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

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 123-123
Author(s):  
Najibah Aliyu Galadanci ◽  
Julie Kanter ◽  
Virginia Howard ◽  
Walter Johnson ◽  
April Carson ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Board Of Directors ◽  
Sickle Cell ◽  
Left Atrial ◽  
Left Ventricular ◽  
Advisory Committees ◽  
Factors Associated ◽  
Cardiopulmonary Complications ◽  
The Relationship ◽  
Left Atrial Dilatation

Abstract Introduction Cardiopulmonary 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. Method This 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. Results A 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). Conclusion Overall 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. Figure 1 Figure 1. Disclosures Kanter: 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.

Evaluation of STOP Protocol Implementation for Abnormal TCD in Children with Sickle Cell Anemia at Risk for Stroke: Displace Consortium

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 22-23
Author(s):  
Shannon Phillips ◽  
Alyssa M Schlenz ◽  
Mary Dooley ◽  
Martina Mueller ◽  
Logan P Sirline ◽  
...  
Keyword(s):  
At Risk ◽  
Ischemic Stroke ◽  
Board Of Directors ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Stroke Prevention ◽  
Advisory Board ◽  
Electronic Data Capture ◽  
Advisory Committees ◽  
Electronic Data Capture System

Introduction: Without intervention, children with sickle cell anemia (SCA) have an 11% chance of overt ischemic stroke. The Stroke Prevention Trial in Sickle Cell Anemia (STOP) proved that children with SCA at increased risk of stroke can be identified using transcranial Doppler ultrasound (TCD) and, for those at risk, chronic red cell transfusion (CRCT) therapy is effective at preventing stroke. The 2014 National Heart, Lung, and Blood Institute (NHLBI) guidelines include annual TCD screening for children with SCA ages 2 - 16, and CRCT for primary and secondary ischemic stroke prevention. The NHLBI-funded Dissemination and Implementation of Stroke Prevention Looking at the Care Environment (DISPLACE) project was designed to 1.) evaluate current stroke screening and prevention practices in a 28-site consortium through intensive medical record review and an electronic data capture system, 2.) determine barriers and facilitators to stroke prevention practices through qualitative methods, and 3.) design and deliver interventions to increase rates of 'sickle stroke screening' using implementation strategies. The purpose of this abstract is to describe initial (pre-study) consortium actions following abnormal TCD results including whether all children had a repeat TCD within the next 4 weeks, whether they initiated CRCT, characteristics of which children received CRCT, and what alternate treatments were used. Methods: DISPLACE data collection years were 2012 - 2016. 5247 children with SCA who met criteria for annual TCD screening were entered into the electronic data capture system with clinical and demographic information. 163 children with abnormal TCD results were identified from the cohort database. Additional data were collected and subsequently adjudicated including timing of follow-up testing (repeat TCD or MRI) after abnormal TCD, implementation of CRCT following abnormal TCD, alternate treatment following abnormal TCD, and whether the STOP protocol was implemented. Data were analyzed using descriptive statistics. Results: In response to abnormal TCD, 75% of children had a repeat TCD ordered (Table 1). Of these, most repeat TCDs were completed within 3 months, with <10% delayed (longer than 12 weeks). CRCT was initiated in 69% of children with abnormal TCD (Table 2); of these, 17% had delayed initiation of CRCT. After abnormal TCD, 10% of families declined CRCT though suggested by providers. When some of these children later suffered an ischemic stroke, (20%) started CRCT at that time. The TWiTCH protocol (CRCT transitioning to HU in children without severe vasculopathy) was followed in about 1/4 of children on CRCT. Additional treatments following abnormal TCD included initiation of HU (64%) and bone marrow transplant (4%) (Table 3). Characteristics of children on CRCT are described in Table 4. Notably, of the 19 children whose CRCT was delayed, 15 (79%) had a stroke. There were 48 instances in which the STOP protocol was not implemented following abnormal TCD. Half of these were the result of decisions at the parent level (e.g., the parent refused CRCT, parent requested HU instead of CRCT). Five were provider decisions (e.g., provider suggested HU), and 15 were systems-level issues (e.g., repeat TCD was delayed). One was a combination of parent decision and system-level issue, and in 4 cases, the reason was unknown. Conclusions: In this nationally representative sample of children with SCA at risk for stroke, nearly ¾ of children had a repeat TCDs, suggesting confirmation of abnormal results was common prior to beginning CRCT. Notably, there were a large number of ischemic strokes in children when CRCT was delayed futher confirming the utility of the screening and stroke prevention protocol. An additional key concern identified in this study were the barriers to STOP protocol implementation. Common reasons for lack of implementation included the parent's decision for HU instead of CRCT, delays in CRCT initiation, and delays in obtaining repeat TCDs. Difficulties implementing the STOP protocol suggest the need for interventions for more rapid initiation of CRCT and stroke prevention. Disclosures Kanter: AGIOS: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Sanofi: Consultancy; bluebird bio, inc: Consultancy, Honoraria; 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; BEAM: Membership on an entity's Board of Directors or advisory committees.

Abstract P709: Risk Factors Associated With Atrial Fibrillation Detection by Mobile Cardiac Outpatient Telemetry Following Acute Ischemic Stroke

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Ovais Inamullah ◽  
Alec McConnell ◽  
Hussein Al-khalidi ◽  
Gerald S Bloomfield ◽  
Shreyansh Shah
Keyword(s):  
Atrial Fibrillation ◽  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Patient Selection ◽  
Left Atrial ◽  
Cryptogenic Stroke ◽  
Left Ventricular ◽  
Stepwise Logistic Regression ◽  
Internal Diameter ◽  
Atrial Area

Background: Mobile Cardiac outpatient telemetry (MCOT) is often used for patients (pts) with cryptogenic ischemic stroke following hospital discharge to detect atrial fibrillation (AFib) but criteria for patient selection remains a subject of debate. Methods: We identified 297 pts hospitalized with acute ischemic stroke who had an inpatient transthoracic echocardiogram (TTE) and underwent MCOT upon discharge between 2016 and 2018 at a large academic comprehensive stroke center. Pts characteristics between AFib vs. no AFib were compared by Fisher’s exact test for categorical and Wilcoxon rank-sum test for continuous variables. A multivariable stepwise logistic regression model was developed to determine the predictors of AFib detection. Statistical hypotheses were tested as two-sided at 0.05 level of significance. Results: Of the 297 pts, AFib was detected in 24 (8.1%) on 30-day MCOT. Pts with AFib detected were older, white, and have had a larger left atrial area (Table). The final logistic model demonstrated that white race (vs. non-white) (OR 4.86, 1.53-15.41), left atrial area (OR 1.15, 1.05-1.25) and left ventricular internal diameter in diastole (OR 0.33, 0.16-0.67) were associated with AFib detection by MCOT. Conclusion: Although rates of AFib detection on 30-day MCOT post-discharge was low, there are important patient characteristics and TTE features that can improve patient selection. Further studies are needed to determine if this data can be used prospectively to clinically decide which pts with cryptogenic stroke should be given 30-day MCT to detect atrial fibrillation.

scholarly journals Splenomegaly in Children with Sickle Cell Anemia Receiving Hydroxyurea in Sub-Saharan Africa

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 993-993
Author(s):  
Leon Tshilolo ◽  
George A. Tomlinson ◽  
Patrick T. McGann ◽  
Teresa S. Latham ◽  
Peter Olupot-Olupot ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Growth Parameters ◽  
Sub Saharan Africa ◽  
Advisory Committees ◽  
Splenic Enlargement ◽  
Hydroxyurea Treatment ◽  
Lower Blood ◽  
Sub Saharan

Introduction. Children with sickle cell anemia enrolled in Realizing Effectiveness Across Continents with Hydroxyurea (REACH, NCT01966731) received open-label hydroxyurea at maximum tolerated dose (MTD) in four countries within sub-Saharan Africa (Tshilolo et al, NEJM 2019;380:121-131). Unlike children in the United States or Europe, a substantial proportion of REACH participants had splenomegaly at enrollment, and more developed splenomegaly while receiving hydroxyurea. Splenic enlargement in association with hydroxyurea treatment in sub-Saharan Africa is previously unrecognized, and its causes and consequences remain unclear. Methods. Palpable splenomegaly was evaluated at both the mid-clavicular and mid-axillary lines at each scheduled and unscheduled sick visit. The size of the spleen, defined as the greatest distance (cm) below the subcostal margin, was recorded in the REDCap trial database at all four clinical sites. Cross-sectional analysis was performed at baseline enrollment using four spleen categories (Not Palpable, 1-4 cm, ≥5 cm, or Splenectomy) with correlations for age, sex, site, growth parameters, alpha-thalassemia trait and G6PD deficiency. This analysis was repeated using the largest spleen size over the first two years on hydroxyurea, but examining two-year laboratory values and also the hydroxyurea dose at MTD, time to MTD, dose-limiting toxicities, and clinical outcomes including acute splenic sequestration, malaria infections, and sepsis. Results. A total of 606 children started hydroxyurea study treatment, including 6 (1.0%) with previous splenectomy, 59 (9.7%) with previous splenic sequestration, and 99 (16.3%) with palpable splenomegaly at enrollment (52 children with 1-4 cm and 47 with ≥5 cm). Large spleens (≥5 cm) were commonly observed at baseline at all clinical sites except Uganda, which identified only 1 child. Compared to those with no palpable spleen, children with large spleens at baseline had similar age and growth parameters, but were significantly more likely to have alpha-thalassemia (78.7% versus 56.2%, P=0.004) and also G6PD deficiency among males (28.0% versus 17.6%, P=0.32). Children with large spleens at enrollment also had a lower hemoglobin (Hb = 6.5 versus 7.3 g/dL, P<0.001) and lower platelet count (platelets = 227 versus 410 x 109/L, P<0.001), but equivalent fetal hemoglobin (HbF = 10.2 versus 9.4%, P=0.82). On hydroxyurea treatment with escalation to MTD, 262 children (43.7%) had palpable splenomegaly recorded, including 120 (20.0%) with spleens ≥5 cm. These large spleens were observed at all four clinical sites, with DRC having the most (52) and Uganda with the least (14). After 24 months of hydroxyurea treatment, laboratory differences were noted according to the cumulative occurrence of splenomegaly including a significantly lower hemoglobin and platelet count, higher absolute reticulocyte count, and lower hydroxyurea dose at MTD (Table). Large spleens were associated with a high cumulative incidence of laboratory dose-limiting toxicities, as well as a significantly higher risk of having clinically symptomatic malaria and receiving blood transfusions (Table). A total of 31 children (5.2%) on hydroxyurea treatment received elective splenectomy, including one partial splenectomy using arterial embolization. Conclusion. Children with sickle cell anemia living in sub-Saharan Africa have an increased risk of having palpable splenomegaly, which is further increased while receiving hydroxyurea treatment. Large spleen at baseline were associated with lower blood counts, consistent with hypersplenism. On hydroxyurea treatment, children with large spleens had significantly lower blood counts and more dose-limiting toxicities, which lowered their eventual hydroxyurea dose at MTD but still led to robust HbF responses. Children with large spleens were also at higher risk of developing malaria infections, receiving transfusions, and requiring surgical splenectomy. Splenic enlargement in association with hydroxyurea treatment was common in children with sickle cell anemia in the REACH trial; its cause remains unclear but the consequences include substantial laboratory toxicity and clinical morbidity. Investigating the etiologies and management of children with chronically enlarged spleens is crucial before expanding hydroxyurea access across Africa for sickle cell anemia. Disclosures Ware: Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Other: Research Drug Donation; Nova Laboratories: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: DSMB; Agios: Membership on an entity's Board of Directors or advisory committees; Addmedica: Other: Research Drug Donation.

scholarly journals Sickle Stroke Screen: A Patient-Centered Educational Initiative for Children with Sickle Cell Anemia in the Displace Consortium

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 43-44
Author(s):  
Alyssa M Schlenz ◽  
Shannon Phillips ◽  
Martina Mueller ◽  
Cathy L Melvin ◽  
Robert J Adams ◽  
...  
Keyword(s):  
Needs Assessment ◽  
Board Of Directors ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Stroke Prevention ◽  
Stroke Risk ◽  
Advisory Board ◽  
Educational Initiative ◽  
Advisory Committees ◽  
Board Membership

Introduction: The NHLBI funded Dissemination and Implementation of Stroke Prevention Looking at the Care Environment (DISPLACE) study was designed to improve implementation of stroke prevention guidelines in children with sickle cell anemia (SCA), particularly implementation of transcranial Doppler (TCD) ultrasound for identifying individuals at risk of stroke. The study consists of 3 phases: 1) evaluating current stroke risk screening practices, 2) exploring barriers and facilitators to guideline implementation (needs assessment), and 3) designing and implementing interventions to improve stroke risk screening. A key barrier identified through qualitative methods during the needs assessment was a gap in education, including an overall lack of understanding among patients and caregivers of the purpose of TCD screening. This abstract describes the process of developing one of the interventions for phase 3, a rebranding and educational initiative. Methods: During the needs assessment, 27 key informant interviews and 173 complete surveys were conducted with individuals with SCA and their caregivers. Transcripts from the interviews and survey responses were reviewed to better understand the extent of educational gaps described by families as well as to guide initial rebranding prototypes. Prototypes were developed by the study team, including a new name and logo for TCD as well as an infographic. An interview guide was then created to obtain feedback on the prototypes from individuals with SCA and/or the parent or primary caregiver from two sites in the consortium. Cue cards with prototypes were included with prompts for the "think aloud" method to be applied during interviews. Cue cards were presented first with prototypes for the new name in black font on a white background to solicit feedback on the wording alone. Then, cue cards included various layouts, fonts, and graphics with the prototype names for in-depth feedback on the logo appearance. Finally, participants were asked questions pertaining to the infographic. Results: Twenty interviews were conducted with individuals with SCA and/or the parent/caregiver at two DISPLACE sites. Almost all participants (95%) made the connection between the wording prototypes and TCD without prompting. Many participants expressed that the word "stroke" in both options was "scary," and sometimes chose the option that was "less scary to them." However, many participants also felt that the word "stroke" was necessary to explain the reason for the procedure and would prompt families to ask about the screening as opposed to making them more fearful. The majority of participants (60%) chose "Sickle Stroke Screen" over "Stroke Risk Screen." Participants reported preferring this wording because it is specific to SCA, was easier to remember and represented a less "scary" option. The most commonly preferred logo is presented in Figure 1. Participant reasons for selecting this option were: it is easier to read; they preferred the stacked layout; it is less spread out; they liked the bold letters; it is more eye catching; and it includes the words "sickle cell" in the logo. When asked about preferences for an infographic, the majority described including a picture of a brain. Nearly all participants believed a reassuring message was needed to balance out the fear of the word "stroke." The message, "knowledge is power" provided this balance and resonated with nearly all participants (95%). Figure 2 presents the infographic developed based on participant feedback. Conclusions: Results from this educational rebranding effort highlight the importance of understanding patient and family educational gaps and incorporating their perspective and feedback into educational campaigns. The new logo and infographic were integrated into an educational pamphlet, informative posters and other material designed by the DISPLACE site principal investigators. Part 3 of the study is underway including implementation of the educational initiative at the DISPLACE sites. The new terminology and logo have also been broadly distributed throughout the US through community-based organizations to other patients, families, and stakeholders. Disclosures Kanter: AGIOS: Membership on an entity's Board of Directors or advisory committees; 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; Wells Fargo: Honoraria; Jeffries: Honoraria; Cowen: Honoraria; bluebird bio, inc: Consultancy, Honoraria; Novartis: Consultancy; Sanofi: Consultancy; Medscape: Honoraria; Guidepoint Global: Honoraria; GLG: Honoraria; BEAM: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Clonal Tracking By Whole Genome Sequencing Permits Comprehensive Mapping of the Genomic Landscape in Pre- and Post-Gene Therapy Sickle Cell Patients

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 559-559
Author(s):  
Alyssa H. Cull ◽  
Michael Spencer Chapman ◽  
Marioara Ciuculescu ◽  
Emily Mitchell ◽  
Myriam Armant ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Stem Cell ◽  
Board Of Directors ◽  
Sickle Cell ◽  
Research Funding ◽  
Phylogenetic Trees ◽  
Insertion Site ◽  
Advisory Board ◽  
Advisory Committees ◽  
Genomic Landscape

Abstract Recent advances in clonal stem cell tracking strategies have enabled interrogation of unperturbed human hematopoiesis. Whole genome sequencing (WGS) can be used to map the clonal dynamics of hematopoietic stem and progenitor cells (HSPCs) by employing spontaneous somatic mutations as unique clonal tags (Lee-Six et al., Nature, 2018). These tags allow for retrospective analysis of individual stem cell clones and the construction of phylogenetic trees mapping out stem cell relatedness, with mutations being acquired in a near-linear fashion over the course of an individual's life. The unprecedented level of information obtained in these studies is particularly well-suited to understanding genomic changes in gene therapy trials aimed at curing diseases such as sickle cell disease (SCD). In addition to mapping relatedness between stem cells, sequencing data can be used to better define mutational signatures for HSPC clones that have been successfully gene-modified as well as those that lack an integrated copy of the therapeutic vector. Given this method's ability to identify low frequency mutations in individual HSPC clones, mutations with extremely low variant allele frequencies can be detected much more readily than through traditional bulk sequencing approaches, something that is particularly relevant given recent safety concerns in some SCD gene therapy trials. In this study, we have mapped the clonal dynamics of HSPCs obtained from pre- and post-gene therapy samples from 4 SCD patients who have undergone autologous gene therapy performed using a BCL11A shmiR lentivirus vector (NCT 03282656, 12-36 months follow-up). HSPCs from mobilized peripheral blood (pre-gene therapy), bone marrow aspirates (both pre- and post-gene therapy) or unmobilized peripheral blood (post-gene therapy) were expanded as single clones and 1508 individual colonies were then sequenced using WGS to an average sequencing depth of 12.3x. Initial results indicate that the mean mutation burden per cell in a pre-gene therapy sample is elevated for some patients compared to what would be expected based on patient age in similar studies. In pre-gene therapy samples, the structure of the phylogenetic trees appeared to be highly polyclonal, indicating that there were no significant clonal expansion events prior to gene therapy. In one patient where we undertook extensive profiling, approximately 15-20 excess mutations per HSPC were observed across the entire genome 24 months after transplantation, presumably acquired as a consequence of gene therapy and/or reconstitution post-transplantation, which is equivalent to approximately one year of normal ageing without a transplantation intervention. However, no clonal expansions or driver mutations were identified at this 24 month follow-up timepoint, suggesting that no strong selective advantage or pre-leukemic events were present prior to or following the gene therapy protocol. Extending this approach to a wider range and larger number of patients will allow for comprehensive mapping of the genomic landscape and clonal evolution of stem cells in sickle cell patients and will also set the stage for improved assessment of safety and potential leukemia-initiating events in the context of gene therapy. Disclosures Esrick: bluebird bio: Consultancy. Williams: bluebird bio: Membership on an entity's Board of Directors or advisory committees, Other: Insertion Site Analysis Advisory Board, Patents & Royalties: BCH licensed certain IP relevant to hemoglobinopathies to bluebird bio. The current license includes the potential for future royalty/milestone income. Bluebird has indicated they will not pursue this as a clinical program and BCH is negotiating return of, Research Funding; BioMarin: Membership on an entity's Board of Directors or advisory committees, Other: Insertion Site Advisory Board; Beam Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other: Scientific Advisory Board; Emerging Therapy Solutions: Membership on an entity's Board of Directors or advisory committees, Other: Chief Scientific Chair; Geneception: Membership on an entity's Board of Directors or advisory committees, Other: Scientific Advisory Board; Alerion Biosciences: Other: Co-founder (now licensed to Avro Bio, potential for future milestones/royalties); Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Steering Committee, Novartis ETB115E2201 (eltrombopag in aplastic anemia). Advisory fees donated to NAPAAC.; Orchard Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other: Membership on a safety advisory board (SAB): SAB position ended 05/20/2021. Co-founder , Patents & Royalties: Potential for future royalty/milestone income, X-SCID. Provided GMP vector for clinical trial, Research Funding. Campbell: Mu Genomics: Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees. Kent: STRM.bio: Research Funding.

scholarly journals Clinical and Biomarker Predictors for Avascular Necrosis in Sickle Cell Disease

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3091-3091
Author(s):  
Michael Rabaza ◽  
Maria Armila Ruiz ◽  
Liana Posch ◽  
Faiz Ahmed Hussain ◽  
Franklin Njoku ◽  
...  
Keyword(s):  
Risk Factors ◽  
Sickle Cell Disease ◽  
Board Of Directors ◽  
Avascular Necrosis ◽  
Sickle Cell ◽  
Research Funding ◽  
Medical Attention ◽  
Cell Disease ◽  
Advisory Committees ◽  
Early Management

Abstract Introduction Sickle cell disease (SCD) affects 1 in 365 African Americans and approximately 25 million people world-wide. A common skeletal system complication is avascular necrosis (AVN), which can cause substantial pain and a reduced quality of life. While early management of AVN is focused on increasing range of motion with physical therapy and pain relief, there are no clear predictors for who is more likely to develop AVN and earlier institution of these preventive measure could help decrease disease progression. Vascular endothelial growth factor (VEGF) is a biomarker of endothelial injury and may indicate reduced vascular supply to the femoral or humeral head. Here we describe potential risk factors and biologic pathways for AVN in SCD, as understanding these may lead to improvements in future monitoring, early detection, and early intervention practices. Methods We investigated clinical and laboratory risk factors associated with AVN in a cohort of 435 SCD patients from our center. Blood samples, clinical, and laboratory data were collected at the time of enrollment during a clinic visit. Genotyping for alpha thalassemia was performed by PCR and the serum concentration of VEGF was measured by ELISA. AVN status was confirmed by review of the medical record and available imaging. We conducted a cross-sectional analysis comparing categorical and linear variables by AVN status using the chi-square and Kruskal-Wallis test, respectively. The independent association of the clinical and laboratory variables with AVN status was determined by logistic regression analysis. The initial model included variables with a P-value < 0.1 on univariate analysis and the final model was ascertained by stepwise forward and backward selection. Median values and interquartile range (IQR) are provided. Results The median age of the cohort was 32 (IQR, 24 - 43) years, 57% (250/435) were female, and 46% (198/435) were on hydroxyurea. AVN was observed in 34% (149/435) of SCD patients. SCD patients with AVN were older, had more frequent vaso-occlusive crises requiring medical attention, and had a higher body mass index (Table I) (P ≤ 0.002). We measured VEGF in 241 of the SCD patients with serum samples available at the time of enrolment. Serum VEGF concentrations trended higher in SCD patients with versus without AVN (420 vs. 359 pg/mL, respectively; P = 0.078). In the multivariate analysis model, AVN was independently associated with increased number of vaso-occlusive crises (OR 1.1, 95% CI: 1.0 - 1.14; P = 0.02), AST concentration (natural log OR 0.5, 95% CI: 0.2 - 0.9; P = 0.03), VEGF concentration (natural log OR 1.4, 95% CI: 1.0 - 1.9; P = 0.047), and tobacco use (OR 1.9, 95% CI: 0.9 - 3.7; P = 0.078). Discussion In conclusion, we demonstrate a high prevalence of AVN in an adult cohort of SCD patients. The presence of AVN was independently associated with a greater frequency of vaso-occlusive pain episodes, which may demonstrate a shared pathophysiology between AVN and vaso-occlusion that merits further investigation. We demonstrate that serum VEGF concentrations are higher in SCD patients with AVN and may be a clinical tool to identify those at high-risk and for earlier intervention for this complication. Figure 1 Figure 1. Disclosures Gordeuk: Modus Therapeutics: Consultancy; Novartis: Research Funding; Incyte: Research Funding; Emmaus: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; CSL Behring: Consultancy. Saraf: Pfizer: Research Funding; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Predictors of Maternal Morbidity Among Participants Enrolled in the Sickle Cell Disease Implementation Consortium Registry

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 3-3
Author(s):  
Rita V Masese ◽  
Dominique Bulgin ◽  
Liliana Preiss ◽  
Mitchell Knisely ◽  
Eleanor Stevenson ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Sickle Cell ◽  
Research Funding ◽  
Transfusion Requirement ◽  
The United States ◽  
Acute Chest Syndrome ◽  
Maternal Outcomes ◽  
Maternal Complications ◽  
Advisory Committees ◽  
Increased Risk

Introduction Pregnancy in sickle cell disease (SCD) is associated with an exacerbation of SCD-related complications and an increased risk of maternal complications. The increased risk is partly due to physiologic adaptations in pregnancy, which include increased metabolic demands and a hypercoagulable state. The maternal death rate for SCD is 629 per 100,000 deliveries, compared to 12 per 100,000 deliveries in black women and 6 per 100,000 deliveries in the general population (Raider et al., 2016). Studies on maternal and perinatal outcomes of patients with SCD present inconsistent and conflicting results. Some studies have reported an increase in maternal complications such as pre-eclampsia, acute chest syndrome and thromboembolic events, while other studies have reported no significant risk in adverse maternal outcomes. The inconsistent findings reported in prior studies may be attributed to small sample sizes and single-centered sites. Our study aims to determine the prevalence and predictors of maternal morbidity among participants enrolled in the SCD Implementation Consortium (SCDIC) registry, which is the largest, most geographically diverse SCD participant sample in the United States. Methods This cross-sectional study included women enrolled in the SCDIC registry who had at least one pregnancy event. The SCDIC is composed of eight academic SCD centers across the United States and one data-coordinating center. Participants were enrolled in the SCDIC registry if they were 18 to 45 years of age and had a confirmed diagnosis of SCD. Enrolled participants completed a series of surveys that collected sociodemographic information, SCD and pregnancy history and data abstractions of participants' medical records was completed. Medical complications queried during pregnancy included: vaso-occlusive episodes, acute chest syndrome, blood transfusion requirement, preeclampsia, maternal diabetes and deep venous thrombosis. Descriptive analysis of sociodemographic, clinical and maternal characteristics was conducted. Bivariate analysis was performed using Chi-Square test, Mann-Whitney U test, t-test, and logistic regressions, as appropriate. A p-value of ≤ 0.05 was considered statistically significant for all analysis. Results The study sample included 743 women who had at least one pregnancy event, and a total of 1066 live births. Almost all women (96.3%) were African American, with a median age of 21 years (inter-quartile range of 19 to 23 years) at first birth. The majority had Hb SS SCD genotype (69.5%; 513 of the 738 with SCD genotype data). Of all reported pregnancies, participants did not use hydroxyurea during conception (78%), and pregnancy (84.5%). Only 2.7 % of the women reported using fertility drugs or assisted reproductive procedures. Seventy five percent of the pregnancies that ended in live births had maternal complications. The leading complications were vaso-occlusive episodes (61.2%), pregnancy requiring blood transfusion(s) (33.2%), preeclampsia (15.4%), deep venous thrombosis (5.6%) and acute chest syndrome (7.7%). When the pregnancies were stratified by SCD genotype, women with Hb SS had a higher occurrence of acute chest syndrome (63.4% vs. 26.7%), transfusion requirement (70.8% vs. 21%) and preeclampsia (66.7% vs 22.4%). In the univariate logistic regressions, multiparous women, with a history of adverse maternal outcomes in a previous pregnancy, had higher odds of vaso-occlusive episodes (OR: 3.42; 95% CI: 2.42-4.94) acute chest syndrome (OR:4.99; 95% CI:2.56- 9.48), transfusion requirement (OR:3.86; 95% CI:2.64- 5.69), and pre-eclampsia (OR:3.36; 95% CI:2.05-5.45). Conclusion In this large multicenter registry, we found pregnant women with SCD have significant maternal complications. Early antenatal care by healthcare providers knowledgeable about risk factors for adverse maternal outcomes in SCD is essential improve maternal and fetal outcomes and reduce the maternal death rate for SCD. Disclosures Hankins: Novartis: Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; MJH Life Sciences: Consultancy, Patents & Royalties; UptoDate: Consultancy; National Heart, Lung, and Blood Institute: Honoraria, Research Funding; LINKS Incorporate Foundation: Research Funding; American Society of Pediatric Hematology/Oncology: Honoraria. Treadwell:Global Blood Therapeutics: Consultancy; UpToDate: Honoraria. King:Amphivena Therapeutics: Research Funding; Bioline: Consultancy; Celgene: Consultancy; Cell Works: Consultancy; Incyte: Consultancy; Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novimmune: Research Funding; RiverVest: Consultancy; Tioma Therapuetics: Consultancy; WUGEN: Current equity holder in private company. Gordeuk:CSL Behring: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; Imara: Research Funding; Ironwood: Research Funding; Novartis: Consultancy. Kanter: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; Novartis: Consultancy; 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; Medscape: Honoraria; Guidepoint Global: Honoraria; bluebird bio, inc: Consultancy, Honoraria; Sanofi: Consultancy. Glassberg:Pfizer: Research Funding; Global Blood Therapeutics: Consultancy; Eli Lilly and Company: Research Funding. Shah:Novartis: Consultancy, Research Funding, Speakers Bureau; Alexion: Speakers Bureau; CSL Behring: Consultancy; Bluebird Bio: Consultancy; Global Blood Therapeutics: Consultancy, Research Funding, Speakers Bureau.

scholarly journals Left atrial appendage orifice area and morphology is closely associated with flow velocity in patients with nonvalvular atrial fibrillation

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Lei Chen ◽  
Changjiang Xu ◽  
Wensu Chen ◽  
Chaoqun Zhang
Keyword(s):  
Atrial Fibrillation ◽  
Flow Velocity ◽  
Left Atrial ◽  
Left Atrial Appendage ◽  
Linear Regression Analysis ◽  
Left Ventricular ◽  
Atrial Appendage ◽  
Mechanical Function ◽  
Orifice Area ◽  
The Relationship

Abstract Background Thromboembolic events are the most serious complication of atrial fibrillation (AF), and the left atrial appendage (LAA) is the most important site of thrombosis in patients with AF. During the period of COVID-19, a non-invasive left atrial appendage detection method is particularly important in order to reduce the exposure of the virus. This study used CT three-dimensional reconstruction methods to explore the relationship between LAA morphology, LAA orifice area and its mechanical function in patients with non-valvular atrial fibrillation (NVAF). Methods A total of 81 consecutive patients with NVAF (36 cases of paroxysmal atrial fibrillation and 45 cases of persistent atrial fibrillation) who were planned to undergo catheter radiofrequency ablation were enrolled. All patients were examined by transthoracic echocardiography (TTE), TEE, and computed tomography angiography (CTA) before surgery. The LAA orifice area was obtained according to the images of CTA. According to the left atrial appendage morphology, it was divided into chicken wing type and non-chicken wing type. At the same time, TEE was performed to determine left atrial appendage flow velocity (LAAFV), and the relationship between the left atrial appendage orifice area and LAAFV was analyzed. Results The LAAFV in Non-chicken wing group was lower than that in Chicken wing group (36.2 ± 15.0 cm/s vs. 49.1 ± 22.0 cm/s, p-value < 0.05). In the subgroup analysis, the LAAFV in Non-chicken wing group was lower than that in Chicken wing group in the paroxysmal AF (44.0 ± 14.3 cm/s vs. 60.2 ± 22.8 cm/s, p-value < 0.05). In the persistent AF, similar results were observed (29.7 ± 12.4 cm/s vs. 40.8 ± 17.7 cm/s, p-value < 0.05). The LAAFV in persistent AF group was lower than that in paroxysmal AF group (34.6 ± 15.8 cm/s vs. 49.9 ± 20.0 cm/s, p-value < 0.001). The LAAFV was negatively correlated with left atrial dimension (R = − 0.451, p-value < 0.001), LAA orifice area (R= − 0.438, p-value < 0.001) and left ventricular mass index (LVMI) (R= − 0.624, p-value < 0.001), while it was positively correlated with LVEF (R = 0.271, p-value = 0.014). Multiple linear regression analysis showed that LAA morphology (β = − 0.335, p-value < 0.001), LAA orifice area (β = −  0.185, p-value = 0.033), AF type (β = − 0.167, p-value = 0.043) and LVMI (β = − 0.465, p-value < 0.001) were independent factors of LAAFV. Conclusions The LAA orifice area is closely related to the mechanical function of the LAA in patients with NVAF. The larger LAA orifice area and LVMI, Non-chicken wing LAA and persistent AF are independent predictors of decreased mechanical function of LAA, and these parameters might be helpful for better management of LA thrombosis.

scholarly journals Treating Acute Leukemia during the COVID-19 Pandemic: A Multicenter Latin American Registry

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 41-42
Author(s):  
Roberta Demichelis ◽  
Martha Alvarado ◽  
Jule F Vasquez ◽  
Nancy Delgado ◽  
Cynthia Gómez ◽  
...  
Keyword(s):  
High Risk ◽  
Maintenance Therapy ◽  
Acute Leukemia ◽  
Board Of Directors ◽  
Latin American ◽  
Refractory Disease ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Factors Associated ◽  
Latin American Countries

Introduction The COVID-19 pandemic has affected the entire world. Health systems have been affected in such a way that patients with diseases other than COVID-19 have suffered serious consequences. In Latin America, the disease has emerged in a fragile system with more disparities, making our patients more vulnerable. Acute leukemia patients have a high risk of severe COVID-19 disease. Various expert recommendations have emerged with the aim of minimizing the risk of COVID-19 without affecting leukemia-related outcomes. However, multiple logistical issues tangentially associated with the pandemic have also appeared, potentially limiting the quality of management of these patients. The objective of this study was to register treatment modifications associated with the COVID-19 pandemic and its short-term consequences in Latin American countries. Methods We included patients older than 14 years, from 14 centers of 4 Latin American countries (Mexico, Peru, Guatemala and Panama), with the diagnosis of acute leukemia, who were on active treatment since the first case of COVID-19 was documented in each country. We documented their baseline characteristics and followed the patients prospectively until July 15, were data-cutoff for this pre-planned analysis was performed. The primary outcome was the incidence of COVID-19 disease and its complications. Secondary outcomes included treatment and consult modifications, and cause of death during the study period. Logistic regression was performed to determine factors associated with COVID-19 and all-cause mortality. Results We recorded the information of 635 patients: 58.1% Ph-negative ALL, 25.7% AML, 9% APL and 7.2% Ph+ALL. The median age was 35 years (14-90 years); 58.8% were consideredf high-risk patients. The majority were on CR (68.3%) receiving consolidation or maintenance therapy, while 14.5% were newly diagnosed and 17.2% with relapsed/refractory disease. The majority (91.8%) were treated in centers that were also receiving COVID-19 patients, 40.2% in centers were patients could not be electively hospitalized for leukemia treatment because of the COVID-19 pandemic. The COVID-pandemic led to treatment-modifications in 40.8% of the cases. Reasons for modifications were associated with logistical issues (22.4%), medical decisions (15.1%) or patient choice (3.3%). The most frequent modification was chemotherapy delay (17.3%) followed by regimen modification (13.4%) and dose-reductions (10.1%). (Figure 1) 83 patients (13.1%) developed COVID-19 disease, the majority mild-moderate disease (54.2%), 27.7% severe disease and 18.1% critically ill; 27.7% required mechanical ventilation and 37.7% died from COVID-19 disease, representing 4.9% of the entire cohort. We identify as risk factors for COVID-19 disease the presence of active leukemia (newly diagnosed or relapsed) (OR 3.46 [95% CI: 2.16-5.5], p&lt;0.001), high-risk leukemia (OR 1.63 [95% CI: 1.54-4.52], p&lt;0.001) and being treated in a center were elective hospitalization was possible (OR 2.17 [95% CI 1.29-3.67], p=0.004). Treatment modifications, appointment prolongations or the use of virtual consultation were not associated with a reduction in the risk of COVID-19. On the other hand, 16.7% of patients died during period analyzed due to leukemia (57.5%), COVID-19 (29.2%) or treatment related-mortality (13.2%). Independent factors associated with mortality were AML vs. ALL (OR 1.89 [95% CI: 1.12-3.18], p=0.016), relapsed-refractory disease (OR 8.34 [95% CI: 4.83-14.41], p&lt;0.001), induction/consolidation vs. maintenance therapy (OR 2.20 [95% CI: 1.25-3.18], p&lt;0.001) and the use of virtual consultation (OR 0.35 [95% CI: 0.13-0.94] p=0.037). (Table 1) Discussion/Conclusions The COVID-19 pandemic led to significant modifications in the standard of care treatment of patients with acute leukemia. The incidence of COVID-19 disease in acute leukemia patients was considerable and more than a third of the patients with acute leukemia and COVID-19 disease died. Despite a short-follow up, 16.7% of the patients died and leukemia-related deaths were the most frequent. In low- and middle-income countries with fragile health systems, the collateral damage for patients with acute leukemia may be just as important as the direct consequences of COVID-19. Disclosures Alvarado: Roche: Speakers Bureau; Novartis: Speakers Bureau; Amgen: Speakers Bureau; Celgene: Speakers Bureau; Alexion: Speakers Bureau. De la Peña-Celaya:Amgen: Speakers Bureau; Janssen: Speakers Bureau; Novartis: Speakers Bureau. Perez:Roche: Speakers Bureau; Celgene: Speakers Bureau; Novartis: Speakers Bureau. Gomez-Almaguer:Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Sign in / Sign up

Export Citation Format

Share Document