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Sickle cell disease (SCD) is an inherited disorder of hemoglobin (Hb); approximately 300,000 babies are born worldwide with SCD each year. In SCD, fibers of polymerized sickle Hb (HbS) form in red blood cells (RBCs), which cause RBCs to develop their characteristic "sickled" shape, resulting in hemolytic anemia and numerous vascular complications including vaso-occlusive crises. The development of novel antisickling compounds will provide new therapeutic options for patients with SCD. We developed a high-throughput "sickling assay" that is based on an automated high-content imaging system to quantify the effects of hypoxia on the shape and size of RBCs from HbSS SCD patients (SS RBCs). We used this assay to screen thousands of compounds for their ability to inhibit sickling. In the assay, voxelotor (an FDA-approved medication used to treat SCD) prevented sickling with a

The integration of genomic testing into clinical care enables the use of individualized approaches to the management of rare diseases. We describe the use of belzutifan, a potent and selective small-molecule inhibitor of the protein hypoxia-inducible factor 2α (HIF2α), in a patient with polycythemia and multiple paragangliomas (the Pacak-Zhuang syndrome). The syndrome was caused in this patient by somatic mosaicism for an activating mutation in EPAS1. Treatment with belzutifan led to a rapid and sustained tumor response along with resolution of hypertension, headaches, and long-standing polycythemia. This case shows the application of a targeted therapy for the treatment of a patient with a rare tumor-predisposition syndrome. (Funded by the Morin Family Fund for Pediatric Cancer and Alex's Lemonade Stand Foundation.).

Sickle cell disease (SCD) requires coordinated, specialized medical care for optimal outcomes. There are no United States (US) guidelines that define a pediatric comprehensive SCD program. We report a modified Delphi consensus-seeking process to determine essential, optimal, and suggested elements of a comprehensive pediatric SCD center. Nineteen pediatric SCD specialists participated from the US. Consensus was predefined as 2/3 agreement on each element's categorization. Twenty-six elements were considered essential (required for guideline-based SCD care), 10 were optimal (recommended but not required), and five were suggested. This work lays the foundation for a formal recognition process of pediatric comprehensive SCD centers.

Background Sickle cell disease (SCD) is a severe and devastating hematological disorder that affects over 100,000 persons in the USA and millions worldwide. Hydroxyurea is the primary disease-modifying therapy for the SCD, with proven benefits to reduce both short-term and long-term complications. Despite the well-described inter-patient variability in pharmacokinetics (PK), pharmacodynamics, and optimal dose, hydroxyurea is traditionally initiated at a weight-based dose with a subsequent conservative dose escalation strategy to avoid myelosuppression. Because the dose escalation process is time consuming and requires frequent laboratory checks, many providers default to a fixed dose, resulting in inadequate hydroxyurea exposure and suboptimal benefits for many patients. Results from a single-center trial of individualized, PK-guided dosing of hydroxyurea for children with SCD suggest that individualized dosing achieves the optimal dose more rapidly and provides superior clinical and laboratory benefits than traditional dosing strategies. However, it is not clear whether these results were due to individualized dosing, the young age that hydroxyurea treatment was initiated in the study, or both. The Hydroxyurea Optimization through Precision Study (HOPS) aims to validate the feasibility and benefits of this PK-guided dosing approach in a multi-center trial. Methods HOPS is a randomized, multicenter trial comparing standard vs. PK-guided dosing for children with SCD as they initiate hydroxyurea therapy. Participants (ages 6 months through 21 years), recruited from 11 pediatric sickle cell centers across the USA, are randomized to receive hydroxyurea either using a starting dose of 20 mg/kg/day (Standard Arm) or a PK-guided dose (Alternative Arm). PK data will be collected using a novel sparse microsampling approach requiring only 10 μL of blood collected at 3 time-points over 3 h. A protocol-guided strategy more aggressive protocols is then used to guide dose escalations and reductions in both arms following initiation of hydroxyurea. The primary endpoint is the mean %HbF after 6 months of hydroxyurea. Discussion HOPS will answer important questions about the clinical feasibility, benefits, and safety of PK-guided dosing of hydroxyurea for children with SCD with potential to change the treatment paradigm from a standard weight-based approach to one that safely and effectively optimize the laboratory and clinical response. Trial registration ClinicalTrials.gov NCT03789591. Registered on 28 December 2018.

The congenital sideroblastic anemias (CSAs) can be caused by primary defects in mitochondrial iron-sulfur (Fe-S) cluster biogenesis. HSCB (heat shock cognate B), which encodes a mitochondrial cochaperone, also known as HSC20 (heat shock cognate protein 20), is the partner of mitochondrial heat shock protein A9 (HSPA9). Together with glutaredoxin 5 (GLRX5), HSCB and HSPA9 facilitate the transfer of nascent 2-iron, 2-sulfur clusters to recipient mitochondrial proteins. Mutations in both HSPA9 and GLRX5 have previously been associated with CSA. Therefore, we hypothesized that mutations in HSCB could also cause CSA. We screened patients with genetically undefined CSA and identified a frameshift mutation and a rare promoter variant in HSCB in a female patient with non-syndromic CSA. We found that HSCB expression was decreased in patient-derived fibroblasts and K562 erythroleukemia cells engineered to have the patient-specific promoter variant. Furthermore, gene knockdown and deletion experiments performed in K562 cells, zebrafish, and mice demonstrate that loss of HSCB results in impaired Fe-S cluster biogenesis, a defect in RBC hemoglobinization, and the development of siderocytes and more broadly perturbs hematopoiesis in vivo. These results further affirm the involvement of Fe-S cluster biogenesis in erythropoiesis and hematopoiesis and define HSCB as a CSA gene.

BACKGROUND Opioids are indicated for moderate-to-severe pain caused by trauma, ischemia, surgery, cancer and sickle cell disease, and vaso-occlusive episodes (SCD-VOC). There is only limited evidence regarding the appropriate number of doses to prescribe for specific indications. Therefore, we developed and implemented an opioid prescribing algorithm with dosing guidelines for specific procedures and conditions. We aimed to reach and sustain 90% compliance within 1 year of implementation. METHODS We conducted this quality improvement effort at a pediatric academic quaternary care institution. In 2018, a multidisciplinary team identified the need for a standard approach to opioid prescribing. The algorithm guides prescribers to evaluate the medical history, physical examination, red flags, pain type, and to initiate opioid-sparing interventions before prescribing opioids. Opioid prescriptions written between January 2015 and September 2020 were included. Examples from 2 hospital departments will be highlighted. Control charts for compliance with guidelines and variability in the doses prescribed are presented for selected procedures and conditions. RESULTS Over 5 years, 83 037 opioid prescriptions in 53 804 unique patients were entered electronically. The encounters with ≥1 opioid prescription decreased from 48% to 25% between 2015 and 2019. Compliance with the specific guidelines increased to ∼85% for periacetabular osteotomies and SCD-VOC and close to 100% for anterior-cruciate ligament surgery. In all 3 procedures and conditions, variability in the number of doses prescribed decreased significantly. CONCLUSION We developed an algorithm, guidelines, and a process for improvement. The number of opioid prescriptions and variability in opioid prescribing decreased. Future evaluation of specific initiatives within departments is needed.

Current screening guidelines may not be adequate to identify iron deficiency (ID) and iron deficiency anemia (IDA) in adolescent and young adults. Adolescent and young adult outpatients from 4 hospital-based clinics (N = 493) reported on diet, health, and bleeding, and had phlebotomy for iron and hematologic tests. We examined sex-specific factors associated with ID and IDA and ability of universal and risk factor–based screening using hemoglobin and hemoglobin plus ferritin to detect ID and IDA. Among females (n = 350), 34.6% had ID and 6.3% had IDA. Nearly 1 in 3 females with ID had no risk factors. Among males, 12.6% had ID; none had IDA. More than 1 in 3 males with ID did not have risk factors. Current screening approaches would have missed ID in 47% to 82% of females and 95% to 100% of males. ID was prevalent in both male and female adolescents and young adult outpatients. New approaches to screening for ID are needed to accurately evaluate iron status in this population.

Background: Sickle cell disease (SCD) is a group of genetic blood disorders characterized by hemolytic anemia, multi-organ damage and acutely painful events (vaso-occlusive crises [VOCs]) that can cause life-threatening complications. Vaso-occlusion is mediated, in part, by P-selectin, an adhesion molecule expressed on endothelial cells and platelets. Adults and children with SCD have similar P-selectin expression levels; however, disease severity worsens with increasing age because of cumulative endothelial damage caused by repeated vaso-occlusion events. Crizanlizumab is a humanized anti-P-selectin monoclonal antibody that binds P-selectin and blocks its interaction with its ligands. SUSTAIN, a Phase 2 study in adults with SCD, has shown that crizanlizumab, compared with placebo, is well tolerated and significantly decreases the number of VOCs requiring a healthcare visit (Ataga et al. N Engl J Med 2017). Aim: To describe the design of the first crizanlizumab study in pediatric patients (pts) with SCD and report demographics and baseline characteristics of a subset of enrolled pts (aged 6 to Methods: Primary objectives of this Phase 2, multicenter, open-label study are to confirm crizanlizumab dosing and assess safety. Pts aged 6 mo to Secondary objectives include assessment of crizanlizumab efficacy, measured by annualized rate of VOCs leading to a healthcare visit (clinic, emergency room [ER] or hospital), and annualized rate of VOCs managed at home. VOC subcategories (uncomplicated pain crisis, acute chest syndrome, hepatic and splenic sequestration, and priapism), overall hospitalizations and ER visits and dactylitis events are also assessed. Safety measures include frequency and severity of adverse events. Long-term PK and PD will also be characterized by measuring pre-dose concentrations and percentage of P-selectin inhibition prior to each study drug dose. Part A in each age group will confirm PK dose, beginning with ≥8 pts in G1. If unconfirmed, dose will be adjusted based on population PK model, and ≥8 additional pts enrolled. Once dose is confirmed, recruitment will be expanded for long-term safety and efficacy evaluation of the PK confirmed dose (Part B). This process will then repeat for G2 then G3 (2 to Results: As of January 28, 2020, 59 pts were enrolled: 46 pts in G1 (11 pts in Part A and 35 pts Part B) and 13 pts in G2 Part A. Pt demographics are available for Part A in G1 and 2 (Table), based on 2 Data Monitoring Committee analyses. The median age of G1 was 17.0 yr (range 13-17), 6 (54.5%) were male and 11 (100%) were Black/African American. 9 (81.8%) had HbSS disease, 1 (9.1%) HbSC and 1 (9.1%) HbSβ0. The median age of G2 was 9.0 yr (range 6-11), 8 (61.5%) were male, 7 (53.8%) were Black/African American, 4 (30.8%) were White, and 2 were of multiple race, specifically 'White, Asian' (n=1, 7.7%) and 'White, Black/African American' (n=1, 7.7%). 12 (92.3%) pts had HbSS disease and 1 (7.7%) had HbSC. Conclusions: This study aims to address an unmet treatment need in pediatric pts, exploring appropriate dosing and the safety of crizanlizumab. The annualized rates of VOCs, hospitalizations and ER visits will be assessed as secondary objectives. The primary analyses for Parts A and B of G1 and 2, and then G3, will occur consecutively when all pts enrolled in each group have either completed 26 weeks of treatment or discontinued the study treatment. Disclosures Heeney: UpToDate: Patents & Royalties: Author royalties; Micelle: Consultancy, Other; Keros: Consultancy; Novartis: Consultancy, Other; AstraZeneca: Consultancy, Other; Cyclerion: Consultancy, Other; Forma Therapeutics: Consultancy; Dova: Consultancy; Global Blood Therapeutics: Consultancy; Emerging Therapy Solutions (ETS): Consultancy. Rees:Alnylam Pharmaceuticals: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; AstraZeneca: Other: Data monitoring committee membership; Emmanus Medical: Consultancy, Honoraria; TauRx: Other: Data And Safety Monitoring. de Montalembert:Vertex: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bluebird bio: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Addmedica: Honoraria, Membership on an entity's Board of Directors or advisory committees. Odame:Novo Nordisk: Other: Study Advisory Board; Global Blood Therapeutics: Other: Study Data Safety Monitoring Board; Novartis: Other: Study Steering Committee. Wali:Novartis: Research Funding. Nguyen:Novartis: Current Employment. Lam:Novartis: Current Employment. Herranz:Novartis: Current Employment. Kanter:NHLBI Sickle Cell Advisory Board: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; bluebird bio, inc: Consultancy, Honoraria; 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; Guidepoint Global: Honoraria; Cowen: Honoraria; Jeffries: Honoraria; Wells Fargo: Honoraria; Medscape: Honoraria; GLG: Honoraria; Sanofi: Consultancy. OffLabel Disclosure: Crizanlizumab is a monoclonal antibody to P-selectin indicated in the USA for the prevention of vaso-occlusive crises in patients aged 16 years and over with sickle cell disease. This abstract described the new pediatric trial of crizanlizumab, which is not indicated for patients aged less than 16 years of age

This study compared outcomes following total (TS) or partial splenectomy (PS) among patients with hereditary spherocytosis. Seventy-nine patients (TS = 33, PS = 46) were identified. The follow-up p...

The phase 3 HESTIA3 study assessed the efficacy and safety of the reversible P2Y12 inhibitor ticagrelor vs placebo in preventing vaso-occlusive crises in pediatric patients with sickle cell disease (SCD). Patients aged 2 to 17 years were randomly assigned 1:1 to receive weight-based doses of ticagrelor or matching placebo. The primary end point was the rate of vaso-occlusive crises, a composite of painful crises and/or acute chest syndrome (ACS). Key secondary end points included number and duration of painful crises, number of ACS events, and number of vaso-occlusive crises requiring hospitalization or emergency department visits. Exploratory end points included the effect of ticagrelor on platelet activation. In total, 193 patients (ticagrelor, n = 101; placebo, n = 92) underwent randomization at 53 sites across 16 countries. The study was terminated 4 months before planned completion for lack of efficacy. Median ticagrelor exposure duration was 296.5 days. The primary end point was not met: estimated yearly incidence of vaso-occlusive crises was 2.74 in the ticagrelor group and 2.60 in the placebo group (rate ratio, 1.06; 95% confidence interval, 0.75-1.50; P = .7597). There was no evidence of efficacy for ticagrelor vs placebo across secondary end points. Median platelet inhibition with ticagrelor at 6 months was 34.9% predose and 55.7% at 2 hours’ postdose. Nine patients (9%) in the ticagrelor group and eight patients (9%) in the placebo group had at least one bleeding event. In conclusion, no reduction of vaso-occlusive crises was seen with ticagrelor vs placebo in these pediatric patients with SCD. This trial was registered at www.clinicaltrials.gov as #NCT03615924.

The congenital sideroblastic anemias (CSAs) are a heterogeneous group of inherited disorders of erythropoiesis characterized by pathologic deposits of iron in the mitochondria of developing erythroblasts. Mutations in the mitochondrial glycine carrier SLC25A38 cause the most common recessive form of CSA. Nonetheless, the disease is still rare, there being fewer than 70 reported families. Here we describe the clinical phenotype and genotypes of 31 individuals from 24 families, including 11 novel mutations. We also review the spectrum of reported mutations and genotypes associated with the disease, describe the unique localization of missense mutations in transmembrane domains and account for the reoccurrence of several alleles in different populations.

Vaso-occlusive episodes (VOEs) are a common complication of sickle cell disease (SCD) and a significant cause of morbidity. Managing VOE pain can be difficult and complex. Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has been used to manage VOE pain. This systematic literature review synthesizes research published from 2010 to 2020 on the use of ketamine infusion to decrease VOE pain. The review demonstrates that ketamine, a safe and effective treatment for VOE pain, could be considered more widely. However, the significant variability among published clinical studies with regard to dosing, timing of initiation, duration of infusion, and timing of discontinuation highlights the need for standardized ketamine infusion protocols for the management of VOE pain. We conclude with a brief discussion of key components of a potential standardized protocol supported by the literature reviewed as well as areas for future investigation.

Sickle cell disease is characterized by hemolytic anemia, pain, and progressive organ damage. A high level of erythrocyte fetal hemoglobin (HbF) comprising α- and γ-globins may ameliorate these manifestations by mitigating sickle hemoglobin polymerization and erythrocyte sickling.We enrolled patients with sickle cell disease in a single-center, open-label pilot study. The investigational therapy involved infusion of autologous CD34+ cells transduced with the BCH-BB694 lentiviral vector, which encodes a short hairpin RNA (shRNA) targetingAs of October 2020, six patients had been followed for at least 6 months after receiving BCH-BB694 gene therapy; median follow-up was 18 months (range, 7 to 29). All patients had engraftment, and adverse events were consistent with effects of the preparative chemotherapy. All the patients who could be fully evaluated achieved robust and stable HbF induction (percentage HbF/(F+S) at most recent follow-up, 20.4 to 41.3%), with HbF broadly distributed in red cells (F-cells 58.9 to 93.6% of untransfused red cells) and HbF per F-cell of 9.0 to 18.6 pg per cell. Clinical manifestations of sickle cell disease were reduced or absent during the follow-up period.This study validates BCL11A inhibition as an effective target for HbF induction and provides preliminary evidence that shmiR-based gene knockdown offers a favorable risk-benefit profile in sickle cell disease. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT03282656).

BACKGROUND: Total splenectomy (TS) and partial splenectomy (PS) are used for children with congenital hemolytic anemia (CHA), although the long-term outcomes of these procedures are poorly defined. This report describes long-term outcomes of children with CHA requiring TS or PS. PROCEDURE: We collected data from children ages 2-17 with hereditary spherocytosis (HS) or sickle cell disease (SCD) requiring TS or PS from 1996 to 2016 from 14 sites in the Splenectomy in Congenital Hemolytic Anemia (SICHA) consortium using a prospective, observational patient registry. We summarized hematologic outcomes, clinical outcomes, and adverse events to 5 years after surgery. Hematologic outcomes were compared using mixed effects modeling. RESULTS: Over the study period, 110 children with HS and 97 children with SCD underwent TS or PS. From preoperatively compared to postoperatively, children with HS increased their mean hemoglobin level by 3.4 g/dL, decreased their mean reticulocyte percentage by 6.7%, and decreased their mean bilirubin by 2.4mg/dL. Hematologic improvements and improved clinical outcomes were sustained over 5 years of follow-up. For children with SCD, there was no change in hemoglobin after PS or TS following surgery, although all clinical outcomes were improved. Over 5 years, there was one child with HS and 5 children with SCD who developed post-splenectomy sepsis. CONCLUSIONS: For children with HS, there are excellent long-term hematologic and clinical outcomes following either PS or TS. Although hemoglobin levels do not change after TS or PS in SCD, the long-term clinical outcomes for children with SCD are favorable.

Novel therapies for sickle cell disease (SCD) based on genetically engineered autologous hematopoietic stem and progenitor cells (HSPCs) are critically dependent on a safe and effective strategy for cell procurement. We sought to assess the safety and efficacy of plerixafor when used in transfused patients with SCD for HSC mobilization. Six adult patients with SCD were recruited to receive a single dose of plerixafor, tested at lower than standard (180 µg/kg) and standard (240 µg/kg) doses, followed by CD34+ cell monitoring in peripheral blood and apheresis collection. The procedures were safe and well-tolerated. Mobilization was successful, with higher peripheral CD34+ cell counts in the standard vs the low-dose group. Among our 6 donors, we improved apheresis cell collection results by using a deep collection interface and starting apheresis within 4 hours after plerixafor administration. In the subjects who received a single standard dose of plerixafor and followed the optimized collection protocol, yields of up to 24.5 × 106 CD34+ cells/kg were achieved. Interestingly, the collected CD34+ cells were enriched in immunophenotypically defined long-term HSCs and early progenitors. Thus, we demonstrate that plerixafor can be employed safely in patients with SCD to obtain sufficient HSCs for potential use in gene therapy.

We have entered an era of exploding interest in therapeutics for sickle cell disease. The expansion in our understanding of sickle cell disease pathophysiology has enhanced the range of potential therapeutic targets. From induction of fetal hemoglobin to antiadhesion molecules, we are potentially on the cusp of making life-altering modifications for individuals with sickle cell disease. This disease population cannot afford to let the current momentum wane. Studies exploring combinations of therapies affecting multiple steps in the pathophysiology and exploring novel and clinically relevant outcomes are incumbent.

Red blood cell transfusions have become standard of care for the prevention of life-threatening anemia in patients with β-thalassemia and sickle cell disease (SCD). However, frequent transfusions can lead to accumulation of iron that can result in liver cirrhosis, diabetes mellitus, arthritis, arrhythmias, cardiomyopathy, heart failure, and hypogonadotropic hypogonadism. Iron chelation therapy has been shown to reduce serum ferritin levels and liver iron content, but limitations of trial design have prevented any demonstration of improved survival. The objective of this systematic review was to investigate the impact of iron chelation therapy on overall and event-free survival in patients with β-thalassemia and SCD. Eighteen articles discussing survival in β-thalassemia and 3 in SCD were identified. Overall iron chelation therapy resulted in better overall survival, especially if it is instituted early and compliance is maintained. Comparative studies did not show any significant differences between available iron chelation agents, although there is evidence that deferiprone is better tolerated than deferoxamine and that compliance is more readily maintained with the newer oral drugs, deferiprone and deferasirox. Iron chelation therapy, particularly the second-generation oral agents, appears to be associated with improved overall and event-free survival in transfusion-dependent patients with β-thalassemia and patients with SCD.

Pyruvate kinase deficiency (PKD) is the most frequent red blood cell enzyme abnormality of the glycolytic pathway and the most common cause of hereditary nonspherocytic hemolytic anemia. Over 250 PKLR-gene mutations have been described, including missense/nonsense, splicing and regulatory mutations, small insertions, small and gross deletions, causing PKD and hemolytic anemia of variable severity. Alu retrotransposons are the most abundant mobile DNA sequences in the human genome, contributing to almost 11% of its mass. Alu insertions have been associated with a number of human diseases either by disrupting a coding region or a splice signal. Here, we report on two unrelated Middle Eastern patients, both born from consanguineous parents, with transfusion-dependent hemolytic anemia, where sequence analysis revealed a homozygous insertion of AluYb9 within exon 6 of the PKLR gene, causing precipitous decrease of PKLR RNA levels. This Alu element insertion consists a previously unrecognized mechanism underlying pathogenesis of PKD.

Background: Hospitalization due to vaso-occlusive crisis (H-VOC) is common in individuals with sickle cell disease (SCD), with an increasing occurrence of SCD-related complications, including organ damage, as the disease progresses. Evidence regarding the relationship between H-VOC and SCD-related organ damage, however, is lacking. Aim: To assess whether H-VOC is associated with hospitalization due to SCD-related organ damage, through retrospective analysis of data collected prospectively during a 3-year, multicenter, observational US study (NCT01220115) that aimed to better understand disease burden and management of SCD in individuals aged ≥2 years. Methods: Of the 498 individuals with SCD who were recruited into the US study, data were analyzed from 202 (100 men and 102 women) who were aged ≥16 years and had available hospital admission data. Organ damage was defined based on hospital discharge diagnosis. 1 Variables tested at baseline, in addition to H-VOC, included demographics, blood measures, and treatment history. Age and sex were included by default in all models based on literature suggesting they are relevant factors influencing organ damage. Hazard ratios (HRs) for the time from H-VOC to the first subsequent hospitalization due to SCD-related organ damage were estimated using multivariable Cox regression. Worsening of pre-existing organ damage was not considered as an event due to potential confounding (ie worsening of organ damage related to the pre-existing condition rather than as a consequence of the VOC). Results: During median 3-year follow-up, 55 (27%) individuals experienced at least one hospitalization due to SCD-related organ damage; 2 19 (9%) had multiple visits. Within the 12 months preceding baseline, 22 (11%) individuals had a history of organ damage, there was a median of two H-VOC in the 90 (45%) individuals with history of H-VOC, and 43 (21%) individuals had received chronic transfusion (≥6). History of H-VOC (HR 2.54, 95% confidence interval [CI] 1.46 to 4.43 in past 12 months), genotype (HR 2.69, 95% CI 1.34 to 5.41 for HbSS), and sex (HR 1.90, 95% CI 1.08 to 3.34 for women) were all significantly associated with subsequent hospitalization for SCD-related organ damage. Discussion and conclusion: This analysis demonstrates that history of H-VOC within the preceding 12 months is significantly associated with a higher rate of subsequent hospitalization due to SCD-related organ damage, independent of age, sex, and genotype, and may therefore help identify individuals at high risk of developing organ damage. Despite 21% of individuals receiving chronic transfusions at baseline, this factor did not remain significantly associated with the outcome when also considering genotype and H-VOC. Age and sex were unexpectedly insignificantly associated with the outcome; this is likely due to the relatively short follow-up time. Extending the historical timeframe of organ damage to 5 years did not change our findings, except that age also became significantly associated with subsequent hospitalization for organ damage. Acute chest syndrome and pneumonia were the most common types of historical (baseline) organ damage, whilst gallbladder disease was the most common organ damage observed during the follow-up period that was not observed at baseline. Our data have limited statistical power and generalizability; additional studies are required to confirm these findings. Nevertheless, our findings support the existing evidence of the impact that VOCs may have on individuals with SCD, and highlights the importance of preventing and reducing H-VOC. 1Acute chest syndrome or pneumonia; avascular bone necrosis of hip(s), shoulder(s) or spine; cardiac failure; central nervous system disease (ie abnormal transcranial Doppler, silent infarct, stroke and transient ischemic attack); gallbladder disease; leg ulcer; liver disease (ie hepatic fibrosis/ cirrhosis, hepatic sequestration/sickle-hepatopathy/intrahepatic sickling, pulmonary fibrosis, pulmonary hypertension); priapism; renal disease (ie acute renal failure, chronic renal failure-supportive, dialysis, microalbuminuria/ proteinuria, transplant); retinopathy; and splenic sequestration. 2The top 3 reasons for hospitalization due to SCD-related organ damage were acute chest syndrome or pneumonia (n=29; 53%), renal disease (n=7; 13%) and gallbladder disease (n=6; 11%). Figure 1 Figure 1. Disclosures Heeney: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; FORMA: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Vertex / Crispr Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: DSMB; bluebird bio: Consultancy; Keros: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: DSMB; Cyclerion: Consultancy, Membership on an entity's Board of Directors or advisory committees. Pattipaka: Novartis: Current Employment, Current holder of individual stocks in a privately-held company. Fermont: Novartis Pharma AG, Basel, Switzerland: Current Employment, Current equity holder in publicly-traded company.

Background: Vaso-occlusive crises (VOCs) are the hallmark of SCD. The cell adhesion molecule P-selectin plays a key role in the multicellular interactions that can lead to VOCs. In the SUSTAIN trial in adults, crizanlizumab 5.0 mg/kg, a humanized monoclonal antibody that blocks P-selectin, significantly reduced the median annualized rate of VOCs vs placebo and had a favorable safety profile (Ataga et al. N Engl J Med 2017). Aim: To describe initial safety and efficacy results for patients (pts) with SCD aged 12- Methods: SOLACE-kids is a Phase II study to confirm and establish appropriate dosing and evaluate safety of crizanlizumab in pediatric pts with SCD (any genotype) and ≥1 VOC leading to a healthcare (HC) visit within 12 mo prior to screening. Pts (N≥100) are stratified by age: Group 1 (G1; 12- Results: As of 28 August 2020, 50 pts were enrolled in G1 of SOLACE-kids. Mean (SD) age of pts was 15.0 (1.92) yr, 29 (58%) were female, 44 (88%) had the HbSS genotype, 32 (64%) were Black/African American and 42 (84%) were receiving HU. Median (range) duration of exposure to crizanlizumab was 36.6 (6-98) wk; 44 (88%) pts received treatment for ≥26 wk. The most commonly reported AEs were headache (n=14 [28%]), vomiting (n=12 [24%]) and back pain (n=9 [18%]). Grade ≥3 AEs were reported in 13 (26%) pts; most common were anemia (n=3 [6%]) and back pain (n=2 [4%]). Serious AEs were reported in 11 (22%) pts; none were deemed related to treatment. Incidence of AEs of special interest (AESI) is shown in Table 1. No AESI led to treatment discontinuation except 1 pt who died of meningitis (not related to treatment). No infusion-related reactions were serious; all had resolved at data cut-off (except for 1 case of Grade 1 dizziness). No case of anaphylactic reaction to crizanlizumab was reported. Pain events on the day of crizanlizumab infusion suspected to be related to treatment were reported in 3 (6%) pts. All pain events, regardless of relationship to treatment, were Grade 1/2, except for two Grade 3 events reported in the same pt (back pain and pain in extremity), which resolved on day of onset. All hemorrhage events were mild and not considered related to treatment. Increase from baseline (BL) in total bilirubin, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) was reported in 29 (58%), 17 (34%) and 20 (40%) pts, respectively. 2 (4%) pts had Grade 4 total bilirubin significantly above normal (1 pt was Grade 4 and 1 pt was Grade 3 at BL); 21 (42%) pts had Grade 3 total bilirubin significantly above normal (5 pts were Grade 3 at BL). Grade 3 increase in ALT and AST was reported in 2 (4%) pts each. All reported liver function parameters did not meet study criteria for severe drug-induced liver injury. The median (range) number of VOCs leading to a HC visit was 3.0 (1.0-26.0) at BL and 1.6 (0.0-12.7) on treatment (median absolute reduction: 1.0 [range: -13.3 to 5.8]). 18 (36%) pts did not experience a VOC leading to a HC visit while on treatment. The median (range) annualized rate of hospitalizations/ER visits at BL was 4.0 (1.0-36.0) vs 1.54 (0.0-14.3) on treatment (median reduction: 2.35 [range: -21.7 to 5.3]) (Table 2). Conclusion: This initial analysis of SOLACE-kids shows crizanlizumab 5.0 mg/kg is safe and well tolerated in pts aged 12- Figure 1 Figure 1. Disclosures Heeney: FORMA: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Vertex / Crispr Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: DSMB; bluebird bio: Consultancy; Keros: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: DSMB; Cyclerion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Rees: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Addmedica: Honoraria; TauRx: Membership on an entity's Board of Directors or advisory committees. De Montalembert: Vertex: Membership on an entity's Board of Directors or advisory committees; bluebird bio: Membership on an entity's Board of Directors or advisory committees; Addmedica: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Odame: Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Steering Committee; Global Blood Therapeutics: Other: DSMB. Brown: Imara: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Novo Nordisk: Consultancy; Forma Therapeutics: Research Funding; Pfizer: Research Funding; Global Blood Therapeutics: Consultancy, Research Funding. Wali: Novatis Oncology: Research Funding. Nguyen: Novartis: Current Employment. Lam: Novartis Pharmaceuticals Corporation: Current Employment, Current equity holder in publicly-traded company. Pfender: Novartis: Current Employment, Current equity holder in publicly-traded company. 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.

Background/Aims: Patients with sickle cell anemia can experience recurrent pain episodes, which affect quality of life. The reported prevalence of pain is higher in studies using patient diaries than in healthcare facility utilization data. Determining Effects of Platelet Inhibition on Vaso-Occlusive Events was a multinational study that assessed the efficacy and safety of prasugrel in reducing the rate of vaso-occlusive events in children with sickle cell anemia (NCT01794000) and included an electronic patient-reported outcome diary to record pain occurrence. We aimed to capture diary completion rates and compliance in children who used the electronic patient-reported outcome diary during the Determining Effects of Platelet Inhibition on Vaso-Occlusive Events study and examine factors contributing to diary completion rates and compliance. Methods: Daily electronic patient-reported outcome diary data were collected for up to 9 months in Determining Effects of Platelet Inhibition on Vaso-Occlusive Events participants aged 4 to Results: A total of 311 participants received a diary; 268 provided diary data through Month 9. Diary completion rates and compliance were high throughout the collection period and across all groups and regions, despite no games being included on the device. For subjective data, the overall completion rate was 94.4%, and 92.6% of participants were compliant. For objective data, the overall completion rate was 93.3%, and 89.7% of participants were compliant. Completion rates and compliance differed significantly by age and region and were higher for 4 to Conclusion: With appropriate design, participant training, and sufficient monitoring, an electronic patient-reported outcome diary can capture daily sickle cell–related pain data in large multinational studies. Providing a mechanism for caregiver reporting is particularly valuable for participants

Sickle cell disease (SCD) is a hematologic disorder with complex pathophysiology that includes chronic hemolysis, vaso-occlusion and inflammation. Increased leukocyte-erythrocyte-endothelial interactions, due to upregulated expression of adhesion molecules and activated endothelium, are thought to play a primary role in initiation and progression of SCD vaso-occlusive crisis and end-organ damage. Several new pathophysiology-based therapeutic options for SCD are being developed, chiefly targeting the inflammatory pathways. Omega-3 fatty acids are polyunsaturated fatty acids that are known to have effects on diverse physiological processes. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are the principal biologically active omega-3 fatty acids. The therapeutic effects of DHA and EPA on chronic inflammatory disorders and cardiovascular diseases are well recognized. The therapeutic effects of omega-3 fatty acids are attributed to their anti-inflammatory and anti-thrombotic eicosanoids, and the novel class of EPA and DHA derived lipid mediators: resolvins, protectins and maresins. Blood cell membranes of patients with SCD have abnormal fatty acids composition characterized by high ratio of pro-inflammatory arachidonic acid (AA) to anti-inflammatory DHA and EPA (high omega-6/omega-3 ratio). In addition, experimental and clinical studies provide evidence that treatment with DHA does confer improvement in rheological properties of sickle RBC, inflammation and hemolysis. The clinical studies have shown improvements in VOC rate, markers of inflammation, adhesion, and hemolysis. In toto, the results of studies on the therapeutic effects of omega-3 fatty acids in SCD provide good body of evidence that omega-3 fatty acids could be a safe and effective treatment for SCD.

Congenital disorders of glycosylation (CDGs) are clinically heterogeneous disorders defined by a decreased ability to modify biomolecules with oligosaccharides. Critical disruptions in protein recognition, interaction, binding, and anchoring lead to broad physiological effects. Patients present with endocrinopathy, immunodeficiency, hepatopathy, coagulopathy, and neurodevelopmental impairment. Patients may experience mortality/morbidity associated with shock physiology that is frequently culture negative and poorly responsive to standard care. Oedema, pleural and pericardial effusions, ascites, proteinuria, and protein-losing enteropathy are observed with an exaggerated inflammatory response. The negative serum protein steady state results from several mechanisms including reduced hepatic synthesis and secretion, increased consumption, and extravasation. Disruption of the glycocalyx, a layer of glycosylated proteins that lines the endothelium preventing thrombosis and extravasation, is a suspected cause of endothelial dysfunction in CDG patients. We performed a retrospective review of CDG patients admitted to our institution with acute illness over the past 2 years. Longitudinal clinical and laboratory data collected during the sick and well states were assessed for biomarkers of inflammation and efficacy of interventions. Six patients representing 4 CDG subtypes and 14 hospitalisations were identified. Acute D-dimer elevation, proteinuria, decreased serum total protein levels, coagulation proteins, and albumin were observed with acute illness. Infusion of fresh frozen plasma, and in some cases protein C concentrate, was associated with clinical and biomarker improvement. This was notable with intra-patient comparison of treated vs untreated courses. Use of endothelial barrier support therapy may reduce endothelial permeability by restoring both regulatory serum protein homeostasis and supporting the glycocalyx and is likely a critical component of care for this population.

Background: DOVE (Determining Effects of Platelet Inhibition on Vaso-Occlusive Events) was a Phase 3, randomized, double-blind, placebo-controlled study conducted in children with sickle cell anemia at 51 sites in 13 countries across four continents. Procedure: Data from DOVE were assessed for regional differences in subject phenotype and treatment. Demographics, baseline clinical and laboratory data, hydroxyurea (HU) use, vaso-occlusive crisis (VOCs, composite endpoint of painful crisis or acute chest syndrome (ACS, Beijing, China)), serious adverse events (SAEs, Florence, Italy), hospitalization, and treatments were compared across the Americas, Europe, North Africa/Middle East, and Sub-Saharan Africa (SSA). Results: Race, body mass index, and blood pressures differed by region. Pre-enrollment VOCs were highest in the Americas. For subjects not on HU, baseline hemoglobin was lowest in SSA, reticulocyte count was lowest in the Americas. Within SSA, Kenya subjects presented higher baseline hemolysis. Painful crisis was the most common SAE, followed by ACS in the Americas and infections in other regions. VOC rate and percentage of VOC hospitalizations were highest in Europe. Regardless of region, most VOCs were treated with analgesics, approximately half were treated with intravenous fluids. The proportion of VOC-related transfusions was greatest in Europe. Lengths of hospital stay were similar across regions. Conclusions: Overall differences in SAEs and hospitalization for VOCs may be due to cultural diversities, resource utilization, disease severity, or a combination of factors. These data are of importance for the planning of future trials in SCA in a multinational setting.

The congenital sideroblastic anemias (CSAs) are a heterogeneous group of inherited blood disorders characterized by pathological mitochondrial iron deposition in erythroid precursors. Each known cause has been attributed to a mutation in a protein associated with heme biosynthesis, iron-sulfur cluster biogenesis, mitochondrial translation, or a component of the mitochondrial respiratory chain. Here, we describe a recurring mutation, c.276_278del, p.F93del, in NDUFB11, a mitochondrial respiratory complex I-associated protein encoded on the X chromosome, in 5 males with a variably syndromic, normocytic CSA. The p.F93del mutation results in respiratory insufficiency and loss of complex I stability and activity in patient-derived fibroblasts. Targeted introduction of this allele into K562 erythroleukemia cells results in a proliferation defect with minimal effect on erythroid differentiation potential, suggesting the mechanism of anemia in this disorder.

OBJECTIVES: Pediatric pain management has rapidly changed over the last 2 decades. In this study, we describe the changing practices and adverse events (AEs) related to patient-controlled analgesia (PCA) and/or nurse-controlled analgesia (NCA) over a 22-year period. METHODS: After institutional review board approval, retrospective data from a single tertiary-care pediatric hospital were collected between 1994 and 2016. Subgroup analyses were done for surgical and medical case patients. We reported the number of times that PCA and/or NCA was ordered annually, the median and interquartile ranges for age, PCA and/or NCA duration and length of stay, and AE frequencies. RESULTS: Over 22 years, 32 338 PCAs and/or NCAs were ordered in this institution. Morphine and hydromorphone were used most commonly. Between 1994 and 2006, initial orders for PCA and/or NCA increased 2.5-fold. After 2007, initial orders for PCA and/or NCA rapidly decreased; after 2013, the decrease continued at a slower rate, with a total of 1007 orders in 2016. This decrease occurred despite increased hospital admissions and surgeries. Between 2007 and 2012, peripheral nerve blocks rapidly increased (10-fold). After 2002, 146 AEs were reported (1.0%). Of those, 50.5% were nonintercepted, and 20.6% were intercepted AEs; 5.5% and 6.2% were preventable and nonpreventable AEs, respectively. CONCLUSIONS: PCA and/or NCA usage continues to be common in pediatric patients, although usage has declined and stabilized in the setting of other emerging methods of analgesia and increases in the number of minimally invasive surgical procedures. The overall rate of AEs was extremely low. However, improvements to eliminate all errors are needed, especially with medications with a great risk of harm (such as opioids).

The utility of bronchodilators to treat acute chest syndrome (ACS) in patients with sickle cell disease is unknown. Our objectives were to examine the variability in bronchodilator use for ACS among pediatric hospitals contributing to a large database and to examine the relationship between bronchodilator use and length of stay (LOS) and mortality. Between 2005 and 2011, bronchodilators were used during 6812/11 328 hospitalizations (60.1%) and use varied from 0.0% to 97.0% (median = 46.0%, interquartile range = 37.0% to 74.0%). Median LOS was 4 days, and interquartile range was 2 to 6 days. Bronchodilator use was associated with a 13.2% increase in LOS (95% confidence interval = 9.2% to 17.3%, P < .001). However, in the subgroup with asthma, bronchodilator use was associated with a 17.9% decrease in LOS (95% confidence interval = 1.7% to 31.4%, P = .03). There is wide variability in bronchodilator use for ACS, and it has variable association with LOS, depending on comorbid asthma. Prospective trials are needed to evaluate bronchodilators for ACS.

We have entered an era of exploding interest in therapeutics for sickle cell disease. The expansion in our understanding of sickle cell disease pathophysiology has enhanced the range of potential therapeutic targets. From induction of fetal hemoglobin to antiadhesion molecules, we are potentially on the cusp of making life-altering modifications for individuals with sickle cell disease. This disease population cannot afford to let the current momentum wane. Studies exploring combinations of therapies affecting multiple steps in the pathophysiology and exploring novel and clinically relevant outcomes are incumbent.

Summary Background For children with sickle cell anaemia and high transcranial doppler (TCD) flow velocities, regular blood transfusions can effectively prevent primary stroke, but must be continued indefinitely. The efficacy of hydroxycarbamide (hydroxyurea) in this setting is unknown; we performed the TWiTCH trial to compare hydroxyurea with standard transfusions. Methods TWiTCH was a multicentre, phase 3, randomised, open-label, non-inferiority trial done at 26 paediatric hospitals and health centres in the USA and Canada. We enrolled children with sickle cell anaemia who were aged 4–16 years and had abnormal TCD flow velocities (≥200 cm/s) but no severe vasculopathy. After screening, eligible participants were randomly assigned 1:1 to continue standard transfusions (standard group) or hydroxycarbamide (alternative group). Randomisation was done at a central site, stratified by site with a block size of four, and an adaptive randomisation scheme was used to balance the covariates of baseline age and TCD velocity. The study was open-label, but TCD examinations were read centrally by observers masked to treatment assignment and previous TCD results. Participants assigned to standard treatment continued to receive monthly transfusions to maintain 30% sickle haemoglobin or lower, while those assigned to the alternative treatment started oral hydroxycarbamide at 20 mg/kg per day, which was escalated to each participant's maximum tolerated dose. The treatment period lasted 24 months from randomisation. The primary study endpoint was the 24 month TCD velocity calculated from a general linear mixed model, with the non-inferiority margin set at 15 cm/s. The primary analysis was done in the intention-to-treat population and safety was assessed in all patients who received at least one dose of assigned treatment. This study is registered with ClinicalTrials.gov, number NCT01425307. Findings Between Sept 20, 2011, and April 17, 2013, 159 patients consented and enrolled in TWiTCH. 121 participants passed screening and were then randomly assigned to treatment (61 to transfusions and 60 to hydroxycarbamide). At the first scheduled interim analysis, non-inferiority was shown and the sponsor terminated the study. Final model-based TCD velocities were 143 cm/s (95% CI 140–146) in children who received standard transfusions and 138 cm/s (135–142) in those who received hydroxycarbamide, with a difference of 4·54 (0·10–8·98). Non-inferiority (p=8·82 × 10 −16 ) and post-hoc superiority (p=0·023) were met. Of 29 new neurological events adjudicated centrally by masked reviewers, no strokes were identified, but three transient ischaemic attacks occurred in each group. Magnetic resonance brain imaging and angiography (MRI and MRA) at exit showed no new cerebral infarcts in either treatment group, but worsened vasculopathy in one participant who received standard transfusions. 23 severe adverse events in nine (15%) patients were reported for hydroxycarbamide and ten serious adverse events in six (10%) patients were reported for standard transfusions. The most common serious adverse event in both groups was vaso-occlusive pain (11 events in five [8%] patients with hydroxycarbamide and three events in one [2%] patient for transfusions). Interpretation For high-risk children with sickle cell anaemia and abnormal TCD velocities who have received at least 1 year of transfusions, and have no MRA-defined severe vasculopathy, hydroxycarbamide treatment can substitute for chronic transfusions to maintain TCD velocities and help to prevent primary stroke. Funding National Heart, Lung, and Blood Institute, National Institutes of Health.

Background In malaria-endemic countries in West Africa, sickle cell disease (SCD) contributes to childhood mortality. Historically, Liberia had regions wherein hemoglobin S and beta-thalassemia trait were mutually exclusive. Data on hemoglobinopathies in the Monrovia, the capital, are outdated and do not reflect urban migration. Updating the epidemiology of SCD is necessary to plan a public health and clinical agenda. Neither newborn screening (NBS) nor screening tools were available in country. This pilot study aimed to determine the feasibility of NBS using a South–South partnership and define the incidence of sickle cell trait (SCT) and SCD in Monrovia. Procedure This descriptive epidemiologic feasibility study collected dried blood spots from 2,785 consecutive newborns delivered at a hospital in Monrovia. Samples were analyzed by isoelectric focusing at a regional reference laboratory. Infants with SCD were referred for preventive care. Results SCT occurred in 10.31% of infants screened. SCD occurred in 33 infants screened [1.19% (95% confidence interval [CI]: 0.79–1.59%)] (FS: 28/33, FSB: 2/33, FSA: 2/33, FSX: 1/33). There were no infants with FSC phenotype observed. Nonsickling hemoglobin phenotypes “FC” and “F” were each present in three infants screened. Seventy-six percent of infants with SCD were brought to care, demonstrating the feasibility of our approach. Conclusions The incidence of SCD and other hemoglobinopathies remains high in Liberia. Additional studies are needed to clarify sickle genotypes and identify the contribution of silent beta-thalassemia alleles. By developing regional partnerships, countries similar to Liberia can acquire current data to inform NBS as an important public health initiative toward improving child health.

The purpose of this study was to define the hematologic response to total splenectomy (TS) or partial splenectomy (PS) in children with hereditary spherocytosis (HS) or sickle cell disease (SCD).The Splenectomy in Congenital Hemolytic Anemia (SICHA) consortium registry collected hematologic outcomes of children with CHA undergoing TS or PS to 1 year after surgery. Using random effects mixed modeling, we evaluated the association of operative type with change in hemoglobin, reticulocyte counts, and bilirubin. We also compared laparoscopic to open splenectomy.The analysis included 130 children, with 62.3% (n=81) undergoing TS. For children with HS, all hematologic measures improved after TS, including a 4.1g/dl increase in hemoglobin. Hematologic parameters also improved after PS, although the response was less robust (hemoglobin increase 2.4 g/dl, p0.001). For children with SCD, there was no change in hemoglobin. Laparoscopy was not associated with differences in hematologic outcomes compared to open. TS and laparoscopy were associated with shorter length of stay.Children with HS have an excellent hematologic response after TS or PS, although the hematologic response is more robust following TS. Children with SCD have smaller changes in their hematologic parameters. These data offer guidance to families and clinicians considering TS or PS.

Transcranial Doppler (TCD) With Transfusions Changing to Hydroxyurea (TWiTCH) trial is a randomized, open-label comparison of hydroxycarbamide (also termed hydroxyurea) versus continued chronic transfusion therapy for primary stroke prevention in patients with sickle cell anaemia (SCA) and abnormal TCD. Severity and location of iron overload is an important secondary outcome measure. We report the baseline findings of abdominal organ iron burden in 121 participants. At enrollment, patients were young (9·8 ± 2·9 years), predominantly female (60:40), and previously treated with transfusions (4·1 ± 2·4 years) and iron chelation (3·1 ± 2·1 years). Liver iron concentration (LIC; 9·0 ± 6·6 mg/g dry weight) and serum ferritin were moderately elevated (2696 ± 1678 μg/l), but transferrin was incompletely saturated (47·2 ± 23·6%). Spleen R2* was 509 ± 399 Hz (splenic iron ~13·9 mg/g) and correlated with LIC (r(2) = 0·14, P = 0·0008). Pancreas R2* was increased in 38·3% of patients but not to levels associated with endocrine toxicity. Kidney R2* was increased in 80·7% of patients; renal iron correlated with markers of intravascular haemolysis and was elevated in patients with increased urine albumin-creatinine ratios. Extra-hepatic iron deposition is common among children with SCA who receive chronic transfusions, and could potentiate oxidative stress caused by reperfusion injury and decellularized haemoglobin.

Noninvasive, quantitative, and accurate assessment of liver iron concentration (LIC) by MRI is useful for patients receiving transfusions, but R2 and R2* MRI techniques have not been systematically compared in sickle cell anemia (SCA). We report baseline LIC results from the TWiTCH trial, which compares hydroxyurea with blood transfusion treatment for primary stroke prophylaxis assessed by transcranial Doppler sonography in pediatric SCA patients. Liver R2 was collected and processed using a FDA-approved commercial process (FerriScan®), while liver R2* quality control and processing were performed by a Core Laboratory blinded to clinical site and patient data. Baseline LIC studies using both MRI techniques were available for 120 participants. LICR2* and LICR2 results were highly correlated (r2 = 0.93). A proportional bias of LIC(R2*)/LIC(R2), decreasing with average LIC, was observed. Systematic differences between LICR2* and LICR2 were also observed by MRI manufacturer. Importantly, LICR2* and LICR2 estimates had broad 95% limits of agreement with respect to each other. We recommend LICR2 and LICR2* not be used interchangeably in SCA patients to follow individual patient trends in iron burden.Am. J. Hematol. 90:806–810, 2015. © 2015 Wiley Periodicals, Inc.

TO THE EDITOR: Iron-refractory iron deficiency anemia (IRIDA) is characterized by congenital iron deficiency (ID) that is poorly responsive to oral iron treatment. Biallelic mutations in TMPRSS6 are found in most patients with IRIDA.[1][1] TMPRSS6 negatively regulates synthesis of the iron

This phase 2 study was designed to characterize the relationship among prasugrel dose, prasugrel's active metabolite (Pras-AM), and platelet inhibition while evaluating safety in children with sickle cell disease. It was open-label, multicenter, adaptive design, dose ranging, and conducted in 2 parts. Part A: Patients received escalating single doses leading to corresponding increases in Pras-AM exposure and VerifyNow®P2Y12 (VN) platelet inhibition and decreases in VNP2Y12 reaction units and vasodilator-stimulated phosphoprotein platelet reactivity index. Part B: Patients were assigned daily doses (0.06, 0.08, and 0.12 mg/kg) based on VN pharmacodynamic measurements at the start of 2 dosing periods, each 14±4 days. Platelet inhibition was significantly higher at 0.12 mg/kg (56.3%±7.4%; least squares mean±SE) compared with 0.06 mg/kg (33.8%±7.4%) or 0.08 mg/kg (37.9%±5.6%). Patients receiving 0.12 mg/kg achieved ≥30% platelet inhibition; only 1 patient receiving 0.06 mg/kg exceeded 60% platelet inhibition. High interpatient variability in response to prasugrel and the small range of exposures precluded rigorous characterization of the relationship among dose, Pras-AM, and platelet inhibition.No hemorrhagic events occurred in Part A; 3 occurred in Part B, all mild and self-limited.Most children with sickle cell disease may achieve clinically relevant platelet inhibition with titration of daily-dose prasugrel.