Key Clinical Message Acute liver dysfunction in the perioperative period may increase the risk of epidural hematoma in a patient with a neuraxial catheter. Coagulation testing needs to be carefully monitored in these patients. An epidural hematoma should be ruled out urgently by CT or MRI in cases of a persistent motor block.

Abstract Introduction: The TCD with Transfusions Changing to Hydroxyurea (TWiTCH) trial was an NHLBI-funded multicenter phase 3 randomized trial that demonstrated non-inferiority of hydroxyurea versus continued transfusion therapy in children with sickle cell anemia and abnormal TCD velocities but no severe vasculopathy. Children who were randomized to continue transfusions (Standard Arm) received conventional iron chelation therapy with deferasirox, while children receiving hydroxyurea (Alternative Arm) received serial phlebotomy (10 mL/kg, maximum 500 mL) every 4 weeks. Extrahepatic iron burden was monitored by R2* MRI in the kidney, pancreas, and spleen to monitor the changes in iron overload phenotype between the two groups. Methods: R2* MRI of the abdomen was performed at baseline, 1 year, and 2 years following enrollment. Liver, spleen, pancreas, and kidney R2* were measured from axial and coronal multiecho, gradient echo images. Images were analyzed centrally at an experienced core laboratory using an exponential plus constant model for signal decay. Iron burden in the different organs was assessed using repeated measures analysis of variance (ANOVA) using JMP 11.0. Results: 120 patients underwent baseline R2* assessment, 83 completed the midpoint, and 89 patients completed the endpoint examination. Figure 1 (left) summarizes the changes in kidney R2* across the three time points. Kidney R2* was elevated at baseline in both treatment arms and correlated with LDH (r2 =0.28, p<0.0001) and total iron binding capacity, but not with age, sex, LIC, serum ferritin, years of transfusion and years of chelation. Kidney R2* and markers of hemolysis (LDH, total bilirubin), remained stable in the transfusion arm. In contrast, kidney R2* declined monotonically in the patients on hydroxyurea (F value 6.9, p=0.0021 for time-treatment interaction). These changes paralleled reductions in LDH (F value 8.1, p=0.0007) and total bilirubin (F value 28, p<0.0001) in the hydroxyurea group compared to the transfusion group. There were no group differences in mean serum creatinine or urine albumin to creatinine ratio (ACR). However, the frequency and severity of albuminuria (ACR > 30 mg albumin per g creatinine) trended lower in patients on hydroxyurea, (5/45 at baseline (p=1), 1/44 at midpoint (p=0.03), and 4/52 at endpoint (p=0.33). Figure 1 (right) demonstrates the temporal evolution of ACR in 11 study participants with baseline albuminuria; 4/6 patients on standard arm continued to have significant proteinuria on their terminal examination compared with only 1/5 patients on hydroxyurea (p=0.24). There were no groupwise differences in mean pancreas R2* at any time point and clinically significant pancreas iron deposition (R2* > 100 Hz) was only observed in two patients at the mid timepoint. Spleen R2* was markedly elevated at baseline (503 ± 396 Hz), but did not change systematically over time in either group. The change in spleen R2* was correlated with the change in liver iron (r2=0.21, p=0.003), regardless of the treatment group, suggesting that the spleen iron stores are part of the dynamic iron storage pool. 37% of the patients had no MRI-detectable spleen (surgical + autosplenectomy). The change of liver iron was not different in patients with or without a spleen. Conclusion: Hydroxyurea therapy was associated with lower intravascular hemolysis and kidney iron deposition. Further studies are necessary to determine whether these changes are associated with decreased proteinuria or improved renal function. Splenic iron burden remained high but stable in all patients, and its role in iron unloading needs further investigation. Pancreas iron loading remained rare, consistent with the low prevalence of endocrinopathies in SCD. Figure 1 Figure 1. Disclosures Wood: Apopharma: Consultancy; Ionis Pharmaceuticals: Consultancy; Vifor: Consultancy; Vifor: Consultancy; Biomed Informatics: Consultancy; AMAG: Consultancy; Biomed Informatics: Consultancy; Ionis Pharmaceuticals: Consultancy; World Care Clinical: Consultancy; World Care Clinical: Consultancy; Celgene: Consultancy; Apopharma: Consultancy; Celgene: Consultancy; AMAG: Consultancy. Heeney:Sancilio and Company: Consultancy, Research Funding; Eli Lilly and Company: Research Funding; Pfizer: Research Funding. Ware:Global Blood Therapeutics: Consultancy; Nova Laboratories: Consultancy; Biomedomics: Research Funding; Bristol Myers Squibb: Research Funding; Addmedica: Research Funding; Bayer Pharmaceuticals: Consultancy.

Abstract Background: PKD causes a defect in glycolysis resulting in a hereditary non-spherocytic hemolytic anemia. The prevalence of iron overload is not well described for PKD. Aim: We aim to describe the demographic features and prevalence of iron overload in transfusion dependent and transfusion independent patients with PKD. Methods: Between March 2014 and April 2016, 203 patients enrolled on the PKD Natural History Study at 29 IRB approved sites. All patients were confirmed to have two compound heterozygous or homozygous mutations in the PKLR gene. Children < 1 year of age (n=9) were excluded from this analysis, because elevated ferritin levels are less reliably related to iron overload. Patients were designated with iron overload at the time of enrollment if the plasma ferritin was >1000 ng/mL or the patient was on chelation therapy at any time during the prior 12 months. Patients were designated with having had iron overload if a MRI ever showed liver iron content (LIC) >3 mg/g dry weight or if they had ever received chelation therapy. Tests of association were performed using Fisher's exact test (categorical) and Wilcoxon rank sum test (continuous). Linear associations between variables were measured by Pearson correlation coefficient. P-values <0.05 were considered statistically significant. Results: Of the 194 patients, 111 (57%) were adults ≥18 years and 83 (43%) were children. The median age of enrollment was 20.6 y (range: 1.3-69.9). Splenectomy had been performed in 65% (126/194). Screening ferritin levels were available for 72% (140/194) and LIC for 32% (62/194). At enrollment, 48% (70/147) had iron overload as defined by ferritin and/or current chelation. Using the LIC criterion, iron overload had been present at some point in 86% (95/110) of patients. Ferritin positively correlated with LIC (n=45); r=0.62, p<0.0001. However, of 29 patients with an LIC measurement and a mean ferritin <1000 ng/mL, 15 (52%) had a LIC >3 mg/g DW. Baseline characteristics in patients with and without iron overload are shown in the Table. Notably, even in patients that were never regularly transfused and had a hemoglobin (Hb) >8.7 g/dl, the prevalence of iron overload was 26% (8/31). The frequency of iron overload was significantly higher in patients who had a prior splenectomy (p<0.0001), even after controlling for transfusion history (p<0.0001). Age was associated with iron overload (p=0.046); although, the age range of patients with iron overload was broad (1.3-69.9 years). The frequency of iron overload was significantly higher in those with a lower baselineHb(p=0.004) and higher bilirubin (p=0.03). Data on cardiac iron status was available for 66 patients.Only 2 had cardiac iron overload (defined as T2*<20ms); they were age 5 (T2* 17.8ms, LIC 5 mg/g) and 22 years (T2* 19.7ms, LIC 14 mg/g) at the time of the MRI. Of the 194 patients, 52 (27%) were from the Pennsylvania Amish community. These patients were managed differently than the non-Amish, in that only 2% of the Amish patients were on iron chelation therapy in the 12 months prior to enrollment compared with 43% among the non-Amish cohort. In addition, the Amish had a significant higher prevalence of splenectomy (96% vs 52%, p<0.0001) and proportion who had been historically transfused (79% vs 32%, p<0.0001). Despite these differences, the Amish patients had a lower prevalence of iron overload (34% vs. 51%). There was no significant difference inHbor enrollment age between the Amish and non-Amish cohorts. Conclusion: Iron overload is a common, serious complication in PKD, regardless of age, disease severity, or transfusion status. Although ferritin correlates with LIC for the PKD population overall, at the individual patient level, ferritin is not a good predictor of LIC and a ferritin <1000 ng/ml does not exclude hepatic iron overload. Therefore, we recommend that all patients with PKD starting at age 1 year should be screened annually for iron overload using ferritin and, at least once, using MRI. Disclosures Barcellini: Agios: Consultancy. Neufeld:Novartis: Consultancy. Morton:Agios Pharmaceuticals: Research Funding. Yaish:Octapharma: Other: Study investigator. Kuo:Agios Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Alexion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Apotex: Other: unrestricted educational grant; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Thompson:bluebird bio: Consultancy, Research Funding; Eli Lily: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mast: Research Funding; Baxalta (now part of Shire): Research Funding; ApoPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Amgen: Research Funding. Grace:Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Summary‘Paradoxical’ embolization via intracardiac or intrapulmonary right‐to‐left shunts (RLS) is an established cause of stroke. Hypercoagulable states and increased right heart pressure, which both occur in sickle cell anaemia (SCA), predispose to paradoxical embolization. We hypothesized that children with SCA and overt stroke (SCA + stroke) have an increased prevalence of potential RLS. We performed contrasted transthoracic echocardiograms on 147 children (aged 2–19 years) with SCA + stroke) mean age 12·7 ± 4·8 years, 54·4% male) and a control group without SCA or stroke (n = 123; mean age 12·1 ± 4·9 years, 53·3% male). RLS was defined as any potential RLS detected by any method, including intrapulmonary shunting. Echocardiograms were masked and adjudicated centrally. The prevalence of potential RLS was significantly higher in the SCA+stroke group than controls (45·6% vs. 23·6%, P < 0·001). The odds ratio for potential RLS in the SCA + stroke group was 2·7 (95% confidence interval: 1·6–4·6) vs controls. In post hoc analyses, the SCA + stroke group had a higher prevalence of intrapulmonary (23·8% vs. 5·7%, P < 0·001) but not intracardiac shunting (21·8% vs. 18·7%, P = 0·533). SCA patients with potential RLS were more likely to report headache at stroke onset than those without. Intrapulmonary and intracardiac shunting may be an overlooked, independent and potentially modifiable risk factor for stroke in SCA.

Transcranial Doppler (TCD) screening in children with sickle cell anemia (SCA) identifies abnormally elevated cerebral artery flow velocities that confer an elevated risk for primary stroke. Chronic transfusions offer effective stroke prophylaxis in this setting, but must be continued indefinitely and lead to transfusional iron overload. An alternative treatment strategy that offers similar effective protection against primary stroke, and provides control of iron overload, is needed. TCD With Transfusions Changing to Hydroxyurea (TWiTCH, NCT01425307) was an NHLBI-funded Phase III multicenter randomized clinical trial comparing 24-months of standard treatment (transfusions) to alternative treatment (hydroxyurea) in children with SCA and abnormal TCD velocities. All eligible children had received at least 12 months of transfusions. TWiTCH had a non-inferiority trial design; the primary study endpoint was the 24-month TCD velocity obtained from a linear mixed model, controlling for baseline (enrollment) values, with a non-inferiority margin of 15 cm/sec. The transfusion arm maintained children at HbS <30%; an elevated liver iron concentration (LIC) identified by R2 MRI FerriScan® was managed with chelation. The hydroxyurea arm included an overlap period with transfusions until a stable maximum tolerated dose (MTD) of hydroxyurea was reached; transfusions were then replaced by serial phlebotomy to reduce iron overload. In both arms, TCD velocities were obtained every 12 weeks and reviewed centrally, with local investigators masked to the results. A centralized TCD alert algorithm monitored changes from enrollment velocities. A total of 159 children were enrolled but 38 failed screening due primarily to severe vasculopathy on brain MRA or inadequate TCD exams; 121 children were randomized (61 to transfusions, 60 to hydroxyurea) with balanced characteristics including enrollment maximum TCD velocities (145 ± 21 versus 145 ± 26 cm/sec), age, duration of transfusions, serum ferritin, and LIC. Study participants randomized to transfusions maintained an average HbS <30% throughout the study, while those on hydroxyurea reached MTD after 7 ± 2 months at an average dose of 27 mg/kg/day, with expected hematological changes including HbF ~25% throughout the treatment period. After 37% of the participants exited the study, a scheduled interim analysis suggested the primary study endpoint was likely to be achieved. NHLBI allowed the study to continue until 50% of the children exited, at which time the statistical analysis was confirmed and the study was terminated; all remaining participants moved to the exit phase. The final analysis included 42 on the transfusion arm who completed all treatment, 11 with truncated treatment, and 8 withdrawn; the hydroxyurea arm included 41 who completed all treatment, 13 with truncated treatment, and 6 withdrawn. The final calculated TCD velocities (mean ± standard error) in the transfusion and hydroxyurea arms were 143 ± 1.6 and 138 ± 1.6 cm/sec, respectively; by intention-to-treat analysis, the p-value for non-inferiority = 8.82 x 10-16 and by post-hoc analysis the p-value for superiority = 0.046. Among 29 new neurological events, all centrally adjudicated by masked reviewers, there were no strokes but 6 transient ischemic attacks (3 in each arm). One child (transfusion arm) was withdrawn per the TCD alert algorithm after developing on-study TCD velocities >240 cm/sec. Exit brain MRI/MRA exams documented no new parenchymal abnormalities but one child (transfusion arm) developed new vasculopathy. Sickle cell related serious adverse events were more common in the hydroxyurea arm than the transfusion arm (23 to 15), but none was related to study treatment or study procedures. Iron overload improved more in the hydroxyurea arm than in the transfusion arm, with a greater average change in serum ferritin (-1085 compared to -38 ng/mL, p<0.001) and LIC (average -1.9 compared to +2.4 mg/g dry weight liver, p=0.001). In the multicenter Phase III TWiTCH trial, which treated children with SCA and abnormal TCD velocities but without severe MRA vasculopathy, hydroxyurea at MTD was non-inferior and possibly superior to chronic transfusions for maintaining TCD velocities. Serial phlebotomy effectively managed iron overload. Hydroxyurea may represent an effective alternative to indefinite transfusions for the prevention of primary stroke in this high risk population.

Children with sickle cell anemia (SCA; HbSS and HgbSβ 0 thalassemia) suffer stroke at a rate 220x higher than other children, but are typically less extensively investigated for modifiable risk factors. In patients without SCA, “paradoxical embolization” via intracardiac or intrapulmonary "right-to-left" shunting is a recognized stroke risk factor. Hypercoagulable states and increased right heart pressures predispose to paradoxical embolization and both occur in SCA. We hypothesized that children with SCA and overt stroke have an increased prevalence of potential right-to-left shunting compared to controls. We performed contrasted transthoracic echocardiograms (conventional 2D, color Doppler, and 4 contrast injections with agitated saline, including 2 during Valsalva) on children (ages 2-19y) with SCA and history of overt stroke, and a control group of children with neither SCA nor stroke, at 14 institutions in the US and UK. Potential right-to-left shunting was defined as any potential shunt detected by any method, including “late bubbles” (contrast appearing in the left heart >5 cardiac cycles following injection). Echocardiograms were reviewed locally and centrally, with adjudication of conflicts. We enrolled 153 children with SCA and stroke and 129 controls. There were no significant differences in age or gender between the groups. The prevalence of potential right-to-left shunting was significantly higher in the SCA and stroke group (43.1% vs. 20.0% in controls (p<0.001). There was no significant difference in intracardiac shunting (22.9% vs. 16.2%, p=0.157) but there was a higher proportion with intrapulmonary shunting (“late bubbles” only) in the SCA and stroke group (27.5% vs. 5.5% in controls, p<0.001). Our findings suggest that intracardiac and intrapulmonary shunting could be an independent, potentially modifiable risk factor for stroke or stroke recurrence in children with SCA. Additional therapeutic interventions in patients at risk of stroke or stroke recurrence via paradoxical embolization, including antiplatelet agents or shunt closure, should be evaluated in children with SCA.

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 fl ow 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-totreat 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 x 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.

Abstract Background: An international, multicenter registry was established to collect clinical data on patients with PKD, the most common glycolytic defect causing congenital non-spherocytic hemolytic anemia. Aim: To describe and categorize the phenotypic spectrum of PKD, including the range of lab parameters, management, and complications. Methods: 144 patients enrolled on the PKD NHS at 23 sites from 3/2014 to 6/2015. For this report, baseline and retrospective data were included. PKD patients were categorized into 4 severity groups (Gp1-Gp4), with increasing severity of the disease: Gp1. Never regularly transfused +/- prior acute transfusions; Gp2. Regular transfusions prior to splenectomy, post-splenectomy baseline hemoglobin (hb) >8.7 g/dl; Gp3. Regular transfusions prior to splenectomy, post-splenectomy baseline hb ≤8.7 g/dl; and Gp4. Post-splenectomy and currently regularly transfused. To reduce the risk of chance associations when dividing the cohort by phenotype, the cohort was divided into a test set (n=73) to define the categories and a subsequent validation set (n=71). Results: Median age at enrollment was 19.9 years (0.1-70.7) with 47% males. This cohort was 95% Caucasian and 38% Amish. Perinatal complications were frequently reported including preterm birth (33%), perinatal transfusions (35%), and hydrops (10%). Newborn jaundice was common, requiring phototherapy (91%) and/or exchange transfusion (46%). 68% (98/144) had undergone splenectomy at a median age of 3.1 years (0.6-28.1). Common indications for splenectomy included reducing transfusion burden, improving anemia, and enhancing quality of life. The median pre-splenectomy hb was 7.0 g/dl (4.5-12.5). Splenectomy reduced the transfusion burden in 91%. Triggers for hemolysis included: pregnancy (59%), infections (61%), stress (35%), and medications (6%). In the 37% (53/144) who required a cholecystectomy, the median age was 14 years (2.6-60.4) and 35 (66%) occurred post-splenectomy. In both the test and validation cohorts, increased severity was associated with a younger age at diagnosis (p<0.01) and higher ferritin (p<0.01, Table). More severe patients were more likely to receive iron chelation (p<0.01). Reticulocyte counts and MCV were incrementally higher with increasing severity in the non-regularly transfused Gps (p=0.02). Gp4 pts required regular transfusions even after splenectomy (11/98). In this group, the median age of splenectomy was 5.0 y (2.1-11.8). Ferritin was higher in those who had a splenectomy, even after adjusting for transfusion status (p<0.0001). In the Gp1 pts with available iron studies, even in the absence of regular transfusions, the majority had evidence of iron overload; 7/10 (70%) had a liver iron concentration (LIC) >4 mg/g dry weight and 9/11 (82%) had ferritin >500 ng/ml. Chelation was used in 35 patients at a median age of 11.8 years (1-53.7) with a median ferritin 815 ng/ml (182-5630) and median LIC 5.7 mg/g dry weight (1.7-46.0). Conclusions: This NHS cohort is the largest assembly of PKD patients to date. We defined 4 severity Groups, based on transfusion history, anemia, and splenectomy status. Complications (e.g. iron overload) correlate with disease severity but also occur in milder phenotypes. Based on these findings, regular monitoring of iron status and screening for gallstones should be considered. Transfusion dependence persisted despite splenectomy in 11% of patients. Prospective data from the NHS will provide guidance for monitoring and treatment in this rare anemia. Figure 1. Figure 1. Disclosures Grace: Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Morton:Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees. Eber:Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees. Yaish:Agios: Membership on an entity's Board of Directors or advisory committees. Nottage:Janssen Pharmaceuticals: Employment. Kuo:Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees. Neufeld:Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Abstract Background: PKD is the most common enzyme defect of the glycolytic pathway causing hereditary non-spherocytic chronic hemolytic anemia. PKD is transmitted as an autosomal recessive trait, caused by both homozygous and compound heterozygote mutations in the PKLR gene, and is characterized by molecular heterogeneity with > 200 different mutations reported. Aim: To describe the PKLR genotypes in the PKD NHS with an in depth characterization of 20 newly reported mutations. Methods: Participants (pts) were enrolled in the PKD NHS, a prospective international study open at 23 sites in North America and Europe. Pts with prior PKLR gene sequencing were not resequenced. DNA from all other pts was extracted and the PKLR gene analyzed by Sanger sequencing at 1 of 2 central labs. All new missense mutations affected highly conserved residues in multiple domains of the PKLR gene, were not detected in 1000 genomes and LOVD database, and were considered pathogenic by NCBI and/or UniProtKB and by Polyphen analysis. Results: Genotype information was available on 140 enrolled pts. Of these, 66 (47%) were related to other subjects enrolled in the study. Molecular characterization confirmed the wide heterogeneity of PKD with 65 different mutations identified, including: 42 missense, 20 disruptive mutations (7 splicing, 6 frameshift, 3 stop codons, and 4 large deletions), 2 inframe insertion/deletions, and 1 promoter variant. Sixty-six pts were homozygous, of whom 55 were of Amish origin carrying the p.R479H mutation. Of the 55, 46 had been transfusion dependent prior to splenectomy and 9 had only received transfusions for acute stressors; 93% had been splenectomized, and all were transfusion independent post-splenectomy. Thirty-nine cases had 2 different missense mutations; 18 had one missense and one disruptive mutation, and 16 had 2 disruptive mutations; 1 patient with 17% residual PK activity displayed 3 different mutations (R510W, E241X and V276WXfs45). Besides R479H, the most common mutations were: R510W (16% of the mutated alleles), R486W (12%), and G241X (9%). Frequencies of R510W and R486W were less than those reported in Europe (41% and 30%, respectively). Twenty mutations, all affecting the PK structural domains, have not been previously described: 14 missense, 3 splicing (c.966(-9) a>g; c.1116(+2) t>c; c.375(+1) g>a), 1 frameshift (R40R fsX7), 1 inframe insertion of 2 amino acids, and 1 large deletion spanning intron 2 to intron 3 (Table). The 3 new splice site mutations were predicted to affect normal splicing when analyzed by HSF3.0, using both HSF and MaxEnt algorithms; in particular, homozygous c.966(-9) a>g was detected in a patient with moderate anemia, reticulocytosis, and mental retardation of unclear etiology. The two new missense mutations detected at a homozygous level (A137V and N156G) were associated with moderate or severe anemia and need for regular transfusions. The latter is located in the Aβ3 catalytic domain/K binding site and probably affects the catalytic efficiency of the enzyme. All the remaining new variants were detected in compound heterozygosity making it difficult to predict their effect on clinical phenotype. Intra-family clinical variability was observed; no correlation was found among the kinds of mutations and the residual PK activity. Conclusion: The molecular features of the largest international cohort of PKD pts are described, including a report of 20 new mutations, thus confirming the wide heterogeneity of the molecular genotype in PKD. Figure 1. Figure 1. Disclosures Morton: Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees. Eber:Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees. Yaish:Agios: Membership on an entity's Board of Directors or advisory committees. Nottage:Janssen Pharmaceuticals: Employment. Kuo:Novartis Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees. Grace:Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Little is known about what factors affect the health-related quality of life (HRQoL) of adolescents and young adults (AYAs) with sickle cell disease (SCD), and how their HRQoL changes over time. This retrospective study included 87 AYAs attending a SCD Adolescent Clinic who completed a measure of HRQoL at each visit over the course of approximately 1.3 years. Results suggested that the following were associated with poorer physical HRQoL: being female, more healthcare utilization events, and presence of internalizing symptoms. Internalizing and externalizing symptoms were the only factors correlated with poorer psychosocial HRQoL. Generalized linear mixed models indicated that physical and psychosocial HRQoL improved among all participants during the assessment period, and those with externalizing behaviors reported faster improvement in physical HRQoL over time. AYAs with SCD may benefit from early mental health screening and intervention to optimize clinical care.

Background. Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative therapy for sickle cell disease (SCD) in children. Despite excellent outcomes of matched sibling donor (MSD) HSCT, there is still 5-10% chance of rejection and transplant related mortality (TRM) with 12-23% incidence of graft versus host disease (GVHD). We postulated that an intermediate dose of rabbit anti-thymocyte globulin (r-ATG, 10 mg/kg cumulative) would be effective in preventing both rejection and GVHD. Patients and Methods. Fifteen patients, median age 5 (range 1.5-18) years, underwent MSD HSCT using busulfan (>= 12.8 mg/kg with first dose pharmacokinetics), cyclophosphamide (total 200 mg/kg) and r-ATG. Bone marrow was the stem cell source; tacrolimus and methotrexate were given for GVHD prophylaxis. Results. All patients achieved donor engraftment and there was no TRM. One patient rejected donor cells at 2 months post-transplant. Majority of the patients had high and sustained level of donor chimerism. None of the patients developed >= Grade II GVHD. Incidence of CMV(10%) and EBV (9%) reactivations was low with rapid immune-reconstitution. Overall survival was 100% with event free survival of 93%. Conclusions. Eliminating the risks of TRM and GVHD by optimizing the regimen may lead to further acceptance of HSCT for SCD. (c) 2014 Wiley Periodicals, Inc.

PURPOSE The purpose of this study was to characterize the impact of sickle cell disease (SCD) on oral health and examine its impact on quality of life. METHODS Fifty-four study subjects were recruited from the sickle cell clinic and 52 control subjects from the adolescent medicine clinic at Nationwide Children's Hospital, Columbus, Ohio. A dental exam was performed to determine each participant's caries burden. The Child Oral Health Impact Profile survey was used to assess their oral health-related quality of life (OHRQoL). RESULTS Most subjects in both the SCD and control groups rated their overall health and oral health as "good" or "excellent." There was no statistically significant difference in OHRQoL between these groups. Additionally, no significant relationship was found between white blood cell count, medication intake, or the number of sickle cell crises as related to the caries burden. Statistically significant differences were detected in caries burden between the control group and the sickle cell hemoglobin C disease (HbSC) group (P<.02) and between the sickle cell anemia and HbSC subjects (P=.04). CONCLUSIONS Adolescents with sickle cell hemoglobin C disease had fewer caries than peers with sickle cell anemia or controls, though the cause of this finding is not clear.

BACKGROUNDSilent cerebral infarcts are the most common neurologic injury in children with sickle cell anemia and are associated with the recurrence of an infarct (stroke or silent cerebral infarct). We tested the hypothesis that the incidence of the recurrence of an infarct would be lower among children who underwent regular blood transfusion therapy than among those who received standard care.METHODSIn this randomized, single-blind clinical trial, we randomly assigned children with sickle cell anemia to receive regular blood transfusions (transfusion group) or standard care (observation group). Participants were between 5 and 15 years of age, with no history of stroke and with one or more silent cerebral infarcts on magnetic resonance imaging and a neurologic examination showing no abnormalities corresponding to these lesions. The primary end point was the recurrence of an infarct, defined as a stroke or a new or enlarged silent cerebral infarct.RESULTSA total of 196 children (mean age, 10 years) were randomly assigned to the observation or transfusion group and were followed for a median of 3 years. In the transfusion group, 6 of 99 children (6%) had an end-point event (1 had a stroke, and 5 had new or enlarged silent cerebral infarcts). In the observation group, 14 of 97 children (14%) had an end-point event (7 had strokes, and 7 had new or enlarged silent cerebral infarcts). The incidence of the primary end point in the transfusion and observation groups was 2.0 and 4.8 events, respectively, per 100 years at risk, corresponding to an incidence rate ratio of 0.41 (95% confidence interval, 0.12 to 0.99; P = 0.04).CONCLUSIONSRegular blood-transfusion therapy significantly reduced the incidence of the recurrence of cerebral infarct in children with sickle cell anemia. (Funded by the National Institute of Neurological Disorders and Stroke and others; Silent Cerebral Infarct Multi-Center Clinical Trial ClinicalTrials.gov number, NCT00072761, and Current Controlled Trials number, ISRCTN52713285.)

The differential diagnosis of abdominal pain is broad in any child, and further complicated in children with sickle cell disease (SCD). Acute causes of abdominal pain may require emergent surgery, such as for appendicitis or obstruction caused by a bezoar. Rapid intervention is necessary and life-saving in children with SCD and acute splenic or hepatic sequestration. The majority of children with SCD presenting to the physician's office or emergency department will have subacute reasons for their abdominal pain, including but not limited to constipation, urinary tract infection, peptic ulcer disease, and cholecystitis. Vaso-occlusive pain often presents in children as abdominal pain, but is a diagnosis of exclusion. The case of a 10-year-old girl with intermittent abdominal pain is used as a starting point to review the pathophysiology, diagnosis, and treatment of the most acute and common causes of abdominal pain in children with SCD.

Children with sickle cell anemia have a higher‐than‐expected prevalence of poor educational attainment. We test two key hypotheses about educational attainment among students with sickle cell anemia, as measured by grade retention and use of special education services: (1) lower household per capita income is associated with lower educational attainment; (2) the presence of a silent cerebral infarct is associated with lower educational attainment. We conducted a multicenter, cross‐sectional study of cases from 22 U.S. sites included in the Silent Infarct Transfusion Trial. During screening, parents completed a questionnaire that included sociodemographic information and details of their child's academic status. Of 835 students, 670 were evaluable; 536 had data on all covariates and were used for analysis. The students' mean age was 9.4 years (range: 5–15) with 52.2% male; 17.5% of students were retained one grade level and 18.3% received special education services. A multiple variable logistic regression model identified that lower household per capita income (odds ratio [OR] of quartile 1 = 6.36, OR of quartile 2 = 4.7, OR of quartile 3 = 3.87; P = 0.001 for linear trend), age (OR = 1.3; P < 0.001), and male gender (OR, 2.2; P = 0.001) were associated with grade retention; silent cerebral infarct (P = 0.31) and painful episodes (P = 0.60) were not. Among students with sickle cell anemia, household per capita income is associated with grade retention, whereas the presence of a silent cerebral infarct is not. Future educational interventions will need to address both the medical and socioeconomic issues that affect students with sickle cell anemia. Am. J. Hematol. 89:E188–E192, 2014. © 2014 Wiley Periodicals, Inc.

American Journal of HematologyVolume 88, Issue 12 p. E1-E83 AbstractFree Access 7th Annual Sickle Cell Disease Research and Educational Symposium and 36th National Sickle Cell Disease Scientific Meeting Correction(s) for this article 413 Effectiveness of educational intervention in improving knowledge and perception among healthcare providers at a community-based hospital Volume 95Issue 6American Journal of Hematology pages: 727-727 First Published online: July 23, 2018 First published: 22 November 2013 https://doi.org/10.1002/ajh.23621AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Volume88, Issue12December 2013Pages E1-E83 RelatedInformation