Gene Therapy is on the Way

“Bubble baby” stem cell treatment looks like a cure and paves way for Sickle Cell Disease Treatment

The first therapeutics based on genome-editing tools will treat diseases caused by single genes, but many other factors dictate what is currently possible.

Data Back Transplant as Cure for Sickle Cell

More than 90% of patients with sickle cell disease remained alive and free of clinical events 3 years after receiving HLA-matched sibling stem-cell transplantation, data from an international registry showed.

The 3-year overall survival (OS) was 94%, and event-free survival (EFS, survival with engraftment) was 90% among the 1,000 pediatric patients included in the analysis. Good results were obtained with bone marrow-derived or peripheral blood stem cells, but a multivariate analysis showed that bone marrow as the source of stem cells led to significantly better EFS.

The findings reinforce stem cell transplantation as curative therapy for sickle cell disease and should encourage pediatric hematologists to engage parents of patients with sickle cell disease in discussions about stem cell transplantation as a therapeutic option, said Barbara Cappelli, MD, of the International Observatory on Sickle Cell Disease at Hospital Saint Louis in Paris.

Hemoglobin modifier appears safe, effective for sickle cell disease

GBT440, a novel oral small molecule hemoglobin modifier, reduced hemolysis and improved anemia without causing tissue hypoxia among patients with sickle cell disease, according to results of a placebo-controlled, double blind study presented at the ASH Annual Meeting and Exposition.

Treatment with GBT440 (Global Blood Therapeutics) also substantially reduced sickle cells in the peripheral blood of patients, according to researchers.
GBT440 works by increasing hemoglobin oxygen affinity. Preclinical data indicated that the therapy is a potent anti-sickling agent with a high specificity for hemoglobin. Further, results suggested between 10% and 30% modification of hemoglobin could safely prevent sickle hemoglobin (HbS) polymerization.

“These data further support the promising potential of GBT440 as a disease-modifying treatment for patients with sickle cell disease,” Claire Jane Hemmaway, MD, the lead hematology consultant at Queens Hospital in Essex, United Kingdom, told HemOnc Today. “GBT 440 is designed to bind hemoglobin to prevent polymerization of sickle hemoglobin, stop red blood cell destruction and improve oxygen delivery to tissues. Our expanding experience in sickle cell patients is consistent with GBT440 having these effects in patients and also shows that the drug is very well tolerated.”

Hemmaway and colleagues sought to explore the safety, pharmacokinetics and pharmacodynamics, and efficacy of the therapy in 30 patients (aged 18 to 60 years) with the HbSS genotype of sickle cell disease, as well as in 64 healthy volunteers (aged 18 to 55 years). Patients with sickle cell disease had baseline hemoglobin levels between 6 g/dL and 10 g/dL and had not experienced a vaso-occlusive crisis or received blood transfusion within 30 days prior to entering the study.

Hydroxyurea Prevents Stroke in Pediatric Sickle Cell Anemia

Stroke is a devastating complication of sickle cell anemia that occurs in young children, and while blood transfusions protect against primary stroke, they must be continued indefinitely and have associated morbidity.

But findings from a new study, presented here at the plenary session of the American Society Hematology (ASH) 57th Annual Meeting, showed that oral agent hydroxyurea was noninferior and possibly superior to long-term transfusions. This truly is one of the abstracts that can be defined as practice changing. Dr Alexis A. Thompson

“This truly is one of the abstracts that can be defined as practice changing,” commented Alexis A. Thompson, MD, MPH, professor of pediatrics at the Ann & Robert H. Lurie Children’s Hospital of Chicago, Illinois. “There are many families who have had great difficulty accepting the realities of their children being transfused lifelong.”

“Given this is a noninferiority trial, this clearly offers a family a choice of continuing on transfusions if they so choose, but certainly for many families, to be confident that if they choose to switch to hydroxyurea that their child will not be at an increased risk for a stroke,” said Dr Thompson, who moderated a press briefing where highlights of the study were presented.

New technology may standardize sickle cell disease screening for infants

Researchers from Seidman Cancer Center at University Hospitals Case Medical Center and Case Western Reserve University School of Medicine presented new research findings this weekend at the 57th Annual Meeting of the American Society of Hematology (ASH) in Orlando.

In a poster presentation (Abstract #3379), Yunus Alapan, Umut Gurkan PhD and Jane Little, MD presented promising findings related to new technology aimed at facilitating early detection of sickle cell disease for infants in developing countries. Current standardized screening methods are too costly and take too much time to enable equitable and timely diagnosis to save lives in economically challenged nations. However, an innovative mobile biochip device, the HemeChip, has the unique ability to rapidly screen for sickle cell disease with just a few drops of blood.

Boy with Sickle Cell Anemia grows into child prodigy

While most toddlers were learning to walk and play nicely on the playground, one little boy name Caesar Santos was learning to play the violin.According to his father, he already knew multiplication at the age of four. Now, at the age of seven, the child prodigy is having trouble navigating through the tiniest things due to his Sickle Cell Anemia Disease. The disease is an inherited blood disorder that not only clots your blood vessels, but also causes organ damage and strokes. He has had three strokes related to Sickle Cell and he has to have blood transfusions every three weeks to prevent future strokes. His doctors want to eventually do a stem cell transplant.

NHLBI’s Novel, Innovative Tools to Increase Public Awareness and Knowledge of Sickle Cell Disease Undergraduate Challenge

The goals of the Challenge are to: 1) generate novel, innovative tools that may be used to increase public awareness and knowledge of SCD and associated complications that could potentially improve patient care; 2) advance the field of implementation science through research training, mentoring, and highlighting the contributions of a new generation of undergraduate researchers using a systems science approach to address multi-faceted problems; and 3) encourage “team science” by providing undergraduate students valuable experiences to pursue science collectively as they engage in complex problem solving to improve health outcomes for SCD.

Rules for Participating in the Challenge

This Challenge is open to any “Student Team”, defined as a group of at least 3 and not more than 5 individuals each of whom is at least 18 years of age and currently enrolled as a full-time student pursuing an undergraduate or associates degree. The Student Team Captain must be a citizen or permanent resident of the United States.
The Student Team must also be trans-disciplinary, that is, composed of undergraduate students from diverse disciplines such as fine arts, performing arts, humanities, psychology, science, engineering, graphic design, IT (hardware, software), mathematics, statistics, environmental science, computational modeling, and others.

Challenge announced: Oct. 21, 2015
Submissions accepted: Nov. 30, 2015 to March 7, 2016 11:59 p.m. PDT


New CDC Chronic Pain Treatment Guidelines open for comment

The CDC has posted the Guideline for Prescribing Opioids for Chronic Pain, along with supporting documents on the Federal Register for a 30 day public comment period ending January 13, 2016. The link to these documents and to submit comments is!documentDetail;D=CDC-2015-0112-0001

The notice is on the Federal Register

Sickle cell in the Medical Literature

1.  Haematologica. 2015 Dec 24. pii: haematol.2015.136523. [Epub ahead of print]
Cannabinoid receptor-specific mechanisms to ameliorate pain in sickle cell anemia via inhibition of mast cell activation and neurogenic inflammation.
Vincent L1, Vang D1, Nguyen J1, Benson B1, Lei J1, Gupta K2.
Sickle cell anaemia is a manifestation of a single point mutation in haemoglobin, but inflammation and pain are the insignia of this disease which can start in infancy and continue throughout life. Earlier studies showed that mast cell activation contributes to neurogenic inflammation and pain in sickle mice. Morphine is the common analgesic treatment but also remains a major challenge due to the side effects and ability to activate mast cells. Therefore, we examined the cannabinoid receptor-specific mechanisms to ameliorate mast cell activation, neurogenic inflammation and hyperalgesia, using HbSS-BERK sickle and cannabinoid receptor 2 deleted sickle mice. We show that cannabinoids ameliorate mast cell activation, inflammation and neurogenic inflammation in sickle mice via both cannabinoid receptors 1 and 2. Thus, cannabinoids influence systemic and neural mechanisms, ameliorating the disease pathobiology and hyperalgesia in sickle mice. This study provides a “proof of principle” for the potential of cannabinoid/cannabinoid receptor-based therapeutics to treat several manifestations of sickle cell anaemia.
Copyright © 2015, Ferrata Storti Foundation.
Free Article
PMID: 26703965 [PubMed – as supplied by publisher]

2. Br J Sports Med. 2015 Dec 23. pii: bjsports-2015-095317. doi: 10.1136/bjsports-2015-095317. [Epub ahead of print]
Does physical activity increase or decrease the risk of sickle cell disease complications?
Martin C1, Pialoux V2, Faes C1, Charrin E1, Skinner S1, Connes P2.
Sickle cell disease (SCD) is the most common inherited disease in the world. Red blood cell sickling, blood cell-endothelium adhesion, blood rheology abnormalities, intravascular haemolysis, and increased oxidative stress and inflammation contribute to the pathophysiology of SCD. Because acute intense exercise may alter these pathophysiological mechanisms, physical activity is usually contra-indicated in patients with SCD. However, recent studies in sickle-cell trait carriers and in a SCD mice model show that regular physical activity could decrease oxidative stress and inflammation, limit blood rheology alterations and increase nitric oxide metabolism. Therefore, supervised habitual physical activity may benefit patients with SCD. This article reviews the literature on the effects of acute and chronic exercise on the biological responses and clinical outcomes of patients with SCD.
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to
PMID: 26701924 [PubMed – as supplied by publisher]

3. Pediatr Pulmonol. 2015 Dec 22. doi: 10.1002/ppul.23367. [Epub ahead of print]
Longitudinal assessment of lung function in children with sickle cell disease.
Lunt A1,2, McGhee E1, Sylvester K1, Rafferty G1,2, Dick M3, Rees D3, Height S3, Thein SL4, Greenough A1,2.
To prospectively assess longitudinal lung function in children with sickle cell disease (SCD).
Lung function in SCD children deteriorates with increasing age and the decline is more marked in younger children who have recently suffered ACS episodes.
Two prospective longitudinal studies.
Two cohorts of SCD children and age and ethnic matched controls were recruited. Cohort One (47 SCD and 26 controls) had a median age of 8.8 years and follow up of 2 years and Cohort Two (45 SCD and 26 controls) a median age of 10.2 years and follow up of 10 years.
Forced expiratory volume in one second (FEV1 ), vital capacity (VC), forced expiratory flow between 25% and 75% of VC (FEF 25-75 ), total lung capacity (TLC) and residual volume (RV) were measured on two occasions.
In both groups of SCD children, lung function declined significantly, but in neither control group. ACS episodes were more frequent during the follow up period in Cohort One than Cohort Two (P < 0.0001). The rate of decline was greater in Cohort One than Cohort Two for FEV1 (P = 0.008), VC (P = 0.001), FEF25-75 (P = 0.030), TLC (P = 0.004), and RV (P = 0.043). In Cohort Two restrictive abnormalities were more common at follow up (P = 0.006).
Lung function deteriorated with increasing age in SCD children and the rate of decline was greater in younger children in whom ACS episodes were more common. Pediatr Pulmonol. © 2015 Wiley Periodicals, Inc.
© 2015 Wiley Periodicals, Inc.
PMID: 26694220 [PubMed – as supplied by publisher]

4. Hip Int. 2015 Dec 14:0. doi: 10.5301/hipint.5000317. [Epub ahead of print]
Cementless total hip replacements in sickle cell disease.
Jack CM1, Howard J1, Aziz ES1, Kesse-Adu R1, Bankes MJ1.
Sickle cell disease (SCD) affects around 80,000 people in the USA and 12,000 in the UK. Up to 40% of patients will get osteonecrosis of the femoral head. Cemented acetabular components yield poor results with the rate of osteolysis ranging from 13.5 to 46%. We report on a consecutive cohort of patients with SCD who underwent uncemented THA with ceramic-on-ceramic (CoC) bearings.
Since 2002 52 primary THAs were carried out in 40 patients. The average age was 36.1 years (17-54). 48 cases had exchange blood transfusion preoperatively and 3 had top-up transfusions.An S-ROM was used in 47 hips a Solutions stem in 4 hips and an AML in 1. It was necessary to drill the femur during 12 hips. There were 5 intra-operative peri-prosthetic fractures. 2 dislocations were observed. 2 superficial infections were detected.
All components have in-grown. There have been no cases of radiographic osteolysis, migration or loosening of the hip with average 5-year (2-10.1) follow-up.
The combination of a multidisciplinary team approach and uncemented implants, with ceramic-on-ceramic bearings used, has made THA in patients with SCD a safe and reliable procedure in our hospital.
PMID: 26692246 [PubMed – as supplied by publisher]
Similar articles
Am J Hematol. 2015 Dec 21. doi: 10.1002/ajh.24281. [Epub ahead of print]
Secondhand smoke is associated with more frequent hospitalizations in children with sickle cell disease.
Sadreameli SC1, Eakin MN2, Robinson KT3, Alade RO3, Strouse JJ3,4.
Tobacco smoke exposure has been associated with more frequent hospitalizations in children with sickle cell disease (SCD), but previous studies have not quantified the exposure by objective methods. We enrolled 50 children and young adults with SCD in a retrospective and prospective cohort study and quantified tobacco smoke exposure by objective (salivary cotinine) and survey measures. We used a multivariable negative binomial regression model to evaluate the association between salivary cotinine and hospital admissions. Forty-five percent (22/49) of participants had significant elevation of salivary cotinine (≥ 0.5 ng/mL). The incidence risk ratio (IRR) for hospital admission for those with elevated cotinine was 3.7 (95% CI 1.8-8). Those exposed to secondhand smoke but not primary smokers (cotinine between 0.5 ng/ml and 10 ng/mL) had a similarly increased risk of hospitalization [IRR 4.3 (95% CI 1.8-10)]. We show that an objective measure of tobacco smoke exposure, salivary cotinine, is strongly associated with the rate of hospital admissions in children and young adults with SCD. This association underscores the importance of screening for tobacco smoke exposure in people with SCD. Further investigation is warranted to determine the mechanisms of and to evaluate interventions to decrease tobacco smoke exposure. This article is protected by copyright. All rights reserved.
© 2015 Wiley Periodicals, Inc.
PMID: 26690323 [PubMed – as supplied by publisher]

6.  Clin J Oncol Nurs. 2015 Oct;19(5):562-7. doi: 10.1188/15.CJON.562-567.
Sickle cell disease in adults: developing an appropriate care plan.
Matthie N, Jenerette C.
Sickle cell disease (SCD) is primarily characterized by pain. This chronic pain with acute exacerbations is the most common reason for hospital visits, admissions, and readmissions, particularly in young adults (aged 18–39 years). People who present to the hospital for pain crises often report that nurses lack knowledge of SCD and, consequently, they do not provide appropriate, timely care.
Because pain episodes often result in hospital admissions, this article highlights prominent issues that staff nurses need to know.
Using a review of the literature and case studies, the authors provide recommendations to improve care of adults with SCD.
No objective signs of a sickle cell pain crisis exist. Patients react to pain in different ways and use various coping mechanisms in response. Suspected opioid addiction should not affect the provision of nursing care. Pain must be treated appropriately to decrease the potential for prolonged admissions and/or readmissions. Patients are to be acknowledged as experts and collaborated with in developing an appropriate plan of care. Advocacy on behalf of the patient is important for better communication with providers. With this knowledge, nurses will be better equipped to provide the appropriate and timely care required to manage pain crises experienced by individuals living with SCD.
PMID: 26688919 [PubMed – in process]

7.  Cochrane Database Syst Rev. 2015 Dec 18;12:CD010155. [Epub ahead of print]
Low-molecular-weight heparins for managing vaso-occlusive crises in people with sickle cell disease.
van Zuuren EJ1, Fedorowicz Z.
Sickle cell disease is one of the most common and severe genetic disorders in the world. It can be broadly divided into two distinct clinical phenotypes characterized by either haemolysis or vaso-occlusion. Pain is the most prominent symptom of vaso-occlusion, and hypercoagulability is a well-established pathogenic phenomenon in people with sickle cell disease. Low-molecular-weight heparins might control this hypercoagulable state through their anticoagulant effect. This is an update of a previously published version of this review.
To assess the effects of low-molecular-weight heparins for managing vaso-occlusive crises in people with sickle cell disease.
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register comprising references identified from comprehensive electronic database searches. We also searched abstract books of conference proceedings and several online trials registries for ongoing trials.Date of the last search of the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register: 28 September 2015.
Randomised controlled clinical trials and controlled clinical trials that assessed the effects of low-molecular-weight heparins in the management of vaso-occlusive crises in people with sickle cell disease.
Study selection, data extraction, assessment of risk of bias and analyses were carried out independently by the two review authors.
Two studies comprising 287 participants were included. One study (with an overall unclear to high risk of bias) involved 253 participants and the quality of the evidence for most outcomes was very low. This study, reported that pain severity at day two and day three was lower in the tinzaparin group than in the placebo group (P < 0.01, analysis of variance (ANOVA)) and additionally at day 4 (P < 0.05 (ANOVA)). Thus tinzaparin resulted in more rapid resolution of pain, as measured with a numerical pain scale. The mean difference in duration of painful crises was statistically significant at -1.78 days in favour of the tinzaparin group (95% confidence interval -1.94 to -1.62). Participants treated with tinzaparin had statistically significantly fewer hospitalisation days than participants in the group treated with placebo, with a mean difference of -4.98 days (95% confidence interval -5.48 to -4.48). Two minor bleeding events were reported as adverse events in the tinzaparin group, and none were reported in the placebo group. The second study (unclear risk of bias) including 34 participants and was a conference abstract with limited data and only addressed one of the predefined outcomes of the review; i.e. pain intensity. After one day pain intensity reduced more, as reported on a visual analogue scale, in the dalteparin group than in the placebo group, mean difference -1.30 (95% confidence interval -1.60 to -1.00), with the quality of evidence rated very low. The most important reasons for downgrading the quality of evidence were serious risk of bias and imprecision (due to low sample size or low occurrence of events).
Based on the results of two studies, evidence is incomplete to support or refute the effectiveness of low-molecular-weight heparins in people with sickle cell disease. Vaso-occlusive crises are extremely debilitating for sufferers of sickle cell disease; therefore well-designed placebo-controlled studies with other types of low-molecular-weight heparins, and in participants with different genotypes of sickle cell disease, still need to be carried out to confirm or dismiss the results of this single study.
PMID: 26684281 [PubMed – as supplied by publisher]

8. Blood. 2015 Dec 17. pii: blood-2015-09-667923. [Epub ahead of print]
Pomalidomide reverses γ-globin silencing through the transcriptional reprogramming of adult hematopoietic progenitors.
Dulmovits BM1, Appiah-Kubi AO1, Papoin J1, Hale J2, He M3, Al-Abed Y3, Didier S1, Gould M4, Husain-Krautter S1, Singh SA4, Chan KW5, Vlachos A4, Allen SL6, Taylor N7, Marambaud P8, An X2, Gallagher PG9, Mohandas N2, Lipton JM10, Liu JM10, Blanc L11.
Current therapeutic strategies for sickle cell anemia are aimed at reactivating fetal hemoglobin. Pomalidomide, a third-generation immunomodulatory drug, was proposed to induce fetal hemoglobin production by an unknown mechanism. Here, we report that pomalidomide induced a fetal-like erythroid differentiation program, leading to a reversion of γ-globin silencing in adult human erythroblasts. Pomalidomide acted early by transiently delaying erythropoiesis at the BFU-E/CFU-E transition, but without affecting terminal differentiation. Further, the transcription networks involved in γ-globin repression were selectively and differentially affected by pomalidomide including BCL11A, SOX6, IKZF1, KLF1, and LSD1. IKAROS (IKZF1), a known target of pomalidomide, was degraded by the proteasome, but was not the key effector of this program, since genetic ablation of IKZF1 did not phenocopy pomalidomide treatment. Notably, the pomalidomide-induced reprogramming was conserved in hematopoietic progenitors from individuals with sickle cell anemia. Moreover, multiple myeloma patients treated with pomalidomide presented increased in vivo γ-globin levels in their erythrocytes. Together, these data reveal the molecular mechanisms by which pomalidomide reactivates fetal hemoglobin, reinforcing its potential as a treatment for patients with β-hemoglobinopathies.
Copyright © 2015 American Society of Hematology.
PMID: 26679864 [PubMed – as supplied by publisher]

9.  Urology. 2015 Dec 7. pii: S0090-4295(15)01086-9. doi: 10.1016/j.urology.2015.11.023. [Epub ahead of print]
Trends in Sickle-Cell-Disease-Related Priapism in U.S. Children’s Hospitals.
Wang HS1, Herbst KW2, Rothman JA3, Shah NR4, Wiener JS5, Routh JC6.
To define rates of priapism diagnosis and inpatient admission among males with SCD.
We retrospectively reviewed the Pediatric Health Information System database for males aged <21 years treated 2004-2012. We identified patients with SCD and priapism based on ICD-9-CM diagnosis codes. Logistic regression and generalized estimating equation models were used to control for confounding and to adjust for within-hospital clustering of similar patients.
We identified 17,186 males who were admitted 137,710 times during the study period. Of these, 362 (2.1%) were diagnosed with priapism on 748 admissions. There was a significant decrease in the number of priapism admissions among patients with SCD over time (0.81% in 2004 to 0.44% in 2012, p<0.001). The number of patients diagnosed with SCD-related priapism varied over time without a statistically significant trend (2.3% in 2004, 2.69% in 2008, 1.01% in 2012, p=0.34). Rates of priapism admissions (0-4.4%) varied widely between hospitals. Older patient age was associated with an increased likelihood of a priapism admission in the multivariate logistic regression model after adjusting for treatment year, hospital region, and for hospital-level clustering of similar patients.
From 2004-2012, the number of admissions for SCD-related priapism declined while the number of individual patients diagnosed with SCD-related priapism did not. Rates of priapism-related admissions in males with SCD vary widely among PHIS hospitals.
Copyright © 2015. Published by Elsevier Inc.
PMID: 26674747 [PubMed – as supplied by publisher]

10.  Pain Manag Nurs. 2015 Dec 7. pii: S1524-9042(15)00169-1. doi: 10.1016/j.pmn.2015.09.002. [Epub ahead of print]
Acute Pain and Depressive Symptoms: Independent Predictors of Insomnia Symptoms among Adults with Sickle Cell Disease.
Moscou-Jackson G1, Allen J2, Kozachik S2, Smith MT3, Budhathoki C2, Haywood C Jr4.
No studies to date have systematically investigated insomnia symptoms among adults with sickle cell disease (SCD). The purpose of this study was to (1) describe the prevalence of insomnia symptoms and (2) identify biopsychosocial predictors in community-dwelling adults with SCD. Cross-sectional analysis of baseline data from 263 African American adults with SCD (aged 18 years or older). Measures included the Insomnia Severity Index (ISI), Center for Epidemiologic Studies in Depression scale, Urban Life Stress Scale, Brief Pain Inventory, and a chronic pain item. SCD genotype was extracted from the medical record. A slight majority (55%) of the sample reported clinically significant insomnia symptomatology (ISI ≥ 10), which suggests that insomnia symptoms are prevalent among community-dwelling African American adults with SCD. While insomnia symptoms were associated with a number of biopsychosocial characteristics, depressive symptoms and acute pain were the only independent predictors. Given the high number of participants reporting clinically significant insomnia symptoms, nurses should screen for insomnia symptoms and explore interventions to promote better sleep among adults with SCD, with an emphasis on recommending treatment for pain and depression. In addition, current pain and depression interventions in this population could add insomnia measures and assess the effect of the intervention on insomnia symptomatology as a secondary outcome.
Copyright © 2015 American Society for Pain Management Nursing. Published by Elsevier Inc. All rights reserved.
PMID: 26673730 [PubMed – as supplied by publisher]

11. Crit Rev Oncol Hematol. 2015 Nov 27. pii: S1040-8428(15)30087-1. doi: 10.1016/j.critrevonc.2015.11.018. [Epub ahead of print]
Pregnancy and sickle cell disease: A review of the current literature.
Boga C1, Ozdogu H2.
Sickle cell disease (SCD) is the most common hereditary disease worldwide, presenting with anemia and intermittent severe pain. Pregnancy in a patient with SCD is associated with high levels of maternal and fetal morbidity and mortality; the maternal and fetal death rates during pregnancy can attain 11.4% and 20%, respectively. Patient care has improved over time. However, certain management issues remain unresolved; these include the optimum policy in terms of prophylactic blood transfusion, and the use of antiplatelet drugs. Such issues are attributable to the heterogeneous nature of clinical SCD features, and the limitations of uncontrolled and prospective trials. In this review, we seek to facilitate a better understanding of relevant issues via creation of a comparative data profile extracted from current studies. This report may also encourage the drafting of standard operating procedure for management of pregnancy in SCD patients.
Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
PMID: 26672916 [PubMed – as supplied by publisher]

12.  Clin J Am Soc Nephrol. 2015 Dec 15. pii: CJN.03940415. [Epub ahead of print]
Kidney Disease among Patients with Sickle Cell Disease, Hemoglobin SS and SC.
Drawz P1, Ayyappan S2, Nouraie M3, Saraf S4, Gordeuk V5, Hostetter T6, T Gladwin M7, Little J8.
Sickle cell disease (SCD) is an inherited anemia that afflicts millions worldwide. Kidney disease is a major contributor to its morbidity and mortality. We examined contemporary and historical SCD populations to understand how renal disease behaved in hemoglobin SS (HbSS) compared with HbSC.
Kidney function was examined in the multicentered Treatment of Pulmonary Hypertension and Sickle Cell Disease with Sildenafil Therapy (Walk-PHaSST) Trial (HbSS=463; HbSC=127; years 2007-2009) and historical comparator populations from the Cooperative Study of Sickle Cell Disease (CSSCD; HbSS=708) and the Multicenter Study of Hydroxyurea in Sickle Cell Disease (MSH; HbSS=299).
In adults with SCD, eGFR was lower among older individuals: -1.78 ml/min per 1.73 m2 per year of age (95% confidence interval [95% CI], -2.06 to -1.50; Walk-PHaSST Trial), -1.75 ml/min per 1.73 m2 per year of age (95% CI, -2.05 to -1.44; MSH), and -1.69 ml/min per 1.73 m2 per year of age (95% CI, -2.00 to -1.38; CSSCD) in HbSS compared with -1.09 ml/min per 1.73 m2 per year of age (95% CI, -1.39 to -0.75) in HbSC (Walk-PHaSST Trial). Macroalbuminuria was seen in 20% of participants with SCD (HbSS or HbSC; P=0.45; Walk-PHaSST Trial), but microalbuminuria was more prevalent in HbSS (44% versus 23% in HbSC; P<0.002). In the Walk-PHaSST Trial, albuminuria was associated with hemolysis (higher lactate dehydrogenase, P<0.001; higher absolute reticulocyte count, P<0.02; and lower Hb, P=0.07) and elevated systolic BP (P<0.001) in HbSS. One half of all participants with HbSS (20 of 39) versus one fifth without (41 of 228) elevated tricuspid regurgitant jet velocity (≥3 m/s; adverse prognostic indicator in SCD) had macroalbuminuria (P<0.001). In the CSSCD, overt proteinuria, detected (less sensitively) by urine dipstick, associated with higher 3-year mortality (odds ratio, 2.48; 95% CI, 1.07 to 5.77). Serum bicarbonate was lower in HbSS (23.8 versus 24.8 mEq/dl in HbSC; P<0.05) and associated with reticulocytopenic anemia and decreased renal function.
In SCD, albuminuria or proteinuria was highly prevalent, in HbSS more than in HbSC. Proteinuria associated with mortality in HbSS. Older individuals had a lower than expected eGFR, and this was more prominent in HbSS. Current management does not routinely address renal complications in SCD, which could plausibly reduce morbidity and mortality.
Copyright © 2015 by the American Society of Nephrology.
PMID: 26672090 [PubMed – as supplied by publisher]

13.  BJOG. 2015 Dec 15. doi: 10.1111/1471-0528.13786. [Epub ahead of print]
Pregnancy outcomes in women with sickle-cell disease in low and high income countries: a systematic review and meta-analysis.
Boafor TK1, Olayemi E2, Galadanci N3, Hayfron-Benjamin C4, Dei-Adomakoh Y2, Segbefia C5, Kassim AA3, Aliyu MH3, Galadanci H6, Tuuli MG7, Rodeghier M8, DeBaun MR3, Oppong SA9.
Pregnancy in women with sickle-cell disease (SCD) is associated with increased adverse outcomes. Findings on the association between SCD and adverse pregnancy outcomes are conflicting, and the results do not address whether these associations are similar in both low- and high-income countries.
We conducted a systematic review and meta-analysis to evaluate pregnancy outcomes associated with SCD.
The MEDLINE database was searched using medical subject headings (MeSH) and keywords for articles on pregnancy outcomes in women with SCD.
We used full research articles published in English that compared women with SCD with women who did not have SCD, as controls.
Data were abstracted and analysed using comprehensive Meta-analysis 2.2. The primary outcomes were intrauterine growth restriction and perinatal mortality. Secondary outcomes were rates of caesarean sections, pre-eclampsia, eclampsia, postpartum haemorrhage, maternal mortality, prematurity, and low birthweight. Random-effects models were used to calculate pooled odds ratios (ORs) with 95% confidence intervals (95% CIs).
Sixteen studies met all of the selection criteria and were included in the analysis. SCD was associated with intrauterine growth restriction (pooled OR 2.79, 95% CI 1.85-4.21), perinatal mortality (pooled OR 3.76, 95% CI 2.34-6.06), and low birthweight (pooled OR 2.00, 95% CI 1.42-2.83). SCD was also associated with an increased risk of pre-eclampsia (pooled OR 2.05, 95% CI 1.47-2.85), maternal mortality (pooled OR 10.91, 95% CI 1.83-65.11, P = 0.009), and eclampsia (pooled OR 3.02, 95% CI 1.20-7.58).
Pregnancy in women with SCD is associated with increased risks of adverse perinatal and maternal outcomes in both low- and high-income countries.
This meta-analysis showed worse pregnancy outcomes in women with sickle-cell disease compared with controls.
© 2015 Royal College of Obstetricians and Gynaecologists.
PMID: 26667608 [PubMed – as supplied by publisher]

14. Sports Med. 2015 Dec 14. [Epub ahead of print]
Role of Exercise-Induced Oxidative Stress in Sickle Cell Trait and Disease.
Chirico EN1,2, Faës C1,3, Connes P1,3,4, Canet-Soulas E2, Martin C1,3, Pialoux V5,6,7.
Sickle cell disease is a class of hemoglobinopathy in humans, which is the most common inherited disease in the world. Although complications of sickle cell disease start from polymerization of red blood cells during its deoxygenating phase, the oxidative stress resulting from the biological processes associated with this disease (ischaemic and hypoxic injuries, hemolysis and inflammation) has been shown to contribute to its pathophysiology. It is widely known that chronic exercise reduces oxidative stress in healthy people, mainly via improvement of antioxidant enzyme efficiency. In addition, recent studies in other diseases, as well as in sickle cell trait carriers and in a mouse model of sickle cell disease, have shown that regular physical activity could decrease oxidative stress. The purpose of this review is to summarize the role of oxidative stress in sickle cell disease and the effects of acute and chronic exercise on the pro-oxidant/antioxidant balance in sickle cell trait and sickle cell disease.
PMID: 26666745 [PubMed – as supplied by publisher]

15. Mol Ther Methods Clin Dev. 2015 Dec 2;2:15045. doi: 10.1038/mtm.2015.45. eCollection 2015.
Amelioration of murine sickle cell disease by nonablative conditioning and γ-globin gene-corrected bone marrow cells.
Pestina TI1, Hargrove PW1, Zhao H1, Mead PE2, Smeltzer MP3, Weiss MJ1, Wilber A4, Persons DA1.
Patients with severe sickle cell disease (SCD) are candidates for gene therapy using autologous hematopoietic stem cells (HSCs), but concomitant multi-organ disease may contraindicate pretransplant conditioning with full myeloablation. We tested whether nonmyeloablative conditioning, a regimen used successfully for allogeneic bone marrow transplantation of adult SCD patients, allows engraftment of γ-globin gene-corrected cells to a therapeutic level in the Berkeley mouse model of SCD. Animals transplanted according to this regimen averaged 35% engraftment of transduced hematopoietic stem cells with an average vector copy < 2.0. Fetal hemoglobin (HbF) levels ranged from 20 to 44% of total hemoglobin and approximately two-thirds of circulating red blood cells expressed HbF detected by immunofluorescence (F-cells). Gene therapy treatment of SCD mice ameliorated anemia, reduced hyperleukocytosis, improved renal function, and reduced iron accumulation in liver, spleen, and kidneys. Thus, modest levels of chimerism with donor cells expressing high levels of HbF from an insulated γ-globin lentiviral vector can improve the pathology of SCD in mice, thereby illustrating a potentially safe and effective strategy for gene therapy in humans.
PMCID: PMC4667717 Free PMC Article
PMID: 26665131 [PubMed]
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16. N Engl J Med. 2015 Dec 8. [Epub ahead of print]
A Multinational Trial of Prasugrel for Sickle Cell Vaso-Occlusive Events.
Heeney MM1, Hoppe CC, Abboud MR, Inusa B, Kanter J, Ogutu B, Brown PB, Heath LE, Jakubowski JA, Zhou C, Zamoryakhin D, Agbenyega T, Colombatti R, Hassab HM, Nduba VN, Oyieko JN, Robitaille N, Segbefia CI, Rees DC; DOVE Investigators.
Background Sickle cell anemia is an inherited blood disorder that is characterized by painful vaso-occlusive crises, for which there are few treatment options. Platelets mediate intercellular adhesion and thrombosis during vaso-occlusion in sickle cell anemia, which suggests a role for antiplatelet agents in modifying disease events. Methods Children and adolescents 2 through 17 years of age with sickle cell anemia were randomly assigned to receive oral prasugrel or placebo for 9 to 24 months. The primary end point was the rate of vaso-occlusive crisis, a composite of painful crisis or acute chest syndrome. The secondary end points were the rate of sickle cell-related pain and the intensity of pain, which were assessed daily with the use of pain diaries. Results A total of 341 patients underwent randomization at 51 sites in 13 countries across the Americas, Europe, Asia, and Africa. The rate of vaso-occlusive crisis events per person-year was 2.30 in the prasugrel group and 2.77 in the placebo group (rate ratio, 0.83; 95% confidence interval, 0.66 to 1.05; P=0.12). There were no significant differences between the groups in the secondary end points of diary-reported events. The safety end points, including the frequency of bleeding events requiring medical intervention, of hemorrhagic and nonhemorrhagic adverse events that occurred while patients were taking prasugrel or placebo, and of discontinuations due to prasugrel or placebo, did not differ significantly between the groups. Conclusions Among children and adolescents with sickle cell anemia, the rate of vaso-occlusive crisis was not significantly lower among those who received prasugrel than among those who received placebo. There were no significant between-group differences in the safety findings. (Funded by Daiichi Sankyo and Eli Lilly; number, NCT01794000 .).
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PMID: 26644172 [PubMed – as supplied by publisher]

17. JAMA. 2015 Dec 15;314(23):2514-23. doi: 10.1001/jama.2015.13977.
Effect of Transfusion of Red Blood Cells With Longer vs Shorter Storage Duration on Elevated Blood Lactate Levels in Children With Severe Anemia: The TOTAL Randomized Clinical Trial.
Dhabangi A1, Ainomugisha B2, Cserti-Gazdewich C3, Ddungu H4, Kyeyune D5, Musisi E5, Opoka R6, Stowell CP7, Dzik WH7.
Comment in
Storage Duration and Other Measures of Quality of Red Blood Cells for Transfusion. [JAMA. 2015]
Although millions of transfusions are given annually worldwide, the effect of red blood cell (RBC) unit storage duration on oxygen delivery is uncertain.
To determine if longer-storage RBC units are not inferior to shorter-storage RBC units for tissue oxygenation as measured by reduction in blood lactate levels and improvement in cerebral tissue oxygen saturation among children with severe anemia.
Randomized noninferiority trial of 290 children (aged 6-60 months), most with malaria or sickle cell disease, presenting February 2013 through May 2015 to a university-affiliated national referral hospital in Kampala, Uganda, with a hemoglobin level of 5 g/dL or lower and a lactate level of 5 mmol/L or higher.
Patients were randomly assigned to receive RBC units stored 25 to 35 days (longer-storage group; n = 145) vs 1 to 10 days (shorter-storage group; n = 145). All units were leukoreduced prior to storage. All patients received 10 mL/kg of RBCs during hours 0 through 2 and, if indicated per protocol, an additional 10 mL/kg during hours 4 through 6.
The primary outcome was the proportion of patients with a lactate level of 3 mmol/L or lower at 8 hours using a margin of noninferiority equal to an absolute difference of 25%. Secondary measures included noninvasive cerebral tissue oxygen saturation during the first transfusion, clinical and laboratory changes up to 24 hours, and survival and health at 30 days after transfusion. Adverse events were monitored up to 24 hours.
In the total population of 290 children, the mean (SD) presenting hemoglobin level was 3.7 g/dL (1.3) and mean lactate level was 9.3 mmol/L (3.4). Median (interquartile range) RBC unit storage was 8 days (7-9) for shorter storage vs 32 days (30-34) for longer storage without overlap. The proportion achieving the primary end point was 0.61 (95% CI, 0.52 to 0.69) in the longer-storage group vs 0.58 (95% CI, 0.49 to 0.66) in the shorter-storage group (between-group difference, 0.03 [95% CI, -0.07 to ∞], P < .001), meeting the prespecified margin of noninferiority. Mean lactate levels were not statistically different between the 2 groups at 0, 2, 4, 6, 8, or 24 hours. Kaplan-Meier analysis and global nonlinear regression revealed no statistical difference in lactate reduction between the 2 groups. Clinical assessment, cerebral oxygen saturation, electrolyte abnormalities, adverse events, survival, and 30-day recovery were also not significantly different between the groups.
Among children with lactic acidosis due to severe anemia, transfusion of longer-storage compared with shorter-storage RBC units did not result in inferior reduction of elevated blood lactate levels. These findings have relevance regarding the efficacy of stored RBC transfusion for patients with critical tissue hypoxia and lactic acidosis due to anemia.
TRIAL REGISTRATION: Identifier: NCT01586923.
PMID: 26637812 [PubMed – in process]

18. Hematology Am Soc Hematol Educ Program. 2015 Dec 5;2015(1):436-43. doi: 10.1182/asheducation-2015.1.436.
Optimizing hydroxyurea therapy for sickle cell anemia.
Ware RE1.
Hydroxyurea has proven efficacy in numerous clinical trials as a disease-modifying treatment for patients with sickle cell anemia (SCA) but is currently under-used in clinical practice. To improve the effectiveness of hydroxyurea therapy, efforts should be directed toward broadening the clinical treatment indications, optimizing the daily dosage, and emphasizing the benefits of early and extended treatment. Here, various issues related to hydroxyurea treatment are discussed, focusing on both published evidence and clinical experience. Specific guidance is provided regarding important but potentially unfamiliar aspects of hydroxyurea treatment for SCA, such as escalating to maximum tolerated dose, treating in the setting of cerebrovascular disease, switching from chronic transfusions to hydroxyurea, and using serial phlebotomy to alleviate iron overload. Future research directions to optimize hydroxyurea therapy are also discussed, including personalized dosing based on pharmacokinetic modeling, prediction of fetal hemoglobin responses based on pharmacogenomics, and the risks and benefits of hydroxyurea for non-SCA genotypes and during pregnancy/lactation. Another critical initiative is the introduction of hydroxyurea safely and effectively into global regions that have a high disease burden of SCA but limited resources, such as sub-Saharan Africa, the Caribbean, and India. Final considerations emphasize the long-term goal of optimizing hydroxyurea therapy, which is to help treatment become accepted as standard of care for all patients with SCA.
© 2015 by The American Society of Hematology. All rights reserved.
PMID: 26637755 [PubMed – in process]

19. Hematology Am Soc Hematol Educ Program. 2015 Dec 5;2015(1):420-5. doi: 10.1182/asheducation-2015.1.420.
The five key things you need to know to manage adult patients with sickle cell disease.
Lanzkron S1, Haywood C Jr1.
The lack of a strong evidence base to guide the management of adults with sickle cell disease (SCD) makes it difficult for patients to receive high quality care outside of specialty centers. As there is a dearth of providers with sickle cell expertise, the purpose of this article is to identify some of the key things every provider who manages the care of adults with SCD should know. Managing adults with SCD requires excellent clinical skills, as it can affect every organ and cause life-threatening complications but it also requires a willingness to manage patients who often have psychosocial issues that are complex and impact care and care delivery in very significant ways. We have chosen topics for which there is a limited evidence base but which have significant clinical consequences if left unrecognized or poorly managed. The topics that will be addressed include chronic pain, neurocognitive dysfunction, renal disease, venous thromboembolism, and avoiding the inappropriate use of red cell transfusions.
© 2015 by The American Society of Hematology. All rights reserved.
PMID: 26637752 [PubMed – in process]

20. Hematology Am Soc Hematol Educ Program. 2015 Dec 5;2015(1):426-32. doi: 10.1182/asheducation-2015.1.426.
Can selectin and iNKT cell therapies meet the needs of people with sickle cell disease?
Field JJ1.
Recent insights into the pathogenesis of microvascular occlusion downstream of the sickled red cell have revealed new therapeutic targets for sickle cell disease (SCD). After the formation of sickle cells, tissue injury spurs inflammation, which leads to receptor-mediated contacts between sickle cells, leukocytes, and vascular endothelium. Specifically, selectins decelerate sickled red cells and leukocytes in the circulation to facilitate endothelial adhesion and other cell-cell interactions, ultimately leading to vascular occlusion. Invariant NKT (iNKT) cells, activated during reperfusion, generate a broad inflammatory response, which further increases cellular adhesion and vascular occlusion. Novel therapies are in development that target selectins and iNKT cells to prevent or interrupt the vicious cycle of adhesion and inflammation. Although the therapies hold promise for the treatment of SCD, an underappreciated threat to their development is poor access to care for people with SCD. Unless the majority of people with SCD have access to consistent, high-quality care, they will not have the opportunity to participate in a clinical trial or receive any new therapy, regardless of its efficacy.
© 2015 by The American Society of Hematology. All rights reserved.
PMID: 26637753 [PubMed – in process]

21. Hematology Am Soc Hematol Educ Program. 2015 Dec 5;2015(1):160-7. doi: 10.1182/asheducation-2015.1.160.
Sickle cell trait diagnosis: clinical and social implications.
Naik RP1, Haywood C Jr2.
The sickle hemoglobin (HbS) point mutation has independently undergone evolutionary selection at least five times in the world because of its overwhelming malarial protective effects in the heterozygous state. In 1949, homozygous Hb S or sickle cell disease (SCD) became the first inherited condition identified at the molecular level; however, since then, both SCD and heterozygous Hb S, sickle cell trait (SCT), have endured a long and complicated history. Hasty adoption of early mass screening programs for SCD, recent implementation of targeted screening mandates for SCT in athletics, and concerns about stigmatization have evoked considerable controversy regarding research and policy decisions for SCT. Although SCT is a largely protective condition in the context of malaria, clinical sequelae, such as exercise-related injury, renal complications, and venous thromboembolism can occur in affected carriers. The historical background of SCD and SCT has provided lessons about how research should be conducted in the modern era to minimize stigmatization, optimize study conclusions, and inform genetic counseling and policy decisions for SCT.
© 2015 by The American Society of Hematology. All rights reserved.
PMID: 26637716 [PubMed – in process]

Sickle Cell Conferences and Events

4th Caribbean Conference on SCD to be held in Kingston, Jamaica during January 20-22, 2016. For information: