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Genome-wide association studies have successfully identified many genetic risk loci for dementia, but exact biological mechanisms through which genetic risk factors contribute to dementia remains unclear. Integrating CSF proteomic data with dementia risk loci could reveal intermediate molecular pathways connecting genetic variance to the development of dementia. We tested to what extent effects of known dementia risk loci can be observed in CSF levels of 665 proteins (proximity extension-based (PEA) immunoassays) in a deeply-phenotyped mixed-memory clinic cohort (n=502, mean age (sd) = 64.1 [8.7] years, 181 female [35.4%]), including patients with Alzheimer's disease (AD, n=213), dementia with Lewy bodies (DLB, n=50) and frontotemporal dementia (FTD, n=93), and controls (n=146). Validation was assessed in independent cohorts (n=99 PEA platform, n=198, MRM-targeted mass spectroscopy and multiplex assay). We performed additional analyses stratified according to diagnostic status (AD, DLB, FTD and controls separately), to explore whether associations between CSF proteins and genetic variants were specific to disease or not. We identified four AD risk loci as protein quantitative trait loci (pQTL): CR1-CR2 (rs3818361, P=1.65e-08), ZCWPW1-PILRB (rs1476679, P=2.73e-32), CTSH-CTSH (rs3784539, P=2.88e-24) and HESX1-RETN (rs186108507, P=8.39e-08), of which the first three pQTLs showed direct replication in the independent cohorts. We identified one AD-specific association between a rare genetic variant of TREM2 and CSF IL6 levels (rs75932628, P = 3.90e-7). DLB risk locus GBA showed positive trans effects on seven inter-related CSF levels in DLB patients only. No pQTLs were identified for frontotemporal dementia, either for the total sample as for analyses performed within FTD only. pQTL variants were involved in the immune system, highlighting the importance of this system in the pathophysiology of dementia. We further identified pQTLs in stratified analyses for AD and DLB, hinting at disease-specific pQTLs in dementia. Dissecting the contribution of risk loci to neurobiological processes aids in understanding disease mechanisms underlying dementia.
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BACKGROUND AND AIMS: Pulmonary embolism (PE) is a frequent complication in COVID19 hospitalized patients. Inflammatory storm and endothelial dysfunction due to the virus seem to be the two major risk factors for PE. Consequently, PE related to COVID19 could be consider as triggered by a transient inflammatory acute phase and treated for no longer than 3 months. However, few data are available on management of anticoagulation and risk of venous thromboembolic (VTE) recurrences in these patients and guidelines are still undefined. Aim of the present study is to evaluate the long-term follow-up of a cohort of covid-19 patients with PE. METHODS: We conducted a retrospective multicenter study in four Italian hospitals between March 1st, 2020, and May 31st, 2021 in patients who experienced a PE during hospitalization for a COVID-19 pneumonia, excluding patients who died during hospitalization. Baseline characteristics were collected and patients were grouped according to duration of anticoagulant treatment (< 3 months or > 3 months). The primary outcome was incidence of VTE recurrence while secondary outcome was the composite of deaths, major hemorrhages and VTE recurrence during follow-up. RESULTS: 106 patients with PE were discharged, of these 95 (89.6 %) had follow up longer than 3 months (seven patients were lost to follow up and four died within three months). The median follow-up was 13 months (IQR 1-19). Overall, 23 % of subjects (22/95) were treated for 3 months or less and 76.8 % (73/95) received anticoagulation for >3 months. Of patients in the short treatment group, 4.5 % died, compared with 5.5 % of those in the longer treatment group (p = NS); no difference was shown in risk of VTE recurrence (0 % vs 4.1 %, p = NS), major bleeding (4.5 % vs 4.1 %, p = NS) or in composite outcome (9.1 % vs 11 %, p = NS). No difference was found between the two treatment groups for composite outcome using the Kaplan-Meier analysis (Log Rank Test p = 0.387). CONCLUSION: In our retrospective multi-center cohort, prolongation of duration of anticoagulation seems not to affect risk of VTE recurrences, deaths and bleeding after a PE related to COVID-19.
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COVID-19 , Embolia Pulmonar , Tromboembolia Venosa , Humanos , Seguimentos , Tromboembolia Venosa/etiologia , Tromboembolia Venosa/induzido quimicamente , COVID-19/complicações , Recidiva Local de Neoplasia/induzido quimicamente , Recidiva Local de Neoplasia/complicações , Embolia Pulmonar/epidemiologia , Anticoagulantes/uso terapêutico , Hemorragia/complicações , RecidivaRESUMO
The evolution of established cancers is driven by selection of cells with enhanced fitness. Subclonal mutations in numerous epigenetic regulator genes are common across cancer types, yet their functional impact has been unclear. Here, we show that disruption of the epigenetic regulatory network increases the tolerance of cancer cells to unfavorable environments experienced within growing tumors by promoting the emergence of stress-resistant subpopulations. Disruption of epigenetic control does not promote selection of genetically defined subclones or favor a phenotypic switch in response to environmental changes. Instead, it prevents cells from mounting an efficient stress response via modulation of global transcriptional activity. This "transcriptional numbness" lowers the probability of cell death at early stages, increasing the chance of long-term adaptation at the population level. Our findings provide a mechanistic explanation for the widespread selection of subclonal epigenetic-related mutations in cancer and uncover phenotypic inertia as a cellular trait that drives subclone expansion.
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Neoplasias , Humanos , Mutação , Neoplasias/genética , Neoplasias/patologia , FenótipoRESUMO
OBJECTIVE: Pancreatic ductal adenocarcinomas (PDACs) include heterogeneous mixtures of low-grade cells forming pseudoglandular structures and compact nests of high-grade cells organised in non-glandular patterns. We previously reported that low-grade PDAC cells display high expression of interferon regulatory factor 1 (IRF1), a pivotal transcription factor of the interferon (IFN) system, suggesting grade-specific, cell-intrinsic activation of IFN responses. Here, we set out to determine the molecular bases and the functional impact of the activation of IFN-regulated responses in human PDACs. DESIGN: We first confirmed the correlation between glandular differentiation and molecular subtypes of PDAC on the one hand, and the expression of IRF1 and IFN-stimulated genes on the other. We next used unbiased omics approaches to systematically analyse basal and IFN-regulated responses in low-grade and high-grade PDAC cells, as well as the impact of IRF1 on gene expression programmes and metabolic profiles of PDAC cells. RESULTS: High-level expression of IRF1 in low-grade PDAC cells was controlled by endodermal lineage-determining transcription factors. IRF1-regulated gene expression equipped low-grade PDAC cells with distinctive properties related to antigen presentation and processing as well as responsiveness to IFN stimulation. Notably, IRF1 also controlled the characteristic metabolic profile of low-grade PDAC cells, suppressing both mitochondrial respiration and fatty acid synthesis, which may in part explain its growth-inhibiting activity. CONCLUSION: IRF1 links endodermal differentiation to the expression of genes controlling antigen presentation and processing as well as to the specification of the metabolic profile characteristic of classical PDAC cells.
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Regulação da Expressão Gênica , Neoplasias Pancreáticas , Humanos , Fator Regulador 1 de Interferon/genética , Fator Regulador 1 de Interferon/metabolismo , Interferons , Neoplasias Pancreáticas/genética , Neoplasias PancreáticasRESUMO
INTRODUCTION: Individuals in the Alzheimer's disease (AD) continuum with mild cognitive impairment (prodromal AD) are at increased risk to develop dementia. Still, underlying pathophysiological processes remain unclear. We studied whether cerebrospinal fluid (CSF) proteome changes are related to time to clinical progression in prodromal AD. METHODS: We measured 671 CSF proteins in 49 prodromal AD individuals (67±7 years old, 22 [45%] female) from the Amsterdam Dementia Cohort. Associations of protein levels with time to dementia onset were tested with Cox regression models, followed by biological pathway enrichment analysis. RESULTS: Eighteen (36%) individuals developed dementia during follow-up. In total, 128 (98%) proteins were associated with a 1.4- to 17-fold increased risk of progression to dementia (all P < .05). These proteins showed enrichment for immune system processes, signal transduction, neuronal death, and neurodevelopmental biology. DISCUSSION: CSF proteome changes related to rate of progression to dementia can be detected in prodromal AD, providing more insight into processes involved in early AD pathophysiology.
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BACKGROUND: During the COVID-19 crisis it was necessary to generate a specific care network and reconvert operating rooms to attend emergency and high-acuity patients undergoing complex surgery. The aim of this study is to classify postoperative complications and mortality and to assess the impact that the COVID-19 pandemic may have had on the results. METHODS: this is a non-inferiority retrospective observational study. Two different groups of surgical patients were created: Pre-pandemic COVID and Pandemic COVID. Severity of illness was rated according to the Diagnosis-related Groups (DRG) score. Comparisons were made between groups and between DRG severity score-matched samples. Non-inferiority was set at up to 10 % difference for grade III to V complications according to the Clavien-Dindo classification, and up to 2 % difference in mortality. RESULTS: A total of 1649 patients in the PreCOVID group and 763 patients in the COVID group were analysed; 371 patients were matched for DRG severity score 3-4 (236 preCOVID and 135 COVID). No differences were found in relation to re-operation (22.5 % vs. 21.5 %) or late admission to critical care unit (5.1 % vs. 4.5 %). Clavien grade III to V complications occurred in 107 patients (45.3 %) in the PreCOVID group and in 56 patients (41.5 %) in the COVID group, and mortality was 12.7 % and 12.6 %, respectively. During the pandemic, 3 % of patients tested positive for Covid-19 on PCR: 12 patients undergoing elective surgery and 11 emergency surgery; there were 5 deaths, 3 of which were due to respiratory failure following Covid-19-induced pneumonia. CONCLUSIONS: Although this study has some limitations, it has shown the non-inferiority of surgical outcomes during the COVID pandemic, and indicates that resuming elective surgery is safe. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT04780594 .
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COVID-19/epidemiologia , Complicações Pós-Operatórias/epidemiologia , Procedimentos Cirúrgicos Operatórios , Idoso , COVID-19/mortalidade , Causalidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Gravidade do Paciente , Complicações Pós-Operatórias/mortalidade , Estudos Retrospectivos , Medição de Risco , SARS-CoV-2 , Espanha/epidemiologiaRESUMO
Pancreatic ductal adenocarcinoma (PDAC), one of the most highly lethal tumors, is characterized by complex histology, with a massive fibrotic stroma in which both pseudo-glandular structures and compact nests of abnormally differentiated tumor cells are embedded, in different proportions and with different mutual relationships in space. This complexity and the heterogeneity of the tumor component have hindered the development of a broadly accepted, clinically actionable classification of PDACs, either on a morphological or a molecular basis. Here, we discuss evidence suggesting that such heterogeneity can to a large extent, albeit not exclusively, be traced back to two main classes of PDAC cells that commonly coexist in the same tumor: cells that maintained their ability to differentiate toward endodermal, mucin-producing epithelia and epithelial cells unable to form glandular structures and instead characterized by various levels of squamous differentiation and the expression of mesenchymal lineage genes. The underlying gene regulatory networks and how they are controlled by distinct transcription factors, as well as the practical implications of these two different populations of tumor cells, are discussed.
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Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Transcrição Gênica/genética , Animais , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Diferenciação Celular/genética , Células Epiteliais/patologia , Epitélio/patologia , Regulação Neoplásica da Expressão Gênica/genética , Redes Reguladoras de Genes/genética , Humanos , Fatores de Transcrição/genéticaRESUMO
Many tumors of endodermal origin are composed of highly secretory cancer cells that must adapt endoplasmic reticulum (ER) activity to enable proper folding of secreted proteins and prevent ER stress. We found that pancreatic ductal adenocarcinomas (PDACs) overexpress the myelin regulatory factor (MYRF), an ER membrane-associated transcription factor (TF) released by self-cleavage. MYRF was expressed in the well-differentiated secretory cancer cells, but not in the poorly differentiated quasi-mesenchymal cells that coexist in the same tumor. MYRF expression was controlled by the epithelial identity TF HNF1B, and it acted to fine-tune the expression of genes encoding highly glycosylated, cysteine-rich secretory proteins, thus preventing ER overload. MYRF-deficient PDAC cells showed signs of ER stress, impaired proliferation, and an inability to form spheroids in vitro, while in vivo they generated highly secretory but poorly proliferating and hypocellular tumors. These data indicate a role of MYRF in the control of ER homeostasis in highly secretory PDAC cells.
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Retículo Endoplasmático/metabolismo , Homeostase , Proteínas de Membrana/metabolismo , Neoplasias Pancreáticas/metabolismo , Fatores de Transcrição/metabolismo , Diferenciação Celular/genética , Linhagem Celular Tumoral , Proliferação de Células , Cromatina/metabolismo , DNA de Neoplasias/metabolismo , Retículo Endoplasmático/ultraestrutura , Estresse do Retículo Endoplasmático/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Proteínas de Membrana/genética , Gradação de Tumores , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/ultraestrutura , Ligação Proteica , Fatores de Transcrição/genéticaRESUMO
Many Alzheimer's disease (AD) genes including Apolipoprotein E (APOE) are found to be expressed in blood-derived macrophages and thus may alter blood protein levels. We measured 91 neuro-proteins in plasma from 316 participants of the Rotterdam Study (incident AD = 161) using Proximity Extension Ligation assay. We studied the association of plasma proteins with AD in the overall sample and stratified by APOE. Findings from the Rotterdam study were replicated in 186 AD patients of the BioFINDER study. We further evaluated the correlation of these protein biomarkers with total tau (t-tau), phosphorylated tau (p-tau) and amyloid-beta (Aß) 42 levels in cerebrospinal fluid (CSF) in the Amsterdam Dementia Cohort (N = 441). Finally, we conducted a genome-wide association study (GWAS) to identify the genetic variants determining the blood levels of AD-associated proteins. Plasma levels of the proteins, CDH6 (ß = 0.638, P = 3.33 × 10-4) and HAGH (ß = 0.481, P = 7.20 × 10-4), were significantly elevated in APOE ε4 carrier AD patients. The findings in the Rotterdam Study were replicated in the BioFINDER study for both CDH6 (ß = 1.365, P = 3.97 × 10-3) and HAGH proteins (ß = 0.506, P = 9.31 × 10-7) when comparing cases and controls in APOE ε4 carriers. In the CSF, CDH6 levels were positively correlated with t-tau and p-tau in the total sample as well as in APOE ε4 stratum (P < 1 × 10-3). The HAGH protein was not detected in CSF. GWAS of plasma CDH6 protein levels showed significant association with a cis-regulatory locus (rs111283466, P = 1.92 × 10-9). CDH6 protein is implicated in cell adhesion and synaptogenesis while HAGH protein is related to the oxidative stress pathway. Our findings suggest that these pathways may be altered during presymptomatic AD and that CDH6 and HAGH may be new blood-based biomarkers.
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Doença de Alzheimer/metabolismo , Apolipoproteína E4/metabolismo , Caderinas/metabolismo , Triagem de Portadores Genéticos , Tioléster Hidrolases/metabolismo , Apolipoproteína E4/genética , Biomarcadores/sangue , HumanosRESUMO
BACKGROUND: Physical activity in people with haemophilia (PWH) reduces the development of severe arthropathy, but it must be performed after regular, proper prophylaxis. Strict adherence to treatment is crucial to achieving effectiveness and established outcomes. The primary aim of this study was to collect prospective data on adherence to prophylaxis for over 36 months. A secondary aim was to verify whether adherence correlates with physical activity. MATERIALS AND METHODS: Italian patients with severe haemophilia A treated on prophylaxis with octocog alfa were included in the study. Physical findings were assessed by the Haemophilia and Exercise Project (HEP)-Test-Q and the Early Prophylaxis Immunologic Challenge (EPIC)-Norfolk Physical Activity Questionnaire; orthopaedic status was assessed by the Hemophilia Joint Health Score (HJHS). Adherence was measured as percentage of empty vials returned with respect to the prescribed amount. RESULTS: Forty-two PWH were enrolled: 31% children, 21.4% adolescents, and 47.6% adults. Type, frequency and impact of physical activities differed among the three groups. The HEP-Test-Q showed the highest impairments in the domains "endurance" and "strength/co-ordination". Eight percent of patients were classified as adherent to prophylaxis. Among them, 50% had at least one bleeding episode in the year before enrolment; this percentage dropped during the three years of the study. While remaining stable in the "non-adherent" group, the HJHS score decreased in the "adherent" patients. The mean number of school/work days lost was lower in adherent patients (from 3.4±6.8 to 0.2±0.9) than in non-adherent ones. DISCUSSION: PWH with better orthopaedic scores reported better physical performance. Adherence to long-term prophylaxis proved to be high and correlated with a reduction in bleeds, target joints, school/work days lost, and with a performance improvement in endurance sports activities over time.
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Fator VIII/uso terapêutico , Hemofilia A/prevenção & controle , Adolescente , Adulto , Criança , Exercício Físico , Feminino , Hemofilia A/epidemiologia , Humanos , Itália/epidemiologia , Masculino , Cooperação do Paciente , Estudos Prospectivos , Adulto JovemRESUMO
Differentiation of normal and tumor cells is controlled by regulatory networks enforced by lineage-determining transcription factors (TFs). Among them, TFs such as FOXA1/2 bind naïve chromatin and induce its accessibility, thus establishing new gene regulatory networks. Pancreatic ductal adenocarcinoma (PDAC) is characterized by the coexistence of well- and poorly differentiated cells at all stages of disease. How the transcriptional networks determining such massive cellular heterogeneity are established remains to be determined. We found that FOXA2, a TF controlling pancreas specification, broadly contributed to the cis-regulatory networks of PDACs. Despite being expressed in both well- and poorly differentiated PDAC cells, FOXA2 displayed extensively different genomic distributions and controlled distinct gene expression programs. Grade-specific functions of FOXA2 depended on its partnership with TFs whose expression varied depending on the differentiation grade. These data suggest that FOXA2 contributes to the regulatory networks of heterogeneous PDAC cells via interactions with alternative partner TFs.
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Diferenciação Celular , Regulação Neoplásica da Expressão Gênica , Fator 1-beta Nuclear de Hepatócito/metabolismo , Fator 3-beta Nuclear de Hepatócito/metabolismo , Proteínas de Homeodomínio/metabolismo , Neoplasias Pancreáticas/patologia , Elementos Reguladores de Transcrição , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Movimento Celular , Proliferação de Células , Redes Reguladoras de Genes , Fator 1-beta Nuclear de Hepatócito/genética , Fator 3-alfa Nuclear de Hepatócito/genética , Fator 3-alfa Nuclear de Hepatócito/metabolismo , Fator 3-beta Nuclear de Hepatócito/genética , Proteínas de Homeodomínio/genética , Humanos , Gradação de Tumores , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Células Tumorais CultivadasRESUMO
BACKGROUND: Increasing evidence suggests that cerebral vascular dysfunction is associated with the early stages of Alzheimer's disease (AD). Vascular endothelial growth factor (VEGF) is one of the key players involved in the development and maintenance of the vasculature. Here, we hypothesized that VEGF levels in cerebrospinal fluid (CSF) may be altered in AD patients with vascular involvement, characterized by the presence of microbleeds (MB), and in vascular dementia (VaD) patients compared to controls. METHODS: VEGF levels were determined by electrochemilumiscence Meso Scale Discovery (MULTI-SPOT Assay System) in CSF from age-matched groups of controls with subjective cognitive decline (n = 21), AD without MB (n = 25), AD with MB (n = 25), and VaD (n = 21) patients. RESULTS: The average level of VEGF in the different groups was 2.8 ± 1 pg/ml CSF. Adjusted for age and gender, no significant differences were detected between groups (p > 0.5). However, we detected a significant correlation between the concentration of VEGF in the CSF and age (r = 0.22, p = 0.03). In addition, males (n = 54) revealed higher VEGF levels in their CSF compared to females (n = 38) (males = 3.08 ± 0.769 pg/ml (mean ± SD), females = 2.6 ± 0.59; p = 0.006), indicating a gender-related regulation. CONCLUSION: Our study suggests that VEGF levels in the CSF do not reflect the cerebral vascular alterations in either AD or VaD patients. The observed associations of VEGF with age and gender may indicate that VEGF reflects normal aging and that males and females may differ in their aging process.
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Doença de Alzheimer/líquido cefalorraquidiano , Demência Vascular/líquido cefalorraquidiano , Fator A de Crescimento do Endotélio Vascular/líquido cefalorraquidiano , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/complicações , Doença de Alzheimer/diagnóstico por imagem , Transtornos Cognitivos/etiologia , Estudos de Coortes , Correlação de Dados , Demência Vascular/complicações , Demência Vascular/diagnóstico por imagem , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-IdadeRESUMO
Tandem repeats (TRs) are generated by DNA replication errors and retain a high level of instability, which in principle would make them unsuitable for integration into gene regulatory networks. However, the appearance of DNA sequence motifs recognized by transcription factors may turn TRs into functional cis-regulatory elements, thus favoring their stabilization in genomes. Here, we show that, in human cells, the transcriptional repressor ZEB1, which promotes the maintenance of mesenchymal features largely by suppressing epithelial genes and microRNAs, occupies TRs harboring dozens of copies of its DNA-binding motif within genomic loci relevant for maintenance of epithelial identity. The deletion of one such TR caused quasi-mesenchymal cancer cells to reacquire epithelial features, partially recapitulating the effects of ZEB1 gene deletion. These data demonstrate that the high density of identical motifs in TRs can make them suitable platforms for recruitment of transcriptional repressors, thus promoting their exaptation into pre-existing cis-regulatory networks.
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Sequências de Repetição em Tandem/genética , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo , Adulto , Animais , Sequência de Bases , Linhagem Celular Tumoral , Imunoprecipitação da Cromatina , Feminino , Expressão Gênica , Humanos , Masculino , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Nus , MicroRNAs/genética , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Mucosa Bucal/metabolismo , Polimorfismo de Nucleotídeo Único , Ligação Proteica , Fatores de Transcrição/metabolismo , Homeobox 1 de Ligação a E-box em Dedo de Zinco/deficiência , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genéticaRESUMO
: The development of alloantibodies against the replacement of Factor VIII (FVIII) is the major complication in haemophilia A treatment. The gold standard to eradicate inhibitors is the immune tolerance induction (ITI), but in some cases it fails requiring another immune tolerance, defined ITI rescue (ITI-R), using a different concentrate, even though it is still debated. We report a successful case of a poor risk (titre of inhibitor at start of ITIâ>â10âBU/ml, peak titre on ITIâ>â200âBU/ml, >2 years since the inhibitor diagnosis) haemophilia A child treated with a high-dose regimen (200âUI/kg/day) turoctocog-alfa after a failed first-line ITI with octocog-alfa lasting 29 months. At 22 months of ITI-R, the inhibitor titre was undetectable, the FVIII recovery was 74%, of the expected level and the FVIII half-life more than 7âh. A complete successful ITI-R was then achieved with turoctocog-alfa.
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Fator VIII/uso terapêutico , Hemofilia A/tratamento farmacológico , Criança , Fator VIII/farmacologia , Humanos , Fatores de RiscoRESUMO
: Bypassing agents are the first-line therapy in the treatment of acquired hemophilia A (AHA), but not the only one. Other options as recombinant porcine factor VIII or plasmaderived concentrates (pdFVIII) are available to clinicians. Aim of this study was to evaluate whether the pdFVIII can still play a role in the treatment of AHA, and which patients could benefit from this therapy. All patients with AHA, presenting severe cardiovascular comorbidities, and treated with pdFVIII with or without von Willebrand factor (vWF), referred to two different hospitals, were initially considered. Eight patients were studied and divided into two groups: first, patients treated with daily infusion of pdFVIII; second, patients treated with pdFVIII continuous infusion. After 6 months of follow-up, all patients reached complete response. Mean consumption of clotting factor (219â000 vs. 142â000âIU), mean duration of therapy (61.5 vs. 10.5 days), and mean time necessary to disappearance of the inhibitors (INHs) (64 vs. 9 days) were higher in group 1, and the differences between the two groups were statistically significant (Pâ<â0.05). Patients in group 1 also had a mean INH titer of 20.4âBU, higher than that of group 2 patients (8.4âBU), with a lower detectable FVIII level. Our study showed that pdFVIII can be an effective option for patients at high thromboembolic risk, even for those with high-titer INHs, especially if combined with vWF. The immunomodulatory role of vWF should, however, be better investigated in wider trials. The days of treatment with pdFVIII continuous infusion was proven to be similar to those reported with other drugs.
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Fator VIII/administração & dosagem , Hemofilia A/tratamento farmacológico , Idoso , Feminino , Hemofilia A/patologia , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Recent advances in the care of von Willebrand's disease (vWD) have allowed the majority of patients to be managed adequately. Even in the more severe forms, it is now possible to control recurrent bleeding through secondary long-term prophylaxis with von Willebrand factor-containing concentrates. Moreover, in the setting of surgical prophylaxis, the combination of interdisciplinary management and close patient monitoring yields a positive outcome in nearly all cases, although safety concerns remain. In clinical practice, the effectiveness of therapy is hindered by the difficulties in making a rapid, yet accurate diagnosis, in identifying the subgroup of bleeders who may benefit most from a specific strategy, and in selecting the optimal product and regimen.Since specific guidelines for heavy bleeders requiring short- and long-term prophylaxis are still lacking, sharing the experience of experts dealing with vWD patients on a daily basis is crucial to fill gaps in information relating to patient management. To address this important issue, 13 Italian haematologists met in Milan on April, 2, 2016 and in Florence on July, 9, 2016. A 30-question survey constituted the input to discuss (i) optimisation of the diagnostic workflow for vWD, (ii) the characteristics of patients who may benefit from secondary long-term prophylaxis (in particular with the purified von Willebrand factor concentrate with a low content of factor VIII), (iii) the key elements to consider when selecting a concentrate and (iv) the pre-operative and post-operative management of vWD patients. A summary of the main points covered is provided in this report.
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Doenças de von Willebrand/diagnóstico , Doenças de von Willebrand/prevenção & controle , Congressos como Assunto , Humanos , Itália , Guias de Prática Clínica como Assunto , Doenças de von Willebrand/epidemiologiaRESUMO
BACKGROUND: The association between venous and arterial thrombotic disorders is still unclear. We assessed the association between residual vein thrombosis (RVT) and subclinical atherosclerosis in a cohort of patients with unprovoked (or associated with weak risk factors) proximal deep-vein thrombosis (DVT). METHODS: In a multicenter cross-sectional study, consecutive patients over 40years free from atherosclerotic disorders received the ultrasound assessment of the leg vein system and that of carotid arteries approximately three months after an episode of proximal DVT. In each center the evaluation was done by two independent assessors. The presence of RVT was defined as the incompressibility of at least 4mm in either the popliteal or the common femoral vein, and that of subclinical atherosclerosis as the presence of increased (>0.9mm) intima-media tickness (IMT) and/or carotid plaques. RESULTS: Out of 252 patients (mean age, 67; males, 53%; unprovoked, 77%), the presence of RVT was found in 139 (55.2%). An increased IMT was shown in 76 (54.7%) patients with and in 35 (31.0%) without RVT (p<0.001). At least one carotid plaque was found in 80 (57.6%) patients with and in 36 (31.9%) without RVT (p<0.001). After adjusting for the baseline characteristics, the odds ratio of subclinical atherosclerosis (increased IMT and/or carotid plaques) was 2.8 (95% CI, 1.6 to 4.7). CONCLUSION: The ultrasound detection of RVT after an episode of proximal DVT that is either unprovoked or triggered by weak risk factors is associated with a higher prevalence of subclinical atherosclerosis. These findings may have implications for patient prognosis.
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Aterosclerose/complicações , Trombose Venosa/etiologia , Idoso , Estudos Transversais , Feminino , Humanos , Masculino , Fatores de Risco , Trombose Venosa/patologiaRESUMO
BACKGROUND: Prophylaxis is the gold standard for the treatment of children with severe hemophilia. In the last years a new approach to prophylaxis based on annual bleeding rate (ABR), pharmacokinetics (PK) and lifestyle of each patient has begun to be adopted in hemophilia treatment. AIM: Aim of our observational retrospective study was to evaluate whether in a group of children with severe hemophilia A (HA) a tailored approach may be used to replace standard therapy, reducing costs. METHODS: PK evaluation was carried out in six hemophiliac children followed at our Hemophilia Center, and already receiving recombinant factor VIII (rFVIII) on prophylaxis, using a computing program (MyPKfit®). Bayesian curve was created for each child and tailored prophylaxis was estimated considering a trough level of 1%. RESULTS: The weekly frequency of infusions was reduced in one patient, while it was slightly increased in three children. As to the remaining children, only the dosage was changed. Scheduled follow-up revealed a complete adherence to treatment, a reduction of bleeds using PK-regimen and a general improvement in the quality of life. The comparison between the direct and indirect costs of treatment during standard and PK-driven prophylaxis showed a total saving of 54,797.40 (-10.67%) in case of tailored prophylaxis. CONCLUSION: A therapeutic approach based on PK and clinical characteristics of each patient may change standard treatment. Based on our results, tailored prophylaxis could be an effective option for children with HA reducing costs.