Summary Bleeding Assessment Tools (BATs) have been developed to aid in the standardized evaluation of bleeding symptoms. The Vicenza Bleeding Questionnaire (BQ), published in 2005, established a common framework and scoring key that has undergone subsequent modification over the years, culminating in the publication of the ISTH-BAT in 2010. Understanding the normal range of bleeding scores is critical when assessing the utility of a BAT. Within the context of The Merging Project, a bioinformatics system was created to facilitate the merging of legacy data derived from four different (but all Vicenza-based) BATs; the MCMDM1-VWD BQ, the Condensed MCMDM-1VWD BQ, the Pediatric Bleeding Questionnaire and the ISTH-BAT. Data from 1040 normal adults and 328 children were included in the final analysis, which showed that the normal range is 0–3 for adult males, 0–5 for adult females and 0–2 in children for both males and females. Therefore, the cut-off for a positive or abnormal BS is ≥4 in adult males, ≥6 in adult females and ≥3 in children. This information can now be used to objectively assess bleeding symptoms as normal or abnormal in future studies.
Background Challenges in reporting subjective hemorrhagic symptoms consistently has led to the need for standardized, quantitative Bleeding Assessment Tools (BATs), some of which assign Bleeding Scores (BSs). The ISTH-BAT (International Society on Thrombosis and Hemostasis – Bleeding Assessment Tool (Rodeghiero et al JTH 2010; 8:2063)) aimed to consolidate and optimize advances made by its predecessors, which were based on the 2005 “Vicenza Bleeding Questionnaire”. It is important to note, however, that the scoring systems differ among the BATs, with each bleeding symptom scored from 0 to +3 for the original Vicenza, -1 to +4 for the MCMDM-1VWD and Condensed MCMDM-1VWD Bleeding Questionnaires and the PBQ (Pediatric Bleeding Questionnaire), and 0 to +4 for the ISTH-BAT. As a result, the normal ranges of BSs vary among questionnaires. To date, the normal range for the ISTH-BAT has not been established; the objective of this study was to determine the normal range of bleeding scores for the ISTH-BAT for both adults and pediatric patients. Patients and Methods BS data from different studies, originally generated using 4 different Vicenza-based BATs, were compiled using a bioinformatics system created to facilitate the collation and analysis using different scoring systems. Demographic and BS data, along with blood group, VWF:Ag/VWF:RCo/FVIII:C (when available) were collected from all enrolled subjects. Data were derived from multiple studies; all defined normal subjects as those without a known problem with bleeding or bruising. All BATs were expert-administered. The normal range for both adults and pediatrics was determined by: 1) removing outliers > 3 SD away from the mean and then, 2) selecting the mid-95th %ile. Results 1,422 normal subjects were included (adult: n=1,079, pediatric: n=343). Adult data were collected using MCMDM-1VWD (n=294), Condensed MCMDM-1VWD (n=660), and ISTH-BAT (n=125), while pediatric data were collected using PBQ (n=324) and ISTH-BAT (n=19). 48 adults were removed from the analysis because they had BSs > 6.3, (i.e., >3 SD away from the mean), leaving n=1,031 for determination of the normal range. For children, BSs > 3.5 were judged to be outliers and therefore 18 children were removed, leaving n=325 children for determination of the normal range. The remaining adults had a mean age of 43 yrs (range 18 – 88) with 695 females and 336 males. The remaining children had a mean age of 9 yrs (range 0.4 – 17 yrs), with 169 females and 156 males. The relationship between BSs and demographic and lab data are given in Table 1. For the ISTH-BAT, the normal range of BSs was 0 - 4 in adults (meaning that for individuals 18 yrs or older, a BS 5 or greater is positive or abnormal) and 0 - 2 in children (meaning that for individuals < 18 yrs, a BS 3 or greater is positive or abnormal). Conclusion The newly established normal BS ranges can now be used to objectively assess the bleeding symptoms of individuals by administration of the ISTH-BAT. They also highlight the strength of merging existing datasets to generate meaningful results. By making these data accessible to all investigators using the web-based ISTH-BAT system housed at Rockefeller University we hope to aid investigators initiating new studies and facilitate correlating bleeding symptoms with genotypic, molecular, and environmental data. Disclosures: Mauer: CSL Behring: Honoraria. James:CSL Behring: Honoraria, Research Funding; Octapharma: Honoraria, Research Funding; Baxter: Honoraria; Bayer: Honoraria.
Protective immunity to protein vaccines is controlled by Flt3L-dependent classical LN-resident dendritic cells, and dampened by migratory dendritic cells.
Skin-derived dendritic cells (DC) are potent antigen presenting cells with critical roles in both adaptive immunity and tolerance to self. Skin DC carry antigens and constitutively migrate to the skin draining lymph nodes (LN). In mice, Langerin-CD11b− dermal DC are a low-frequency, heterogeneous, migratory DC subset that traffic to LN (Langerin-CD11b-migDC). Here, we build on the observation that Langerin-CD11b− migDC are Fms-like tyrosine kinase 3 ligand (Flt3L) dependent and strongly Flt3L responsive, which may relate them to classical DCs. Examination of DC capture of FITC from painted skin, DC isolation from skin explant culture, and from the skin of CCR7 knockout mice which accumulate migDC, demonstrate these cells are cutaneous residents. Langerin-CD11b-Flt3L responsive DC are largely CD24(+) and CX3CR1low and can be depleted from Zbtb46-DTR mice, suggesting classical DC lineage. Langerin-CD11bmigDC present antigen with equal efficiency to other DC subsets ex vivo including classical CD8α cDC and Langerin+CD103+ dermal DC. Finally, transcriptome analysis suggests a close relationship to other skin DC, and a lineage relationship to other classical DC. This work demonstrates that Langerin- CD11b− dermal DC, a previously overlooked cell subset, may be an important player in the cutaneous immune environment.
Mobilized peripheral blood has become the primary source of hematopoietic stem cells for both autologous and allogeneic stem cell transplantation. Granulocyte Colony-Stimulating Factor (G-CSF) is currently the standard agent used in the allogeneic setting. Despite the high mobilization efficacy in most donors, G-CSF requires 4-5 days of daily administration, and a small percentage of the donors fail to mobilize an optimal number of stem cells necessary for a safe allogeneic stem cell transplant. In this study, we retrospectively reviewed 1361 related allogeneic donors who underwent stem cell mobilization at Washington University. We compared the standard mobilization agent G-CSF with five alternative mobilization regimens, including GM-CSF, G-CSF+GM-CSF, GM-CSF + Plerixafor, Plerixafor and BL-8040. Cytokine-based mobilization strategies (G-CSF or in combination with GM-CSF) induce higher CD34 cell yield after 4-5 consecutive days of treatment, while CXCR4 antagonists (plerixafor and BL-8040) induce significantly less but rapid mobilization on the same day. Next, using a large dataset containing the demographic and baseline laboratory data from G-CSF-mobilized donors, we established machine learning (ML)-based scoring models that can be used to predict patients who may have less than optimal stem cell yields after a single leukapheresis session. To our knowledge, this is the first prediction model at the early donor screening stage, which may help identify allogeneic stem cell donors who may benefit from alternative approaches to enhance stem cell yields thus insuring safe and effective stem cell transplantation.
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