Sickle Cell in the Medical Literature - December 2014

1. J Pediatr Hematol Oncol. 2015 Jan;37(1):1-9. doi: 10.1097/MPH.0000000000000291. Prasugrel in Children With Sickle Cell Disease: Pharmacokinetic and Pharmacodynamic Data From an Open-label, Adaptive-design, Dose-ranging Study. Styles L1, Heiselman D, Heath LE, Moser BA, Small DS, Jakubowski JA, Zhou C,Redding-Lallinger R, Heeney MM, Quinn CT, Rana SR, Kanter J, Winters KJ. Abstract INTRODUCTION: 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. SAFETY: No hemorrhagic events occurred in Part A; 3 occurred in Part B, all mild and self-limited. CONCLUSIONS: Most children with sickle cell disease may achieve clinically relevant platelet inhibition with titration of daily-dose prasugrel. PMID: 25493452 [PubMed - in process] Related citations

2. Br J Haematol. 2014 Dec 18. doi: 10.1111/bjh.13270. [Epub ahead of print] Pregnancy outcome in patients with sickle cell disease in the UK - a national cohort study comparing sickle cell anaemia (HbSS) with HbSC disease. Oteng-Ntim E1, Ayensah B, Knight M, Howard J. Abstract We describe the findings from a national study of maternal and fetal outcomes of pregnancy in women with sickle cell disease (SCD). Data were collected via the United Kingdom Obstetric Surveillance System between 1 February 2010 and 31 January 2011 from 109 women, of whom 51 (46·8%) had HbSS and 44 (40·4%) had HbSC. Data included antenatal, maternal and fetal outcomes. Comparisons were made between women with HbSS and HbSC. Incidence of complications were acute pain (57%), blood transfusion (26%), urinary tract infection (UTI; 12%) and critical care unit admission (23%) and these were all more common in women with HbSS than HbSC. There was no difference in the incidence of acute chest syndrome, hypertension and venous thromboembolism between HbSS and HbSC. Women with HbSS were more likely to deliver at <37 weeks gestation (P = 0·01) and their babies were more likely to have reduced birth weight. Delivery at <34 weeks was increased in both HbSS and HbSC women (5·9% vs. 4·6%) compared to national data. This study confirms a high rate of maternal and fetal complications in mothers with SCD, even in women with HbSC, which has previously been considered to have a more benign phenotype in pregnancy. © 2014 John Wiley & Sons Ltd. PMID: 25522142 [PubMed - as supplied by publisher] 3. Curr Med Res Opin. 2014 Dec 15:1-30. [Epub ahead of print] Multicenter COMPACT study of complications in patients with sickle cell disease and utilization of iron chelation therapy. Jordan L1, Adams-Graves P, Kanter-Washko J, Oneal PA, Sasane M, Vekeman F, Bieri C, Magestro M, Marcellari A, Duh MS. Abstract Abstract Background Over the past few decades, lifespans of sickle cell disease (SCD) patients have increased; hence, they encounter multiple complications. Early detection, appropriate comprehensive care, and treatment may prevent or delay onset of complications. Objective We collected longitudinal data on sickle cell disease (SCD) complication rates and associated resource utilization relative to blood transfusion patterns and iron chelation therapy (ICT) use in patients aged ≥ 16 years to address a gap in the literature. Research Design and Methods Medical records of 254 SCD patients ≥ 16 years were retrospectively reviewed at three U.S. tertiary care centers. Main Outcome Measures We classified patients into cohorts based on cumulative units of blood transfused and ICT history: <15 units, no ICT (Cohort 1 [C1]), ≥15 units, no ICT (Cohort 2 [C2]), and ≥15 units with ICT (Cohort 3 [C3]). We report SCD complication rates per patient per year; cohort comparisons use rate ratios (RRs). Results Cohorts had 69 (C1), 91 (C2), and 94 (C3) patients. Pain led to most hospitalizations (76%) and emergency department (ED) (82%) visits. Among transfused patients (C2+C3), those receiving ICT were less likely to experience SCD complications than those who did not (RR [95% CI] C2 vs. C3: 1.33 [1.25-1.42]). Similar trends (RR [95% CI]) were observed in ED visits and hospitalizations associated with SCD complications (C2 vs. C3, ED: 1.94 [1.70-2.21]; hospitalizations: 1.61 [1.45-1.78]), but not in outpatient visits. Conclusions Although the most commonly reported SCD complication among all patients was pain, patients who received ICT were less likely to experience pain and other complications than those who did not. These results highlight the need for increased patient and provider education on the importance of comprehensive disease management. PMID: 25495135 [PubMed - as supplied by publisher] 4. J Child Neurol. 2014 Dec 14. pii: 0883073814563140. [Epub ahead of print] The Association of Cytokine Levels With Cognitive Function in Children With Sickle Cell Disease and Normal MRI Studies of the Brain. Andreotti C1, King AA2, Macy E3, Compas BE4, DeBaun MR5. Abstract Children with sickle cell disease, including those without evidence for cerebral infarcts, are at increased risk for cognitive deficits that can contribute to difficulties in academic and social functioning. Chronic inflammatory processes are endemic to sickle cell disease and are apparent in common comorbidities including asthma. Cytokines mediating inflammatory processes can influence cognition. The authors examined the relationship between plasma levels of cytokines commonly associated with asthma and cognitive functioning using standardized neuropsychological measures in 25 children with sickle cell disease with normal magnetic resonance imaging studies of the brain. Children with sickle cell disease performed significantly below the normative mean on tests of cognitive function. Pearson correlations indicated significant negative relations between cytokines (IL-4, IL-5, IL-8, and IL-13) and standardized tests of executive function (r = -.54 to -.74). Preliminary evidence suggests an association between cytokine levels and executive function in children with sickle cell disease, indicating a potential role for inflammatory processes in cognitive outcomes in these children. © The Author(s) 2014. PMID: 25512362 [PubMed - as supplied by publisher] 5. MMWR Morb Mortal Wkly Rep. 2014 Dec 12;63(49):1155-8. Incidence of sickle cell trait - United States, 2010. Ojodu J, Hulihan MM, Pope SN, Grant AM. Abstract Persons with sickle cell trait (SCT) are heterozygous carriers of an abnormal ß-globin gene that results in the production of an abnormal hemoglobin, Hb S, which can distort red blood cells (http://www.cdc.gov/ncbddd/sicklecell/facts.html). All state newborn screening (NBS) programs have provided universal sickle cell disease (SCD) screening for newborns since 2006. Screening for SCD detects both SCD and SCT. To obtain up-to-date measures of the occurrence of SCT among newborns by race/ethnicity and state of birth, data collected by state NBS programs in 2010 were examined. In 2010, the incidence of SCT in participating states was 15.5 per 1,000 newborns overall; 73.1 among black newborns and 6.9 among Hispanic newborns. Incidence by state ranged from 0.8 per 1,000 screened newborns in Montana to 34.1 per 1,000 in Mississippi. Although the occurrence of SCT varies greatly from state-to-state and among different races and ethnicities, every state and racial/ethnic population includes persons living with the condition. The period immediately following NBS is ideal for primary care providers and genetic counselors to begin educating the families of identified persons with SCT about potential health complications and reproductive considerations. Free Article PMID: 25503918 [PubMed - in process] 6. Clin J Pain. 2014 Dec 11. [Epub ahead of print] Changes in Coping, Pain and Activity following Cognitive-Behavioral Training: A Randomized Clinical Trial for Pediatric Sickle Cell Disease using Smartphones. Schatz J1, Schlenz A, McClellan CB, Puffer ES, Hardy S, Pfeiffer M, Roberts CW. Abstract OBJECTIVES:: We examined the outcomes of a cognitive-behavioral therapy (CBT) intervention for pain in pediatric sickle cell disease (SCD) using smartphones as a novel delivery method. METHODS:: Forty-six children with SCD received CBT coping skills training using a randomized, waitlist control design. The intervention involved a single-session of CBT training and home-based practice using smartphones for eight weeks. Pre-post questionnaires between the randomized groups were used to evaluate changes in active psychological coping and negative thinking using the Coping Strategies Questionnaire. Daily diaries completed by the full sample during the treatment period were used to assess if CBT skill use was related to reductions in next day pain intensity and increases in same day functional activity. RESULTS:: The pre-post group comparison suggested that youth increased active psychological coping attempts with the intervention. Daily diary data indicated that when children used CBT skills on days with higher pain, there were reductions in next day pain intensity. There was no such association between skill use and functional activity. DISCUSSION:: CBT coping skills training supported via smartphones can increase coping and reduce pain intensity for children with SCD; however, additions to the study protocols are recommended in future studies. Advantages and caveats of using smartphones are also discussed. PMID: 25503599 [PubMed - as supplied by publisher] 7. Am J Med. 2014 Dec 8. pii: S0002-9343(14)01148-6. doi: 10.1016/j.amjmed.2014.11.020. [Epub ahead of print] Quality Improvement Process in a Sickle Cell Infusion Center. Whiteman LN1, Lanzkron S2, Stewart RW3, Haywood C Jr4, Strouse JJ3, Feldman L3. Abstract BACKGROUND: The American Pain Society recommends individuals experiencing sickle cell crisis receive parenteral pain medication within 30 minutes of assessment. We examined factors affecting achievement of this standard at the Johns Hopkins Sickle Cell Infusion Center. METHODS: Baseline patient care time intervals and data on variables affecting the ability to achieve the American Pain Society goal were measured. Time to first parenteral opiate administration was modeled using simple and multivariable linear regression. RESULTS: Mean time from initial assessment to first dose was initially 41 minutes. Increased nurse to patient ratio decreased time to first dose. CONCLUSION: Of the factors associated with improved times to first dose, only nurse to patient ratio is amenable to process change, suggesting it as a potential target for future interventions. Copyright © 2014 Elsevier Inc. All rights reserved. PMID: 25498167 [PubMed - as supplied by publisher] 8. Cochrane Database Syst Rev. 2014 Dec 8;12:CD008394. [Epub ahead of print] Interventions for treating leg ulcers in people with sickle cell disease. Martí-Carvajal AJ1, Knight-Madden JM, Martinez-Zapata MJ. Abstract BACKGROUND: The frequency of skin ulceration makes it an important contributor to the morbidity burden in people with sickle cell disease. Many treatment options are available to the healthcare professional, although it is uncertain which treatments have been assessed for effectiveness in people with sickle cell disease. OBJECTIVES: To assess the clinical effectiveness and safety of interventions for treating leg ulcers in people with sickle cell disease. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register.We searched LILACS (1982 to August 2012), the African Index Medicus (up to August 2012), ISI Web of Knowledge (1985 to August 2012), and the Clinical Trials Search Portal of the World Health Organization (August 2012). We checked the reference lists of all the trials identified. We also contacted those groups or individuals who may have completed relevant randomised trials in this area.Date of the last search of the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register: 21 July 2014; date of the last search of the Cochrane Wounds Group Trials Register: 18 September 2014. SELECTION CRITERIA: Randomised controlled trials of interventions for treating leg ulcers in people with sickle cell disease compared to placebo or an alternative treatment. DATA COLLECTION AND ANALYSIS: Two authors independently selected studies for inclusion. All three authors independently assessed the risk of bias of the included studies and extracted data. MAIN RESULTS: Six studies met the inclusion criteria (198 participants with 250 ulcers). Each trial investigated a different intervention and within this review we have grouped these as systemic pharmaceutical interventions (L-cartinine, arginine butyrate, isoxsuprine) and topical pharmaceutical interventions (Solcoseryl® cream, RGD peptide dressing, topical antibiotics). Three interventions reported on the change in ulcer size (arginine butyrate, RGD peptide, L-cartinine). Of these, RGD peptide matrix significantly reduced ulcer size compared with a control group, mean reduction 6.60cm2 (95% CI 5.51 to 7.69; very low quality of evidence). Three trials reported on the incidence of complete closure (isoxsuprine, arginine butyrate, RGD peptide matrix; ranging between low and very low quality of evidence). None reported a significant effect. No trial reported on: the time to complete ulcer healing; ulcer-free survival following treatment for sickle cell leg ulcers; quality of life measures; or incidence of amputation. There was no reported information on the safety of these interventions. AUTHORS' CONCLUSIONS: There is evidence that a topical intervention (RGD peptide matrix) reduced ulcer size in treated participants compared to controls. This evidence of efficacy is limited by the generally high risk of bias associated with these reports.We planned to analyse results according to general groups: pharmaceutical interventions (systemic and topical); and non-pharmaceutical interventions (surgical and non-surgical). However, we were unable to pool findings due to the heterogeneity in outcome definitions, and inconsistency between the unit of randomisation and the unit of analysis. This heterogeneity, along with a paucity of identified trials, prevented us performing any meta-analyses.This Cochrane review provides some evidence for the effectiveness of one topical intervention - RGD peptide matrix. However, this intervention was assessed as having a high risk of bias due to inadequacies in the single trial report. Other included studies were also assessed as having a high risk of bias. We recommend that readers interpret the trial results with caution. The safety profile of the all interventions was inconclusive. PMID: 25485858 [PubMed - as supplied by publisher] Related citations

9. Blood. 2014 Dec 4;124(24):3538-3543. Reproductive issues in sickle cell disease. Smith-Whitley K1. Abstract As medical advances improve survival, reduce disease-related morbidity, and improve quality of life, reproductive issues will take higher priority in the sickle cell disease (SCD) community. A wide variety of topics are addressed in this chapter, including fertility, gonadal failure, erectile dysfunction, and menstrual issues in SCD. Etiologies of impaired male fertility are multifactorial and include hypogonadism, erectile dysfunction, sperm abnormalities, and complications of medical therapies. Much less is known about the prevalence and etiology of infertility in women with SCD. Other reproductive issues in women included in this review are pain and the menstrual cycle, contraception, and preconception counseling. Finally, long-term therapies for SCD and their impact on fertility are presented. Transfusional iron overload and gonadal failure are addressed, followed by options for fertility preservation after stem cell transplantation. Focus is placed on hydroxyurea therapy given its benefits and increasing use in SCD. The impact of this agent on spermatogenesis, azoospermia, and the developing fetus is discussed. © 2014 by The American Society of Hematology. All rights reserved. PMID: 25472967 [PubMed - as supplied by publisher] Related citations 10. Am J Hematol. 2014 Dec 2. doi: 10.1002/ajh.23912. [Epub ahead of print] Intensive management of high-utilizing adults with sickle cell disease lowers admissions. Koch KL1, Karafin MS, Simpson P, Field JJ. Abstract A minority of super-utilizing adults with sickle cell disease (SCD) account for a disproportionate number of emergency department (ED) and hospital admissions. We performed a retrospective cohort study comparing the rate of admission before and after the opening of a clinic for adults with SCD. Unique to this clinic was an intensive intervention management strategy, focusing on super-utilizing adults with 12 or more admissions per year. ED/hospital and 30 days admission rates were compared, 1 year pre- and post-intervention, for those adults who established in the clinic. Prior to the intervention, 17 super-utilizers, comprising 15% of the pre-intervention cohort (n=115), accounted for 58% of the total admissions and had an admission rate of 28 per patient-year. When pre- and post-intervention years were compared, rate of ED/hospital admission per patient-year for super-utilizers decreased from 27.9 to 13.5 (P< 0.001), while there was not a significant reduction for the entire cohort (7.1 vs. 6.1, P=0.84). Similarly, the decrease in rate of 30 day re-admission was larger for the super-utilizers (13.5 per patient-year to 1.8, P<0.001), than the whole cohort (2.6 per patient-year to 0.7, P=0.006). Among the super-utilizers, the reduced rate of admission from the pre- to post-clinic intervention year equated to 252 fewer ED/hospital admissions and 227 fewer 30 day re-admissions. This management strategy focusing on super-utilizing adults with SCD lowered admission and 30 day re-admission rate. This article is protected by copyright. All rights reserved. Copyright © 2014 Wiley Periodicals, Inc., A Wiley Company. PMID: 25469750 [PubMed - as supplied by publisher] Related citations 11. Medicine (Baltimore). 2014 Dec;93(28):e215. doi: 10.1097/MD.0000000000000215. From infancy to adolescence: fifteen years of continuous treatment with hydroxyurea in sickle cell anemia. Hankins JS1, Aygun B, Nottage K, Thornburg C, Smeltzer MP, Ware RE, Wang WC. Abstract Despite documented laboratory and clinical benefits of hydroxyurea for children with sickle cell anemia (SCA), the drug's long-term safety and efficacy remains poorly defined. The HUSOFT trial and extension study examined feasibility, toxicity, and hematological efficacy of hydroxyurea in infants with SCA.This report describes HUSOFT participants who have continued hydroxyurea therapy for 15 years. With IRB approval, medical records were reviewed for clinical, laboratory, and growth parameters.Twenty-eight infants enrolled in the original 2-year HUSOFT study received open-label liquid hydroxyurea at 20 mg/kg/day; 17 completed the extension study with dose escalation to 30 mg/kg/day. Eight of these 17 (6 girls and 2 boys, all HbSS) have continued on daily hydroxyurea for at least 15 years (median age at last follow-up 17.6 years) without interruption. All hematologic indices (Hb concentration, mean corpuscular volume (MCV), fetal hemoglobin) showed sustained effect after 15 years. The median maximum tolerated dose of hydroxyurea has decreased from 30 to 26 mg/kg/day (range 19.5-31.2); neutropenia [absolute neutrophil count (ANC) < 1.0 × 10/L] prompting temporary drug discontinuation occurred a total of 10 times in 4 subjects and there was no severe neutropenia (ANC < 0.5 × 10/L). Growth rates over 15 years continued at the 50th percentile for both height and weight, and puberty occurred without delay (age range 10-14 years). There were 5.1 vaso-occlusive events (pain and acute chest syndrome)/100 patient years, 7.3 packed red blood cell transfusions/100 patient years. No malignancies, strokes, or deaths occurred. At last follow up, all subjects were at appropriate grade level (10-12 grade) with no history of repeated grades.A cohort of young teenagers with SCA who initiated treatment in infancy have had sustained and continued hematological benefits for a decade and a half. Growth and sexual development are normal and comparable to the general pediatric population. Continuous hydroxyurea therapy since infancy appears safe and efficacious in SCA. PMID: 25526439 [PubMed - in process] 12. South Med J. 2014 Dec;107(12):768-72. doi: 10.14423/SMJ.0000000000000209. Edmonton symptom assessment system for outpatient symptom monitoring of sickle cell disease. Lopez G1, Liles DK1, Knupp CL1. Abstract OBJECTIVES: Although the extension of palliative care methodology to sickle cell disease (SCD) care has been proposed, there is no current standard for symptom assessment. Our goal was to assess the feasibility of integrating the Edmonton Symptom Assessment System (ESAS) into the outpatient management of SCD. METHODS: Seventy-five adult patients presenting for outpatient visits at a comprehensive SCD center were enrolled. Patients completed the ESAS (self-report of 10 symptoms during the last 24 hours) and a survey regarding their opinion of the ESAS at enrollment and follow-up. RESULTS: Pain (P = 0.0272) was the only symptom score that changed significantly between the initial and follow-up visits. In patients with a self-reported pain crisis, pain (P < 0.0001), fatigue (P = 0.0025), depression (P = 0.0458), nausea (P = 0.0384), and symptom distress scores (P = 0.0019) were significantly higher than for patients without a pain crisis. On the initial visit, 92% of all patients agreed or strongly agreed that the ESAS was easy to complete; 83% were satisfied or very satisfied with the ESAS as a way to report symptoms. CONCLUSIONS: Our data suggest that the ESAS is well received and can be successfully included as part of the longitudinal symptom management strategy for SCD. PMID: 25502156 [PubMed - in process] 13. J Clin Sleep Med. 2014 Nov 2. pii: jc-00262-14. [Epub ahead of print] Sleep Disorders in Adult Sickle Cell Patients. Sharma S, Efird JT, Knupp C, Kadali R, Liles D, Shiue K, Boettger P, Quan SF. Abstract Study Objectives: While sleep apnea has been studied in children with sickle cell disease (SCD), little is known about sleep disorders in adult sickle cell patients. The objective of this study was to evaluate sleep disordered breathing and its polysomnographic characteristics in adult patients with sickle cell disease. Methods: The analysis cohort included 32 consecutive adult SCD patients who underwent a comprehensive sleep evaluation and overnight polysomnography in an accredited sleep center after reporting symptoms suggesting disordered sleep or an Epworth Sleepiness Scale score ≥10. Epworth score, sleep parameters, comorbid conditions, and narcotic use were reviewed and compared in patients with and without sleep disordered breathing. SCD complication rates in the two groups also were compared. Results: In adult SCD patients who underwent overnight polysomnography, we report a high prevalence (44%) of sleep disordered breathing. Disease severity was mild to moderate (mean apnea hypopnea index = 17 /h (95% CI: 10-24 /h). Concomitant sleep disorders, including insomnia complaints (57%) and delayed sleep-phase syndrome (57%), also were common in this population. In this limited cohort, we did not find increased SCD complications associated with sleep disordered breathing in adult patients with sickle cell disease. Conclusions: A high burden of sleep disordered breathing and other sleep-related complaints were identified in the adult sickle cell population. Our results provide important information on this unique population. © 2014 American Academy of Sleep Medicine. PMID: 25515282 [PubMed - as supplied by publisher] 14. PLoS One. 2014 Dec 9;9(12):e114540. doi: 10.1371/journal.pone.0114540. eCollection 2014. Evaluation of a density-based rapid diagnostic test for sickle cell disease in a clinical setting in zambia. Kumar AA1, Chunda-Liyoka C2, Hennek JW3, Mantina H2, Lee SY3, Patton MR3,Sambo P2, Sinyangwe S2, Kankasa C2, Chintu C2, Brugnara C4, Stossel TP5,Whitesides GM6. Abstract Although simple and low-cost interventions for sickle cell disease (SCD) exist in many developing countries, child mortality associated with SCD remains high, in part, because of the lack of access to diagnostic tests for SCD. A density-based test using aqueous multiphase systems (SCD-AMPS) is a candidate for a low-cost, point-of-care diagnostic for SCD. In this paper, the field evaluation of SCD-AMPS in a large (n = 505) case-control study in Zambia is described. Of the two variations of the SCD-AMPS used, the best system (SCD-AMPS-2) demonstrated a sensitivity of 86% (82-90%) and a specificity of 60% (53-67%). Subsequent analysis identified potential sources of false positives that include clotting, variation between batches of SCD-AMPS, and shipping conditions. Importantly, SCD-AMPS-2 was 84% (62-94%) sensitive in detecting SCD in children between 6 months and 1 year old. In addition to an evaluation of performance, an assessment of end-user operability was done with health workers in rural clinics in Zambia. These health workers rated the SCD-AMPS tests to be as simple to use as lateral flow tests for malaria and HIV. PMCID: PMC4260838 Free PMC Article PMID: 25490722 [PubMed - in process] Related citations