. Age was viewed as a potential confounding variable for some of the characteristics (i.e., provider type, insurance status). Logistic regression was also used to examine associations between specific characteristics and CRCT status after adjusting for age.Results: The patient population included 143 patients with SCD at high risk for stroke. At the time of the assessment, 13 patients were deceased. Thus, the remaining 130 patients were used for subsequent analysis (current age: M = 23.2, SD = 8.1; 68 male, 62 female). Of those living, 52% (68/130) were being treated with CRCT, 24% (31/130) were still being seen but were not receiving CRCT, and 24% (31/130) were LTFU. Older patients were more likely to be off CRCT or LTFU (p < 0.0001). Over 91% of patients on CRCT had a provider with training in SCD whereas 55% of patients not on CRCT had a provider without SCD training (p < 0.0001), and this effect remained significant after adjusting for age. Distance from comprehensive care did not predict CRCT status, but was related to those LTFU (p = 0.005). Of the patients who remained on CRCT treatment, indication for treatment was history of stroke for 62% of patients versus 48% of patients who were not being treated and 77% of those LTFU (p = 0.020).Conclusions: Current NHLBI guidelines strongly recommend CRCT for patients with SCD at high risk for stroke; however, our study suggests that there has been poor implementation of this guideline. Despite the improved capacity to screen for patients at risk for stroke using TCD (per the STOP study), patients are not maintained on this therapy regardless of the lack of a safe stopping point. In our hospital, close to half of patients were either not receiving CRCT for stroke prevention or had been LTFU. In terms of patient and health-care characteristics, adult patients without a SCD specialty provider were less likely to be on CRCT for stroke prevention even if they continued to receive care in the hospital system. Indication for treatment was also associated with CRCT status, such that those with a history of prior stroke were more likely to be on treatment versus those with other neurological indications (such as abnormal TCD). The results were also notable for a distinct group of individuals at high risk for stroke who were LTFU. This particular patient group was mostly comprised of adult patients with a history of prior stroke who resided far from specialty care and may never have been transitioned into adult care. To further assess the barriers to dissemination and implementation of CRCT and further explore our preliminary results, we are planning a multi-site investigation, including assessment of patient-reported concerns and evaluation of different types of care environments for SCD. DisclosuresNo relevant conflicts of interest to declare.

Effects of Chronic Transfusion Therapy on transcranial Doppler Ultrasonography Velocities in Children with Sickle Cell Anemia at Risk for Primary Stroke: Baseline Findings from the Twitch Trial

Introduction: Transcranial Doppler ultrasonography (TCD) is an established screening modality used to predict stroke in children with sickle cell anemia (SCA). Children with abnormal TCD velocities are at high risk for primary stroke. Based on STOP and STOP 2 data, indefinite chronic red cell transfusion therapy is recommended for children with SCA and abnormal TCD velocity, defined as a maximum time-averaged mean velocity (TAMV) ≥200 cm/sec. The aim of the current analysis was to evaluate the long term effects of transfusion therapy on TCD velocities, in a large cohort of children with SCA who received chronic red cell transfusion therapy for primary stroke prophylaxis.Methods: The TCD With Transfusions Changing to Hydroxyurea (TWiTCH) study is a phase III, randomized, controlled, multicenter non-inferiority trial comparing hydroxyurea to transfusions for primary stroke prevention in children with SCA and abnormal TCD velocities (ClinicalTrials.gov NCT01425307). Children with SCA and a history of abnormal TCD who received at least 12 months of transfusion therapy were eligible to participate. All subjects’ index TCD velocities (the TCD examination that prompted the start of chronic transfusion therapy) were reviewed centrally to confirm study eligibility. At enrollment, study TCD velocities were obtained using the SONARA/tek TCD Module by trained examiners and reviewed centrally. In addition, all children were evaluated with brain magnetic resonance angiography (MRA) scans, which were also reviewed centrally. Associations between demographic, clinical, radiological, and laboratory findings and index/enrollment TCD velocities were examined.Results: One hundred and thirty eight children with complete data were included in this analysis. Mean age for the entire cohort at enrollment was 9.8±2.8 years; 40% were male and 98.8% had HbSS. Mean age at the diagnosis of index TCD was 5.5±2 years. The mean duration of transfusion therapy was 4.3±2.4 years with 63% receiving simple transfusions, 30% receiving partial exchange transfusions, and 7% undergoing erythrocytapheresis. The mean pre-transfusion hemoglobin at study entry was 9.1±0.8 gm/dL and the mean pre-transfusion %HbS for the last 6 months prior to study entry was 29.5±8.3%. The average index TCD TAMV was 217±22 cm/sec (range 147-325). At study entry, the average TAMV was lower at 150±27cm/sec overall (142±27 cm/sec on the left and 140±29 cm/sec on the right). In 77% of the subjects, the TCD velocities had decreased to normal levels (<170 cm/sec), while they remained conditional in 21% and abnormal in 3%. The average decline from index to study entry TCD was 67±31 cm/sec. Nineteen subjects (13.7%) had severe vasculopathy on brain MRA. Higher recent pre-transfusion %HbS (p=.04), fewer years of transfusion therapy (p<.001), and the presence of severe vasculopathy (p<.001) were associated with higher TCD velocities at study entry and with larger declines in velocity from index to study entry. Higher index TCD values were also associated with larger declines in velocity from index to study entry (p<.001). Age and transfusion type did not have an effect on TCD values.Conclusions: Most of the children with SCA at high risk for primary stroke enrolled in the TWiTCH study have normal TCD velocities at study entry, although 21% have conditional and 3% still have abnormal velocities. Longer duration of transfusion therapy was associated with lower TCD velocities, while the presence of severe vasculopathy on brain MRA and recent higher pre-transfusion %HbS values were associated with higher TCD velocities. The TWiTCH trial will serially perform TCD examinations to compare the effects of hydroxyurea versus transfusions. DisclosuresOff Label Use: Use of hydroxyurea in children with sickle cell disease.

Deleterious Consequences of Diamond Blackfan Anemia on Reproductive Health and Pregnancy Outcomes: A Report from the Diamond Blackfan Anemia Registry (DBAR)

Background: Diamond Blackfan anemia (DBA) is a rare, congenital bone marrow failure syndrome characterized by red cell aplasia, birth anomalies, and a predisposition to cancer. Due to a primarily autosomal dominant mode of inheritance, DBA affects males and females at a ratio of 1:1. Treatment consists of corticosteroid administration and chronic red cell transfusion therapy and in some cases hematopoietic stem cell transplantation. Current clinical observations suggest that women with DBA may experience delayed puberty, irregular menstrual cycles, and decreased fertility. Women who do become pregnant may sustain a higher than average risk of pregnancy complications, including miscarriage, placental abruption, and stillbirth, and others of vascular-placental origin (Faivre et al. Haematologica, 2006). Anecdotal reports suggest that DBA women experience changes to treatment response and remission status during periods characterized by hormonal fluctuations; namely, puberty and pregnancy. The etiology of these complications is unclear.Methods: Questionnaires were sent to females greater than 15 years of age (n=224) participating in the Diamond Blackfan Anemia Registry of North America (DBAR), a comprehensive database of 720 patients who are enrolled after obtaining informed consent. The questionnaires ask about menstrual and gynecologic health and pregnancies, focusing on complications, treatment requirements, and outcomes. We grouped patients by steroid and/or transfusion dependence status and/or remission before age 12 to analyze the effects of treatment on menarche. The patients were regrouped based on the majority of their treatment to evaluate for gynecologic health and pregnancy complications. The Fisher’s exact test was used to examine associations between variables. When compared to the general population, normal values were obtained from a variety of sources including the American Academy of Pediatrics, the National Institutes of Aging and the March of Dimes.Results and Conclusions: We reviewed results from 84 women aged 15 to 62 years (median age 28.6 years). Menarche was delayed in both steroid dependent and transfusion dependent girls, with 39.5% and 77.8%, respectively experiencing menarche at age 15 or later (vs 2% normal). Transfusion dependent girls were significantly more likely to have delayed menarche compared to the steroid dependent and remission groups (p<.005). Additionally, transfusion dependent females were significantly more likely to experience premature ovarian failure, compared to those who were either steroid dependent or in remission (32.1% vs 8.6%; p<.025). Of those who report entering menopause, 75% stopped by age 40 or younger (vs average, 51 years). Women who are transfusion dependent were more likely to report having taken medication to regulate their menstrual cycle, as compared to steroid dependent and remission groups (48.1% vs 22.9%; p<.06). Of the 50 pregnancies reported in 23 women, 30 resulted in live births (60%). Of the total live births, 43.3% were preterm (vs 11.5% normal). Interestingly, steroid dependent women as well as those in remission had the highest percentage of preterm deliveries at 66.7% and 63.6%, respectively. 26% of the pregnancies resulted in miscarriage, and 4.3% resulted in stillbirth (vs normal, 15% and 0.6%, respectively) and 4.3% of pregnancies were complicated by placental abruption (vs normal, <1%). During pregnancy, 52.2% of women reported requiring transfusions; specifically, 100% of the women who were steroid dependent at conception required transfusions during pregnancy. 7.4% of women in the study had a hysterectomy, half of whom were under age 40. We also noted an increased incidence of endocrinopathies: transfusion dependent women reported a significantly higher prevalence of thyroid disorders compared to the steroid dependent group (42.9% vs 11.1%; p<.03). Additionally, there was a higher prevalence of diabetes in the transfusion group as compared to the steroid dependent group (14.3% vs 0%, p=NS). These findings suggest an important role of iron overload in menstrual abnormalities, reproductive issues and endocrinopathies in DBA women. Pregnancy complications are in excess of those seen in the normal population. Future analyses will determine whether there is a correlation between menstrual abnormalities and/or pregnancy complications and specific DBA genotypes. DisclosuresNo relevant conflicts of interest to declare.

Effect of chronic red cell transfusion therapy on vasculopathies and silent infarcts in patients with sickle cell disease

Regular, chronic red cell transfusions (CTX) have been shown to be effective prophylaxis against stroke in sickle cell disease (SCD) in those at risk. Because serial brain imaging is not routinely performed, little is known about the impact of CTX on silent infarcts (SI) and cerebral vascular pathology. Thus, we retrospectively evaluated the magnetic resonance imaging reports of a cohort of SCD patients who were prescribed CTX for either primary or secondary stroke prophylaxis. Seventeen patients with Hb SS were included (mean age 15 years, mean follow-up 4.3 years). Eight patients were on CTX for primary prophylaxis. New SI occurred in 17.6% of patients corresponding to an SI rate of 5.42 per 100 patient-years. Vasculopathy of the cerebral arteries was present in 65% of patients and progressed in 63% of these patients. Those who developed progressive vasculopathy were on CTX for an average of 8 years before lesions progressed. Patients on CTX for secondary prophylaxis had more SIs and evidence of progressive vascular disease than patients on CTX for primary prophylaxis. We conclude that adherence to CTX does not necessarily prevent SI or halt cerebral vasculopathy progression, especially in those with a history of overt stroke.

Identification of hemochromatosis gene polymorphisms in chronically transfused patients with sickle cell disease.

Three polymorphic gene mutations in the human hemochromatosis (HFE) gene (C282Y, H63D, S65C) are associated with non-transfusion-related iron overload in Caucasians. More recently, these mutations have also been identified in African-Americans. However, the prevalence of HFE gene mutations in African-Americans with sickle cell disease (SCD) has not been described. The presence of these mutations in this population is particularly important, because patients with SCD may be placed on chronic red cell transfusion therapy and are thus at further risk for iron overload. Thus, we attempted to establish the gene mutation prevalence in African-Americans with SCD, to compare this frequency with published gene frequencies in African-Americans, and to evaluate their significance with regard to transfusion-related iron overload. Eighty-nine African-American patients with SCD, all of whom were receiving chronic red cell transfusion therapy, were screened by DNA analysis for the three HFE gene mutations. Two patients were heterozygous for the C282Y HFE mutation (2.3%), six were heterozygous for the H63D mutation (6.8%), none carried the S65C mutation (0.0%), and no homozygous or compound heterozygous subjects were identified. The prevalence of C282Y and H63D in the SCD population was similar to that observed in the general African-American population. In addition, there was no increased mutation prevalence when comparing those SCD patients on chronic transfusion therapy who had ferritin levels greater than 2,500 ng/mL and those less than 2,500 ng/mL. This study represents the first identification of the known HFE gene mutations by DNA analysis in the SCD population. We conclude that the presence of recognized HFE coding region mutations do not seem to have an impact on the degree of iron overload in patients with SCD receiving chronic transfusion therapy.