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.

Concentrating APs and washing APs and RBCs substantially reduces ATRs, suggesting that the plasma component of APs and RBCs has an essential role in the etiology of ATRs.

Objective To determine if, in children, plasma glial fibrillary acidic protein (GFAP) is associated with brain injury during extracorporeal membrane oxygenation (ECMO) and with mortality. Design Prospective, observational study. Setting Pediatric intensive care unit in an urban tertiary care academic center. Patients Neonatal and pediatric ECMO patients (n=22). Interventions Serial blood sampling for GFAP measurements. Measurements and Main Results Prospective patients age 1 day-18 years who required ECMO from April 2008 to August 2009 were studied. GFAP was measured using an electrochemiluminescent immunoassay developed at Johns Hopkins. Control samples were collected from 99 healthy children (0.5-16 years) and 59 NICU infants without neurologic injury. In controls, the median GFAP concentration was 0.055 ng/mL (IQR: 0-0.092 ng/mL) and the 95th percentile of GFAP was 0.436ng/mL. In ECMO patients, plasma GFAP was measured at 6, 12 and every 24 hours after cannulation. We enrolled 22 children who underwent ECMO. Median age was 7 days (IQR, 2 days-9 years), and primary ECMO indication was: cardiac failure, 6/22 (27.3%), respiratory failure, 12/22 (54.5%), ECPR, 3/22 (13.6%), and sepsis, 1/22 (4.6%). Seven of 22 (32%) patients developed acute neurologic injury (intracranial hemorrhage, brain death or cerebral edema diagnosed by imaging). Fifteen of 22 (68%) survived to hospital discharge. In the ECMO group, peak GFAP levels were higher in children with brain injury than those without (median, 5.9 vs 0.09ng/mL, p=0.04) and in non-survivors compared to survivors to discharge (median, 5.9 vs 0.09ng/mL, p=0.04). The odds ratio (OR) for brain injury for GFAP >0.436ng/mL vs normal was 11.5 (95%CI: 1.3-98.3) and the OR for mortality was 13.6 (95%CI: 1.7-108.5). Conclusions High GFAP during ECMO is significantly associated with acute brain injury and death. Brain injury biomarkers may aid in outcome prediction and neurologic monitoring of ECMO patients to improve outcomes and benchmark new therapies.

Objective GFAP is specific to astrocytes in the central nervous system. We hypothesized that serum GFAP would be increased in neonates with hypoxic-ischemic encephalopathy (HIE) treated with whole body cooling. Study Design We measured GFAP at birth and daily for up to 7 days for neonates in the intensive care unit. We compared neonates with HIE treated with whole body cooling to gestational age matched controls without neurologic injury and neonates with HIE by brain abnormalities on MRI. Results Neonates with HIE had increased GFAP levels compared to controls. Neonates with HIE and abnormal brain imaging had elevated GFAP levels compared to neonates with HIE and normal imaging. Conclusions Serum GFAP levels during the first week of life were increased in neonates with HIE and were predictive of brain injury on MRI. Biomarkers like GFAP could help triage neonates with HIE to treatment, measure treatment efficacy and provide prognostic information.

Background Sickle cell disease is associated with extensive healthcare utilization; estimated lifetime costs exceed $460,000 per patient. Approximately 30% of chronically transfused sickle cell patients become alloimmunized to red cell antigens, but these patients cannot be identified a priori. Prospective antigen-matching can prevent alloimmunization, but is costly and may not benefit most patients. Study Design and Methods A Markov-based model was constructed to compare the health and financial implications of four alternative antigen-matching strategies for chronically transfused sickle cell patients. The strategies varied by the selection method of patients receiving matched blood (contingent on prior alloimmunization or prospectively for all patients) and the extent of antigen-matching (limited or extensive). Direct medical costs and alloimmunization events were assessed over 10 and 20-year periods, for a hypothetical cohort of initially transfusion-naïve patients and for a dynamic population. Results Within a hypothetical cohort of initially transfusion-naïve patients, implementing prophylactic limited matching for chronically transfused patients instead of history-based limited matching is expected to cost an additional $766 million over 10 years, but result in 2,072 fewer alloimmunization events. Within the same cohort, implementing prospective extensive matching is expected to cost $1.86 billion more than history-based extensive matching, but result in 2,424 fewer alloimmunization events. Averting a single alloimmunization event using prospective matching would cost $369,482–769,284. Among a dynamic population over 10 years, prospective limited matching is expected to cost $358 million more than history-based limited matching. Conclusions While prospective matching for all transfused patients would reduce alloimmunization, this benefit requires considerable expenditure.

Age-group analyses were conducted of patients in the prophylactic platelet dose trial (PLADO), which evaluated the relation between platelet dose per transfusion and bleeding. Hospitalized patients with treatment-induced hypoproliferative thrombocytopenia were randomly assigned to 1 of 3 platelet doses: 1.1 ؋ 10 11 , 2.2 ؋ 10 11 , or 4.4 ؋ 10 11 platelets/m 2 per transfusion, given for morning counts of < 10 000 platelets/L. Daily hemostatic assessments were performed. The primary end point (percentage of patients who developed grade 2 or higher World Health Organization bleeding) was evaluated in 198 children (0-18 years) and 1044 adults. Although platelet dose did not predict bleeding for any age group, children overall had a significantly higher risk of grade 2 or higher bleeding than adults (86%, 88%, 77% vs 67% of patients aged 0-5 years, 6-12 years, 13-18 years, vs adults, respectively) and more days with grade 2 or higher bleeding (median, 3 days in each pediatric group vs 1 day in adults; P < .001). The effect of age on bleeding differed by disease treatment category and was most pronounced among autologous transplant recipients. Pediatric subjects were at higher risk of bleeding over a wide range of platelet counts, indicating that their excess bleeding risk may be because of factors other than platelet counts. This trial was registered at www. clinicaltrials.gov as #NCT00128713. (Blood. 2012;120(4):748-760)

Allergic transfusion reactions (ATRs) are a spectrum of hypersensitivity reactions that are the most common adverse reaction to platelets and plasma, occurring in up to 2% of transfusions. Despite the ubiquity of these reactions, little is known about their mechanism. In a small subset of severe reactions, specific antibody has been implicated as causal, although this mechanism does not explain all ATRs. Evidence suggests that donor, product, and recipient factors are involved, and it is possible that many ATRs are multi-factorial. Further understanding of the mechanisms of ATRs is necessary so that rationally designed and cost-effective prevention measures can be developed.