Background: Red cell transfusions remain a mainstay of therapy for patients with sickle cell disease (SCD), but pose significant clinical challenges. Guidance for specific indications and administration of transfusion, as well as screening, prevention, and management of alloimmunization, delayed hemolytic transfusion reactions (DHTRs), and iron overload may improve outcomes. Objective: Our objective was to develop evidence-based guidelines to support patients, clinicians, and other healthcare professionals in their decisions about transfusion support for SCD and the management of transfusion-related complications. Methods: The American Society of Hematology formed a multidisciplinary panel that was balanced to minimize bias from conflicts of interest and that included a patient representative. The panel prioritized clinical questions and outcomes. The Mayo Clinic Evidence-Based Practice Research Program supported the guideline development process. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to form recommendations, which were subject to public comment. Results: The panel developed 10 recommendations focused on red cell antigen typing and matching, indications, and mode of administration (simple vs red cell exchange), as well as screening, prevention, and management of alloimmunization, DHTRs, and iron overload. Conclusions: The majority of panel recommendations were conditional due to the paucity of direct, high-certainty evidence for outcomes of interest. Research priorities were identified, including prospective studies to understand the role of serologic vs genotypic red cell matching, the mechanism of HTRs resulting from specific alloantigens to inform therapy, the role and timing of regular transfusions during pregnancy for women, and the optimal treatment of transfusional iron overload in SCD.

Ischemia-reperfusion injury (IRI) triggers an inflammatory cascade that is initiated

Objective-To determine the role of platelets in stimulating mouse and human neutrophil activation and pulmonary injury in sickle cell disease (SCD). Methods and Results-Both platelet and neutrophil activation occur in SCD, but the interdependence of these events is unknown. Platelet activation and binding to leukocytes were measured in mice and patients with SCD and in controls.Relative to controls, blood obtained from mice or patients with SCD contained significantly elevated platelet-neutrophil aggregates (PNAs). Both platelets and neutrophils found in sickle PNAs were activated. Multispectral imaging (ImageStream) and conventional flow cytometry revealed a subpopulation of activated neutrophils with multiple adhered platelets that expressed significantly more CD11b and exhibited greater oxidative activity than single neutrophils. On average, wild-type and sickle PNAs contained 1.1 and 2.6 platelets per neutrophil, respectively. Hypoxia/reoxygenation induced a further increase in PNAs in mice with SCD and additional activation of both platelets and neutrophils. The pretreatment of mice with SCD with clopidogrel or P-selectin antibody reduced the formation of PNAs and neutrophil activation and decreased lung vascular permeability. Conclusion-Our findings suggest that platelet binding activates neutrophils and contributes to a chronic inflammatory state and pulmonary dysfunction in SCD. The inhibition of platelet activation may be useful to decrease tissue injury in SCD, particularly during the early stages of vaso-occlusive crises. Key Words: platelet activation Ⅲ sickle cell disease inflammation Ⅲ neutrophil activation Ⅲ oxidative burst Ⅲ clopidogrel Ⅲ P-selectin antiplatelet drugs Ⅲ leukocytes Ⅲ platelets Ⅲ transgenic models S ickle cell disease (SCD) is the most common genetic hematologic disorder in the United States. The vasoocclusive characteristics of SCD have been viewed historically as resulting from deformed red blood cells (RBCs) that mechanically obstruct capillaries to produce tissue hypoxia. 1 Present therapies for SCD are geared toward decreasing the concentration or polymerization rate of sickle hemoglobin. 2 Recently, a modified paradigm has emerged suggesting that the wide spectrum of clinical manifestations of SCD results in part from recurrent episodes of disseminated microvascular ischemia-reperfusion injury. 3,4 Ischemia-reperfusion injury triggers vascular inflammation, characterized by increased adhesion of leukocytes [5][6][7][8] and sickle RBCs 9 to vascular endothelium and activation of coagulation, 10 -12 blood platelets, 13-20 neutrophils, 7 monocytes, 8,21-23 and natural killer T cells. 24 Because blockade of P-selectin-mediated plateletleukocyte aggregation is beneficial in the animal models of vascular injury, 25 we reasoned that platelet-leukocyte aggregation might contribute to the vascular inflammation and tissue injury that occurs in SCD. Although increased formation of platelet-monocyte 21 and platelet-RBC 15 aggregates in SCD is well established, conflicting data exist reg...

563A irway hyperresponsiveness (AHR) is believed to refl ect infl ammation in the airways that is relatively specifi c for asthma. 1 The diagnostic evaluation for asthma includes measures of AHR, most commonly using methacholine provocation. In children with sickle cell disease (SCD), AHR is present in up to 78% of those tested, 2,3 whereas the prevalence of asthma in children with SCD is 20% to 48%. [4][5][6] Given that AHR is more prevalent than asthma in children with SCD, mechanisms other than asthmarelated infl ammation may be causing this high rate of AHR. Among children with HbSS or sickle cell anemia (SCA), a doctor diagnosis of asthma has been associated with an increased rate of pain, acute chest syndrome, and death. 4,5,7,8 Although these data imply that asthma has a signifi cant disease-modifying effect in children with SCA, characteristics of SCA, such as episodes of acute chest syndrome, 9 pulmonary function abnormalities, 10-12 and chronic respiratory symptoms, add complexity to the diagnosis of asthma. Thus, it is not clear if descriptions of asthma in these children refl ect the presence of two distinct comorbid conditions or an asthma-like phenotype secondary Background: The high prevalence of airway hyperresponsiveness (AHR) among children with sickle cell anemia (SCA) remains unexplained. Methods: To determine the relationship between AHR, features of asthma, and clinical characteristics of SCA, we conducted a multicenter, prospective cohort study of children with SCA. Dose response slope (DRS) was calculated to describe methacholine responsiveness, because 30% of participants did not achieve a 20% decrease in FEV 1 after inhalation of the highest methacholine concentration, 25 mg/mL. Multiple linear regression analysis was done to identify independent predictors of DRS. Results: Methacholine challenge was performed in 99 children with SCA aged 5.6 to 19.9 years (median, 12.8 years). Fifty-four (55%) children had a provocative concentration of methacholine producing a 20% decrease in FEV 1 , 4 mg/mL. In a multivariate analysis, independent associations were found between increased methacholine responsiveness and age ( P , .001), IgE ( P 5 .009), and lactate dehydrogenase (LDH) levels ( P 5 .005). There was no association between methacholine responsiveness and a parent report of a doctor diagnosis of asthma ( P 5 .986). Other characteristics of asthma were not associated with methacholine responsiveness, including positive skin tests to aeroallergens, exhaled nitric oxide, peripheral blood eosinophil count, and pulmonary function measures indicating airfl ow obstruction.