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Abstract Background Many risk factors for fractures have been documented, including low bone-mineral density (BMD) and a history of fractures. However, little is known about the short-term absolute risk (AR) of fractures and the timing of clinical fractures. Therefore, we assessed the risk and timing of incident clinical fractures, expressed as 5-year AR, in postmenopausal women. Methods In total, 10 general practice centres participated in this population-based prospective study. Five years after a baseline assessment, which included clinical risk factor evaluation and BMD measurement, 759 postmenopausal women aged between 50 and 80 years, were re-examined, including undergoing an evaluation of clinical fractures after menopause. Risk factors for incident fractures at baseline that were significant in univariate analyses were included in a multivariate Cox survival regression analysis. The significant determinants were used to construct algorithms. Results In the total group, 12.5% (95% confidence interval (CI) 10.1–14.9) of the women experienced a new clinical fracture. A previous clinical fracture after menopause and a low BMD (T-score Conclusion In postmenopausal women, clinical fractures cluster in time. One in two women with a recent clinical fracture had a new clinical fracture within 5 years, regardless of BMD. The 5-year AR for a first clinical fracture was much lower and depended on BMD.

Abstract Background Little is known about how sexual and reproductive (SRH) health can be made accessible and appropriate to adolescents. This study evaluates the impact and sustainability of a competitive voucher program on the quality of SRH care for poor and underserved female adolescents and the usefulness of the simulated patient (SP) method for such evaluation. Methods 28,711 vouchers were distributed to adolescents in disadvantaged areas of Managua that gave free-of-charge access to SRH care in 4 public, 10 non-governmental and 5 private clinics. Providers received training and guidelines, treatment protocols, and financial incentives for each adolescent attended. All clinics were visited by female adolescent SPs requesting contraception. SPs were sent one week before, during (with voucher) and one month after the intervention. After each consultation they were interviewed with a standardized questionnaire. Twenty-one criteria were scored and grouped into four categories. Clinics' scores were compared using non-parametric statistical methods (paired design: before-during and before-after). Also the influence of doctors' characteristics was tested using non-parametric statistical methods. Results Some aspects of service quality improved during the voucher program. Before the program started 8 of the 16 SPs returned 'empty handed', although all were eligible contraceptive users. During the program 16/17 left with a contraceptive method (p = 0.01). Furthermore, more SPs were involved in the contraceptive method choice (13/17 vs.5/16, p = 0.02). Shared decision-making on contraceptive method as well as condom promotion had significantly increased after the program ended. Female doctors had best scores before- during and after the intervention. The improvements were more pronounced among male doctors and doctors older than 40, though these improvements did not sustain after the program ended. Conclusion This study illustrates provider-related obstacles adolescents often face when requesting contraception. The care provided during the voucher program improved for some important outcomes. The improvements were more pronounced among providers with the weakest initial performance. Shared decision-making and condom promotion were improvements that sustained after the program ended. The SP method is suitable and relatively easy to apply in monitoring clinics' performance, yielding important and relevant information. Objective assessment of change through the SP method is much more complex and expensive.

Abstract Background The treatment of non-specific chronic low back pain is often based on three different models regarding the development and maintenance of pain and especially functional limitations: the deconditioning model, the cognitive behavioral model and the biopsychosocial model. There is evidence that rehabilitation of patients with chronic low back pain is more effective than no treatment, but information is lacking about the differential effectiveness of different kinds of rehabilitation. A direct comparison of a physical, a cognitive-behavioral treatment and a combination of both has never been carried out so far. Methods The effectiveness of active physical, cognitive-behavioral and combined treatment for chronic non-specific low back pain compared with a waiting list control group was determined by performing a randomized controlled trial in three rehabilitation centers. Two hundred and twenty three patients were randomized, using concealed block randomization to one of the following treatments, which they attended three times a week for 10 weeks: Active Physical Treatment (APT), Cognitive-Behavioral Treatment (CBT), Combined Treatment of APT and CBT (CT), or Waiting List (WL). The outcome variables were self-reported functional limitations, patient's main complaints, pain, mood, self-rated treatment effectiveness, treatment satisfaction and physical performance including walking, standing up, reaching forward, stair climbing and lifting. Assessments were carried out by blinded research assistants at baseline and immediately post-treatment. The data were analyzed using the intention-to-treat principle. Results For 212 patients, data were available for analysis. After treatment, significant reductions were observed in functional limitations, patient's main complaints and pain intensity for all three active treatments compared to the WL. Also, the self-rated treatment effectiveness and satisfaction appeared to be higher in the three active treatments. Several physical performance tasks improved in APT and CT but not in CBT. No clinically relevant differences were found between the CT and APT, or between CT and CBT. Conclusion All three active treatments were effective in comparison to no treatment, but no clinically relevant differences between the combined and the single component treatments were found.

Background: The epidemiology of thrombocytopenia in critically ill patients has not been well characterized. The objective of this study was to systematically review the prevalence, incidence, and consequences of, and risk factors for, thrombocytopenia among critically ill patients.Methods: We searched MEDLINE, EMBASE, the Cochrane Registry for controlled trials (until May 2010), and the Online Computer Library, as well as bibliographies of relevant studies, to identify investigations designed to examine the frequency, risk factors, and/or outcomes associated with thrombocytopenia among patients admitted to the ICU. We independently selected studies, abstracted data, and assessed methodologic quality in duplicate. Heterogeneity of design and analysis precluded statistical pooling of results.Results: We identified 24 studies (12 prospective) enrolling 6,894 patients from medical, surgical, mixed, or trauma ICUs. Prevalent thrombocytopenia (on ICU admission) occurred in 8.3% to 67.6% of patients; incident thrombocytopenia (developing during the course of the ICU stay) occurred in 13.0% to 44.1% of patients. High illness severity, sepsis, and organ dysfunction often correlated with thrombocytopenia. Only one study using multivariate analysis examined whether thrombocytopenia was associated with major bleeding, but it found no association. Six out of eight studies using multivariate analysis found that thrombocytopenia increased the risk of death.Conclusions: The frequency of thrombocytopenia during critical illness varies widely, based on case mix and definition. After confounding factors are adjusted for, thrombocytopenia appears to increase the risk of death. [ABSTRACT FROM AUTHOR]

BACKGROUND: A systematic review and meta-analysis was performed to determine if there were differences between apheresis platelet concentrates (APCs) or platelets (PLTs) derived from whole blood (WBD) for the outcomes acute reactions, alloimmunization, refractoriness, corrected count increment (CCI), radiolabeled recovery and survival, time to next transfusion, and bleeding. STUDY DESIGN AND METHODS: We searched Medline, Embase, the Cochrane Registry of Controlled Trials, PapersFirst, ProceedingsFirst, and AABB and ASH abstracts for randomized controlled trials (RCTs) comparing APCs and WBD PLTs for clinical outcomes. Study selection, data extraction, and methodologic quality assessments were performed in duplicate. Results were pooled using meta-analytic methods. RESULTS: Ten RCTs met the inclusion criteria. Acute reactions per patient were lower for APCs (relative risk [RR], 0.65; 95% CI, 0.44-0.98); however, when controlling for leukoreduction, there was no significant difference (leukoreduced [LR]-APCs vs. LR-WBDs; odds ratio, 1.78; 95% CI, 0.87-3.62). There was no difference between products when reaction frequencies were assessed per transfusion (RR, 0.65; 95% CI, 0.33-1.28). APCs were associated with significantly higher CCIs than WBD PLTs at both 1 hour (weighted mean difference [WMD], 2.49; 95% CI, 2.21-2.77) and 18 to 24 hours (WMD, 1.64; 95% CI, 0.60-2.67). No conclusions could be made for the outcomes of alloimmunization and refractoriness. No studies addressed outcomes of time to next transfusion or bleeding. CONCLUSIONS: Owing to the small number of trials and lack of comparability of PLT products for leukoreduction, we were unable to draw definitive conclusions about the clinical benefits of APCs compared with WBD PLTs. Rigorous RCTs using clinically important end points are needed to settle this issue. [ABSTRACT FROM AUTHOR]

Objectives: To identify and characterize cases of potentially preventable venous thromboembolism (VTE): cases for which thromboprophylaxis was indicated, according to the American College of Chest Physicians (ACCP) consensus guidelines for VTE prevention, yet was administered inadequately.Design: A historical cohort study to examine all cases of deep vein thrombosis and pulmonary embolism from 1996 to 1997 at a large teaching hospital. Of these, we determined the proportion that was potentially preventable. We examined the reasons for inadequacy of prophylaxis and the setting in which preventable VTE occurred.Results: Of 253 objectively diagnosed cases of VTE in 245 patients, 44 cases (17.4%) were considered potentially preventable. This represented two thirds of all VTE cases for which thromboprophylaxis had been indicated (n = 65). Of preventable cases, the most frequent reason for inadequacy of prophylaxis was omission of prophylaxis (47.7%), followed by inadequate duration of prophylaxis (22.7%), and by incorrect type of prophylaxis (20.5%). Surgical and medical indications for thromboprophylaxis that were common among preventable cases included nonorthopedic surgery, admission to hospital for pneumonia, and stroke with lower limb paralysis. Underlying risk factors for VTE that were common among preventable cases included recent immobility, active cancer, and obesity.Conclusions: One of six cases of all VTE and two of three cases of VTE for which thromboprophylaxis had been indicated could potentially have been prevented had physicians followed the recommended ACCP guidelines. Inadequacy of prophylaxis was most often caused by omission of prophylaxis. Missed opportunities for prevention occurred most commonly in the settings of nonorthopedic surgery, pneumonia, and stroke. [ABSTRACT FROM AUTHOR]

Background. Many studies have been performed on the impact of Alzheimer's disease, stroke and cancer on carers. Information on the influence of a myocardial infarction in a patient on the health of the partner is still scarce.Methods. Exposed and non-exposed partners were compared with respect to the occurrence of mortality and predefined diseases, using Cox proportional hazards survival analysis.Results. None of the disease incidence rates differed between exposed partners and control partners. Over 12 times as many male partners of (female) heart patients died as compared to their male control partners, when they had a low educational level.Conclusion. When exposed to myocardial infarction in a patient, the risk of dying in low educated male partners was over 12 times as large as for male low educated unexposed partners. [ABSTRACT FROM AUTHOR]

Focuses on the risk-factor profile and cardiovascular comorbidity of asymptomatic peripheral arterial occlusive disease (PAOD) in Netherlands. Similarity of cardiovascular comorbidity with claudicants; Measure to diminish influence of smoking, diabetes and hypertension; Factors associated with hypertension.

Vaccine-induced immune thrombocytopenia and thrombosis (VITT) is associated with antibodies that target platelet factor 4 (PF4) and are heparin-independent. VITT antibodies are implicated in acute, transient prothrombotic disorders that are triggered by adenoviral vector vaccines against coronavirus disease 2019 or by adenovirus infection. We describe chronic prothrombotic disorders featuring anticoagulant-refractory thromboses and intermittent thrombocytopenia that were associated with VITT-like antibodies in five patients (four patients with newly reported cases and the index patient). The patients had low levels of M proteins (median level, 0.14 g per deciliter); in each patient, we found that the M protein was the VITT-like antibody. The antibody clonotype profiles and binding epitopes on PF4 were different from those observed with the acute disorders occurring after vaccination or viral infection, features that reflect distinct immunopathogenesis. Treatment strategies besides anticoagulation alone are needed for the chronic disorders, referred to as VITT-like monoclonal gammopathy of thrombotic significance. (Funded by the Canadian Institutes of Health Research and others.)., (Copyright © 2025 Massachusetts Medical Society.)

Objectives: Evidence-based protocols for managing bleeding emergencies in patients with immune thrombocytopenia (ITP) are lacking. We conducted a systematic review of treatments for critical bleeding in patients with ITP., Methods: We included all study designs and extracted data in aggregate or individually for patients who received one or more interventions and for whom any of the following outcomes were reported: platelet count response, bleeding, disability, or death., Results: We identified 49 eligible studies reporting 112 critical bleed patients with ITP, including 66 children (median age, 10 years), 36 adults (median age, 41.5 years), and 10 patients with unreported age. Patients received corticosteroids (n = 67), IVIG (n = 49), platelet transfusions (n = 41), TPO-RAs (n = 17), and splenectomy (n = 28) either alone or in combination. Studies reported 29 different treatment combinations, the 5 most common were corticosteroids, platelet transfusion and splenectomy (n = 13), corticosteroids and IVIG (n = 13), or splenectomy alone (n = 13); IVIG alone (n = 11); and corticosteroids, IVIG and TPO-RA (n = 8). Mortality among patients with critical bleeds in ITP was 30.6% for adults and 19.7% for children., Conclusions: The effects of individual treatments on patient outcomes were uncertain due to very low-quality evidence. There is a need for a standardized approach to the treatment of ITP critical bleeds., Systematic Review Registration: CRD42020161206., (© 2024 The Author(s). European Journal of Haematology published by John Wiley & Sons Ltd.)

The McMaster Immune Thrombocytopenia (ITP) Summit, held on October 27, 2023, was an educational seminar from leading experts in immune thrombocytopenia and related disorders geared toward hematologists, internists, immunologists, and clinical and translational scientists. The focus of the Summit was to review the mechanisms, diagnosis, and treatment of primary versus secondary ITP. Specific objectives were to describe the unique features of secondary ITP, and to review its mechanisms in the context of autoimmune disease and infection. The key messages in this Summit were: (1) ITP is a heterogeneous disease, and genetic and immunologic insights may help classify patient subtypes; (2) exploring the autoimmune mechanisms and their association with hypogammaglobulinemia in patients with secondary ITP could improve our understanding of ITP and its subtypes; (3) investigating the mechanisms of ITP in the context of infections caused by viruses such as CMV, HIV, dengue, and hepatitis C, or bacteria such as H. pylori , or vaccinations could provide insight into the causes of ITP. A better understanding of secondary ITP could help elucidate the pathogenesis of ITP., Competing Interests: D.C. reports consulting fees from Novartis and Sanofi. D.C. also serves on a Data Safety Monitoring Board or Advisory Board for Novartis and Sanofi. C.N. has received author royalties from UpToDate. Consulting fees were received from ArgenX, Novartis, Sobi, Sanofi, and Genzyme, while an ongoing consultancy exists with Janssen. Honoraria were received from Sanofi. Payments for expert testimony were received from the U.S. Department of Defense Vaccine Program and Stein Mitchell Beato & Missner LLP. Travel support was received from Sanofi for ISTH 2024. Unpaid roles include being a medical advisor for ITP Australia and The UK ITP Support Association, and a committee member with ASH Committee on Quality, ISTH Meeting Planning Committee 2025, and a chair on the ASPHO review course. H.A. received grants or contracts from Agios, Amgen, Novartis, Vaderis, and Sobi to their institution. Consulting payments were received from Amgen, Novartis, Alnylam, Agios, Argenx, Alpine, Sobi, and Pharmacosmos. N.C. disclosed participation on a data safety monitoring board or advisory board, and payment for honoraria for lectures, presentations, speakers, bureaus, manuscript writing, or educational events from Amgen, Novartis, Griffols, and Sobi. G.M. disclosed support from McMaster University related to the present manuscript. G.M. has received grants or contracts from Amgen, Argenx, Grifols, Novartis, and Sanofi, and consulting fees from Argenx, Grifols, Novartis, Sanofi, Alpine, and Amgen, along with payments from Amgen, Grifols, and Novartis. Support for attending meetings was provided by Amgen, Grifols, and Novartis. C.C.R. disclosed a consultancy role with Pharming, award committee role with Grifols, and data safety monitoring board role with Otsuka since the initial planning of this manuscript. C.C.R. has received grants or contracts from X4 and NIH USIDNET, and serves on a steering committee for NIH USIDNET. Consulting fees were received from Pharming and X4. C.C.R. also attended meetings and events sponsored by the CIS Summer School 2024, CIS National Meeting 2024, and the California Allergy Immunology Society 2024. Patents are planned, issued, or pending for the use of BTK in inflammatory diseases in CVID. C.C.R. holds a leadership role in the Royal PID group in New York City. H.A.L. has received grants or contracts from Sanofi, and consulting fees from Sanofi, Novartis, and Alpine Immune Sciences. J.B.B. has received consulting fees from Amgen, Novartis, SOBI, UCB, Argenx, Janssen, and RallyBio. D.M.A. declares receiving grants or contract support from the Canadian Institutes of Health Research, Rigel, and Alpine Immune Sciences (all related to ITP), royalties or licenses from UpToDate, and consulting fees from Novartis, Rigel, Amgen, Medison, Sobi, and Argenx (all related to ITP). D.M.A. also serves as an unpaid medical advisor for the Platelet Disorders Support Association. D.M., S.R.C., S.M., H.M., V.R.B., and I.N. declare that they have no conflicts of interest., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

A 56-year-old woman required urgent cardiac surgery for Streptococcus mitis mitral valve infective endocarditis complicated by severe autoimmune heparin-induced thrombocytopenia (aHIT). We reasoned that the combination of high-dose intravenous immunoglobulin G (IVIG; to mitigate aHIT antibody-mediated platelet activation in the presence of heparin) together with the high concentrations of heparin attained during cardiac surgery (which typically produces less platelet activation in vitro vs usual therapeutic heparin concentrations) might prove effective. Accordingly, our patient underwent cardiac surgery with heparin following high-dose IVIG (1 g/kg × 2) without intra- or postoperative thrombosis. Serial serotonin release assays, using blood obtained pre-/post-IVIG, showed minimal platelet activation (∼30% serotonin release) post-IVIG at heparin concentrations typically obtained during cardiac surgery (2-5 U/mL) and significantly less than pre-IVIG serum in heparin's absence (∼85% serotonin release). In the setting of urgent cardiac surgery, preoperative high-dose IVIG appears to be a reasonable strategy to reduce platelet-activating effects of heparin-induced thrombocytopenia (including aHIT) antibodies, permitting safe use of standard intraoperative heparin dosing., Competing Interests: Declaration of Competing Interests There are no competing interests to disclose., (Copyright © 2024 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare prothrombotic disorder with a unique clonality-restricted immunological profile. The study by Petito and Bury et al. provides insight into the role of HLA polymorphisms and an inherent predisposition to VITT. Commentary on: Petito et al. Association of human leucocyte antigen loci with vaccine-induced immune thrombotic thrombocytopenia: Potential role of the interaction between platelet factor 4-derived peptides and MHC-II. Br J Haematol 2025; 206:290-295., (© 2024 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Prior studies have suggested that immune thrombotic thrombocytopenic purpura (iTTP) may display seasonal variation; however, methodologic limitations and sample sizes have diminished the ability to perform a rigorous assessment. This 5-year retrospective study assessed the epidemiology of iTTP and determined whether it displays a seasonal pattern. Patients with both initial and relapsed iTTP (defined as a disintegrin and metalloprotease with thrombospondin type motifs 13 activity <10%) from 24 tertiary centers in Australia, Canada, France, Greece, Italy, Spain, and the US were included. Seasons were defined as: Northern Hemisphere-winter (December-February); spring (March-May); summer (June-August); autumn (September-November) and Southern Hemisphere-winter (June-August); spring (September-November); summer (December-February); autumn (March-May). Additional outcomes included the mean temperature in months with and without an iTTP episode at each site. A total of 583 patients experienced 719 iTTP episodes. The observed proportion of iTTP episodes during the winter was significantly greater than expected if equally distributed across seasons (28.5%, 205/719, 25.3%-31.9%; p = .03). Distance from the equator and mean temperature deviation both positively correlated with the proportion of iTTP episodes during winter. Acute iTTP episodes were associated with the winter season and colder temperatures, with a second peak during summer. Occurrence during winter was most pronounced at sites further from the equator and/or with greater annual temperature deviations. Understanding the etiologies underlying seasonal patterns of disease may assist in discovery and development of future preventative therapies and inform models for resource utilization., (© 2024 The Author(s). American Journal of Hematology published by Wiley Periodicals LLC.)

Heparin-induced thrombocytopenia (HIT) is an autoimmune disorder caused by antibodies against platelet factor 4 (PF4) and heparin complexes. Rapid immunoassays (IAs) for detection of these antibodies mark a milestone in HIT diagnosis, despite a higher false-positive rate compared with functional platelet-activation assays. However, combining different rapid IAs may help to improve their diagnostic specificity. Here, we compared the individual performance of the latex immunoturbidimetric assay (LIA; HemosIL HIT-Ab [PF4-H]; sensitivity 91.7%, specificity 68.4%) and chemiluminescence immunoassay (CLIA; HemosIL AcuStarHIT-Ab [PF4-H]; sensitivity 92.4%, specificity 85.8%) with their combined performance using two unique diagnostic algorithms in a single prospective cohort of suspected HIT patients. Using the simultaneous algorithm adapted from Warkentin et al, the combined LIA-CLIA had a sensitivity of 99.0% and specificity of 64.3%. The sequential algorithm adapted from Rittener-Ruff et al was applied in two theoretical scenarios to reflect real-world circumstances in diagnostic laboratories where access to clinical information is limited: (1) assuming all patients had an intermediate 4Ts score and (2) assuming all patients had a high 4Ts score. This algorithm correctly predicted HIT in 94.5% (high 4Ts) and 96.0% (intermediate 4Ts) and excluded HIT in 82.6% (high 4Ts) and 80.1% (intermediate 4Ts) of patients in either scenario, respectively. Although both combined algorithms improved diagnostic performance of individual IAs, the simultaneous algorithm showed fewer false predictions (7.9%) than the sequential algorithm (intermediate 4Ts: 37.6% and high 4Ts: 41.5%) and proved more practical as it does not rely on physician evaluations. Our findings highlight the importance of accounting for clinician and interlaboratory variability when evaluating diagnostic tests for HIT., Competing Interests: I.N. and T.E.W. have received research funding from Instrumentation Laboratory (Werfen). T.E.W. has received lecture honoraria from Instrumentation Laboratory (Werfen), and royalties from Informa (Taylor & Francis) and UptoDate (Wolters Kluwer); has provided consulting services to Arbor Biotechnologies, Paradigm Pharmaceuticals, and Veralox Therapeutics; has provided expert witness testimony relating to HIT and non-HIT thrombocytopenic and coagulopathic disorders., (Thieme. All rights reserved.)

Introduction: Immune thrombocytopenia (ITP) is an acquired autoimmune disorder characterized by low platelets and an increased risk of bleeding. Platelet autoantibodies target major platelet glycoproteins and cause Fc-mediated platelet destruction in the spleen and reticuloendothelial systems. As mechanisms of disease, platelet autoantibodies are important therapeutic targets. Neonatal Fc receptor (FcRn) antagonists are a new class of therapeutics that reduce the half-life of immunoglobulin G including pathogenic platelet autoantibodies. Spleen tyrosine kinase (Syk) inhibitors interfere with Fc-mediated platelet clearance. Bruton's tyrosine kinase (BTK) inhibitors and B-cell activating factor (BAFF) inhibitors reduce antibody production. The efficacy of these targeted therapies provides new support for the role of platelet autoantibodies in pathogenesis of ITP even these antibodies can be difficult to detect., Areas Covered: This review includes an in-depth exploration of the pathophysiologic mechanisms of ITP, focusing on autoantibodies. Treatments outlined in this review include a) FcRn antagonists, b) complement inhibitors, c) B-cell directed therapies such as BTK inhibitors, and anti-BAFF agents, d) Syk inhibitors, e) plasma-cell directed therapies, and f) novel cellular therapeutic products., Expert Opinion: Platelet autoantibodies are often elusive in ITP, yet novel treatments targeting this pathway reinforce their role in the pathogenesis of this autoimmune platelet disorder.

Background: Bleeding is a primary outcome for many transfusion-related trials in acute leukaemia (AL) patients, typically graded using the World Health Organisation (WHO) bleeding scale (clinically significant bleed (CSB) is ≥grade 2). This composite outcome fails to differentiate minor bleeds that may not be significant, poorly represents the total burden of bleeding and lacks input from healthcare providers (HCPs) and patients. As part of a multi-step project to create a better bleeding tool for trials, our objective was to identify HCPs' perspectives on the components of CSB in AL patients., Study Design and Methods: Using qualitative description, we interviewed 19 physicians and nurses who care for AL patients undergoing induction chemotherapy. Participants were recruited from professional organisations, networks and social media. An inductive approach to conventional content analysis was used., Results: HCPs identified features of CSB as the anatomical site of bleeding, amount of bleeding, need for intervention and changes in vital signs. Using these characteristics, bleeding events were categorised into three groups: clinically significant, could evolve into a CSB and not clinically significant. HCPs considered the patient's condition, bleeding history and clinical intuitions when deciding whether a bleed could escalate into serious bleeding., Discussion: Using data from HCPs, we categorised bleeds as clinically significant, could evolve into a CSB, and not significant. A study of patients' perspectives on the importance of different kinds of bleeding is the next step to creating a bleeding definition that is informed by evidence, clinicians and patients., (© 2024 The Author(s). Transfusion Medicine published by John Wiley & Sons Ltd on behalf of British Blood Transfusion Society.)

Abstract: The 2019 American Society of Hematology (ASH) guidelines for immune thrombocytopenia (ITP) included recommendations on the management of adults (recommendations 1-9) and children (recommendations 10-21) with primary ITP . We describe here the results of a review of the 2019 guidelines by a working group of experts requested by ASH to inform decision-making about the need for and timing of a guideline revision. An updated Medline and Embase search applied the same search terms as in the 2019 ASH guidelines, limited to systematic reviews and clinical trials, from May 2017 to July 2022. There were 193 studies identified, 102 underwent abstract reviews, and 54 full reviews. Each study was assessed based on relevance to the previous recommendation with regard to the population, prioritized outcomes, new outcomes, and study design. Reviewers assessed if the data would change the strength or the directionality of the existing recommendation or merit development of a new recommendation. Based on this review, the ASH Committee on Quality endorsed a focused update on second-line management for adults with ITP. In addition, there will be continued annual monitoring and reviewing of the 2019 ASH guidelines on ITP in full to evaluate when there is sufficient new evidence to warrant additional revisions., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Based on emerging evidence from the COVID-19 pandemic, the International Society on Thrombosis and Haemostasis (ISTH) guidelines for antithrombotic treatment in COVID-19 were published in 2022. Since then, at least 16 new randomized controlled trials have contributed additional evidence, which necessitated a modification of most of the previous recommendations. We used again the American College of Cardiology Foundation/American Heart Association methodology for assessment of level of evidence (LOE) and class of recommendation (COR). Five recommendations had the LOE upgraded to A and 2 new recommendations on antithrombotic treatment for patients with COVID-19 were added. Furthermore, a section was added to answer questions about COVID-19 vaccination and vaccine-induced immune thrombotic thrombocytopenia (VITT), for which studies have provided some evidence. We only included recommendations with LOE A or B. Panelists agreed on 19 recommendations, 4 for nonhospitalized, 5 for noncritically ill hospitalized, 3 for critically ill hospitalized, and 2 for postdischarge patients, as well as 5 for vaccination and VITT. A strong recommendation (COR 1) was given for (a) use of prophylactic dose of low-molecular-weight heparin or unfractionated heparin in noncritically ill patients hospitalized for COVID-19, (b) for select patients in this group, use of therapeutic-dose low-molecular-weight heparin/unfractionated heparin in preference to prophylactic dose, and (c) for use of antiplatelet factor 4 enzyme immunoassays for diagnosing VITT. A strong recommendation was given against (COR 3) the addition of an antiplatelet agent in hospitalized, noncritically ill patients. These international guidelines provide recommendations for countries with diverse healthcare resources and COVID-19 vaccine availability., Competing Interests: Declaration of competing interests S.S. has received a research grant from Octapharma; served on data safety monitoring boards for Alexion, Bayer, Boehringer-Ingelheim, and Sanofi; served on event adjudication for Daiichi Sankyo; and served on an advisory board for Servier. D.M.A. received research grants from Rigel Pharmaceuticals and the Public Health Agency of Canada and is a consultant for Amgen, Paradigm, Sobi, Alpine, Novartis, and Argenx. C.A.B. has received a research grant from Amgen, honoraria from BMS-Pfizer, Janssen, and Sanofi, and served on the advisory board for Novartis. L.B. currently owns a stock portfolio with Johnson & Johnson and Pfizer. J.M.C. has received a research grant from CSL Behring and has served on scientific advisory boards for Abbott, Anthos, Bristol Myers Squibb, Pfizer, and Werfen. A.F. has received honoraria from Kedrion and Rovi and served on an advisory board for Sanofi. S.K. has received research grants from Bayer and is a consultant for Inari and Janssen. J.H.L. has served on a data safety monitoring board with Merck, a research study steering committee with Octapharma, and the advisory board for Werfen. S.M. has received research grants from Bayer, Abbvie, Hemab, Viatris, and Sanofi and honoraria from AstraZeneca, Norgine, and Alveron. I.N. has received research grants from Paradigm Pharmaceuticals, Janssen/Johnson & Johnson, UCB Biopharma, AstraZeneca, and the Public Health Agency of Canada and is a consultant for Paradigm Pharmaceuticals, Janssen/Johnson & Johnson, UCB Biopharma, and AstraZeneca. E.R. has received research grants from Bayer, Pfizer, and Novartis and honoraria from Sanofi, Bayer, Ache, Daiichi Sankyo, and Pfizer. C.M.S. served on an advisory board for Norgine Pharma. M.S. has received research grants from Pfizer, Amgen, and Sanofi; received honoraria from Pfizer, Octapharma, Amgen, and Novartis; and served on advisory boards for Amgen and Novartis. A.C.S. has received a research grant from AstraZeneca and honoraria from Janssen, Regeneron, and AstraZeneca. J.T. received honoraria from Bristol Myers Squibb, Pfizer, and Daiichi Sankyo. R.Z. has received research grants from the Canadian Institute of Health Research, LifeArc, Nation Institute of Health, Research Manitoba, CancerCare Manitoba Foundation, Peter Munk Cardiac Centre, Thistledown Foundation, and Manitoba Medical Services Foundation. The remaining authors have no conflicts of interest to declare. S.S. has been primary author and coauthor on review articles on COVID-19. D.M.A. has been coauthor and senior author on articles on diagnosis and treatment of VITT. C.A.B. has been primary author and co-author on articles on heparins and antiplatelet agents for treatment of COVID-19. J.M.C. has been primary author and coauthor on articles on antiplatelet agents, apixaban, and heparin for treatment of COVID-19. A.F. has been coauthor on review articles on treatment of COVID-19, including with heparin. T.I. has been primary author and coauthor on articles on coagulopathy in COVID-19 and in VITT. S.K. has been coauthor on articles on heparin and antiplatelet agents for treatment of COVID-19. J.H.L. has been primary author and coauthor on articles on coagulopathy in COVID-19 and in VITT and on heparin for treatment of COVID-19. S.M. has been coauthor on articles on heparin and oral anticoagulants for the treatment of COVID-19. I.N. has been primary author, senior author, and coauthor on articles on coagulopathy and laboratory diagnosis in VITT and COVID-19. C.M.S. has been coauthor on articles on coagulopathy in COVID-19. M.S. has been primary author on articles on heparin for treatment of COVID-19. A.C.S. has been primary author and senior author on articles on heparin and coauthor on articles on rivaroxaban for treatment of COVID-19. J.T. has been primary author and coauthor on articles on coagulopathy in COVID-19. R.Z. has been primary author and coauthor on articles on heparin and antiplatelet agents, respectively, for treatment of COVID-19. The remaining authors have no intellectual conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: An estimated one-quarter to one-half of people diagnosed with haematological malignancies experience anaemia. There are different strategies for red blood cell (RBC) transfusions to treat anaemia. A restrictive transfusion strategy permits a lower haemoglobin (Hb) level whereas a liberal transfusion strategy aims to maintain a higher Hb. The most effective and safest strategy is unknown., Objectives: To determine the efficacy and safety of restrictive versus liberal RBC transfusion strategies for people diagnosed with haematological malignancies treated with intensive chemotherapy or radiotherapy, or both, with or without a haematopoietic stem cell transplant (HSCT)., Search Methods: We searched for randomised controlled trials (RCTs) and non-randomised studies (NRS) in MEDLINE (from 1946), Embase (from 1974), CINAHL (from 1982), Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2023, Issue 2), and eight other databases (including three trial registries) to 21 March 2023. We also searched grey literature and contacted experts in transfusion for additional trials. There were no language, date or publication status restrictions., Selection Criteria: We included RCTs and prospective NRS that evaluated restrictive versus liberal RBC transfusion strategies in children or adults with malignant haematological disorders receiving intensive chemotherapy or radiotherapy, or both, with or without HSCT., Data Collection and Analysis: Two authors independently screened references, full-text reports of potentially relevant studies, extracted data from the studies, and assessed the risk of bias. Any disagreement was discussed and resolved with a third review author. Dichotomous outcomes were presented as a risk ratio (RR) with a 95% confidence interval (CI). Narrative syntheses were used for heterogeneous outcome measures. Review Manager Web was used to meta-analyse the data. Main outcomes of interest included: all-cause mortality at 31 to 100 days, quality of life, number of participants with any bleeding, number of participants with clinically significant bleeding, serious infections, length of hospital admission (days) and hospital readmission at 0 to 3 months. The certainty of the evidence was assessed using GRADE., Main Results: Nine studies met eligibility; eight RCTs and one NRS. Six hundred and forty-four participants were included from six completed RCTs (n = 560) and one completed NRS (n = 84), with two ongoing RCTs consisting of 294 participants (260 adult and 34 paediatric) pending inclusion. Only one completed RCT included children receiving HSCT (n = 6); the other five RCTs only included adults: 239 with acute leukaemia receiving chemotherapy and 315 receiving HSCT (166 allogeneic and 149 autologous). The transfusion threshold ranged from 70 g/L to 80 g/L for restrictive and from 80 g/L to 120 g/L for liberal strategies. Effects were reported in the summary of findings tables only for the trials that included adults to reduce indirectness due to the limited evidence contributed by the prematurely terminated paediatric trial. Evidence from RCTs Overall, there may be little to no difference in the number of participants who die within 31 to 100 days using a restrictive compared to a liberal transfusion strategy, but the evidence is very uncertain (three studies; 451 participants; RR 1.00, 95% CI 0.27 to 3.70, P=0.99; very low-certainty evidence). There may be little to no difference in quality of life at 0 to 3 months using a restrictive compared to a liberal transfusion strategy, but the evidence is very uncertain (three studies; 431 participants; analysis unable to be completed due to heterogeneity; very low-certainty evidence). There may be little to no difference in the number of participants who suffer from any bleeding at 0 to 3 months using a restrictive compared to a liberal transfusion strategy (three studies; 448 participants; RR 0.91, 95% CI 0.78 to 1.06, P = 0.22; low-certainty evidence). There may be little to no difference in the number of participants who suffer from clinically significant bleeding at 0 to 3 months using a restrictive compared to a liberal transfusion strategy (four studies; 511 participants; RR: 0.94, 95% CI 0.74 to 1.19, P = 0.60; low-certainty evidence). There may be little to no difference in the number of participants who experience serious infections at 0 to 3 months using a restrictive compared to a liberal transfusion strategy (three studies, 451 participants; RR: 1.20, 95% CI 0.93 to 1.55, P = 0.17; low-certainty evidence). A restrictive transfusion strategy likely results in little to no difference in the length of hospital admission at 0 to 3 months compared to a liberal strategy (two studies; 388 participants; analysis unable to be completed due to heterogeneity in reporting; moderate-certainty evidence). There may be little to no difference between hospital readmission using a restrictive transfusion strategy compared to a liberal transfusion strategy (one study, 299 participants; RR: 0.89, 95% CI 0.52 to 1.50; P = 0.65; low-certainty evidence). Evidence from NRS The evidence is very uncertain whether a restrictive RBC transfusion strategy: reduces the risk of death within 100 days (one study, 84 participants, restrictive 1 death; liberal 1 death; very low-certainty evidence); or decreases the risk of clinically significant bleeding (one study, 84 participants, restrictive 3; liberal 8; very low-certainty evidence). No NRS reported on the other eligible outcomes., Authors' Conclusions: Findings from this review were based on seven studies and 644 participants. Definite conclusions are challenging given the relatively few included studies, low number of included participants, heterogeneity of intervention and outcome reporting, and overall certainty of evidence. To increase the certainty of the true effect of a restrictive RBC transfusion strategy on clinical outcomes, there is a need for rigorously designed and executed studies. The evidence is largely based on two populations: adults with acute leukaemia receiving intensive chemotherapy and adults with haematologic malignancy requiring HSCT. Despite the addition of 405 participants from three RCTs to the previous review's results, there is still insufficient evidence to answer this review's primary outcome. If we assume a mortality rate of 3% within 100 days, we would need a total of 1492 participants to have an 80% chance of detecting, at a 5% level of significance, an increase in all-cause mortality from 3% to 6%. Further RCTs are needed overall, particularly in children., (Copyright © 2024 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening thrombotic disorder associated with a severe deficiency of ADAMTS-13-the protease that cleaves von Willebrand factor. Plasma therapy is the current standard of care for managing acute episodes of TTP, which involves removing patient plasma and replacing it with donor plasma to raise the level of ADAMTS-13 activity. Recently, therapies aimed at replacing ADAMTS-13 have been investigated as possible substitutes or add-ons to plasma therapy for congenital and immune-mediated TTP. Enzyme replacement therapy provides recombinant ADAMTS-13 via intravenous (i.v.) infusion to restore enzyme activity. Recombinant ADAMTS-13-loaded platelets localize to the site of thrombus formation in a more concentrated manner than enzyme replacement or plasma therapy. ADAMTS-13-encoding messenger RNA aims to induce a steady supply of secreted protein and gene therapy is a potentially curative strategy. Overall, targeted ADAMTS-13 replacement therapies may provide better outcomes than plasma therapy by achieving higher levels of ADAMTS-13 activity and a more sustained response with fewer adverse events. Herein, we describe targeted ADAMTS-13 replacement therapies for the treatment of TTP and discuss the advantages and limitations of each approach., Competing Interests: Declaration of competing interests None of the authors have any competing interests to disclose., (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)