Journal of Thrombosis and Haemostasis最新文献

Background: The Hokusai Venous Thromboembolism (VTE) Cancer trial demonstrated that edoxaban was noninferior to dalteparin for the treatment of cancer-associated venous VTE.

Objectives: We reanalyzed the trial using the win ratio, an approach that evaluates a composite of outcomes in a hierarchical order.

Methods: Forty-nine thrombosis experts ranked 10 outcomes in order of clinical importance from all-cause death (most important) to clinically relevant nonmajor bleeding (least important). We performed unmatched pairwise comparisons between participants on edoxaban and those on dalteparin at 6- and 12-month follow-up. Within each pair, edoxaban was assigned a win, loss, or tie according to the hierarchy of outcomes. We calculated the win ratio (total wins divided by total losses among edoxaban patients), with more wins than losses indicating the benefit of edoxaban, and the win difference (total wins minus total losses).

Results: Among 273 528 pairs (522 × 524 participants), edoxaban was associated with a win in 34.9%, a loss in 38.5%, and a tie in 26.6%. The win ratio was 0.91 (95% CI, 0.76-1.08), with a win difference of -3.55% (95% CI, -9.9% to 2.9%) at 12 months. The win ratio remained unchanged at 6 months (0.91; 95% CI, 0.75-1.11). The findings were consistent with a hierarchy of only death, recurrent VTE, and major bleeding (win ratio, 0.92; 95% CI, 0.76-1.11), or when replacing all-cause death with VTE-related death or fatal bleeding (win ratio, 0.83; 95% CI, 0.65-1.06).

Conclusion: We observed no significant difference between edoxaban and dalteparin for the treatment of cancer-associated VTE when using the win ratio approach with a hierarchy of 10 prioritized outcomes.

Background: Thrombopoietin receptor agonists (TPO-RAs) have become a cornerstone in the management of relapsed or refractory immune thrombocytopenia (R/R-ITP), with emerging evidence supporting treatment discontinuation in selected patients. However, predictors of sustained response and real-world switching patterns remain underexplored in Asian populations.

Objectives: To evaluate clinical outcomes, switching strategies, and predictors of treatment-free remission following TPO-RA therapy in Korean patients with R/R-ITP.

Methods: We retrospectively analyzed 91 adult R/R-ITP patients treated with eltrombopag, romiplostim (ROMI), or both at a tertiary center in Korea from 2016 to 2021. Clinical responses, platelet count trajectories, loss of response, and sustained response off treatment (SROT) after TPO-RA were assessed. Subgroup analyses identified predictors for response and SROT rates. Notably, Korean reimbursement guidelines mandating drug interruption every 6 months facilitated longitudinal assessment of treatment-free outcomes.

Results: The overall response rate was 93.4%, and 40% of those achieved SROT after TPO-RA. Higher peak platelet count (platelet count at maximal response > 100 × 10⁹/L; odds ratio, 5.28; P = .005) and prior intravenous immunoglobulin (IVIG) responsiveness (odds ratio, 3.93; P = .036) were significantly associated with SROT. Despite a significantly higher platelet count at maximal response with ROMI, response and SROT rates were comparable between eltrombopag and ROMI, likely reflecting differences in dosing and adherence patterns. Patients with high autoimmune burden or poor IVIG response showed higher loss of response and lower SROT rates.

Conclusion: TPO-RAs demonstrated robust efficacy and potential for SROT in R/R-ITP. Baseline immunologic status and prior IVIG response may guide treatment selection and discontinuation strategies. These findings highlight the importance of individualized immune thrombocytopenia management and suggest future directions for patients with persistent refractoriness.

Background: Percutaneous coronary intervention (PCI) is a widely used treatment strategy for coronary artery disease. Optimal long-term antithrombotic therapy after PCI remains challenging.

Objectives: This substudy of the Vienna PCI Registry assessed long-term effects of direct oral anticoagulant (DOAC) use on major adverse cardiac events (MACEs) in patients with chronic coronary syndrome (CCS) after PCI, exploring possible pleiotropic effects.

Methods: We analyzed patients with CCS from the Vienna PCI Registry treated with a drug-eluting stent (DES) between 2015 and 2020. The primary end point was clinically driven target lesion revascularization (TLR). The secondary composite end point (MACE) included TLR, target vessel revascularization (TVR), stent thrombosis (ST), and all-cause death. Patients received either triple antithrombotic therapy (TAT; DOAC, aspirin, and clopidogrel), followed by DOAC monotherapy, or dual antiplatelet therapy (DAPT; aspirin and clopidogrel), followed by single antiplatelet therapy.

Results: Among 1046 patients with CCS, 176 (16.8%) received TAT followed by DOAC monotherapy. The primary end point TLR occurred significantly less often in TAT-treated patients (2.8% vs 8.4%). MACE rates were similar between TAT and DAPT groups (17.0% vs 17.0%). All-cause mortality was higher in the TAT group (11.9% vs 7.8%). Multivariable regression showed that TAT followed by DOAC monotherapy was associated with a reduced 5-year risk of TLR compared with DAPT followed by single antiplatelet therapy (odds ratio, 0.367; 95% CI, 0.147-0.917; P =.032).

Conclusion: Patients treated with TAT demonstrated a statistically significant risk decrease for the primary end point clinically driven TLR in the elective CCS-PCI setting at 5 years' follow-up, which may be in part due to pleiotropic effects of DOACs.

Background: Factor (F)VIIIa acts as a cofactor with FIXa on phospholipid surfaces to convert FX to FXa. Region 1900 to 1908 is a known FVIIIa antibody epitope, with mutations in this region linked to hemophilia A. However, its role in FXase activity is unclear. This study investigates how individual residues within 1900 and 1908 affect interprotein affinity and cofactor activity.

Objectives: This study investigated how individual residues within region 1900 to 1908 contribute to interprotein affinity and cofactor activity.

Methods: The mutations were generated by site-directed mutagenesis. Recombinant FVIII light chain (LC) wild type (WT) and variants were expressed in Bac-to-Bac Baculovirus Expression System and then purified. The activity, stability, and affinity of LC variants were assessed by FXa generation assay and fluorescence anisotropy. The structures of FVIIIa were predicted using PSIPRED (v3.3) and Phyre2.

Results: FXa generation assays revealed that D1903A/E1904A/K1906A/S1907A variants showed 8.4- to 20.3-fold and 3.9- to 5.6-fold increases in apparent dissociation constant for FXase and FVIIIa reconstitution, respectively, compared with WT. Reduced fluorescence anisotropy was observed when fluorescein-Phe-Phe-Arg-FIXa bound to FVIIIa reconstituted with D1903A, E1904A, K1906A, and S1907A variants compared with WT. In both the presence and absence of FIXa, D1903A and E1904A exhibited faster decay rates than WT. While WT FVIIIa showed a 3.26-fold slower decay rate and 0.64-fold shorter half-life in the absence of FIXa compared with its presence, the decay rates and half-lives of FVIIIa reconstituted with D1903A and E1904A remained similar regardless of FIXa presence, suggesting that these mutations abrogate the normal FIXa-mediated stabilization of FVIIIa.

Conclusion: Our study identifies FVIIIa residues 1900 to 1908 as key determinants of FIXa binding, advancing understanding of FXase assembly and A3-domain-mediated regulation of complex stability and activity.

Pulmonary embolism is a common cardiovascular cause of death. Following diagnosis, immediate risk stratification and initiation of treatment are crucial but challenging, as patients may rapidly deteriorate in cases of progressive right heart failure. Multiple approaches to standardized risk stratification and subsequent management have been proposed, including assessment of clinical parameters such as cardiac biomarkers and imaging evidence of right ventricular abnormalities; however, obtaining an overview of the strengths and weaknesses of the multiple proposed approaches to risk stratification and subsequent management might be overwhelming for physicians not routinely involved in the treatment of acute pulmonary embolism. Fourteen international guidelines have been authored by medical societies or expert author groups over the past 20 years, offering recommendations on aspects of the management of pulmonary embolism, some of which are characterized by notable heterogeneity. This review summarizes and compares the main recommendations of each guideline, considers the most recent evidence for each topic, and provides a synthesis of the most common recommendations.

Background: Chronic limb pain following an extremity deep venous thrombosis (DVT) in children is a symptom of postthrombotic syndrome (PTS) and can present with or without physical findings of chronic venous insufficiency. Data on the prevalence, phenotype, and risk factors for PTS-related chronic limb pain in pediatrics are limited.

Objectives: To characterize the prevalence and phenotype of and identify risk factors for PTS-related chronic limb pain in children.

Methods: We analyzed clinical data from patients with an extremity DVT enrolled in a muticenter clinical trial (NCT00687882). Physical examination findings for PTS and patient-reported outcomes on the presence and severity of pain were obtained at 6 months and 1-year post-DVT diagnosis using the Manco-Johnson Instrument. Risk factors for chronic limb pain at 1 year were evaluated via univariate logistic regression, with odds ratios and 95% CIs. Variables with univariate P < .1 were included in the multivariable analysis.

Results: Among 294 patients, the prevalence of chronic limb pain at 1-year post-DVT was 10% (95% CI, 6.5%-13.3%). In univariate analyses, older age, non-CVC-associated DVT, and prior trauma/surgery were associated with chronic limb pain. Non-CVC-associated DVT remained independently associated with pain (odds ratio, 3.02; 95% CI, 1.08-8.45; P = .035) in the adjusted model.

Conclusion: We have identified that 1 in 10 children with provoked DVT experience chronic limb pain at 1-year post-DVT diagnosis and that non-CVC-associated DVT is an independent risk factor for PTS-related chronic limb pain. Future prospective studies and registries are needed to further characterize the phenotype and impact of PTS-related chronic limb pain in children.

Background: In patients with acute pulmonary embolism (PE), echocardiography is currently used to detect right ventricular dysfunction (RVD) and to guide risk stratification and treatment decisions. However, the prognostic value of individual RVD parameters in echocardiography, as well as their combinations, remains uncertain.

Objectives: To assess the association between individual RVD parameters on echocardiography and short-term all-cause death and PE-related death, and to evaluate whether combinations of parameters improve risk stratification.

Methods: We performed an individual patient data meta-analysis of studies reporting on echocardiographic findings and 30-day mortality in patients with acute PE. Outcomes included short-term all-cause death and PE-related death.

Results: Overall, 9233 patients were included, with a 7% rate (95% CI, 6%-9%) of short-term all-cause death. Tricuspid annular plane systolic excursion < 16 mm, an estimated pulmonary artery pressure > 30 mm Hg, a right-to-left ventricle diameter ratio > 1, RV hypokinesis, paradoxical septal motion, and dilated RV were associated with short-term all-cause death and PE-related death in univariate analysis. Among 8905 patients with at least 3 RVD parameters assessed, having a single abnormal parameter was not associated with short-term all-cause death (odds ratio [OR], 1.17; 95% CI, 0.92-1.47), whereas having 2 (OR, 1.52; 95% CI, 1.19-1.54) or 3 or more parameters was (OR, 2.33; 95% CI, 1.79-3.03). Among the couple of parameters, a trend toward an increasing association with death was observed for the combination of right-to-left ventricle diameter ratio > 1 and tricuspid annular plane systolic excursion < 16 mm (OR, 2.49; 95% CI, 1.23-5.01) compared with either parameter alone.

Conclusion: In acute PE patients, RVD parameters from echocardiography are associated with short-term all-cause and PE-related death. The combination of at least 2 RVD parameters identifies PE patients at an increased risk for death.

Background: Venous thromboembolism (VTE) is typically treated with anticoagulation for 3 to 6 months. Decisions about extending treatment require balancing recurrence and bleeding risk. Current prediction models based on clinical markers lack sufficient discriminative accuracy, emphasizing the need for reliable biomarkers.

Objectives: To identify plasma biomarkers associated with VTE recurrence during and after anticoagulation.

Methods: We conducted a case-cohort study using data and samples from the VISTA trial, which followed patients with a first VTE who were treated with vitamin K antagonists (VKAs) for 6 months. Follow-up for recurrence was 2 years. Recurrence cases (N = 96) were compared with a randomly selected subcohort (n = 192). Plasma was collected in the final month of VKA therapy and 1 month after cessation. Unbiased mass spectrometry-based proteomics was used to analyze plasma proteins.

Results: Principal component analysis revealed no global proteomic differences between patients with and without recurrence. In addition, no statistically significant changes in plasma protein levels were associated with recurrence, neither during nor after treatment. While paired sampling demonstrated variability in interindividual responses upon initiation and cessation of VKA treatment, including VKA-dependent coagulation proteins (eg, prothrombin [factor {F}II], coagulation FVII, FXI, FX, vitamin K-dependent protein S, protein C, and protein Z), there were no statistically significant differences in protein-level alterations associated with recurrence.

Conclusion: While plasma proteomics captured anticoagulation effects, it did not reveal biomarkers predictive of VTE recurrence, underscoring the need for alternative approaches.

Background: Computed tomography pulmonary angiography (CTPA) and ventilation-perfusion (VQ) scans are used to diagnose pulmonary embolism (PE), but there are concerns about ionizing radiation exposure from CTPA and its potential to increase cancer risk.

Objectives: This study compared early-onset cancer risk between patients diagnosed with PE who underwent CTPA or VQ imaging.

Methods: We conducted a retrospective, population-based, matched cohort study using linked clinical and administrative health databases in Ontario, Canada. Patients aged 18 to 75 years diagnosed with PE between 2004 and 2021 were included. Each patient who underwent a VQ scan was matched by age and sex to a patient who underwent CTPA. Using a landmark statistical framework, starting at 18 months post-PE diagnosis, cancer diagnoses were identified from the Ontario Cancer Registry. Cox proportional hazards regression models were used to assess the association between imaging modality and cancer risk.

Results: A total of 20 476 patients were included, 10 238 in each cohort. The median follow-up was 5.26 years for patients in the CTPA group and 6.96 years for those in the VQ group. The overall cancer rate was 10.96 per 1000 person-years (95% CI, 10.42-11.52). There was no significant difference in cancer risk between the CTPA (10.93 per 1000 person-years; 95% CI, 10.14-11.78) and VQ scan groups (10.98 per 1000 person-years; 95% CI, 10.26-11.75; P = .93). Multivariable analysis demonstrated no significant association between CTPA and VQ scan (hazard ratio, 0.95; 95% CI, 0.86-1.05).

Conclusions: In this population-based cohort, cancer risk associated with exposure to CTPA was not significantly higher than that associated with VQ lung scans.