bluuebunny/crossref_metadata_2025_split huggingface dataset:
PS1480 INTERLEUKIN‐37 REDUCES INFLAMMATION AND IMPAIRS PHAGOCYTOSIS OF PLATELETS IN IMMUNE THROMBOCYTOPENIA
Authors: Zhao Y. , Li G. , Liu X. , Peng J. , Hou M. 
Published: June 2019

Background:Immune thrombocytopenia (ITP) is an autoimmune and inflammatory disease characterized by low platelet count with heterogeneous bleeding manifestations. Severe bleeding in ITP is not completely related with low platelet count. Thus, there is a great need for reliable indicators of the susceptibility of bleeding in ITP patients. Interleukin‐37 (IL‐37) is an anti‐inflammatory cytokine that participates in the process of several inflammatory and autoimmune diseases. However, the role of IL‐37 in the pathogenesis of ITP is unknown.Aims:Our study aimed to evaluate the regulatory role of IL‐37 in the process of ITP and its association with disease severity.Methods:Plasma IL‐37 was detected by enzyme‐linked immunosorbent assay (ELISA). We cultured the monocytes/macrophages from ITP patients to investigate the regulatory role of IL‐37 on monocytes/macrophages. Fcγ receptors (FcγRs) of macrophages were analyzed using flow cytometry and q‐PCR. Signaling pathways were determined by western blotting. Phagocytic capacity of macrophages was measured by the engulfment of opsonized platelets.Results:Plasma and mRNA levels of the anti‐inflammatory cytokine IL‐37 were elevated in ITP patients with platelet counts below 30 × 109 /L compared to healthy controls and to ITP patients with platelet counts above 30 × 109 /L. Furthermore, plasma IL‐37 levels correlated with the platelet number and IBLS bleeding scores of ITP patients. Specifically, ITP patients with skin and oral bleeding symptoms had higher plasma IL‐37 levels than patients without these bleeding symptoms. Patients with more severe skin and oral bleeding exhibited higher plasma IL‐37 levels, indicating that IL‐37 could be a candidate in evaluating disease severity of ITP. IL‐37 initiated an anti‐inflammatory effect on monocytes/macrophages from ITP patients by down‐regulating the phosphorylation of MAPK, AKT, and NF‐κB signaling pathways, which are pivotal in mediating inflammation. Moreover, IL‐37 restored the balance of activating and inhibitory FcγRs (Figure 1) and decreased antibody‐mediated platelet phagocytosis by monocytes/macrophages, suggesting that IL‐37 might be a potential therapeutic agent in ITP.Summary/Conclusion:Our study demonstrated that ITP patients exhibited higher IL‐37 expression, especially patients with severe hemorrhage or low platelet count. IL‐37 decreased antibody‐mediated platelet phagocytosis, restored the balance of activating and inhibitory FcγRs, and inhibited inflammatory activity via MAPK, AKT, and NF‐κB signaling pathways among monocytes/macrophages. Therefore, IL‐37 might be a candidate in evaluating the severity of ITP and a promising therapeutic agent for the management of ITP.image
PS1487 EFFECT OF PLASMA EXCHANGE ON THE PHARMACOKINETICS AND PHARMACODYNAMICS OF CAPLACIZUMAB
Authors: Sargentini L. , Hansson E. , Bergstrand M. , Callewaert F. , Sousa R. 
Published: June 2019

Background:During clinical trials in patients with acquired thrombotic thrombocytopenic purpura, caplacizumab was administered as a 10 mg intravenous (iv) bolus prior to plasma exchange (PE), followed by 10 mg daily subcutaneous (sc) doses during the daily PE period and at least 30 days thereafter.Aims:The potential effect of different time intervals between the first iv bolus and the subsequent PE, and the effect of different PE schedules, have been investigated.Methods:An integrated pharmacokinetic (PK)/pharmacodynamic (PD) model was developed to describe the interaction between caplacizumab and vWF using non‐linear mixed effects modeling and used to simulate the resulting PK and PD for different predetermined scenarios:1) PE start 3, 5, 11, 23 h post‐caplacizumab 10 mg iv bolus2) PE schedule: daily and twice per day (bid) at the first day or during 7 daysResults:Data from clinical trials indicate complete neutralization of vWF activity for caplacizumab peak plasma concentrations ≥500ng/mL. Simulations suggest that median caplacizumab peak plasma levels would remain above this threshold if the PE starts up to 5 h post‐caplacizumab iv bolus. For longer delays median caplacizumab peak plasma levels can fall below 500ng/mL, and an additional 10 mg sc dose prior to PE can maintain an effective drug exposure.Simulations of the effect of a bid PE for 7 days, suggest that the sc dosing schedule of caplacizumab during the PE period could be adjusted with bid 10 mg caplacizumab sc dosing after each PE treatment during the time of bid PE treatment.Summary/Conclusion:Effective drug levels are expected if PE is started up to 5 h following the first iv dose of caplacizumab. For longer delays, an additional 10 mg sc dose prior to PE can be envisaged.In case of bid PE for 7 days, the sc administration schedule of caplacizumab could be adjusted with bid caplacizumab after each PE treatment.
PS1491 PLATELET KINETICS IN PATIENTS WITH CHRONIC IMMUNE THROMBOCYTOPENIA TREATED WITH THROMBOPOIETIN RECEPTOR AGONISTS
Authors: Pravdic Z. , Mitrovic M. , Todorovic‐Tirnanic M. , Virijevic M. , Sabljic N. , Suvajdzic‐Vukovic N. 
Published: June 2019

Background:Chronic immune thrombocytopenia (ITP) is characterised by antibody‐mediated platelet destruction, shortened platelet survival (PS) and impaired platelets production. Platelet kinetic study (PKS) assesses in vivo the mean PS, platelet production and the platelet sequestration site. Thrombopoietin receptor agonists (TPO‐RA) increase platelets counts (PC) in majority of chronic ITP patients. Moreover, some patients could retain stabile response after TPO‐RA discontinuation, which is attributed to the immunomodulatory effects of the drugs. Addressing this issue only a few studies have been done assessing the effect of TPO‐RA on PKS parameters.Aims:To evaluate the effects of TPO‐RA on PKS parameters.Methods:Ten patients with chronic ITP, median age 55.3 years (range 12–72), gender (f: n = 7, m: n = 3), splenectomised 6/10, were treated with TPO‐RA (eltrombopag, n = 7, romiplostim, n = 3). Response was assessed according to the criteria of the International Working Group (IWG) on ITP. Autologous 111Induim‐oxinate‐labeled PKS were performed in all patients before and 5 months after TPO‐RA therapy initiation.Results:A good treatment response was achieved in 8/10 of patients (eltrombopag, n = 6, romiplostim, n = 2). Two refractory patients were treated with TPO‐RA and low dose prednisolone. Baseline median parameters were as follows: PC 6.5x109/L (range 1–17), PS 0.5 days (range 0.1–1.6, normal: 7–10), platelet production ratio 0.65 (range 0.01–3.2, normal 1 ± 0.2), platelet turnover 30875 Plt/μL/day (range 1731–103500). The post−treatment PKS showed significantly higher median PC of 62.5x109/L (range 5–501) (p = 0.013) and median platelet production ratio of 1.8 (range 0.5–37.9) (p = 0.05). However, median PS of 0.7 days (range 0.1–2.9) (p = 0.09), as well as platelet turnover of 58471.5 Plt/μL/day (range 2800–462236) (p = 0.086) and platelet destruction site remained unaltered. It is of note that two refractory patients (N08 and N010 in table) increased their platelet production (platelet production ratio and platelet turnover), while their PS remained reduced. It is of note that there was no clear correlation between PC and PS. Nevertheless, PC correlated only with platelet turnover prior (p = 0.006) and after TPO‐RA therapy (p = 0.029).Summary/Conclusion:Our prospective study in which PKS was performed initially and during TPO‐RA therapy suggests that TPO‐RA could increase PC by augmented production. Further studies on larger cohorts are needed to confirm this idea.image
PS1494 REDUCED ANTIOXIDANT CAPACITY INDUCED PYROPTOSIS IN PLATELETS IN IMMUNE THROMBOCYTOPENIA PATIENTS
Authors: Wang S. , Liu Y. , Hou M. , Peng J. 
Published: June 2019

Background:The pathophysiology of primary immune thrombocytopenia (ITP) is not fully understood. Antioxidant capacitie (AOC) is reduced in ITP platelets. Mitochondrial reactive oxygen species (ROS) generation can lead to NLRP3 inflammasome activation and pyroptosis. However, the process has not been studied in ITP platelets.Aims:To assess whether the reduced AOC of platelets in ITP can affect the NLRP3 inflammasome signaling pathways and to further explore the pathophysiology of ITP.Methods:We measured mitochondrial membrane potential (MMP) of platelets from patients and healthy donors using JC‐1 by flow cytometry. Next, we investigated AOC of platelets by supplementation of 300 μM H2O2following loading with 50 μM 2’,7’‐dichlorodihydrofluorescein diacetate. ROS level as well as expression of NLRP3, ASC, pro‐caspase‐1 and p20 in platelets after stimulation with H2O2was detected. Besides, co‐localization of NLRP3 and ASC in platelets after stimulation was assessed by immunofluorescence. Blocking experiments were performed using antioxidant N‐Acetyl‐L‐cysteine, NLRP3 inhibitorMCC950 (CP‐456773) and caspase‐1 inhibitorZ‐VAD‐FMK. Furthermore, we studied the pyroptosis of platelets in passive ITP mouse model using NLRP3‐/‐ mice, Caspase‐1‐/‐ mice and wild type mice.Results:The platelets from ITP patients showed significantly reduced antioxidant capacity compared to healthy donors. A significant lower MMP and higher ROS level were detected in ITP platelets. Expression of NLRP3, ASC, pro‐caspase‐1 and p20 was obviously increased and co‐localization of NLRP3 and ASC was more evident in ITP platelets. An increased level of IL‐1β and IL‐18 were observed in culture supernatant. The application of antioxidant N‐Acetyl‐L‐cysteine (NAC), NLRP3 inhibitor MCC950(CP‐456773) and caspase‐1 inhibitor Z‐VAD‐FMK to H2O2‐stimulated ITP platelets significantly inhibit pyroptosis. The indicators of pyroptosis were down‐regulated in NLRP3‐/‐ and Caspase‐1‐/‐ mice.Summary/Conclusion:The reduced AOC of platelets in ITP results in accumulation of intracellular ROS, which contributes to the activation of NLRP3 inflammasome signaling pathways and leads to pyroptosis, which accelerates thrombocytopenia in ITP.image
PS1507 INCREASED VOC FREQUENCY ASSOCIATED WITH REDUCED HRQOL AMONG PATIENTS WITH SCD
Authors: Besser M. , Bailey M. , Brown S. , Thompson M. 
Published: June 2019

Background:Sickle cell disease (SCD) is a global health concern. Each year as many as 200,000 infants are born with this disease worldwide. Despite improvements in outcomes over the last few decades, patient life expectancy remains 10 to 30 years shorter than that of the healthy population. A major cause of morbidity among patients with SCD is the occurrence of intense, recurrent, acute, severely painful episodes, known as vaso‐occlusive crisis (VOCs). As patients age and SCD progresses, an increased frequency of VOCs and other disease‐related complications is correlated with an increased risk of morbidity and mortality.Aims:The aim of the current analysis was to determine whether VOC frequency is associated with a decrease in the health‐related quality of life (HRQoL) and associated utility of patients with SCD.Methods:LEGACY was a prospective, multicenter, observational study that documented the outcomes of 181 adult patients with SCD living in the United States. Patients were assessed at baseline and every six months for 3 years, on several health outcomes, including the number of VOCs experienced and patient health as assessed by the Short Form‐36 (SF‐36) Health Survey. For the cohort of patients aged 18 years and older, the total number of VOCs experienced over the previous 12 months was determined for each administration of the SF‐36. Patients were categorized into three groups:‐ 0 VOCs in the previous 12 months‐ 1 to 2 VOCs in the previous 12 months‐ 3 or more (3+) VOCs in the previous 12 monthsThe SF‐36 scores for individual questionnaires were then mapped to the EuroQoL five‐dimension (EQ‐5D) questionnaire, which is a standardized instrument that can be used to derive a single utility value. The mapping was done using the random effects GLS mapping algorithm published by Rowan and colleagues (2009). Mean EQ‐5D scores were compared between groups using the Student's T‐test. Differences between the groups on the SF‐36 component scores and SF‐36 domains were also assessed.Results:Patients with 3+ VOC events in the previous 12 months had mapped mean EQ‐5D scores that tended to be lower (15%) than those of patients who had no VOC events (see Figure 1). Patients who had 3+ VOC events also showed decreases in both SF‐36 Physical Component Scores and Mental Component Scores compared to patients with no VOC events.Summary/Conclusion:To our knowledge, this is the first analysis to examine the relationship between VOC frequency and HRQoL in patients with SCD. The results of this analysis indicate that patients who have a higher number of VOC events experience a worse HRQoL compared to patients with no events. Additional research is required to understand the drivers of this difference in HRQoL.image
PS1513 ESTIMATING LIFE‐YEAR LOSS OF PRIMARY MYELOFIBROSIS IN EUROPE
Authors: Li Z. , Tang D. , Tang J. , Cavalli L. , Oliva E. 
Published: June 2019

Background:Primary myelofibrosis (PMF) is a myeloid neoplasm impacting patient survival and quality of life. Although JAK2 inhibitors were recently approved for the treatment of patients with PMF, there is still a lack of strong evidence supporting a survival benefit in this patient population.1 Existing published survival data focus on describing duration of survival, however as there is no general population comparator for this outcome, interpretations are often subjective.Aims:This study aimed to quantify the real‐world mortality caused by PMF in comparison with the general population in Germany, France, Italy, Spain, and the UK (EU5).Methods:A simulation model was developed in Microsoft Excel, using parameters sourced from a large‐scale European‐based real‐world retrospective MF study by the International Working Group for Myeloproliferative Neoplasm Research and Treatment.2 Baseline demographics predictive of survival, including age, sex, and International Prognostic Scoring System (IPSS) risk level, were simulated using the patient characteristics statistics published by Cervantes et al. in 2012.2 The survival of patients with PMF was simulated using the exponential survival function. To examine the rate of mortality, the exponential distribution parameter (modeled as a function of age, sex, and IPSS risk level) was estimated using published median survival times and derived hazard ratios. Patient characteristics and survival statistics from the simulation sample were verified with the published data.2 Real‐world life‐year loss was calculated as the difference between simulated survival time and the population‐level life expectancy specific to the patient's age, sex, and country.Results:A total of 5,000 patients were simulated (Table), with 1,000 from each EU5 country. The simulated sample generated similar patient characteristics statistics and median survival years as found by Cervantes et al.2 The additional mean life‐year loss of PMF was estimated at 9.6 years (median 10.7 years; 5 and 95 percentile [−18.7, 33.4]), with a 45% relative survival loss, compared with the general population. Overall, 81% of patients with PMF were estimated to experience life‐year loss. More pronounced life‐year loss was found to be associated with being male (mean 11.3 years; 57% relative survival loss; 86% with life‐year loss), age <65 years (mean 14.3 years; 48% relative survival loss; 84% with life‐year loss), and IPSS Intermediate‐2 to High risk classification (mean 15.4 years; 73% relative survival loss; 95% with life‐year loss). The results were consistent among the EU5 countries modeled.Summary/Conclusion:PMF patients experience significant real‐world life‐year loss when compared with the general population in Europe.image
PS1549 SELF‐REPORTED PHYSICAL ACTIVITY IS PREDICTIVE OF SURVIVAL IN ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION (HCT)
Authors: Jayani R. , Pidala J. , Jim H. , Zhou J. , Mo Q. , Mishra A. 
Published: June 2019

Background:Increased physical activity is associated with improved survival in patients undergoing cancer treatment. However, the association of self‐reported physical activity and activity intensity with HCT outcomes is less clear.Aims:The goal of this study is to evaluate the relationship of self‐reported physical activity and HCT outcomes.Methods:Data was collected from the Moffitt Cancer Center Health Research Informatics and transplant databases. Between 01/01/2011 and 7/5/2018, 587 patients received an allogeneic HSCT and completed IPAQ short form. IPAQ scoring algorithm was used to ascertain metabolic equivalent of task‐minutes (MET‐minutes) per day. Based on MET‐minutes/day aggregate score, patients were subsequently divided into three activity categories: low (n = 337), moderate (n = 52), and vigorous (n = 198).Results:Median follow‐up was 41.7 months (range 11.4–267months). Patients with lower physical activity were older (Age = 59.67 [20.3–75.4] and had more comorbidities (HCT‐CI = 3 [0–9]), in comparison to patients with moderate and vigorous activity. Males reported vigorous activity more commonly (66.7%) in comparison to females (33.3%) whereas low activity level was similar for each gender (females 51.3%, males 48.7%). There was no significant difference in Karnofsky performance status (KPS), Armand disease risk, conditioning intensity, number of prior chemotherapy regimens, and cardiopulmonary function amongst the three categories (Table 1). Patients with vigorous physical activity had lower risk of NRM in comparison to low and moderate activity (Figure 1). In multivariate modeling, after accounting for KPS, graft‐versus host disease, and FEV1, physical activity level was an independent predictor of non‐relapse mortality with lower activity levels associated with increased risk of NRM (HR: low 1.7 (95% CI: 1.07–2.93); moderate 2.11 (95% CI: 1.03–4.31); overall P = 0.049). However, no association was seen between activity level and overall survival or relapse free survival (P = NS).Summary/Conclusion:Self‐reported vigorous activity prior to HCT is an independent predictor of NRM after HCT. This easy to employ tool can be of utility in the clinic to risk stratify HCT candidates. Further studies are warranted to evaluate impact of self‐reported physical activity on HCT outcomes.image
PS1588 FIBRINOLYSIS IN PATIENTS WITH CHEMOTHERAPY INDUCED THROMBOCYTOPENIA AND THE EFFECT OF PLATELET TRANSFUSION
Authors: Heubel‐Moenen F. , Henskens Y. , Verhezen P. , Wetzels R. , Schouten H. , Beckers E. 
Published: June 2019

Background:Bleeding events in chemotherapy induced thrombocytopenic (CIT) patients with similar platelet counts might be influenced by changes in clot lysis potential.Aims:In this observational study we investigated thromboelastographic lysis parameters, alterations in clot strength and susceptibility to clot lysis in CIT patients and identified factors associated with fibrinolytic profiles. Furthermore, the effects of platelet transfusions were evaluated.Methods:Independent determinants of tPA‐ROTEM lysis parameters were identified with multivariable linear regression. Clot formation, strength and lysis parameters were compared with results of healthy individuals. Characteristics of CIT patients with and without hyperfibrinolytic profiles were compared. tPA‐ROTEM results before, 1 hour and 24 hours after platelet transfusion were compared.Results:A total of 72 consecutive CIT patients were included. tPA‐ROTEM lysis parameters correlated with changes in fibrinolytic proteins. Compared to healthy individuals, clot formation time was longer, maximum clot firmness was weaker and lysis times were shorter. CIT patients had low PAI‐1 and TAFI levels and forty percent exhibited hyperfibrinolytic profiles. Platelet transfusions resulted in less hyperfibrinolytic profiles in many, but not all CIT patients. Patients without hyperfibrinolytic profiles had higher fibrinogen, FVIII and a2‐AP levels.Summary/Conclusion:tPA‐ROTEM can be used as a fast and reliable assay to detect hyperfibrinolytic profiles in CIT patients. CIT patients have weaker clots which are more susceptible to clot lysis compared to healthy individuals. Besides platelets, other factors are likely to influence clot susceptibility to fibrinolysis in CIT patients. The impact of a hyperfibrinolytic tPA‐ROTEM profile on bleeding remains to be investigated.
PS1589 RETROSPECTIVE ANALYSIS OF HEMOGLOBIN LEVEL IN 500 TRANSFUSION EVENTS AS A STUDY MODEL FOR THE EVALUATION OF TRANSFUSION APPROPRIATENESS
Authors: Crocchiolo R. , Cuppari I. , Boiani E. , Cesana C. , Cornacchini G. , Ferrera A. , Lando G. , Mazza A.M. , Pugliano M.T. , Sica L. , Volpato E. , Rossini S. 
Published: June 2019

Background:The hemoglobin (Hb) value adopted in the real life setting for the clinical decision of packed red blood cell (RBC) transfusion (transfusion trigger) is sometimes difficult to accurately retrieve and could be different to what is indicated in the blood request. The identification of the transfusion trigger is critical for the analysis of the distinct physicians’ attitudes across the different units within the same hospital and for the dissection of transfusion appropriateness.Aims:The aims of the present analysis is to compare the transfusion trigger across the multiple medical and surgical units at our Center and to describe the Hb values before and after the transfusion events. Further, considerations about the feasibility and the potential applications of this analytical approach are discussed.Methods:Data extraction procedure focused on the first semester 2018, dealing with transfusion episodes of 1–2 packed RBCs administered to patients hospitalised at ASST GOM Niguarda, Milan, Italy. Each single episode was registered, regardless of the number of the total packed RBCs transfused, as well as the Unit where the patient was admitted and the Hb values at admission, before and after the transfusion, together with the respective date and time. Comparisons analyses were made using the classical statistical tests. The Hb value before the transfusion is considered as the trigger for transfusion decision by the physician(s) in charge of the patients.Results:On a total of n = 501 episodes, n = 497 were evaluable for completeness of data. The corresponding number of packed RBCs represents the 2% of all the packed RBCs transfused at our Hospital in one year (n = 22170 in 2018). Median Hb was 10.70 (range: 6.30–16.70), 8.60 (range:3.00–15.10) and 10.30 (range: 5.00–16.30) at admission, before and after transfusion, respectively. Analyzing separately by unit, we observed that the transfusion trigger was higher in Cardiac Surgery, Vascular Surgery and Intensive Care Units, with median values of 9.50, 8.75 and 8.70 respectively. Conversely, transfusion trigger was comparable among the other surgical units (including Orthopedics) and the medical ones: Hb median values were 8.20, 8.20 and 8.30 respectively. Cardiology showed a slightly higher trigger: 8.65 when compared with the other non‐surgical units.Summary/Conclusion:The present analysis, accounting for « only » the 2% of the total transfusion burden at our Hospital in 2018, allows for a satisfactory definition of the transfusion trigger across the multiple medical and surgical units as well as the confirmation of the expected post‐transfusion Hb values. Our analysis model supports the feasibility of such an approach as a potential audit instrument and intervention policies in the area.