Journal of Thrombosis and Haemostasis最新文献

Hemophilia is a rare bleeding disorder that can significantly impact various aspects of life. In recent years, a number of treatments have become available for persons with hemophilia. One of the most novel treatments, now accessible to adolescents and adults in a few countries, is gene therapy. Due to its nature as a single-shot treatment, this treatment regimen not only influences physical health but also exerts a profound impact on psychological well-being. This review paper provides a comprehensive overview of the psychological outcomes associated with gene therapy and explores the role of psychologists at different stages of the treatment process. Additionally, it examines various measurement tools that can be used to assess the psychological aspects of individuals undergoing gene therapy.

Background: Prevention of thromboembolism (TE) remains a priority in children with a high thrombotic risk. While recent trials using direct oral anticoagulants (DOACs) for TE prevention have been completed, these trials had significant limitations.

Objectives: To review the methodology of pediatric DOAC trials for TE prevention to identify design and execution challenges and opportunities for improvement.

Methods: We performed a systematic review of MEDLINE, EMBASE, the Cochrane Library, and clinicaltrials.gov, from January 2002 to April 2025, to identify pediatric trials evaluating DOACs for TE prevention. We compared registered information in clinicaltrials.gov, trial design manuscripts, and final result manuscripts of pivotal TE prevention DOAC trials to highlight changes in methods, study duration, and outcomes.

Results: Eight publications from four trials, one design and one final manuscript each, were included. Each trial targeted a pediatric subpopulation: three in cardiac disease and one in oncology. Together, 984 children enrolled in the four trials. All trials had some modification to methdology from original design, including changes in eligibility criteria, sample size, timing of endpoint ascertainment, outcomes, and analysis. All but one required a longer duration to complete than planned. Only one trial had definitive statistical power calculations.

Conclusions: The pediatric DOAC trials for TE prevention provide an opportunity to understand the unique successes and limitations in studying TE prevention in children. Given lack of power, inconsistent definitions, and limited follow-up duration, questions remain regarding safety, dose intensity, endpoints, and appropriate selection of high-risk populations. Future research should employ innovative methods to overcome these limitations.

Background: Plasma human epididymis protein 4 (HE4) levels have been associated with risk of future venous thromboembolism (VTE) in a proteome-wide study. We aimed to investigate whether plasma HE4 levels were (i) correlated with growth differentiation factor-15 (GDF-15), another marker of oxidative stress, (ii) associated with VTE risk after adjustment for potential confounders, and (iii) genetically regulated assessed by protein quantitative trait loci analyses (pQTL).

Methods: A case-cohort was derived from the Trøndelag Health Study (HUNT3, n=50,800), including 294 incident VTEs during 5 years of follow-up and a randomly sampled age- and sex-weighted subcohort (n=1,066). HE4 and GDF-15 levels were measured by an aptamer-based method in plasma collected at baseline. Weighted Cox regression was used to estimate hazard ratios (HR) for VTE with 95% confidence intervals (CI) according to quartiles of HE4 levels.

Results: HE4 levels correlated with GDF-15 levels (r=0.71, p=3.42 x 10^-211), and both proteins were elevated in smokers. Participants with HE4 levels in the highest quartile (Q4) had a 2.5-fold higher risk of future VTE (HR 2.54, 95% CI 1.60-4.03) than those in Q1 when adjusted for age, sex, and sample batch. The risk remained after multivariable adjustments. Two genetic variants in trans with genome-wide significance explained only 1.6% of the plasma variability of HE4.

Conclusion: HE4 levels were associated with increased risk of future VTE after adjustments for major confounders and appeared not to be strongly genetically regulated. Our findings suggest that HE4 levels might reflect an underlying condition, e.g. oxidative stress, predisposing to VTE.

Background: Fibrinolysis, the breakdown of fibrin-rich clots, is a tightly regulated process that ensures timely clot resolution and maintenance of vascular integrity. Platelets play a critical role in this process but mechanisms remain incompletely understood.

Objectives: Define the contribution of the fibrinogen αC domain to plasminogen binding and plasmin generation on platelets.

Methods: Plasminogen binding to resting or thrombin-stimulated platelets isolated from wild-type (Fga^WT/WT), fibrinogen-knockout (Fga^-/-), or fibrinogen αC-truncated (Fga^270/270) mice was quantified using flow cytometry. Platelet-mediated plasmin generation was determined using the plasmin-specific chromogenic substrate S-2251 and quantified using time-squared analysis.

Results: Thrombin stimulation of Fga^WT/WT or Fga^270/270 platelets enhanced plasminogen binding by 4.3-fold and 2.8-fold, respectively, while thrombin stimulation did not enhance plasminogen binding to Fga^-/- platelets. Activated thrombin-activatable fibrinolysis inhibitor (TAFIa) decreased plasminogen binding to activated Fga^WT/WT platelets by 39%; TAFIa treatment had no impact on plasminogen binding to Fga^270/270 or Fga^-/- platelets. Thrombin stimulation enhanced plasmin generation on Fga^WT/WT platelets by 22.0-fold and this was reduced by 32% by TAFIa. Thrombin stimulation enhanced plasmin generation on Fga^270/270 and Fga^-/- platelets by only 4.7-fold and 6.7-fold, respectively, but TAFIa did not modify this response.

Conclusions: C-terminal lysine residue(s) generated during thrombin-mediated platelet stimulation within the αC domain of fibrinogen confers maximal plasminogen binding and subsequent plasmin generation that is sensitive to suppression by TAFIa.

Monoclonal gammopathies of clinical significance represent a heterogeneous spectrum of non-malignant disorders that may involve multiple organ systems or remain organ-restricted. These conditions are driven by circulating monoclonal proteins (MIg) secreted by small, often indolent, B-cell or plasma cell clones. Accumulating evidence has demonstrated that MIg may possess both thrombogenic and hemorrhagic potential, mediated through complex and multifactorial interactions with coagulation pathways, platelets, and the vascular endothelium. In this review, we critically appraise the spectrum of hemostatic complications associated with monoclonal gammopathies, encompassing entities such as amyloidosis, cold agglutinin disease, M-protein-associated antiphospholipid antibody syndrome, anti-PF4 antibody-mediated disorders, and thrombotic microangiopathies, among others. Given their substantial clinical burden and frequent under recognition, we propose that these MIg-driven hemostatic disorders be classified separately as monoclonal gammopathies of thrombotic/hemorrhagic significance (MGTHS) encompassing both thrombotic and hemorrhagic subtypes. We additionally outline a proposed diagnostic approach emphasizing systematic evaluation for alternative etiologies, characterization of the monoclonal protein, and assessment for clinical, laboratory, and treatment-response features supporting pathogenic attribution. Establishing such a nosological framework highlights the clinical importance of these conditions and underscores the need for systematic recognition, diagnostic evaluation, and multidisciplinary management of these often overlooked but clinically consequential entities.

Background: D-dimer testing is widely integrated into diagnostic algorithms for venous thromboembolism (VTE). However, the lack of standardization across D-dimer assays and reporting may limit comparability of study findings.

Objective: To summarize reporting of essential characteristics of D-dimer testing in VTE diagnostic management studies.

Methods: We systematically searched MEDLINE and Embase from 01/1999-08/2024 for VTE diagnostic management studies that evaluated diagnostic algorithms including D-dimer testing and followed patients for ≥4 weeks after VTE was excluded. The primary outcome was reporting of D-dimer assay characteristics. Secondary outcomes were reporting of patient numbers and failure rates per assay.

Results: Of 9,670 articles screened, 58 studies were included: 36 (62%) enrolled patients with suspected pulmonary embolism, 21 (36%) with suspected deep vein thrombosis, and one with suspected VTE. Sample sizes ranged from 191-5,400; follow-up was 1-6 months. Assay name was fully reported in 52/58 (90%), manufacturer in 49/58 (85%), unit magnitude in 42/46 (91%), and unit type in 8/46 (17%) studies. Detection limit was reported in 3/58 (5.2%) studies; other analytical performance parameters were unreported. Nineteen quantitative assays were used across 19 combinations of thresholds and unit magnitudes. Of 17 studies using multiple assays, 9 reported patient numbers per assay and one reported failure rates per assay.

Conclusion: Key characteristics of D-dimer testing were inconsistently reported in VTE diagnostic management studies. While assay name, manufacturer, unit magnitude, and thresholds were often included, unit type and assay-specific data were frequently omitted. Minimum reporting standards for D-dimer testing are needed for VTE diagnostic management studies.

Introduction: Long-term follow up of children with venous thromboembolism (VTE) is necessary to diagnose post-thrombotic sequelae, though current practice is not standardized. The ASTRO-Kids international survey investigated the current practices among pediatric thrombosis providers for extremity and non-extremity VTE following acute treatment.

Methods: The International Society of Thrombosis and Haemostasis SSC Subcommittee on Pediatric and Neonatal Thrombosis and Haemostasis created and disseminated a 24-question survey between January and July 2024. We collected information on respondent treatment centers, practices on monitoring, diagnosis, and treatment of post-thrombotic sequelae following extremity and non-extremity thrombosis, stratified by the neonatal and non-neonatal age group.

Results: 115 pediatric thrombosis providers participated in the survey. Over half (53%; n=61), were from North America. Overall, 35% (n=40) and 15% (n=5) followed non-neonates and neonates, respectively, for post-thrombotic syndrome beyond 2 years from extremity thrombosis diagnosis. Long-term follow-up of non-extremity thromboses beyond 2 years from acute thrombosis was performed by less than 35% of respondents; 25-31% for non-neonates and 18-27% for neonates. A dedicated post-thrombotic syndrome clinic was present in the centers of 32% (n=35) of respondents; Physical Therapy (48%, n=62) and Interventional Radiology (47%, n=60) were the most common subspecialties to participate in the long-term care of these patients.

Conclusion: Long-term follow-up for pediatric VTE is variable. These findings underscore the imperative for globally applicable guidance that accommodates diverse practice settings, harmonize the management of thrombosis sequelae in children, and catalyzes collaboration to advance research in the field.

Non-extremity thromboses constitute approximately 40% of pediatric venous thromboembolism and are associated with significant organ-specific morbidity. These events may lead to chronic complications such as post-pulmonary embolism syndrome after pulmonary embolism, neurocognitive impairment following cerebral sinus venous thrombosis, portal hypertension after portal vein thrombosis, and hypertension or chronic kidney disease following renal vein thrombosis. Despite their clinical relevance, the epidemiology, natural history, and optimal management of these sequelae remain incompletely defined in children, and existing recommendations, where available, rely largely on expert opinion or extrapolation from adult studies. Long-term follow-up practices are inconsistent, contributing to under recognition of chronic morbidity. In this JTH in Clinic review, we present four representative cases illustrating the spectrum of post-thrombotic sequelae arising from commonly encountered non-extremity thrombotic events in children. For each scenario, we summarize epidemiology, pathophysiology, and management considerations highlighting areas where pediatric-specific data are limited. This case-based approach aims to provide clinicians with our collective approach for recognizing, assessing, and managing long-term complications of non-extremity thrombosis. By emphasizing systematic surveillance and multidisciplinary follow-up, we aim to promote earlier identification and more consistent management of long-term sequelae in children with non-extremity VTE.