Journal of Thrombosis and Haemostasis最新文献

The path to the development of enoxaparin (Lovenox/Clexane), one of the most widely used low molecular weight heparins (LMWH) worldwide, was far from smooth. This narrative review, presented from the personal perspective of the senior author who lived this journey, describes the pivotal research conducted at McMaster University in Canada that transformed enoxaparin from a promising laboratory compound into a cornerstone of prevention and treatment of thrombosis. The story begins in the late 1970s with the observation that a LMWH, produced through controlled depolymerization, exhibited comparable antithrombotic efficacy to unfractionated heparin with a reduced risk of bleeding in animal models. It ends in the 1990s with the successful evaluation in clinical trials and the regulatory approval of enoxaparin for the prevention of deep vein thrombosis after orthopedic surgery.

Background: Post-thrombotic syndrome (PTS) is a common complication of deep vein thrombosis (DVT) of the lower extremities, associated with reduced quality of life and high healthcare costs. No reliable estimates exist of PTS risk by DVT location and its burden in the general population.

Objectives: To estimate: (1) the risk of PTS by anatomical location of DVT; (2) the age- and sex-specific incidence and prevalence of PTS in Europe.

Methods: We performed a systematic review and mixed-effects meta-analysis of studies reporting the cumulative incidence of PTS defined by Villalta score in patients with iliofemoral, femoropopliteal, and distal DVT. We then applied location-specific risk estimates to age- and sex-specific European DVT incidence data using a life table approach with Monte Carlo simulations to calculate the annual incidence and prevalence of PTS.

Results: Among 49 studies (N=14 171, 15 interventional, 34 observational), estimated PTS risk was 51.1% (95%CI: 39.5-62.7%) for iliofemoral, 30.7% (21.4-39.9%) for femoropopliteal, and 22.8% (17.1-29.8%) for distal DVT, assuming no systematic use of compression stockings for proximal DVT. We estimate 250 000 (95%CI: 220 000-315 000) new PTS cases annually in Europe (incidence 0.34 [0.29-0.42] per 1 000), and 4.86 million (4.11-5.88) prevalent cases (prevalence 6.5 [5.5-7.9] per 1 000).

Conclusion: PTS risk increases with proximal DVT extent. Approximately 5 million individuals in Europe are estimated to live with PTS, underscoring the need for targeted prevention and treatment strategies.

Introduction: Despite the global burden of disseminated intravascular coagulation (DIC) and decades of scoring-system development, no international assessment has evaluated global current practices among clinicians.

Methods: The International Society on Thrombosis and Hemostasis (ISTH) Scientific Standardization Subcommittee (SSC) on DIC conducted an international survey (Mar 2024-Feb 2025) to assess global diagnostic and treatment practices. Data was analyzed in light of participants' country level based on world bank classification RESULTS: A total of 153 clinicians from 27 countries completed the survey. Most respondents were from high-income countries (64%). The most suggestive clinical features of DIC were bleeding (89%), petechiae (77%), and shock (63%). Standard laboratory tests were commonly used (platelet count 93%, PT/INR 85%, fibrinogen 78%), but middle-income countries had reduced access to fibrinogen testing, serial monitoring, and advanced diagnostics. Only 28% of clinicians used a formal scoring system (ISTH 21%, SIC 14%) despite 76% reporting familiarity with the ISTH definition. First-line treatments most often included fresh frozen plasma (65%), platelets (38%), cryoprecipitate (32%), and whole blood (24%), with marked resource-driven differences between high- and middle-income countries. Major challenges included difficulty diagnosing DIC due to variable underlying disorders (59%) and clinical heterogeneity (47%), along with significant resource constraints, particularly in middle-income regions (limited test availability 57%, inadequate transfusion supply 54%, lack of critical care support 38%).

Conclusion: Despite strong global awareness, major gaps persist between recommended and real-world DIC practice, particularly in resource-limited settings. Expanding access to diagnostics, supporting guideline-based management, and developing innovative tools - including AI-driven models- are needed.

Background: All hospital laboratories in Sweden use the Owren prothrombin time (PT) method primarily to monitor anticoagulant treatment. Direct international normalised ratio (INR) calibration was introduced in 1999 under the supervision of Equalis, the national organisation for external quality assessment (EQA) in laboratory medicine. We present 25 years of combined experience in developing a national calibration procedure and conducting EQA of INR.

Methods: Since the introduction of direct INR calibration, 14 different Equalis INR calibrator kits have been produced. Variability between laboratories and different reagents and calibrator lots have been determined (>51 000 results, 96 EQA materials). The stability of the calibrators and the calibration procedure were studied from remeasurements of calibrators, weekly warfarin dosing in patient records and a comparison study with an international reference thromboplastin (RBT/05).

Results: Interlaboratory variability was improved significantly after the introduction of direct INR calibration. Results were consistent over 25 years, with mean coefficient of variation (CV) < 6% in the therapeutic range. The INR calibrators showed reproducible measured results, and the calibration procedure has been stable over time. Furthermore, anticoagulated patients had a stable mean weekly dose of warfarin in relation to mean INR. The Owren's PT agrees with Quick PT in a direct comparison with RBT/05.

Conclusions: There is a good agreement between the PT measurements in Swedish laboratories, and non-significant reagent differences. The user-friendly and unique calibration procedure, including the preparation of certified plasmas, improved the performance of the national PT measurements and was also proved to be stable over decades.

Patients often need to interrupt anticoagulation for invasive procedures or surgery. Periprocedural bleeding can contribute to substantial morbidity and mortality. Procedural bleed risk stratification informs whether anticoagulation needs to be interrupted, for how long, and when to restart anticoagulation post-procedure. Guidance on procedure-specific bleed risk varies and contributes to discordant perioperative anticoagulation management. To address this important knowledge gap, the Perioperative and Critical Care Thrombosis and Hemostasis Subcommittee of the International Society on Thrombosis and Haemostasis undertook a review of contemporary procedural bleed risk stratification schemas and developed a practical bleed risk stratification approach for use in anticoagulated adult patients having a planned elective surgery or procedure.

Background: Recombinant activated Factor VII (rFVIIa) is a key therapeutic agent for managing bleeding in hemophilia patients with inhibitors, but its clinical use is limited by a short half-life requiring frequent dosing. TU7710 is a novel recombinant Factor VIIa-transferrin fusion protein designed to extend circulation time by leveraging transferrin-mediated recycling via the transferrin receptor pathway.

Objective: To investigate the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of single ascending dose intravenous administration of TU7710, in warfarin-pretreated healthy male participants.

Methods: In each cohort, 8 healthy male participants were randomized in a 6:2 ratio to receive either TU7710 or placebo. Participants underwent 8 days of warfarin pretreatment to achieve a stable PT INR of 2.00-3.00 prior to dosing. TU7710 or placebo was administered intravenously (100-1600 μg/kg). Key PK and PD parameters, including FVIIa activity and PT INR, as well as anti-drug antibodies (ADA) were assessed RESULTS: A total of 41 participants were enrolled, and 40 were included in the analyses. Administration of TU7710 resulted in an immediate increase in FVIIa activity (median T_max: 0.25 h), with a mean residence time (MRT_inf) ranging from 6.70 to 10.52 hours. Pharmacodynamic assessments showed a corresponding normalization of PT INR in all participants treated with TU7710. Dose-dependent reductions in PT INR were observed. TU7710 was well tolerated across all dose levels.

Conclusion: TU7710 demonstrated an extended half-life and effectively normalized PT INR levels in warfarin-pretreated healthy participants. These findings support further clinical development of TU7710 as a potential therapeutic option for hemophilia patients.

It might take years for previously untreated patients (PUPs) with hemophilia A on emicizumab prophylaxis to receive 50 factor VIII (FVIII) exposures. This corresponds to the time at risk for FVIII inhibitors under conventional FVIII prophylaxis. During emicizumab prophylaxis, it is unknown whether additional treatment with regular FVIII doses promotes FVIII tolerance, unmask inhibitors or rather induce them. Therefore, we conducted a survey to describe the current global perspectives and practices of hemophilia health care providers (HCPs) in PUPs with severe hemophilia A receiving emicizumab prophylaxis. In 2024, a survey was sent by email to 1193 hemophilia treatment centers, addressing the perceived inhibitor risk with emicizumab, the potential need for concomitant regular FVIII infusions and the perceived parental willingness to use concomitant FVIII. In total, 102 pediatric HCPs (85% physicians, 13% nurses) from 38 countries participated. Perceived inhibitor risk data were available for 63 HCPs (62%). Compared to FVIII prophylaxis, the inhibitor risk on emicizumab was estimated to be higher by 13%, equal by 41%, lower by 32% and unknown by 14%. Among 57 of 102 HCPs with clinical access to emicizumab for children with severe hemophilia A without inhibitors, 30 (53%) offered regular concomitant FVIII infusions. However, in the experience of the HCPs, approximately 45% of parents rejected this option due to concerns about intravenous access. Ultimately, global perspectives on FVIII inhibitor risk and concomitant FVIII use in PUPs on emicizumab prophylaxis are heterogeneous due to lack of evidence, indicating the need for further research to guide treatment strategies.

Pulmonary embolism (PE) poses a considerable burden regarding mortality and sequelae. Up to 50% of patients develop long-term functional impairment, with varying degrees of severity. This may be caused by persistent changes in pulmonary artery flow, pulmonary gas exchange, and/or cardiac function. Consequently, patients may report symptoms such as shortness of breath, reduced exercise tolerance or deconditioning months to years after the event. Another important component of the so-called post-PE syndrome are psychosocial complications such as depression and anxiety, ultimately resulting in a decrease in quality of life. Even though these sequelae have been recognized and follow-up strategies have been proposed, the understanding of the development of PE-related symptoms and strategies to prevent sequelae remain limited. In this "Journal of Thrombosis and Haemostasis in Clinic review", we demonstrate the course of recovery after acute PE, describe determinants of poor recovery and discuss interventions to improve long-term outcomes.

Antithrombotic therapy is highly effective for stroke prevention in patients with atrial fibrillation (AF) but increases bleeding. Direct oral anticoagulants (DOACs) are preferred over vitamin K antagonists (VKAs) for many patients with AF because they provide similar stroke protection with less intracranial bleeding, and greater convenience, yet important knowledge gaps remain. In this review we examine the limitations of current AF risk scores for predicting stroke, bleeding and net benefit; identify AF populations in whom VKAs remain preferred over DOACs, including those with mechanical heart valves, antiphospholipid antibody syndrome or rheumatic mitral stenosis; and describe patient groups in whom the net benefit of oral anticoagulation is uncertain, including those with advanced kidney disease and survivors of intracranial bleeding. We address emerging challenges such as AF detected by implanted devices or consumer wearables, and anticoagulation management after successful AF ablation. We highlight the substantial residual risk of stroke despite guideline-recommended anticoagulation, the high risk of recurrent stroke in patients with "breakthrough" events while anticoagulated and summarize ongoing trials that evaluate intensified pharmacological or combined pharmacological / mechanical approaches, including left atrial appendage closure and implantable carotid filters. Finally, we review the burden of bleeding associated with current antithrombotic therapies and the promise of improved safety with a new class of anticoagulants that target coagulation factor XI. Together, these data underscore the need for more accurate risk stratification and for safer, more effective approaches to stroke prevention in patients with AF.

Background: Recurrent venous thromboembolism (VTE) is a major concern after stopping anticoagulation. Thrombin generation (TG) parameters-including thrombomodulin (TM) sensitivity-have been proposed as biomarkers of recurrence, but findings remain inconsistent. The role of thrombin dynamics (TD) parameters, including prothrombin conversion and thrombin inactivation, is unclear.

Objective: To evaluate whether TG and TD parameters are associated with VTE recurrence.

Methods: In 589 patients from the prospective VISTA study, TG was measured during anticoagulation and one month after stopping VKA therapy. TM sensitivity was quantified as the percentage inhibition of endogenous thrombin potential (ETP) and peak thrombin concentration. TD parameters were derived computationally from TG curves. Cox regression was used to evaluate associations with recurrent VTE over two years, including subgroup analyses excluding hormone-related events.

Results: During the two-year follow-up, 63 patients experienced recurrent VTE. In multivariable Cox regression adjusted for age, sex, index event type, and hormone use, reduced thrombin inactivation by antithrombin (T-AT) was associated with recurrence (per 100-unit decrease: HR: 1.10, 95% CI: 1.00-1.20). In patients without hormone-related VTE, lower ETP and reduced TM-mediated inhibition of peak thrombin concentration were also significantly associated with recurrence (ETP per 100-unit decrease: HR: 1.11, 95% CI: 1.01-1.21; TM sensitivity per 10% decrease: HR: 1.26, 95% CI: 1.00-1.58). Other TG parameters were not significantly associated with recurrence.

Conclusions: Reduced ETP, TM sensitivity and thrombin inactivation were associated with VTE recurrence in people with unprovoked VTE. These biomarkers may have potential to identify patients at higher risk of recurrence.