Prediction of the Risk of Bleeding in People Living with Hemophilia

A tool allowing the prediction of the risk of bleeding in patients with hemophilia would be relevant for patients, stakeholders, and policymakers. We performed a systematic review of the literature searching for available risk assessment models to predict the risk of bleeding in people living with hemophilia, and to determine the key risk factors that the ideal model should include. We also systematically review the literature to determine the acceptability and accuracy of wrist-wearable devices to measure physical activity in the general population. Finally, we validated the performance of a risk assessment model for the prediction of the risk for bleeding in people living with hemophilia. We identified the following risk factors for bleeding in people living with hemophilia: plasma factor levels, history of bleeds, physical activity, antithrombotic treatment, and obesity. The FitBit Charge and FitBit Charge HR are the most accurate devices for measuring steps, and the Apple Watch is the most accurate for measuring heart rate. No device proved to be accurate in measuring energy expenditure. The predictive accuracy of the risk assessment model that we validated does not endorse its use to drive decision making on treatment strategies based on the predicted number of bleeds. This might in part be explained by the methods used in the derivation phase. The need for an accurate risk assessment model to predict the risk of bleeding in people living with hemophilia is still unmet. This should be done by including the relevant risk factors identified through our work, with data on physical activity possibly collected using an accurate wrist-wearable device, and through the application of rigorous methods in the derivation and validation phases.ThesisDoctor of Philosophy (PhD)People living with hemophilia lack a coagulation factor and tend to experience spontaneous bleeds, with frequency and intensity that vary between individuals. Predicting who will experience more bleeds would allow for changing the treatment strategies and directing the best resources to the persons that can benefit more. Through this project, we identified the variables that should be considered to estimate the risk for bleeding in people living with hemophilia, namely the blood levels of the lacking coagulation factor, the bleeding history, the physical activity levels, the concomitant treatment with blood thinners, and the presence of obesity. We determined that Fitbit Charge and Charge HR are the most accurate devices for measuring steps and Apple Watch for heart rate. Lastly, we found that an existing tool for predicting the risk of bleeding is not accurate enough to be used in this setting, and a new model should be produced

Effectiveness of interventions to prevent pre-frailty and frailty progression in older adults:a systematic review

OBJECTIVE: To summarize the best available evidence regarding the effectiveness of interventions for preventing frailty progression in older adults. INTRODUCTION: Frailty is an age-related state of decreased physiological reserves characterized by an increased risk of poor clinical outcomes. Evidence supporting the malleability of frailty, its prevention and treatment, has been presented. INCLUSION CRITERIA: The review considered studies on older adults aged 65 and over, explicitly identified as pre-frail or frail, who had been undergoing interventions focusing on the prevention of frailty progression. Participants selected on the basis of specific illness or with a terminal diagnosis were excluded. The comparator was usual care, alternative therapeutic interventions or no intervention. The primary outcome was frailty. Secondary outcomes included: (i) cognition, quality of life, activities of daily living, caregiver burden, functional capacity, depression and other mental health-related outcomes, self-perceived health and social engagement; (ii) drugs and prescriptions, analytical parameters, adverse outcomes and comorbidities; (iii) costs, and/or costs relative to benefits and/or savings associated with implementing the interventions for frailty. Experimental study designs, cost effectiveness, cost benefit, cost minimization and cost utility studies were considered for inclusion. METHODS: Databases for published and unpublished studies, available in English, Portuguese, Spanish, Italian and Dutch, from January 2001 to November 2015, were searched. Critical appraisal was conducted using standardized instruments from the Joanna Briggs Institute. Data was extracted using the standardized tools designed for quantitative and economic studies. Data was presented in a narrative form due to the heterogeneity of included studies. RESULTS: Twenty-one studies, all randomized controlled trials, with a total of 5275 older adults and describing 33 interventions, met the criteria for inclusion. Economic analyses were conducted in two studies. Physical exercise programs were shown to be generally effective for reducing or postponing frailty but only when conducted in groups. Favorable effects on frailty indicators were also observed after the interventions, based on physical exercise with supplementation, supplementation alone, cognitive training and combined treatment. Group meetings and home visits were not found to be universally effective. Lack of efficacy was evidenced for physical exercise performed individually or delivered one-to-one, hormone supplementation and problem solving therapy. Individually tailored management programs for clinical conditions had inconsistent effects on frailty prevalence. Economic studies demonstrated that this type of intervention, as compared to usual care, provided better value for money, particularly for very frail community-dwelling participants, and had favorable effects in some of the frailty-related outcomes in inpatient and outpatient management, without increasing costs. CONCLUSIONS: This review found mixed results regarding the effectiveness of frailty interventions. However, there is clear evidence on the usefulness of such interventions in carefully chosen evidence-based circumstances, both for frailty itself and for secondary outcomes, supporting clinical investment of resources in frailty intervention. Further research is required to reinforce current evidence and examine the impact of the initial level of frailty on the benefits of different interventions. There is also a need for economic evaluation of frailty interventions

Terminal half-life of FVIII and FIX according to age, blood group and concentrate type: data from the WAPPS database

Background Real-life data on pharmacokinetics of factor (F) VIII/IX concentrates, especially extended half-life (EHL), concentrates in large cohorts of persons with hemophilia are currently lacking. Objectives This cross-sectional study aimed to establish reference values for terminal half-life (THL) for FVIII/IX concentrates according to concentrate type, age, blood group and inhibitor history. Patients/Methods Data were extracted from the Web-Accessible Population Pharmacokinetics Service database. Groups were compared by nonparametric tests. THL was modelled according to patient characteristics and concentrate type. Results Infusion data (n = 8022) were collected from 4832 subjects (including 2222 children) with severe hemophilia (age: 1 month–85 years; 89% hemophilia A; 34% using EHL concentrates, 9.8% with history of inhibitors). THL of FVIII-EHL was longer than of FVIII standard half-life (SHL; median 15.1 vs. 11.1 h). FVIII-THL was dependent on age, concentrate type, blood group, and inhibitor history. THL of FIX-EHL was longer than of FIX-SHL (median 106.9 vs. 36.5 h). FIX-THL increased with age until 30 years and remained stable thereafter. FVIII-THL was shorter in subjects with blood group O. THL was decreased by 1.3 h for FVIII and 22 h for FIX in subjects with a positive inhibitor history. Conclusions We established reference values for FVIII/IX concentrates according to patient characteristics and concentrate type in a large database of hemophilia patients. These reference values may inform clinical practice (e.g., assessment of immune tolerance success), economic implications of procurement processes and value attribution of novel treatments (e.g., mimetics, gene therapy)

Predicting Individual Changes in Terminal Half-Life After Switching to Extended Half-Life Concentrates in Patients With Severe Hemophilia

Predicting individual effects of switching from standard half-life (SHL) to extended half-life (EHL) FVIII/FIX concentrates is pivotal in clinical care, but large-scale individual data are scarce. The aim of this study was to assess individual changes in terminal half-life (THL) after switching to EHL concentrates and identifying determinants of a clinically relevant THL extension in people with severe hemophilia. Data from participants with pharmacokinetic studies on both SHL and EHL were extracted from the Web-Accessible Population Pharmacokinetics Service (WAPPS) database and stratified according to hemophilia type and age groups (children/adults). A 30% increase in THL was considered clinically relevant. Predictors of a relevant increase were identified using logistic regression. Data from 688 persons with severe hemophilia (2174 infusions) were included: 89% hemophilia A; median age: 21.7 (interquartile range [IQR]: 11.5-37.7); positive inhibitor history: 11.7%. THL increased by 38% (IQR: 17%-67%) and 212% (139%-367%) for hemophilia A and B, respectively. All EHL-FIX concentrate users showed clinically relevant THL extension. However, 40% (242/612) of people with hemophilia A showed limited extension or decrease in THL after switching. Relevant FVIII-THL extension was predicted by short baseline THL and blood group non-O in both children and adults. In conclusion, clinically relevant THL extension was observed in all 75/76 participants switching to EHL-FIX, and in 60% of 612 switching to EHL-FVIII. Short THL on SHL-FVIII and blood group non-O were identified as predictors for a relevant THL increase after switching to EHL-FVIII. Individualized pharmacokinetic assessment may guide clinical decision-making when switching from SHL to EHL-FVIII

2025 focused update of the 2020 ISTH guidelines for management of thrombotic thrombocytopenic purpura

Background: Over the past few years, new information has emerged in the management of both immune thrombotic thrombocytopenic purpura (iTTP) and congenital (or hereditary) thrombotic thrombocytopenic purpura (cTTP). Methods: In March 2024, the International Society on Thrombosis and Haemostasis (ISTH) formed a multidisciplinary panel comprising hematologists, intensivists, nephrologists, pathologists, patient representatives, and a methodology team. The panel discussed all treatment questions related to thrombotic thrombocytopenic purpura (TTP) using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) method to appraise evidence and formulate recommendations. Results: For patients with cTTP in remission, a new strong recommendation was issued for the use of recombinant ADAMTS-13 over fresh frozen plasma in the context of moderate certainty evidence. The panel also revised a previous recommendation and suggested using fresh frozen plasma over a watch-and-wait approach for patients with cTTP in remission based on very low certainty evidence should recombinant. The panel reviewed and referenced new publications supporting therapeutic efficacy, potential survival benefit, and cost considerations of adding caplacizumab to therapeutic plasma exchange, corticosteroids, and rituximab, but concluded that no change was warranted to the previous recommendations in the management of iTTP. Good practice statements on the concomitant use of antithrombotic agents were marginally modified. Conclusions: For patients with iTTP, no change to 2020's recommendations. For patients with cTTP, the panel supports ADAMTS-13 replacement. Where accessible, recombinant ADAMTS-13 provides the most favorable balance of benefits and risks. Otherwise, fresh frozen plasma may still be effective. Shared decision-making should include the benefits, the potential harms, and the burden of care. (International Society on Thrombosis and Haemostasis

Benefits and harms of direct oral anticoagulation and low molecular weight heparin for thromboprophylaxis in patients undergoing non-cardiac surgery : systematic review and network meta-analysis of randomised trials

OBJECTIVE To systematically compare the effect of direct oral anticoagulants and low molecular weight heparin for thromboprophylaxis on the benefits and harms to patients undergoing non-cardiac surgery. DESIGN Systematic review and network meta-analysis of randomised controlled trials. DATA SOURCES Medline, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL), up to August 2021. REVIEW METHODS Randomised controlled trials in adults undergoing non-cardiac surgery were selected, comparing low molecular weight heparin (prophylactic (low) or higher dose) with direct oral anticoagulants or with no active treatment. Main outcomes were symptomatic venous thromboembolism, symptomatic pulmonary embolism, and major bleeding. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used for network meta-analyses. Abstracts and full texts were screened independently in duplicate. Data were abstracted on study participants, interventions, and outcomes, and risk of bias was assessed independently in duplicate. Frequentist network meta-analysis with multivariate random effects models provided odds ratios with 95% confidence intervals, and GRADE (grading of recommendations, assessment, development, and evaluation) assessments indicated the certainty of the evidence. RESULTS 68 randomised controlled trials were included (51 orthopaedic, 10 general, four gynaecological, two thoracic, and one urological surgery), involving 45 445 patients. Low dose (odds ratio 0.33, 95% confidence interval 0.16 to 0.67) and high dose (0.19, 0.07 to 0.54) low molecular weight heparin, and direct oral anticoagulants (0.17, 0.07 to 0.41) reduced symptomatic venous thromboembolism compared with no active treatment, with absolute risk differences of 1-100 per 1000 patients, depending on baseline risks (certainty of evidence, moderate to high). None of the active agents reduced symptomatic pulmonary embolism (certainty of evidence, low to moderate). Direct oral anticoagulants and low molecular weight heparin were associated with a 2-3-fold increase in the odds of major bleeding compared with no active treatment (certainty of evidence, moderate to high), with absolute risk differences as high as 50 per 1000 in patients at high risk. Compared with low dose low molecular weight heparin, high dose low molecular weight heparin did not reduce symptomatic venous thromboembolism (0.57, 0.26 to 1.27) but increased major bleeding (1.87, 1.06 to 3.31); direct oral anticoagulants reduced symptomatic venous thromboembolism (0.53, 0.32 to 0.89) and did not increase major bleeding (1.23, 0.89 to 1.69). CONCLUSIONS Direct oral anticoagulants and low molecular weight heparin reduced venous thromboembolism compared with no active treatment but probably increased major bleeding to a similar extent. Direct oral anticoagulants probably prevent symptomatic venous thromboembolism to a greater extent than prophylactic low molecular weight heparin.Peer reviewe

Use of artificial intelligence to support the assessment of the methodological quality of systematic reviews

Introduction: Published systematic reviews display an heterogeneous methodological quality, which can impact decision-making. Large language models (LLMs) can support and make the assessment of the methodological quality of systematic reviews more efficient, aiding in the incorporation of their evidence in guideline recommendations. We aimed to develop a LLM-based tool for supporting the assessment of the methodological quality of systematic reviews. Methods: We assessed the performance of eight large language models (LLMs) in evaluating the methodological quality of systematic reviews. In particular, we provided 100 systematic reviews for eight LLMs (five base models and three fine-tuned models) to evaluate their methodological quality based on a 27-item validated tool (ReMarQ). The fine-tuned models had been trained with a different sample of 300 manually assessed systematic reviews. We compared the answers provided by LLMs with those independently provided by human reviewers, computing the accuracy, kappa coefficient and F1-score for this comparison. Results: The best performing LLM was a fine-tuned GPT-3.5 model (mean accuracy=96.5% [95%CI=89.9-100%]; mean kappa coefficient=0.90 [95%CI=0.71-1.00]; mean F1-score=0.91 [95%CI=0.83-1.00]). This model displayed an accuracy >80% and a kappa coefficient >0.60 for all individual items. When we made this LLM assess 60 times the same set of systematic reviews, answers to 18 of 27 items were always consistent (i.e., were always the same) and only 11% of assessed systematic reviews showed inconsistency. Conclusion: Overall, LLMs have the potential to accurately support the assessment of the methodological quality of systematic reviews based on a validated tool comprising dichotomous items

Outcomes of elective liver surgery worldwide: a global, prospective, multicenter, cross-sectional study

Background: The outcomes of liver surgery worldwide remain unknown. The true population-based outcomes are likely different to those vastly reported that reflect the activity of highly specialized academic centers. The aim of this study was to measure the true worldwide practice of liver surgery and associated outcomes by recruiting from centers across the globe. The geographic distribution of liver surgery activity and complexity was also evaluated to further understand variations in outcomes. Methods: LiverGroup.org was an international, prospective, multicenter, cross-sectional study following the Global Surgery Collaborative Snapshot Research approach with a 3-month prospective, consecutive patient enrollment within January–December 2019. Each patient was followed up for 90 days postoperatively. All patients undergoing liver surgery at their respective centers were eligible for study inclusion. Basic demographics, patient and operation characteristics were collected. Morbidity was recorded according to the Clavien–Dindo Classification of Surgical Complications. Country-based and hospital-based data were collected, including the Human Development Index (HDI). (NCT03768141). Results: A total of 2159 patients were included from six continents. Surgery was performed for cancer in 1785 (83%) patients. Of all patients, 912 (42%) experienced a postoperative complication of any severity, while the major complication rate was 16% (341/2159). The overall 90-day mortality rate after liver surgery was 3.8% (82/2,159). The overall failure to rescue rate was 11% (82/ 722) ranging from 5 to 35% among the higher and lower HDI groups, respectively. Conclusions: This is the first to our knowledge global surgery study specifically designed and conducted for specialized liver surgery. The authors identified failure to rescue as a significant potentially modifiable factor for mortality after liver surgery, mostly related to lower Human Development Index countries. Members of the LiverGroup.org network could now work together to develop quality improvement collaboratives