1.
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Pulm Circ. 2014 Sep;4(3):482-95. doi: 10.1086/677363.
Abstract
Initiation, progression, and resolution of vaso-occlusive pain episodes in sickle cell disease (SCD) have been recognized as reperfusion injury, which provokes an inflammatory response in the pulmonary circulation. Some 5-lipoxygenase (5-lox) metabolites are potent vasoconstrictors in the pulmonary circulation. We studied stimulation of production of the inflammatory eicosanoids leukotrienes (LTs) and prostaglandin E2 (PGE2) by isolated rat lungs perfused with sickle (HbSS) erythrocytes. Our hypothesis is that HbSS erythrocytes produce more LTs than normal (HbAA) erythrocytes, which can induce vaso-occlusive episodes in SCD patients. Lung perfusates were collected at specific time points and purified by high-pressure liquid chromatography, and LTC4 and PGE2 contents were measured by enzyme-linked immunosorbent assay (ELISA). Rat lung explants were also cultured with purified HbAA and HbSS peptides, and 5-lox, cyclooxygenase 1/2, and platelet-activating factor receptor (PAFR) proteins were measured by Western blotting, while prostacyclin and LTs produced by cultured lung explants were measured by ELISA. Lung weight gain and blood gas data were not different among the groups. HbSS-perfused lungs produced more LTC4 and PGE2 than HbAA-perfused lungs: 10.40 ± 0.62 versus 0.92 ± 0.2 ng/g dry lung weight (mean ± SEM; P = 0.0001) for LTC4. Inclusion of autologous platelets (platelet-rich plasma) elevated LTC4 production to 12.6 ± 0.96 and 7 ± 0.60 ng/g dry lung weight in HbSS and HbAA perfusates, respectively. HbSS lungs also expressed more 5-lox and PAFR. The data suggest that HbSS erythrocytes and activated platelets in patient's pulmonary microcirculation will enhance the synthesis and release of the proinflammatory mediators LTC4 and PGE2, both of which may contribute to onset of the acute chest syndrome in SCD.
Free Article
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PMID: 25621162 [PubMed]
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2.
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Am J Hematol. 2015 Jan 23. doi: 10.1002/ajh.23959. [Epub ahead of print]
Abstract
Previous studies have shown that the highest incidence of acute chest syndrome (ACS) in sickle cell disease (SCD) occurs in children less than 4 years old, and a history of ACS at this age is a risk factor for future ACS episodes. However, the interval associated with the highest risk of subsequent ACS or severe pain is not known. Through this mixed retrospective-prospective observational study, the Sleep and Asthma Cohort, we sought to determine the interval after an initial ACS episode during which the majority of children <4 years old are re-hospitalized for ACS or severe pain. The cumulative prevalence of re-hospitalization for ACS or severe pain within 6 months, 1 years, and 2 years was calculated for children with an initial ACS episode <4 years old and compared to children with an initial ACS episode ≥4 years old. A total of 44.8% and 55.2% of participants had an initial ACS episode <4 years and ≥4 years old (Range: 4-17.7 years), respectively. At 1 year following the initial ACS episode, children <4 years old had a significantly higher cumulative prevalence of re-hospitalizations for ACS or pain as compared to children ≥4 years of age, 62.5% and 39.1%, respectively (P = 0.009). After initial ACS episodes, the majority of children <4 years old will be re-hospitalized for ACS or severe pain within one year, suggesting the need for a therapeutic intervention for this high-risk group. This article is protected by copyright. All rights reserved.
Copyright © 2015 Wiley Periodicals, Inc., A Wiley Company.
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PMID: 25619382 [PubMed - as supplied by publisher]
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3.
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Am J Hematol. 2015 Jan 23. doi: 10.1002/ajh.23956. [Epub ahead of print]
Manwani D1, Chen G, Carullo V, Serban S, Olowokure O, Jang J, Huggins M, Cohen HW, Billett H, Atweh GF, Frenette PS, Shi PA.
Abstract
Intravenous immunoglobulin (IVIG) decreases neutrophil adhesion to endothelium and red blood cell-neutrophil interactions in sickle cell mice undergoing vaso-occlusion. In this Phase I clinical trial of sickle cell anemia (SCA) patients admitted with pain crisis, we evaluated the status of adhesion molecules on neutrophils in control and IVIG-treated subjects pre- and post-infusion up to 800mg/kg, the same dose used in murine studies. Mac-1 function significantly decreased from baseline in the low-dose IVIG (200-400mg/kg) cohorts. IVIG-related adverse events may have occurred in the high-dose (600-800mg/kg) cohorts. There were no significant increases in neutrophil and leukocyte counts, suggesting that IVIG may more selectively inhibit Mac-1 function as opposed to neutrophil adhesion. This study provides the first in-human validation of pre-clinical murine studies that IVIG can decrease Mac-1 function. This article is protected by copyright. All rights reserved.
© 2015 Wiley Periodicals, Inc.
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PMID: 25616042 [PubMed - as supplied by publisher]
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4.
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Biol Blood Marrow Transplant. 2015 Jan 20. pii: S1083-8791(15)00037-3. doi: 10.1016/j.bbmt.2015.01.010. [Epub ahead of print]
Abstract
Limited data exists regarding health care utilization (HCU) in patients receiving allogeneic hematopoietic cell transplantation (alloHCT) for sickle cell disease. Financial data from 2002-2011 was analyzed for 26 alloHCT cases and 48 controls (referred but without alloHCT). HCU of alloHCT was determined over three time periods: pre-alloHCT, during alloHCT (day 0 to day +365), and post-alloHCT. The median total cost per patient during the alloHCT year was $413,000 inpatient and $18,000 outpatient. Post-alloHCT HCU decreased when compared to pre-alloHCT and controls. The median cost of post-alloHCT outpatient visits per patient was significantly less when compared to pre-alloHCT (p=0.044). The median cost of post-alloHCT inpatient visits per patient approached significance when compared to that pre-alloHCT (p=0.079). Sixteen post-alloHCT patients, 19 controls, and 14 unaffected siblings were surveyed using Pediatric Quality of Life Inventory (PedsQL™) and EuroQOL (EQ5D™) questionnaires. The mean PedsQL™ and EQ5D™ scores across all 3 patient groups were not statistically significant (p = 0.2638). When adjusted for health-related quality of life (HRQOL), analysis suggests alloHCT has a positive impact on HRQOL over controls. In summary, this pilot data supports our hypothesis that alloHCT in children with SCD reduces HCU in comparison to controls without alloHCT.
Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
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PMID: 25615608 [PubMed - as supplied by publisher]
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5.
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Br J Haematol. 2015 Jan 22. doi: 10.1111/bjh.13280. [Epub ahead of print]
Aygun B1, Mortier NA, Kesler K, Lockhart A, Schultz WH, Cohen AR, Alvarez O,Rogers ZR, Kwiatkowski JL, Miller ST, Sylvestre P, Iyer R, Lane PA, Ware RE; the Stroke With Transfusions Changing to Hydroxyurea (SWiTCH) Trial Investigators.
Abstract
Serial phlebotomy was performed on sixty children with sickle cell anaemia, stroke and transfusional iron overload randomized to hydroxycarbamide in the Stroke With Transfusions Changing to Hydroxyurea trial. There were 927 phlebotomy procedures with only 33 adverse events, all of which were grade 2. Among 23 children completing 30 months of study treatment, the net iron balance was favourable (-8·7 mg Fe/kg) with significant decrease in ferritin, although liver iron concentration remained unchanged. Therapeutic phlebotomy was safe and well-tolerated, with net iron removal in most children who completed 30 months of protocol-directed treatment.
© 2015 John Wiley & Sons Ltd.
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PMID: 25612463 [PubMed - as supplied by publisher]
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6.
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Proc Natl Acad Sci U S A. 2015 Jan 20. pii: 201424111. [Epub ahead of print]
Abstract
We developed a microfluidics-based model to quantify cell-level processes modulating the pathophysiology of sickle cell disease (SCD). This in vitro model enabled quantitative investigations of the kinetics of cell sickling, unsickling, and cell rheology. We created short-term and long-term hypoxic conditions to simulate normal and retarded transit scenarios in microvasculature. Using blood samples from 25 SCD patients with sickle hemoglobin (HbS) levels varying from 64 to 90.1%, we investigated how cell biophysical alterations during blood flow correlated with hematological parameters, HbS level, and hydroxyurea (HU) therapy. From these measurements, we identified two severe cases of SCD that were also independently validated as severe from a genotype-based disease severity classification. These results point to the potential of this method as a diagnostic indicator of disease severity. In addition, we investigated the role of cell density in the kinetics of cell sickling. We observed an effect of HU therapy mainly in relatively dense cell populations, and that the sickled fraction increased with cell density. These results lend support to the possibility that the microfluidic platform developed here offers a unique and quantitative approach to assess the kinetic, rheological, and hematological factors involved in vasoocclusive events associated with SCD and to develop alternative diagnostic tools for disease severity to supplement other methods. Such insights may also lead to a better understanding of the pathogenic basis and mechanism of drug response in SCD.
Free Article
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PMID: 25605910 [PubMed - as supplied by publisher]
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7.
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Haematologica. 2015 Jan 16. pii: haematol.2014.114587. [Epub ahead of print]
Abstract
Hemoglobin SC disease is a very prevalent hemoglobinopathy, however very little is known specifically about this condition. There appears to be an increased risk of thromboembolic events in hemoglobin SC disease, but studies evaluating the hemostatic alterations are lacking. We describe a cross-sectional observational study evaluating coagulation activation markers in adult hemoglobin SC patients, in comparison with sickle cell anemia patients and healthy controls. A total of 56 hemoglobin SC and 39 sickle cell anemia patients were included in the study, all in steady state, and 27 healthy controls. None of the patients were in use of hydroxyurea. Hemoglobin SC patients presented a significantly up-regulated relative expression of tissue factor, as well as elevations in thrombin-antithrombin complex and D-dimer, in comparison to controls (p<0.01). Hemoglobin SC patients presented lower tissue factor expression, and thrombin-antithrombin complex and D-dimer levels when compared to sickle cell anemia patients (p<0.05). Endothelial activation (soluble thrombomodulin and soluble vascular cell adhesion molecule-1), and inflammation (tumor necrosis factor-alpha) markers were both significantly elevated in hemoglobin SC patients when compared to controls, being as high as the levels seen in sickle cell anemia. Overall, in hemoglobin SC patients, higher hemolytic activity and inflammation were associated with a more intense activation of coagulation, and hemostatic activation was associated with two very prevalent chronic complications seen in hemoglobin SC disease: retinopathy and osteonecrosis. In summary, our results demonstrate that hemoglobin SC patients present a hypercoagulable state, although this manifestation was not as intense as that seen in sickle cell anemia.
Copyright © 2015, Ferrata Storti Foundation.
Free Article
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PMID: 25596272 [PubMed - as supplied by publisher]
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8.
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J Pediatr Hematol Oncol. 2015 Jan 8. [Epub ahead of print]
Abstract
Given the availability of various pain severity scales, greater understanding of the agreement between pain scales is warranted. We compared Visual Analog Scale (VAS) and Numeric Rating Scale (NRS) pain severity ratings in children with sickle cell disease (SCD) to identify the relationship and agreement between pain scale ratings. Twenty-eight patients (mean±SD age, 14.65±3.12 y, 50% female) receiving pain interventions within the emergency department completed serial VAS and NRS pain severity ratings every 30 minutes. Data were used to calculate the relationship (Spearman correlation) and agreement (Bland-Altman approach) between the VAS and NRS. One hundred twenty-eight paired VAS-NRS measurements were obtained. VAS and NRS ratings were significantly correlated for the initial assessment (rs=0.88, P<0.001) and all assessments (rs=0.87, P<0.001). Differences between VAS and NRS means were -0.52 (P=0.006) for the initial assessment and -0.86 (P<0.001) across all assessments. The difference between VAS and NRS ratings decreased as pain severity increased across all assessments (P=0.027), but not the initial assessment. Within pediatric patients with SCD, VAS and NRS ratings were found to trend together; however, VAS scores were found to be significantly lower than NRS scores across assessments. The agreement between the 2 measures improved at increasing levels of pain severity. These findings demonstrate that the VAS and NRS are similar, but cannot be used interchangeably when assessing self-reported pain in SCD.
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PMID: 25575295 [PubMed - as supplied by publisher]
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9.
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Hematol Rep. 2014 Dec 3;6(4):5502. doi: 10.4081/hr.2014.5502. eCollection 2014.
Abstract
Sickle cell trait (SCT) occurs in about 8% of African-Americans and is often described to be of little clinical consequence. Over time, a number of risks have emerged, and among these are rare but catastrophic episodes of sudden death in athletes and other individuals associated with physical activities which is often described as exercise collapse associated with sickle trait (ECAST). Despite an epidemiologic link between SCT and sudden death as well as numerous case reports in both medical literature and lay press, no clear understanding of the key pathophysiologic events has been identified. Strategies for identification of individuals at risk and prevention of ECAST have been both elusive and controversial. Stakeholders have advocated for different approaches to this issue particularly with regard to screening for hemoglobin S. Furthermore, the recommendations and guidelines that are in place for the early recognition of ECAST and the prevention and treatment of the illness are not well defined and remain fragmented. Among the cases identified, those in collegiate football players in the United States are often highlighted. This manuscript examines these case studies and the current recommendations to identify areas of consensus and controversy regarding recommendations for prevention, recognition and treatment of ECAST.
PMCID: PMC4274478 Free PMC Article
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PMID: 25568759 [PubMed]
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10.
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Transfusion. 2015 Jan 9. doi: 10.1111/trf.12987. [Epub ahead of print]
Abstract
BACKGROUND:
Extended red blood cell (RBC) antigen matching is recommended to limit alloimmunization in patients with sickle cell disease (SCD). DNA-based testing to predict blood group phenotypes has enhanced availability of antigen-negative donor units and improved typing of transfused patients, but replacement of routine serologic typing for non-ABO antigens with molecular typing for patients has not been reported.
STUDY DESIGNS AND METHODS:
This study compared the historical RBC antigen phenotypes obtained by hemagglutination methods with genotype predictions in 494 patients with SCD. For discrepant results, repeat serologic testing was performed and/or investigated by gene sequencing for silent or variant alleles.
RESULTS:
Seventy-one typing discrepancies were identified among 6360 antigen comparisons (1.1%). New specimens for repeat serologic testing were obtained for 66 discrepancies and retyping agreed with the genotype in 64 cases. One repeat Jk(b-) serologic phenotype, predicted Jk(b+) by genotype, was found by direct sequencing of JK to be a silenced allele, and one N typing discrepancy remains under investigation. Fifteen false-negative serologic results were associated with alleles encoding weak antigens or single-dose Fyb expression.
CONCLUSIONS:
DNA-based RBC typing provided improved accuracy and expanded information on RBC antigens compared to hemagglutination methods, leading to its implementation as the primary method for extended RBC typing for patients with SCD at our institution.
© 2015 AABB.
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PMID: 25573464 [PubMed - as supplied by publisher]
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11.
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Clin J Pain. 2015 Jan 6. [Epub ahead of print]
Abstract
BACKGROUND::
Vaso-occlusive pain, the hallmark of sickle cell disease (SCD), is a major contributor to morbidity, poor health-related quality of life and healthcare utilization associated with this disease. There is wide variation in the burden, frequency and severity of pain experienced by patients with SCD. As compared to healthcare utilization for pain, a daily pain diary captures the breadth of the pain experience and is a superior measure of pain burden and its impact on patients. Electronic pain diaries based on real time data capture methods overcome methodological barriers and limitations of paper pain diaries but their psychometric properties have not been formally established in patients with SCD.
OBJECTIVES::
To develop and establish the content validity of a web-based multi-dimensional pain diary for adolescents and young adults with SCD and conduct an end-user review to refine the prototype.
METHODS::
Following identification of items, a conceptual model was developed. Interviews with adolescents and young adults with SCD were conducted. Subsequently, end-user review with use of the electronic pain diary prototype was conducted.
RESULTS::
Two iterative cycles of in-depth cognitive interviews in adolescents and young adults with SCD informed the design and guided the addition, removal and modification of items in the multi-dimensional pain diary. Potential end-users provided positive feedback on the design and prototype of the electronic diary.
CONCLUSION::
A multi-dimensional web-based electronic pain diary for adolescents and young adults with SCD has been developed and content validity and initial end-user reviews have been completed.
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PMID: 25565585 [PubMed - as supplied by publisher]
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13.
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Mol Med. 2014 Dec 16;20 Suppl 1:S37-42. doi: 10.2119/molmed.2014.00187.
Abstract
In the hydroxyurea era, insights into mechanisms downstream of erythrocyte sickling have led to new therapeutic approaches for patients with sickle cell disease (SCD). Therapies have been developed that target vascular adhesion, inflammation and hemolysis, including innovative biologics directed against P-selectin and invariant natural killer T cells. Advances in hematopoietic stem cell transplant and gene therapy may also provide more opportunities for cures in the near future. Several clinical studies are underway to determine the safety and efficacy of these new treatments. Novel approaches to treat SCD are desperately needed, since current therapies are limited and rates of morbidity and mortality remain high.
Free Article
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PMID: 25549232 [PubMed - in process]
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14.
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Platelets. 2014 Dec 30:1-4. [Epub ahead of print]
Abstract
Abstract The severe pain, ischemia and organ damage that characterizes sickle cell disease (SCD) is caused by vaso-occlusion, which is the blockage of blood vessels by heterotypic aggregates of sickled erythrocytes and other cells. Vaso-occlusion is also a vasculopathy involving endothelial cell dysfunction, leukocyte activation, platelet activation and chronic inflammation resulting in the multiple adhesive interactions between cellular elements. Since platelets mediate inflammation as well as thrombosis via release of pro- and anti-inflammatory molecules, we hypothesized that platelets may play an active inflammatory role in SCD by secreting increased amounts of cytokines. Since platelets have been shown to contain mRNA and actively produce proteins, we also hypothesized that SCD platelets may contain increased cytokine mRNA. In this cross-sectional study, we sought to compare both the quantity of cytokines secreted and the cytokine mRNA content, between SCD and control platelets. We measured the secretion of Th1, Th2, and Th17-related cytokines from platelets in a cohort of SCD patients. We simultaneously measured platelet mRNA levels of those cytokines. Platelets from SCD patients secreted increased quantities of IL-1β, sCD40L, and IL-6 compared to controls. Secretion was increased in patients with alloantibodies. Additionally, mRNA of those cytokines was increased in SCD platelets. Platelets from sickle cell patients secrete increased amounts of inflammatory cytokines, and contain increased cytokine mRNA. These findings suggest a novel immunological role for platelets in SCD vasculopathy, in addition to their thrombotic role, and strengthen the rationale for the use of anti-platelet therapy in SCD.
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PMID: 25548984 [PubMed - as supplied by publisher]
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