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

BACKGROUND: 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. STUDY DESIGN AND METHODS: Adult SCD patients were enrolled in a study of outcome-modifying genes in SCD. Historical records of patients with SCD at two participating institutions were reviewed for data on antigen phenotype and alloimmunization. Differences in demographic, clinical, and laboratory findings; end-organ damage; and overall disease severity were then compared between alloimmunized and nonalloimmunized patients. RESULTS: Of 319 patients, 87 (27%) were alloimmunized. Alloantibody specificities differed from those previously described, especially due to the significantly higher frequency of anti-S. Although alloimmunization was not associated with frequency of vasoocclusive episodes, a higher percentage of alloimmunized patients had chronic pain, as defined by daily use of short-acting narcotics (p = 0.006), long-acting narcotics (p = 0.013), or both (p = 0.03). Additionally, alloimmunized patients had poorer survival (hazard ratio, 1.92; p = 0.01) and were more likely to have avascular necrosis (p = 0.024), end-organ damage (p = 0.049), and red blood cell autoantibodies (p < 0.001), even after controlling for the effects of age, sex, and hemoglobin diagnosis. Alloimmunization was not associated with other SCD-related complications, such as acute chest syndrome or stroke. CONCLUSION: Alloimmunization in SCD may be associated with chronic pain, risk of end-organ damage, and shorter survival. These novel findings suggest new directions for the investigation of immune response-mediated pathways common to alloimmunization and chronic pain.

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.

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. STUDY DESIGN AND METHODS: We performed a retrospective review of all idiopathic TTP cases treated with therapeutic plasma exchange at our institution from 1999 to 2008 to determine whether there was seasonal variation in TTP presentation. Seasons were defined as follows: winter = December to February; spring = March to May; summer = June to August; and fall = September to November. With the use of Poisson regression models, the incidence between seasons was compared. RESULTS: During this study period, a total of 97 cases were recorded. Summer had the highest occurrence of TTP (35%). This was significant compared to the fall (p = 0.012) and the winter (p = 0.019). There were more cases in the summer compared to the spring, but this was not significant. CONCLUSION: In our population, there was a significant difference in the number of TTP cases presenting in summer compared to fall and winter. This supports a possible environmental, infectious, or physiologic influence associated with the summer.

Update on multi-center clinical trials in the United States.

This article reviews numerous multi-center clinical trials, either ongoing or in planning stages, which involve diverse clinical applications and emerging technologies in apheresis and transfusion medicine. The investigations summarized herein involve the following specific areas: platelet dosing strategy, thrombotic thrombocytopenia purpura, inflammatory bowel disease, seven-day platelet storage, dendritic cell vaccines, and age-related macular degeneration.

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. STUDY DESIGN AND METHODS: Genotyping was performed on blood samples from 249 adult patients with HbSS at the Duffy gene (FY) locus GATA site (rs2814778) that determines RBC expression of Duffy antigens. Patients with discordant genotype and phenotype data were excluded (n = 12). Differences in demographic, clinical and laboratory findings, end-organ damage, and overall disease severity were compared between FY+ and FY- patients. RESULTS: Of the 237 patients studied, 174 (73%) were FY-. FY+ patients had a higher mean white blood cell (WBC) count (13.2 x 10(9) +/- 4.1 x 10(9)/L vs. 11.8 x 10(9) +/- 3.3 x 10(9)/L; p = 0.03) and higher rates of treatment with hydroxyurea (72% vs. 49%; p = 0.002). In contrast, FY- status was strongly associated with chronic organ damage (85% of FY- patients vs. 65% of FY+ patients; p = 0.018) and proteinuria (32% vs. 12%; p = 0.02). These associations remained, even after controlling for the effects of age and sex. CONCLUSIONS: Duffy genotype may be a potential biomarker for the development of end-organ damage in SCD, particularly kidney dysfunction. The association of both WBC counts and hydroxyurea use with Duffy expression provides another avenue for investigation of the biologic role of this protein.

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. STUDY DESIGN AND METHODS: A cross-sectional survey of BB medical directors and laboratory supervisors at CSCCs was conducted between October 2004 and March 2005. The survey assessed respondent, hospital, and BB characteristics; pretransfusion procedures; blood product selection; and agreement with statements about consensus in management. Physician respondents were also asked to select their preferred management strategy in four hypothetical transfusion-related cases. RESULTS: Responses were received from 36 of 49 (73.5%) institutions. Pretransfusion procedures and blood product selection were nearly uniform among CSCCs. Of the respondents, 69 percent disagreed with the statement that clear consensus exists on the use of phenotypically matched red blood cells for SCD patients; 55 percent disagreed that clear consensus exists on the use of chronic transfusion programs for SCD patients. Although there was consensus on the use of transfusion therapy for life- or organ-threatening situations, optimal management of preoperative transfusion therapy and severe delayed transfusion reactions appears controversial. CONCLUSION: This study provides the first overview of BB management of patients with SCD at CSCCs and identifies areas where there is perceived and actual lack of consensus. These results suggest that opportunities remain to standardize transfusion practices for SCD patients across all hospital settings.

Opportunities to improve outcomes in sickle cell disease.

Sickle cell disease represents a spectrum of inherited hemoglobin disorders. The pathophysiology involves abnormalities not just in red blood cells but also vascular endothelium, white blood cell function, coagulation, and inflammatory response. Known sequelae of sickle cell disease include invasive infections, painful episodes, acute chest syndrome, strokes, and chronic pulmonary hypertension. Preventive strategies that decrease the risk of infection are the routine use of daily antibiotics until five years of age, immunization of children with the 7-valent pneumococcal conjugate vaccine in addition to the 23-valent polysaccharide pneumococcal vaccine, annual influenza vaccination after six months of age, and meningococcal vaccination after two years of age. A significant advance in stroke prevention is the use of transcranial Doppler ultrasonography to identify asymptomatic, at-risk children who should be considered for chronic blood transfusions. Chronic transfusion therapy for primary or secondary stroke prevention requires careful surveillance for iron overload and chelation therapy. Patients with chest pain, fever, or respiratory symptoms and new pulmonary infiltrates require aggressive medical management for acute chest syndrome. Pain management still represents an important area for aggressive treatment using sickle cell disease-specific guidelines. Newer treatments include hydroxyurea therapy to decrease the frequency of painful episodes and associated comorbidities, and hematopoietic cell transplantation for a limited subset of patients. Family physicians play a crucial role in instituting evidence-based preventive care strategies, initiating timely treatment of acute illness, recognizing life-threatening episodes, and providing a medical home for multidisciplinary management.