Araba Afenyi-Annan

Management of Sickle Cell Disease: Summary of the 2014 Evidence-Based Report by Expert Panel Members

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 (≥200 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 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.

Lack of Duffy antigen expression is associated with organ damage in patients with sickle cell disease

BACKGROUND: The Duffy glycoprotein (Fy) on red blood cells (RBCs) has been hypothesized to promote clearance of inflammatory cytokines, which may play a role in the pathogenesis of vasoocclusion in sickle cell disease (SCD). Persons with the African‐type Fy(a–b–) phenotype—whose RBCs lack expression of Duffy—may less efficiently clear inflammatory cytokines. Therefore, the Duffy‐negative genotype may be associated with more severe disease among patients with SCD.

Cardiogenic shock complicates successful treatment of refractory thrombotic thrombocytopenia purpura with rituximab

BACKGROUND: Treatment of thrombotic thrombo‐cytopenia purpura (TTP) with daily therapeutic plasma exchange (TPE) may be accompanied by a variety of adjunctive interventions including most recently rituximab. Rituximab, a murine and human monoclonal antibody directed against CD20 antigen on B lymphocytes, is primarily used for treatment of non‐Hodgkins lymphomas. Because of severe and fatal infusion reactions including heart failure, rituximab carries a boxed warning.

Blood bank management of sickle cell patients at comprehensive sickle cell centers

BACKGROUND: Transfusion therapy has been integral to decreasing morbidity and mortality in sickle cell disease (SCD). Several studies however, have demonstrated variation in the blood bank (BB) practices for these patients. The purpose of this study was to examine BB practices for SCD patients at NIH Comprehensive Sickle Cell Centers (CSCCs) and to determine whether consensus in BB management exists.

Alloimmunization in sickle cell disease: changing antibody specificities and association with chronic pain and decreased survival.

Alloimmunization remains a significant complication of transfusion and has been associated with multiple factors, including inflammation, an important pathophysiologic mechanism in sickle cell disease (SCD). We explored whether alloimmunization is associated with disease severity in SCD.

Evidence gaps in the management of sickle cell disease: A summary of needed research.

An NHLBI expert panel recently published evidence-based guidelines for the care of people with sickle cell disease (SCD) [1]. The full report (http://www.nhlbi.nih.gov/health-pro/guidelines/sickle-cell-disease-guidelines/) was developed using a set of 30 important clinical questions raised by panel members. The systematic review of the literature, conducted through July 11, 2014, identified 22 randomized controlled trials specific to individuals with SCD. Some aspects of SCD management, e.g. stroke prevention in children and hydroxyurea use, had high quality evidence for specific recommendations. However, often the best available evidence was expert opinion, lower quality observational data, or adaptation of existing guidelines that did not specifically include people with SCD. When caring for individuals with rare diseases such as SCD, this level of evidence is frequently all that is available and thus forms the basis for the current standards of care, e.g. screening and referral decisions. The panel identified many shortcomings in the available evidence that are summarized in this article and reflect the panel’s opinions, expertise, and experience in all aspects of care for people with SCD. While mechanistic studies to improve understanding of SCD pathophysiology are critically needed to inform future clinical studies, a discussion of needed basic science research agendas was outside the scope of the panel’s mission. The domains for the many gaps correspond to the NHLBI guideline chapters on health maintenance, acute complications, chronic complications, and use of hydroxyurea and transfusion. Tables I and II summarize the evidence gaps in these areas.

Pre-transfusion phenotype matching for sickle cell disease patients

In a recent editorial in TRANSFUSION, Rinder and Smith discussed the in vitro evaluation of stored PLTs concluding that all in vitro tests “failed to prove worthy of the goal” of predicting transfusion outcome. I disagree with this conclusion. Although most investigators use an array of in vitro tests, for simplicity, I will discuss only the extent of shape change (ESC), which measures quantitatively the change from discoid to spherical shape of PLTs when activated. This measurement has correlated with in vivo recovery in many studies in humans although there are examples in experimental animals where dissociation has been seen. There has been no correlation of ESC with life span or in vivo function. It is bothersome to many skeptics that the correlation coefficient r for in vivo recovery using isotopes and ESC is only 0.71 (Fig. 1). The r value is as high as it is only because there is a significant number of subjects with very high and very low recoveries. If one only looks at values in the “normal” range for stored PLTs, 30 to 70 percent for recovery and 10 to 25 percent for ESC, the r value would approach zero (Fig. 1). There are two reasons for the unimpressive r value. First, the range of in vivo recovery in normal volunteers is as wide for well-stored PLTs as it is also for fresh PLTs. Nevertheless, if normal volunteers are restudied, they tend to reproduce their high, medium, or low recoveries although there can be some variability over time. Of course, this physiologic variability is present for stored PLTs as well. Thus, isotopic studies generally call for a paired design with control and experimental studies performed in each volunteer, preferably simultaneously with two isotopes. Second, there is also physiologic variability among normal persons in the in vitro tests. Recently, we measured ESC and mean PLT volume (MPV) in 54 conventional PLT concentrates derived from whole blood by the PLT-rich plasma method. They were all more than 18 and less than 48 hours old. ESC was determined according to Holmes et al. MPV was measured with an automated hematology analyzer (Baker 9110+, BioChem Immuno Systems Inc., Allentown, PA). Figure 2 shows that ESC varies among normal blood donors and that it is lower in donors with increased MPV. This relates to the fact that PLT concentration in the blood of normal individuals varies widely, 150 ¥ 10 to 500 ¥ 10 per L and that MPV is larger in patients with lower PLT concentrations. Furthermore, large PLTs are more spherical (less discoid) than small PLTs. Less discoid PLTs will show less ESC even when they are maximally responsive. In an extreme experiment to illustrate the point, one could measure ESC and percentage in vivo recovery for fresh PLTs from 20 normal individuals. There would be substantial variability for the two individual measurements and no correlation between the two. Nevertheless, if one makes the same two measurements for an experimental and control method of PLT storage in 20 normal individuals using a paired design, one finds that the in vitro results taken as a group are predictive of the in vivo results taken as a group. Thus, in vitro tests performed after storage are predictive of in vivo results after storage if a paired design is used so that control and experimental results are compared for each subject for both in vivo and in vitro results. In contrast, an investigator who hopes to find a strong correlation between ESC and in vivo recovery in a group of subjects whose PLTs are either fresh or well stored will generally be disappointed when each subject is studied only once.

Seasonal association of thrombotic thrombocytopenic purpura

BACKGROUND: Thrombotic thrombocytopenic purpura (TTP), a thrombotic microangiopathy, is a clinical diagnosis, characterized by microangiopathic hemolytic anemia and thrombocytopenia without another likely explanation. Some initiators of the disease are well represented in the literature, such as certain drugs, malignancies, and viral illness; however, there are less objective factors still being investigated, with references to hormonal, stress, and seasonal variations considered anecdotally. A better insight of these factors would aid in understanding the pathophysiology of the disease.

Duffy (Fy), DARC, and neutropenia among women from the United States, Europe and the Caribbean

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Hemoglobin D after a red cell exchange for sickle cell disease

A 5-year-old girl with sickle cell disease underwent a red cell exchange with 4 RBC units. The postexchange hemoglobin (Hb) was analyzed using cation-exchange high-performance liquid chromatography (HPLC; Bio-Rad Laboratories, Hercules, CA). A high peak in the D-window that was not present in the preexchange analysis was seen (Fig. 1A [arrow]) with an area under the curve of 18.9 percent. Isoelectric focusing (IEF; Resolve Systems, Turku, Finland) showed bands in the S and A positions (Fig. 1B). HPLC analysis of the retained segments showed one donor with an even higher peak in the D-window (43.6%; Fig. 2A). IEF demonstrated bands suggestive of Hb S and A (Fig. 2B). Repeat screening of the donor with a SICKLEDEX (Streck Laboratories, Omaha, NE) was negative. There are a number of Hbs collectively termed Hb “D.” Because the electrophoretic and IEF mobility of Hb D is frequently identical to Hb S, it is difficult to differentiate between Hb S and Hb D.The genes for Hb D are generally found 1A