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Background: The ISTH Bleeding Assessment Tool (ISTH-BAT) has been validated for clinical screening of suspected von Willebrand disease (VWD) and for bleeding prediction. Recently it has been validated for subjects with inherited platelet disorders (IPD) (BAT-VAL study). Objectives: To determine whether the ISTH-BAT bleeding score (BS) predicts subsequent bleeding events requiring treatment in IPD patients. Methods: Patients with IPD, type 1 VWD (VWD-1) and age- and sex-matched healthy controls enrolled in the BAT-VAL study were prospectively followed-up for 2years and bleeding episodes requiring treatment were recorded. Results: Of the 1098 subjects initially enrolled, 955 were followed-up and 124 suffered hemorrhages during follow-up, 60% of whom had inherited platelet function disorders (IPFD). Total number of events was significantly higher in IPFD (n=235) than VWD-1 (n=52) or inherited thrombocytopenia (IT; n=20). Events requiring transfusions were 66% in IPFD, 5.7% in VWD-1, and 3% in IT. Baseline BS was significantly higher in IPFD patients with a bleeding event at follow-up than in those without (p&nbsp

In Italy, rifampicin-resistant and MDR-TB were high in foreign-born persons, but decreased from 2009 to 2016

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare, life-threatening thrombotic microangiopathy caused by severe ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin motifs 13) deficiency, recurring in 30&ndash, 50% of patients. The common human leukocyte antigen (HLA) variant rs6903608 was found to be associated with prevalent iTTP, but whether this variant is associated with disease relapse is unknown. To estimate the impact of rs6903608 on iTTP onset and relapse, we performed a case-control and cohort study in 161 Italian patients with a first iTTP episode between 2002 and 2018, and in 456 Italian controls. Variation in rs6903608 was strongly associated with iTTP onset (homozygotes odds ratio (OR) 4.68 (95% confidence interval (CI) 2.67 to 8.23), heterozygotes OR 1.64 (95%CI 0.95 to 2.83)), which occurred over three years earlier for each extra risk allele (&beta, &minus, 3.34, 95%CI &minus, 6.69 to 0.02). Of 153 survivors (median follow-up 4.9 years (95%CI 3.7 to 6.1)), 44 (29%) relapsed. The risk allele homozygotes had a 46% (95%CI 36 to 57%) absolute risk of relapse by year 6, which was significantly higher than both heterozygotes (22% (95%CI 16 to 29%)) and reference allele homozygotes (30% (95%CI 23 to 39%)). In conclusion, HLA variant rs6903608 is a risk factor for both iTTP onset and relapse. This newly identified biomarker may help with recognizing patients at high risk of relapse, who would benefit from close monitoring or intensified immunosuppressive therapy.

ObjectivesThe aim of this study was to investigate the association between high on-treatment platelet reactivity (HPR) and the SYNTAX (Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery) score (SS) for risk prediction of major adverse cardiovascular events (MACE) in patients with non–ST-segment elevation acute coronary syndrome (NSTEACS) undergoing percutaneous coronary intervention (PCI).BackgroundPlatelet function testing may be used to optimize antiplatelet therapy in high-risk patients, but identification of this category of patients remains challenging.MethodsThe GEPRESS (Gene Polymorphism, Platelet Reactivity, and the Syntax Score) study was a prospective, multicenter, observational study enrolling 1,053 patients with NSTEACS undergoing PCI and treated with clopidogrel. The platelet reactivity index (PRI) was measured at 3 time points: before PCI, at hospital discharge, and 1 month after PCI. Genetic variants of clopidogrel metabolism were determined in 750 patients. Patients were stratified by the presence of HPR (PRI >50%) and by tertile of the SS (upper SS tertile ≥15). The primary objective of this study was the risk of MACE in the period between 1 month and 1 year.ResultsBetween 1 month and 1 year, 1-month HPR was an independent predictor of MACE in patients with an SS ≥15, but not in those with an SS

Essentials Genetic predisposition to acquired thrombotic thrombocytopenic purpura (aTTP) is mainly unknown. Genetic risk factors for aTTP were studied by Immunochip analysis and replication study. Human leukocyte antigen (HLA) variant rs6903608 conferred a 2.5-fold higher risk of developing aTTP. rs6903608 and HLA-DQB1*05:03 may explain most of the HLA association signal in aTTP. Click to hear Dr Cataland's presentation on acquired thrombotic thrombocytopenic purpura. Summary: Background Acquired thrombotic thrombocytopenic purpura (TTP) is a rare, life-threatening thrombotic microangiopathy associated with the development of autoantibodies against the von Willebrand factor-cleaving protease ADAMTS-13. Similarly to what has been found for other autoimmune disorders, there is evidence of a genetic contribution, including the association of the human leukocyte antigen (HLA) class II complex with disease risk. Objective To identify novel genetic risk factors in acquired TTP. Patients/Methods We undertook a case–control genetic association study in 190 European-origin TTP patients and 1255 Italian healthy controls by using the Illumina Immunochip. Replication analysis in 88 Italian cases and 456 controls was performed with single-nucleotide polymorphism (SNP) TaqMan assays. Results and conclusion We identified one common variant (rs6903608) located within the HLA class II locus that was independently associated with acquired TTP at genome-wide significance and conferred a 2.6-fold increased risk of developing a TTP episode (95% confidence interval [CI] 2.02–3.27, P = 1.64 × 10−14). We also found five non-HLA variants mapping to chromosomes 2, 6, 8 and X that were suggestively associated with the disease: rs9490550, rs115265285, rs5927472, rs7823314, and rs1334768 (nominal P-values ranging from 1.59 × 10−5 to 7.60 × 10-5). Replication analysis confirmed the association of HLA variant rs6903608 with acquired TTP (pooled P = 3.95 × 10-19). Imputation of classic HLA genes followed by stepwise conditional analysis revealed that the combination of rs6903608 and HLA-DQB1*05:03 may explain most of the HLA association signal in acquired TTP. Our results refined the association of the HLA class II locus with acquired TTP, confirming its importance in the etiology of this autoimmune disease.

Background. The gray platelet syndrome (GPS) is a rare inherited bleeding disorder characterized by macrothrombocytopenia and deficiency of alpha-granules in platelets. The genetic defect responsible for GPS was recently identified in biallelic mutations in the NBEAL2 gene. Design and Methods. We studied 11 consecutive families with inherited macrothrombocytopenia of unknown origin and alpha-granule deficiency. All of them underwent NBEAL2 DNA sequencing and evaluation of the platelet phenotype, including a systematic assessment of the alpha-granule content by immunofluorescence analysis for alpha-granule secretory proteins. Results. We identified 9 novel mutations hitting the two alleles of NBEAL2 in 4 probands. They included missense, nonsense and frameshift mutations, as well as nucleotide substitutions that altered the splicing mechanisms as determined at the RNA level. All the individuals with NBEAL2 biallelic mutations showed almost complete absence of platelet -granules. Interestingly, the 13 individuals assumed to be asymptomatic because carriers of a mutated allele had platelet macrocytosis and significant reduction of the -granule content. However, they were not thrombocytopenic. In the remaining 7 probands, we did not identify any NBEAL2 alterations, suggesting that other genetic defect(s) are responsible for their platelet phenotype. Of note, these patients were characterized by a lower severity of the -granule deficiency than individuals with two NBEAL2 mutated alleles. Conclusions. Our data extend the spectrum of mutations responsible for GPS and demonstrate that macrothrombocytopenia with α-granule deficiency is a genetic heterogeneous trait. In terms of practical applications, the screening of NBEAL2 is worthwhile only in patients with macrothrombocytopenia and severe reduction of the α-granules. Finally, individuals carrying one NBEAL2 mutated allele have mild laboratory abnormalities, suggesting that even haploinsufficiency has an effect on platelet phenotype. Fil: Bottega, Roberta. University of Trieste. Department of Medical Science; Italia; Fil: Pecci, Alessandro. University of Pavia and IRCCS Policlinico San Matteo Foundation. Department of Internal Medicine; Italia; Fil: de Candia, Erica. Università Cattolica del Sacro Cuore. Hemostasis and Thrombosis Unit, Policlinico Agostino Gemelli; Italia; Fil: Pujol-Moix, Nuria. Universitat Autònoma de Barcelona. Hospital de la Santa Creu i Sant Pau; España; Fil: Heller, Paula Graciela. Consejo Nacional de Invest.cientif.y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto de Invest.Medicas; Argentina; Fil: Noris, Patrizia. University of Pavia and IRCCS Policlinico San Matteo Foundation. Department of Internal Medicine; Italia; Fil: de Rocco, Daniela. Institute for Maternal and Child Health - IRCCS "Burlo Garofolo"; Italia; Fil: Podda, Gian Marco. Università degli Studi di Milano. Dipartimento di Scienze della Salute; Italia; Fil: Glembotsky, Ana Claudia. Consejo Nacional de Invest.cientif.y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto de Invest.Medicas; Argentina; Fil: Cattaneo Marco. Università degli Studi di Milano. Dipartimento di Scienze della Salute; Italia; Fil: Balduini, Carlo L.. University of Pavia and IRCCS Policlinico San Matteo Foundation. Department of Internal Medicine; Italia; Fil: Savoia Anna. Institute for Maternal and Child Health - IRCCS; Italia

Several guidelines often exist on the same topic, sometimes offering divergent recommendations. For the clinician, it can be difficult to understand the reasons for this divergence and how to select the right recommendations. The aim of this study is to compare different guidelines on the management of atrial fibrillation (AF), and provide practical and affordable advice on its management in the acute setting. A PubMed search was performed in May 2014 to identify the three most recent and cited published guidelines on AF. During the 1-week school of the European School of Internal Medicine, the attending residents were divided in five working groups. The three selected guidelines were compared with five specific questions. The guidelines identified were: the European Society of Cardiology guidelines on AF, the Canadian guidelines on emergency department management of AF, and the American Heart Association guidelines on AF. Twenty-one relevant sub-questions were identified. For five of these, there was no agreement between guidelines; for three, there was partial agreement; for three data were not available (issue not covered by one of the guidelines), while for ten, there was complete agreement. Evidence on the management of AF in the acute setting is largely based on expert opinion rather than clinical trials. While there is broad agreement on the management of the haemodynamically unstable patient and the use of drugs for rate-control strategy, there is less agreement on drug therapy for rhythm control and no agreement on several other topics.

Background: About 40% of clopidogrel-treated patients display high platelet reactivity (HPR). Alternative treatments of HPR patients, identified by platelet function tests, failed to improve their clinical outcomes in large randomized clinical trials. A more appealing alternative would be to identify HPR patients a priori, based on the presence/absence of demographic, clinical and genetic factors that affect PR. Due to the complexity and multiplicity of these factors, traditional statistical methods (TSMs) fail to identify a priori HPR patients accurately. The objective was to test whether Artificial Neural Networks (ANNs) or other Machine Learning Systems (MLSs), which use algorithms to extract model-like 'structure' information from a given set of data, accurately predict platelet reactivity (PR) in clopidogrel-treated patients.Methods: A complete set of fifty-nine demographic, clinical, genetic data was available of 603 patients with acute coronary syndromes enrolled in the prospective GEPRESS study, which showed that HPR after 1 month of clopidogrel treatment independently predicted adverse cardiovascular events in patients with Syntax Score > 14. Data were analysed by MLSs and TSMs. ANNs identified more variables associated PR at 1 month, compared to TSMs.Results: ANNs overall accuracy in predicting PR, although superior to other MLSs was 63% (95% CI 59-66). PR phenotype changed in both directions in 35% of patients across the 3 time points tested (before PCI, at hospital discharge and at 1 month).Conclusions: Despite their ability to analyse very complex non-linear phenomena, ANNs or MLS were unable to predict PR accurately, likely because PR is a highly unstable phenotype. (C) 2017 Elsevier B.V. All rights reserved.