Journal of Thrombosis and Haemostasis最新文献

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

Objectives: This study investigated the safety, pharmacokinetics, and pharmacodynamics 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 prothrombin time (PT)/international normalized ratio (INR) of 2.00 to 3.00 prior to dosing. TU7710 or placebo was administered intravenously (100-1600 μg/kg). Key pharmacokinetic and pharmacodynamic parameters, including FVIIa activity and PT/INR, as well as antidrug antibodies 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 hours), with a mean residence time 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 patients with hemophilia.

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.

Background: Depletion of fibrinogen is an early event in trauma-induced coagulopathy (TIC), while hyperfibrinogenemia increases thrombotic risk in end stage renal disease (ESRD). Viscoelastic tests aim to provide rapid fibrinogen estimates, yet their accuracy to define abnormal fibrinogenemia remains debated.

Objectives: We assessed the accuracy of thrombelastography (TEG) -TEG® 5000, TEG® 6s-in measuring normal and abnormal fibrinogen levels across healthy volunteers, ESRD, and trauma patients at risk for TIC.

Patients/methods: We compared the von Clauss functional fibrinogen (gold standard) with TEG®5000 functional fibrinogen level(FLEV) in 118 healthy volunteers, 52 patients with ESRD undergoing arteriovenous fistula (AVF) surgery and 265 severely injured patients. We compared Clauss fibrinogen with TEG®6s citrated functional fibrinogen (CFF) in 140 trauma patients at high risk for TIC. Pearson correlation was used.

Results: Clauss fibrinogen correlated moderately with TEG®5000-FLEV in healthy volunteers (r=0.52, p<0.0001) and ESRD patients overall (r=0.62, p<0.0001). Correlation, however, deteriorated and became non-significant in ESRD patients with fibrinogen >500 mg/dl. Trauma patients showed moderate overall correlation (r=0.58, p<0.0001), but it decreased substantially with fibrinogen<150 mg/dl (r=0.20, p=0.29). TEG®6s-CFF had better overall correlation (r=0.66, p<0.0001), though decreased at fibrinogen<200mg/dl (r=0.39, p=0.04).

Conclusions: Both TEG®5000-FLEV and TEG®6s-CFF correlated moderately with Clauss fibrinogen but decreased in correlation in both hyperfibrinogenemia and hypofibrinogenemia. Thus, we caution relying on TEG®5000 or TEG®6s to be the only laboratory measurement to guide fibrinogen replacement when resuscitating trauma patients at risk for TIC and TEG®5000-FLEV for assessing fibrinogen in patients with ESRD at risk for thrombotic events.