ABO blood group is associated with cardiovascular disease, with significantly lower risk in blood group O individuals. ABO(H) blood group determinants are expressed on different glycoproteins on platelet surfaces. In addition, ABO(H) structures are also present on VWF glycans. These ABO(H) carbohydrates influence both platelet and VWF function. Previous studies have reported that approximately 5–10% of normal blood donors express abnormally high or low levels of A or B blood group antigens on their platelet surfaces (high expresser phenotype, HXP or low expresser phenotype, LXP respectively). In this study, the biological effects of the ABO Expresser phenotype were investigated. ABO(H) expression on platelets and plasma VWF was studied in a series of 541 healthy blood donors. Overall, 5.6% of our study cohort were classified as HXP, whilst 4.4% satisfied criteria for LXP. We demonstrate that genotype at the ABO blood group locus plays a critical role in modulating the platelet HXP phenotype. In particular, A1A1 genotype is a major determinant of ABO high-expresser trait. Our data further show that ABH loading on VWF is also affected by ABO expresser phenotype. Consequently, A antigen expression on VWF was significantly elevated in HXP individuals and moderately reduced in LXP subjects (P < 0.05). Collectively, these findings suggest that ABO expresser phenotype influences primary hemostasis though several different pathways. Further studies will be required to define whether inter-individual variations in ABO(H) expression on platelets and/or VWF (particularly HXP and LXP) impact upon risk for cardiovascular disease.

Several variant RARA translocations have been reported in acute promyelocytic leukemia (APL) of which the t(11;17)(q23;q21), which results in a ZBTB16-RARA fusion, is the most widely identified and is largely resistant to therapy with all-trans retinoic acid (ATRA). The clinical course together with the cytogenetic and molecular characterization of a case of ATRA-unresponsive ZBTB16-RARA APL is described. Additional mutations potentially cooperating with the translocation fusion product in leukemogenesis have been hitherto unreported in ZBTB16-RARA APL and were sought by application of a next-generation sequencing approach to detect those recurrently found in myeloid malignancies. This technique identified a solitary, low level mutation in the CEBPA gene. Molecular profiling of additional mutations may provide a platform to individualise therapeutic management in patients with this rare form of APL.

2119 Poster Board II-96 ABO(H) blood group antigen expression on platelets varies widely among normal blood donors. An ABO ‚High Expresser' phenotype (HXP) that exhibits significantly increased A and/or B antigen expression on platelets has been identified in ∼7% of normal donors. HXP has been implicated in both platelet-refractoriness and neonatal alloimmune thrombocytopenic purpura, however, the underlying molecular and genetic elements that mediate this phenomenon are not well-defined. To investigate the mechanisms underlying HXP, blood samples were collected from 231 group A (180 A1and 51 A2) and 310 group O individual apheresis platelet donors. Quantitative expression of platelet A and H antigen were then assessed by flow cytometry of platelet-rich plasma. In total, 10 A1 donors (5.6%) exhibited HXP. Analysis of the platelet A antigen expression in these individuals identified 8 HXP donors who exhibited ‚type I' HXP (normal bimodal population of platelets, but with predominant A antigen expression) whereas 2 individuals exhibited ‚type II' HXP (a single uniform population of platelets, strongly positive for blood group A expression). Both types of HXP were found to be a stable donor characteristic. ABO(H) determinants have also been identified on the N-linked glycans of the plasma von Willebrand factor (VWF), and influence plasma VWF levels and susceptibility to proteolysis by ADAMTS13. To determine whether HXP was platelet-specific, blood group A antigen expression on plasma VWF from group A donors was determined. Interestingly, blood group A antigen expression on plasma VWF was concordantly increased in donors with type I and type II HXP, indicative of increased glycosyltransferase expression in HXP individuals. To ascertain whether increased glycosyltransferase expression contributes to HXP, ABO genotype was determined for all 231 group A donors by PCR-RFLP analysis. Genotype at the ABO locus on 9q34 exerts a dosage effect on glycosyltransferase expression. 80% HXP (all type I) donors were genotyped A1A1. suggesting increased A transferase activity contributes to type I HXP. Despite this, the majority of A1A1individuals (67%) did not exhibit HXP, and 2 HXP donors were found to possess the A2 allele, which expresses limited A transferase enzymatic activity. Collectively, this data clearly demonstrates the contribution of additional factors to ABO genotype that contribute to HXP. To identify additional HXP modifiers, potential enhancer repeat elements upstream of the ABO gene were examined in group A donors, including those with HXP. Typically, A1alleles contain a single 43-base pair repeat within a minisatellite positive regulatory region upstream of the ABO gene. In contrast, A2and O1alleles contain four 43bp repeats, which are associated with a 100-fold enhancement of transcriptional activity. Analysis of this enhancer region demonstrated two HXP donors with A1alleles containing four copies of the 43-base pair repeat. Consequently, this allele would be predicted to modulate A transferase expression via enhanced ABO gene transcription. In conclusion, we have demonstrated the multi-factorial nature of the regulatory elements mediating platelet type I and type II HXP. A1alleles containing novel upstream enhancer repeats identified in donor individuals may represent a novel genetic mediator of HXP, and contribute to the pathophysiology associated with this phenomenon independently of ABO genotype. Disclosures: No relevant conflicts of interest to declare.

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Background: While alarms on hospital telemetry units are vital to patient safety, alarm fatigue is a well-established and potentially dangerous consequence. Our goal was to implement an alarm management pilot to systematically determine how to safely reduce alarm burden. Methods: The Brigham and Women’s Hospital Monitoring Steering Committee (BWH MSC) studied the effect of alarm fatigue from March to November 2014 in a multiweek, phased pilot (Figure 1). The intervention groups were two medical/surgical stepdown units (group 1) and three cardiac stepdown units (group 2). The control group was a combination of two medical/surgical units and one cardiac stepdown unit. Various interventions were performed in a stepwise and cumulative manner. Electrodes were switched on a daily basis. The high heart rate (HR) alarm threshold was increased from 120 to 130 beats per minute (bpm) and the low HR threshold was decreased from 50 to 45 bpm. Duplicate alarms (e.g. “tachy” alarm same as high HR parameter alarm) and non-actionable alarms (e.g. “couplets”) were switched to messages (non-audible). Alarm data was pulled and analyzed on a weekly basis. Results: At baseline, there was wide fluctuation in alarms monitored/week across all three groups; however, the peak alarm unit averaged roughly 400 audible, unique alarms/bed/day. Heart rate alarms decreased by 54% after phase 2 in group 1 and 48% after phase 2 in group 2 (Figure 1). Audible alarms were reduced in phase 3 and 4, most notably by making non-actionable alarms inaudible (34% decrease in phase 3 in group 1, 64% decrease in phase 4 in group 2). Electrode alarms appeared to be mildly reduced in phase 1 and 2 (4-24%), however, these findings were not consistent in phase 3 and 4. Conclusions: Alarm type and burden varied widely across time and hospital units, making it difficult to generalize interventions. However, based on the pilot results, the BWH MSC implemented the following changes across all telemetry units: 1) high HR limit and low HR limits were made more permissive as above, and 2) duplicate and non-actionable alarms were made non-audible. The latter intervention was thought to provide the greatest impact based on our experience. While this pilot represented a systematic approach to reduce alarm burden, ongoing efforts to safely improve alarm burden are warranted.