IMPORTANCE Sickle cell disease (SCD) is a life-threatening genetic disorder affecting nearly 100 000 individuals in the United States and is associated with many acute and chronic complications requiring immediate medical attention. Two disease-modifying therapies, hydroxyurea and long-term blood transfusions, are available but underused.OBJECTIVE To support and expand the number of health professionals able and willing to provide care for persons with SCD.EVIDENCE REVIEW Databases of MEDLINE (including in-process and other nonindexed citations), EMBASE, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, CINAHL, TOXLINE, and Scopus were searched using prespecified search terms and keywords to identify randomized clinical trials, nonrandomized intervention studies, and observational studies. Literature searches of English-language publications from 1980 with updates through April 1, 2014, addressed key questions developed by the expert panel members and methodologists.FINDINGS Strong recommendations for preventive services include daily oral prophylactic penicillin up to the age of 5 years, annual transcranial Doppler examinations from the ages of 2 to 16 years in those with sickle cell anemia, and long-term transfusion therapy to prevent stroke in those children with abnormal transcranial Doppler velocity (Ն200 cm/s). Strong recommendations addressing acute complications include rapid initiation of opioids for treatment of severe pain associated with a vasoocclusive crisis, and use of incentive spirometry in patients hospitalized for a vasoocclusive crisis. Strong recommendations for chronic complications include use of analgesics and physical therapy for treatment of avascular necrosis, and use of angiotensin-converting enzyme inhibitor therapy for microalbuminuria in adults with SCD. Strong recommendations for children and adults with proliferative sickle cell retinopathy include referral to expert specialists for consideration of laser photocoagulation and for echocardiography to evaluate signs of pulmonary hypertension. Hydroxyurea therapy is strongly recommended for adults with 3 or more severe vasoocclusive crises during any 12-month period, with SCD pain or chronic anemia interfering with daily activities, or with severe or recurrent episodes of acute chest syndrome. A recommendation of moderate strength suggests offering treatment with hydroxyurea without regard to the presence of symptoms for infants, children, and adolescents. In persons with sickle cell anemia, preoperative transfusion therapy to increase hemoglobin levels to 10 g/dL is strongly recommended with a moderate strength recommendation to maintain sickle hemoglobin levels of less than 30% prior to the next transfusion during long-term transfusion therapy. A strong recommendation to assess iron overload is accompanied by a moderate strength recommendation to begin iron chelation therapy when indicated.CONCLUSIONS AND RELEVANCE Hydroxyurea and transfusion therapy are strongly recommended for many individu...

Hydroxyurea and transfusion therapy are strongly recommended for many individuals with SCD. Many other recommendations are based on quality of evidence that is less than high due to the paucity of clinical trials regarding screening, management, and monitoring for individuals with SCD.

These data confirm prior findings of a significant decrease in mortality for children with SCD. The mortality rate for adults appears to have increased during the same time period. It seems unlikely that this increase is due merely to an influx of younger patients surviving to adulthood and may reflect a lack of access to high-quality care for adults with SCD.

Allogeneic marrow transplantation can cure sickle cell disease; however, HLAmatched donors are difficult to find, and the toxicities of myeloablative conditioning are prohibitive for most adults with this disease. We developed a nonmyeloablative bone marrow transplantation platform using related, including HLAhaploidentical, donors for patients with sickle cell disease. The regimen consisted of antithymocyte globulin, fludarabine, cyclophosphamide, and total body irradiation, and graft-versus-host disease

Among children and adults with sickle cell anemia, the median number of pain crises over 48 weeks was lower among those who received oral therapy with l-glutamine, administered alone or with hydroxyurea, than among those who received placebo, with or without hydroxyurea. (Funded by Emmaus Medical; ClinicalTrials.gov number, NCT01179217 .).

IMPORTANCE The association between sickle cell trait (SCT) and chronic kidney disease (CKD) is uncertain. OBJECTIVE To describe the relationship between SCT and CKD and albuminuria in self-identified African Americans. DESIGN, SETTING, AND PARTICIPANTS Using 5 large, prospective, US population-based studies (the Atherosclerosis Risk in Communities Study [ARIC, 1987–2013; n = 3402], Jackson Heart Study [JHS, 2000–2012; n = 2105], Coronary Artery Risk Development in Young Adults [CARDIA, 1985–2006; n = 848], Multi-Ethnic Study of Atherosclerosis [MESA, 2000–2012; n = 1620], and Women’s Health Initiative [WHI, 1993–2012; n = 8000]), we evaluated 15 975 self-identified African Americans (1248 participants with SCT [SCT carriers] and 14 727 participants without SCT [noncarriers]). MAIN OUTCOMES AND MEASURES Primary outcomes were CKD (defined as an estimated glomerular filtration rate [eGFR] of <60 mL/min/1.73 m2 at baseline or follow-up), incident CKD, albuminuria (defined as a spot urine albumin:creatinine ratio of >30 mg/g or albumin excretion rate >30 mg/24 hours), and decline in eGFR (defined as a decrease of >3 mL/min/1.73 m2 per year). Effect sizes were calculated separately for each cohort and were subsequently meta-analyzed using a random-effects model. RESULTS A total of 2233 individuals (239 of 1247 SCT carriers [19.2%] vs 1994 of 14 722 noncarriers [13.5%]) had CKD, 1298 (140 of 675 SCT carriers [20.7%] vs 1158 of 8481 noncarriers [13.7%]) experienced incident CKD, 1719 (150 of 665 SCT carriers [22.6%] vs 1569 of 8249 noncarriers [19.0%]) experienced decline in eGFR, and 1322 (154 of 485 SCT carriers [31.8%] vs 1168 of 5947 noncarriers [19.6%]) had albuminuria during the study period. Individuals with SCT had an increased risk of CKD (odds ratio [OR], 1.57 [95% CI, 1.34–1.84]; absolute risk difference [ARD], 7.6% [95% CI, 4.7%–10.8%]), incident CKD (OR, 1.79 [95% CI, 1.45–2.20]; ARD, 8.5% [95% CI, 5.1%–12.3%]), and decline in eGFR (OR, 1.32 [95% CI, 1.07–1.61]; ARD, 6.1% [95% CI, 1.4%–13.0%]) compared with noncarriers. Sickle cell trait was also associated with albuminuria (OR, 1.86 [95% CI, 1.49–2.31]; ARD, 12.6% [95% CI, 7.7%–17.7%]). CONCLUSIONS AND RELEVANCE Among African Americans in these cohorts, the presence of SCT was associated with an increased risk of CKD, decline in eGFR, and albuminuria, compared with noncarriers. These findings suggest that SCT may be associated with the higher risk of kidney disease in African Americans.

In adults with sickle cell disease (SCD), an increased tricuspid regurgitation velocity (TRV) by Doppler echocardiography is associated with increased morbidity and mortality. Although sildenafil has been shown to improve exercise capacity in patients with pulmonary arterial hypertension, it has not been evaluated in SCD. We therefore sought to determine whether sildenafil could improve exercise capacity in SCD patients with increased TRV and a low exercise capacity. A TRV > 2.7 m/s and a 6-minute walk distance (6MWD) between 150 and 500 m were required for enrollment in this 16-week, double-blind, placebo-controlled sildenafil trial. After 74 of the screened subjects were randomized, the study was stopped early due to a higher percentage of subjects experiencing serious adverse events in the sildenafil arm (45% of sildenafil, 22% of placebo, P ‫؍‬ .022). Subject hospitalization for pain was the predominant cause for this difference: 35% with sildenafil compared with Continuing Medical Education onlineThis activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of Medscape, LLC and the American Society of Hematology. Medscape, LLC is accredited by the ACCME to provide continuing medical education for physicians. Medscape, LLC designates this Journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test with a 70% minimum passing score and complete the evaluation at http://www.medscape.org/journal/blood; and (4) view/print certificate. For CME questions, see page 1185.

464haematologica | 2013; 98(3)The intensity of hemolytic anemia has been proposed as an independent risk factor for the development of certain clinical complications of sickle cell disease, such as pulmonary hypertension, hypoxemia and cutaneous leg ulceration. A composite variable derived from several individual markers of hemolysis could facilitate studies of the underlying mechanisms of hemolysis. In this study, we assessed the association of hemolysis with outcomes in sickle cell anemia. A hemolytic component was calculated by principal component analysis from reticulocyte count, serum lactate dehydrogenase, aspartate aminotransferase and total bilirubin concentrations in 415 hemoglobin SS patients. Association of this component with direct markers of hemolysis and clinical outcomes was assessed. As primary validation, both plasma red blood cell microparticles and cell-free hemoglobin concentration were higher in the highest hemolytic component quartile compared to the lowest quartile (P≤0.0001 for both analyses). The hemolytic component was lower with hydroxyurea therapy, higher hemoglobin F, and alpha-thalassemia (P≤0.0005); it was higher with higher systemic pulse pressure, lower oxygen saturation, and greater values for tricuspid regurgitation velocity, left ventricular diastolic dimension and left ventricular mass (all P<0.0001). Two-year follow-up analysis showed that a high hemolytic component was associated with an increased risk of death (hazard ratio, HR 3.44; 95% confidence interval, CI: 1.2-9.5; P=0.02). The hemolytic component reflects direct markers of intravascular hemolysis in patients with sickle cell disease and allows for adjusted analysis of associations between hemolytic severity and clinical outcomes. These results confirm associations between hemolytic rate and pulse pressure, oxygen saturation, increases in Doppler-estimated pulmonary systolic pressures and mortality (Clinicaltrials.gov identifier: NCT00492531). The relationship between the severity of hemolysis, clinical manifestations and risk of death in 415 patients with sickle cell anemia in the US and Europe