Joshua J Field

BloodCenter of Wisconsin, Milwaukee, Wisconsin, United States

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Publications (51)188.54 Total impact

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    ABSTRACT: Levels of hepcidin, a key modulator of iron metabolism, are influenced by erythropoiesis, iron, and inflammation, all of which may be increased in patients with sickle cell disease (SCD). The objectives of this study were to determine: 1) the variation in hepcidin level, and 2) the relative contribution of erythropoietic drive, iron, and inflammation to differences in hepcidin level in an adult cohort with SCD. In a prospective study, cross-sectional measurements of hepcidin, reticulocyte percentage, erythropoietin, ferritin, and high-sensitivity CRP were obtained. A regression tree analysis was used to measure the association between these interacting factors and hepcidin level. The cohort was comprised of 40 adults with SCD. Median age was 26 years, 68% were female, and all had HbSS. Hepcidin values ranged from 30 ng/ml to 326 ng/ml, with a median of 87 ng/ml. Regression tree analysis demonstrated that reticulocyte percentage, erythropoietin, ferritin and hs-CRP all were associated with hepcidin. The highest hepcidin values were found in subjects with low reticulocyte percentage and erythropoietin. In conclusion, erythropoietic drive, iron status, and inflammation all contribute to variation in hepcidin level. The strongest contributor is erythropoietic drive. Future studies could determine whether suppression of erythropoiesis with chronic transfusion influences hepcidin level.
    Blood Cells Molecules and Diseases 12/2015; 55(4):304-307. DOI:10.1016/j.bcmd.2015.07.010 · 2.65 Impact Factor
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    ABSTRACT: Interstitial lung disease is common in patients with sickle cell anemia (SCA). Fibrocytes are circulating cells implicated in the pathogenesis of pulmonary fibrosis and airway remodeling in asthma. In this study, we tested the hypotheses that fibrocyte levels are: (1) increased in children with SCA compared to healthy controls, and (2) associated with pulmonary disease. Cross-sectional cohort study of children with SCA who participated in the Sleep Asthma Cohort Study. Fibrocyte levels were obtained from 45 children with SCA and 24 controls. Mean age of SCA cases was 14 years and 53% were female. In children with SCA, levels of circulating fibrocytes were greater than controls (P < 0.01). The fibrocytes expressed a hierarchy of chemokine receptors, with CXCR4 expressed on the majority of cells and CCR2 and CCR7 expressed on a smaller subset. Almost half of fibrocytes demonstrated α-smooth muscle actin activation. Increased fibrocyte levels were associated with a higher reticulocyte count (P = 0.03) and older age (P = 0.048) in children with SCA. However, children with increased levels of fibrocytes were not more likely to have asthma or lower percent predicted forced expiratory volume in 1 sec/forced vital capacity (FEV1 /FVC) or FEV1 than those with lower fibrocyte levels. Higher levels of fibrocytes in children with SCA compared to controls may be due to hemolysis. Longitudinal studies may be able to better assess the relationship between fibrocyte level and pulmonary dysfunction. Pediatr Pulmonol. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    Pediatric Pulmonology 06/2015; DOI:10.1002/ppul.23248 · 2.70 Impact Factor
  • Rehka Chandran · Amy Moran · Mark Barash · Brian Hopper · Amy Rankin · Joshua J Field ·

    American Journal of Hematology 06/2015; 90(9). DOI:10.1002/ajh.24090 · 3.80 Impact Factor
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    ABSTRACT: The National Heart Lung and Blood Institute (NHLBI) hosted a two-day state of the science symposium on therapeutic apheresis in Bethesda, MD on November 28th-29th, 2012. The purpose of the symposium was multifaceted, and included the following aims: (a) To discuss this state of research and key scientific questions in apheresis medicine; (b) To identify gaps in knowledge for relevant cardiovascular diseases, hematological and oncological diseases, infectious diseases and sepsis, renal diseases, and neurological diseases where there may be strong therapeutic rationale for the application of apheresis treatments; (c) To explore ways of coordinating therapeutic apheresis with other medical disciplines and treatment modalities; (d) To identify and prioritize the most important research questions to be answered in apheresis medicine; and (e) To offer NHLBI suggestions on how a structured research approach can be applied to the therapeutic apheresis research agenda in future years. The following document summarizes three such key proposals presented at the meeting for evaluating apheresis therapy for the treatment of pain in sickle cell disease, heparin induced thrombocytopenia, and leukostasis from acute myeloid leukemia. The challenges and limitations regarding apheresis therapy for each disease are discussed, and avenues for future investigation for each disease are outlined. J. Clin. Apheresis, 2015. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    Journal of Clinical Apheresis 05/2015; DOI:10.1002/jca.21400 · 1.79 Impact Factor
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    ABSTRACT: Red cell exchange (RCE) is a common procedure in adults with sickle cell disease (SCD). Implantable dual lumen Vortex (DLV) ports can be used for RCE in patients with poor peripheral venous access. We performed a retrospective cohort study of RCE procedures performed in adults with SCD. The main objective of the study was to compare the inlet speed, duration of procedures and rate of complications performed through DLV ports to those performed through temporary central venous and peripheral catheters. Twenty-nine adults with SCD underwent a total of 318 RCE procedures. Twenty adults had DLV ports placed and 218 procedures were performed using DLV ports. Mean length of follow-up after DLV port placement was 397 ± 263 days. Six DLV ports were removed due to infection and 1 for malfunction after a mean of 171 ± 120 days. Compared to temporary central venous and peripheral catheters, DLV port procedures had a greater rate of procedural complications, a longer duration, and a lower inlet speed (all P < 0.01). When accounting for the maximum allowable inlet speed to avoid citrate toxicity, 40% of DLV port procedures were greater than 10% below maximum speed, compared to 7 and 14% of procedures performed through temporary central venous and peripheral catheters (P < 0.0001). In conclusion, DLV ports can be used for RCE in adults with SCD, albeit with more procedural complications and longer duration. The smaller internal diameter and longer catheter of DLV ports compared to temporary central venous catheters likely accounts for the differences noted. J. Clin. Apheresis, 2015. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    Journal of Clinical Apheresis 03/2015; DOI:10.1002/jca.21393 · 1.79 Impact Factor
  • Kathryn L Koch · Matthew S Karafin · Pippa Simpson · Joshua J Field ·
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    ABSTRACT: A minority of super-utilizing adults with sickle cell disease (SCD) account for a disproportionate number of emergency department (ED) and hospital admissions. We performed a retrospective cohort study comparing the rate of admission before and after the opening of a clinic for adults with SCD. Unique to this clinic was an intensive intervention management strategy, focusing on super-utilizing adults with 12 or more admissions per year. ED/hospital and 30 days admission rates were compared, 1 year pre- and post-intervention, for those adults who established in the clinic. Prior to the intervention, 17 super-utilizers, comprising 15% of the pre-intervention cohort (n=115), accounted for 58% of the total admissions and had an admission rate of 28 per patient-year. When pre- and post-intervention years were compared, rate of ED/hospital admission per patient-year for super-utilizers decreased from 27.9 to 13.5 (P< 0.001), while there was not a significant reduction for the entire cohort (7.1 vs. 6.1, P=0.84). Similarly, the decrease in rate of 30 day re-admission was larger for the super-utilizers (13.5 per patient-year to 1.8, P<0.001), than the whole cohort (2.6 per patient-year to 0.7, P=0.006). Among the super-utilizers, the reduced rate of admission from the pre- to post-clinic intervention year equated to 252 fewer ED/hospital admissions and 227 fewer 30 day re-admissions. This management strategy focusing on super-utilizing adults with SCD lowered admission and 30 day re-admission rate. This article is protected by copyright. All rights reserved. Copyright © 2014 Wiley Periodicals, Inc., A Wiley Company.
    American Journal of Hematology 03/2015; 90(3). DOI:10.1002/ajh.23912 · 3.80 Impact Factor
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    ABSTRACT: BACKGROUND Much effort and resources have been devoted to programs that provide transfusion support for patients with sickle cell disease (SCD). The focus of many donor programs is to prevent alloimmunization by recruiting racially matched African American donors to limit the red blood cell (RBC) antigenic differences that exist between Caucasian donors and patients with SCD.STUDY DESIGN AND METHODS In this study, we evaluated the RBC antigen characteristics of both the recipient population with SCD and the African American donor population from 2010 to 2013. We evaluated the genotype-derived predicted antigen frequencies of the donors and compared these frequencies with those of the population supported by these units. Specific attention was given to the alloimmunization rate over the 3 years and the number of D– units provided to D+ patients.RESULTSWe recruited 6066 African American donors during the 3-year study period with 77.3% of these donors donating no more than twice. The observed genotype-derived predicted antigen frequencies were similar to the expected frequencies, and the antigen frequencies of a cohort of 54 adult patients with SCD (p > 0.05). Twelve patients (22.2%) with SCD had alloantibodies and five of these patients developed these antibodies while receiving Rh and K antigen–matched blood during the study interval. Finally, we found that 607 (37.1%) D– units were diverted to D+ patients.CONCLUSIONS New recruitment and prevention strategies are needed to increase the pool of available antigen-matched RBCs and decrease alloimmunization risk for this patient population.
    Transfusion 03/2015; 55(6 Pt 2). DOI:10.1111/trf.13037 · 3.23 Impact Factor
  • G. Lin · J.J. Field · J.C. Yu · R. Ken · D. Neuberg ·

    PLoS ONE 02/2015; 10(2). DOI:10.1371/journal.pone.0117760 · 3.23 Impact Factor
  • Joshua J Field · David G Nathan ·
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    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.
    Molecular Medicine 12/2014; 20 Suppl 1:S37-42. DOI:10.2119/molmed.2014.00187 · 4.51 Impact Factor
  • Joshua J Field · David G Nathan · Joel Linden ·
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    ABSTRACT: Data suggest a role for adenosine signaling in the pathogenesis of sickle cell disease (SCD). Signaling through the adenosine A2A receptor (A2AR) has demonstrated beneficial effects. Activation of A2ARs decreases inflammation with SCD by blocking activation of invariant natural killer T cells. Decreased inflammation may reduce the severity of vasoocclusive crises. Adenosine signaling through the adenosine A2B receptor (A2BR) may be detrimental in SCD. Whether adenosine signaling predominantly occurs through A2ARs or A2BRs may depend on differing levels of adenosine and disease state (steady state versus crisis). There may be opportunities to develop novel therapeutic approaches targeting A2ARs and/or A2BRs for patients with SCD.
    Hematology/oncology clinics of North America 04/2014; 28(2):287-299. DOI:10.1016/j.hoc.2013.11.003 · 2.30 Impact Factor
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    ABSTRACT: Reperfusion injury following tissue ischemia occurs as a consequence of vaso-occlusion that is initiated by activation of invariant natural killer T (iNKT) cells. Sickle cell disease (SDC) results in widely disseminated microvascular ischemia and reperfusion injury as a result of vaso-occlusion by rigid and adhesive sickle red blood cells. In mice, iNKT cell activation requires NF-κB signaling and can be inhibited by the activation of anti-inflammatory adenosine A2A receptors (A2ARs). Human iNKT cells are divided into subsets of CD4+ and CD4- cells. In this study we found that human CD4+ iNKT cells, but not CD4- cells undergo rapid NF-κB activation (phosphorylation of NF-κB on p65) and induction of A2ARs (detected with a monoclonal antibody 7F6-G5-A2) during SCD painful vaso-occlusive crises. These findings indicate that SCD primarily activates the CD4+ subset of iNKT cells. Activation of NF-κB and induction of A2ARs is concordant, i.e. only CD4+ iNKT cells with activated NF-κB expressed high levels of A2ARs. iNKT cells that are not activated during pVOC express low levels of A2AR immunoreactivity. These finding suggest that A2AR transcription may be induced in CD4+ iNKT cells as a result of NF-κB activation in SCD. In order to test this hypothesis further we examined cultured human iNKT cells. In cultured cells, blockade of NF-κB with Bay 11-7082 or IKK inhibitor VII prevented rapid induction of A2AR mRNA and protein upon iNKT activation. In conclusion, NF-κB-mediated induction of A2ARs in iNKT cells may serve as a counter-regulatory mechanism to limit the extent and duration of inflammatory immune responses. As activated iNKT cells express high levels of A2ARs following their activation, they may become highly sensitive to inhibition by A2AR agonists.
    PLoS ONE 10/2013; 8(10):e74664. DOI:10.1371/journal.pone.0074664 · 3.23 Impact Factor
  • Binod Dhakal · Kristinza Giese · Linus Santo-Thomas · Joshua J Field ·

    American Journal of Hematology 09/2013; 88(9). DOI:10.1002/ajh.23492 · 3.80 Impact Factor
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    ABSTRACT: Background: The contribution of environmental tobacco smoke (ETS) exposure to pulmonary morbidity in children with sickle cell anemia (SCA) is poorly understood. We tested the hypothesis that children with SCA and ETS exposure would have an increased prevalence of obstructive lung disease and respiratory symptoms compared with children with SCA and no ETS exposure. Methods: Parent reports of ETS and respiratory symptom frequency were obtained for 245 children with SCA as part of a multicenter prospective cohort study. One hundred ninety-six children completed pulmonary function testing. Multivariable regression models were used to evaluate the associations between ETS exposure at different time points (prenatal, infant [birth to 2 years], preschool [2 years to first grade], and current) and lung function and respiratory symptoms. Results: Among the 245 participants, a high prevalence of prior (44%) and current (29%) ETS exposure was reported. Of the 196 children who completed pulmonary function testing, those with parent-reported infant and current ETS exposure were more likely to have airway obstruction (defined as an FEV1/FVC ratio below the lower limit normal) compared with unexposed children (22.0% vs 3.1%, P < .001). Those with ETS exposure also had a lower forced expiratory flow, midexpiratory phase/FVC ratio (0.82 vs 0.97, P = .001) and were more likely to have evidence of bronchodilator responsiveness (23% vs 11%, P = .03). Current and prior ETS exposure and in utero smoke exposure were associated with increased frequency of respiratory symptoms. Conclusions: ETS exposure is associated with evidence of lower airway obstruction and increased respiratory symptoms in SCA.
    Chest 05/2013; 144(4). DOI:10.1378/chest.12-1569 · 7.48 Impact Factor
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    ABSTRACT: Adenosine A(2A) receptor (A(2A)R) agonists reduce iNKT cell activation and decrease inflammation in sickle cell disease (SCD) mice. We conducted a phase 1 trial of the A(2A)R agonist regadenoson in adults with SCD. Target dose was 1.44 mcg/kg/hour. iNKT cell activation was evaluated using antibodies targeting the p65 subunit of nuclear factor-kappa B (phospho-NF-κB p65), interferon-gamma (IFN-γ) and A(2A)R. Regadenoson was administered to 27 adults with SCD. Twenty-one patients were examined at steady state and 6 during painful vaso-occlusive crises (pVOC). iNKT cell activation was also measured in 14 African-American controls. During pVOC, the fraction of iNKT cells demonstrating increased phospho-NF-κB p65 and A(2A)R expression was significantly higher compared to controls (p<0.01) and steady state patients (p<0.05). IFN-γ expression was also significantly higher compared to controls (p=0.02). After a 24 hour infusion of regadenoson during pVOC, phospho-NF-κB p65 activation in iNKT cells decreased compared to pre-drug by a median of 48% (p=0.03) to levels similar to controls and steady state SCD. No toxicities were identified. Infusional regadenoson administered to adults with SCD at 1.44 mcg/kg/hour during pVOC decreases activation of iNKT cells to levels observed in controls and steady state patients without toxicity. (Registered at #NCT01085201).
    Blood 02/2013; 121(17). DOI:10.1182/blood-2012-11-465963 · 10.45 Impact Factor
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    ABSTRACT: Sickle cell disease can lead to hepatic complications ranging from acute hepatic crises to chronic liver disease including intrahepatic cholestasis, and iron overload. Although uncommon, intrahepatic cholestasis may be severe and medical treatment of this complication is often ineffective. We report a case of a 37 year-old male patient with sickle cell anemia, who developed liver failure and underwent successful orthotopic liver transplantation. Both pre and post-operatively, he was maintained on red cell transfusions. He remains stable with improved liver function 42 months post transplant. The role for orthotopic liver transplantation is not well defined in patients with sickle cell disease, and the experience remains limited. Although considerable challenges of post-transplant graft complications remain, orthotopic liver transplantation should be considered as a treatment option for sickle cell disease patients with end-stage liver disease who have progressed despite conventional medical therapy. An extended period of red cell transfusion support may lessen the post-operative complications.
    Hematology Reports 01/2013; 5(1):1-4. DOI:10.4081/hr.2013.e1
  • Alan E Mast · Joshua J Field ·

    Transfusion 10/2012; 52(10):2078-80. DOI:10.1111/j.1537-2995.2012.03894.x · 3.23 Impact Factor
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    ABSTRACT: Autopsy and biopsy studies have shown that there is significantly more fibrosis in hearts of patients with hypertensive heart disease compared to normal hearts. Fibrocytes, a population of circulating bone marrow-derived cells, have been shown to home to tissues and promote scar formation in several diseases, but their role in human hypertensive heart disease has not been investigated to date. Our objective was to determine whether fibrocyte levels are elevated in individuals with hypertensive heart disease. We measured peripheral blood fibrocyte levels and their activated phenotypes in 12 individuals with hypertensive heart disease as determined by increased left ventricular mass on noninvasive imaging and compared them to fibrocyte levels from 19 healthy normal controls and correlated them to cardiac MRI findings. Compared to normal controls, individuals with hypertensive heart disease had significantly higher circulating levels of total fibrocytes [median (interquartile range); 149000 (62200-220000) vs. 564500 (321000-1.2900e(+006)), P < 0.0001, respectively] as well as activated fibrocytes [15700 (6380-19800) vs. 478500 (116500-1.2360e(+006)) P < 0.0001]. Moreover, the fibrocyte subsets expressing the chemokine markers CXCR4 (P < 0.0001), CCR2 (P < 0.0001), CCR7 (P < 0.0001) and coexpression of both CXCR4 and CCR2 (P < 0.0001) were significantly elevated in patients with hypertensive heart disease compared to controls. Lastly, in patients with hypertensive heart disease there was a strong correlation between left ventricular mass index and total fibrocytes (r = 0.65, P = 0.037) and activated fibrocytes (r = 0.70, P = 0.016). Our data suggest that bone marrow-derived circulating fibrocytes are associated with the presence and extent of left ventricular hypertrophy in patients with hypertensive heart disease.
    Journal of Hypertension 07/2012; 30(9):1856-61. DOI:10.1097/HJH.0b013e32835639bb · 4.72 Impact Factor
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    ABSTRACT: Interstitial lung disease is a frequent complication in sickle cell disease and is characterized by vascular remodeling and interstitial fibrosis. Bone marrow-derived fibrocytes have been shown to contribute to the pathogenesis of other interstitial lung diseases. The goal of this study was to define the contribution of fibrocytes to the pathogenesis of sickle cell lung disease. Fibrocytes were quantified and characterized in subjects with sickle cell disease or healthy controls, and in a model of sickle cell disease, the NY1DD mouse. The role of the chemokine ligand CXCL12 in trafficking of fibrocytes and phenotype of lung disease was examined in the animal model. We found elevated concentration of activated fibrocytes in the peripheral blood of subjects with sickle cell disease, which increased further during vaso-occlusive crises. There was a similar elevations in the numbers and activation phenotype of fibrocytes in the bone marrow, blood, and lungs of the NY1DD mouse, both at baseline and under conditions of hypoxia/re-oxygenation. In both subjects with sickle cell disease and the mouse model, fibrocytes expressed a hierarchy of chemokine receptors, with CXCR4 expressed on most fibrocytes, and CCR2 and CCR7 expressed on a smaller subset of cells. Depletion of the CXCR4 ligand, CXCL12, in the mouse model resulted in a marked reduction of fibrocyte trafficking into the lungs, reduced lung collagen content and improved lung compliance and histology. These data support the notion that activated fibrocytes play a significant role in the pathogenesis of sickle cell lung disease.
    PLoS ONE 03/2012; 7(3):e33702. DOI:10.1371/journal.pone.0033702 · 3.23 Impact Factor
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    ABSTRACT: A humanized murine sickle cell-disease (SCD) model (NY1DD) has been used to study ischemia/reperfusion injury (IRI) in sickle cell anemia, and iNKT cells (a very small subset of murine and human T cells) have been found to instigate such injury in this model. Furthermore, levels of activated iNKT cells are generally elevated in the circulation of patients with SCD. Because activated iNKT cells are rich in adenosine A2A receptors which, when agonized, down-regulate the inflammatory cytokine expression that characterizes the cells, we have conducted a phase 1 trial of a constant infusion of low-dose regadenoson (an adenosine analogue with high A2A receptor specificity) to determine its safety and the capacity of a safe dose to down-regulate circulating iNKT cells in patients with SCD. We have found two dose rates that are both safe and effective and now plan a controlled Phase 2B clinical trial to determine whether our highest dose, administered as a 48-hour constant infusion, will induce faster remission in both painful vaso-occlusive crisis (pVOC) and acute chest syndrome (ACS).
    Transactions of the American Clinical and Climatological Association 01/2012; 123:312-8.
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    ABSTRACT: Prior studies of asthma in children with sickle cell disease (SCD) were based on reports of a doctor-diagnosis of asthma with limited description of asthma features. Doctor-diagnoses of asthma may represent asthma or wheezing unrelated to asthma. Objectives of this study were to determine if asthma characteristics are present in adults with a doctor-diagnosis of asthma and/or wheezing, and to examine the relationship between doctor-diagnosis of asthma, wheezing and SCD morbidity. This was an observational cohort study of 114 adults with SCD who completed respiratory symptom questionnaires and had serum IgE measurements. A subset of 79 participants completed pulmonary function testing. Survival analysis was based on a mean prospective follow-up of 28 months and data were censored at the time of death or loss to follow-up. Adults reporting a doctor-diagnosis of asthma (N = 34) were more likely to have features of asthma including wheeze, eczema, family history of asthma, and an elevated IgE level (all P < 0.05). However, there was no difference in pain or ACS rate, lung function, or risk of death between adults with and without a doctor-diagnosis of asthma. In contrast, adults who reported recurrent, severe episodes of wheezing (N = 34), regardless of asthma, had twice the rates of pain and ACS, decreased lung function and increased risk of death compared with adults without recurrent, severe wheezing. Asthma features were not associated with recurrent, severe wheezing. Our data suggest that wheezing in SCD may occur independently of asthma and is a marker of disease severity.
    American Journal of Hematology 09/2011; 86(9):756-61. DOI:10.1002/ajh.22098 · 3.80 Impact Factor

Publication Stats

683 Citations
188.54 Total Impact Points


  • 2011-2015
    • BloodCenter of Wisconsin
      • Blood Research Institute
      Milwaukee, Wisconsin, United States
    • Medical College of Wisconsin
      • Department of Medicine
      Milwaukee, Wisconsin, United States
  • 2012
    • Blood Systems Research Institute
      San Francisco, California, United States
  • 2011-2012
    • University of Wisconsin - Milwaukee
      Milwaukee, Wisconsin, United States
  • 2006-2011
    • Washington University in St. Louis
      • • Department of Medicine
      • • Department of Pediatrics
      San Luis, Missouri, United States