Thrombosis and haemostasis最新文献

von Willebrand disease (VWD) type 2 arises from variants in von Willebrand factor (VWF) that disrupt its essential hemostatic functions. As per ISTH guidelines, it is classified as type 2A, 2B, 2M, and 2N based on the affected VWF roles.This population-based study aims to uncover the genotype and laboratory phenotypes in type 2 VWD, providing insights into underlying genetics and genotype-phenotype associations.Our cohort included 247 patients from 196 families. Patients were characterized through multiple VWF phenotypic assays and genetic analyses, including DNA sequencing, copy number variation evaluations, and bioinformatic assessments.A total of 86 index patients (IPs, 44%) were diagnosed with type 2A, the most prevalent subtype. Additionally, 27 IPs (14%) were diagnosed with type 2N, 24 IPs (12%) with type 2B, 17 IPs (9%) with type 2M, and 42 IPs categorized as type U VWD carried VWD-associated variants but could not be assigned to a specific subtype. VWF variants were detected in 187 out of 196 (95%) individuals. A total of 222 VWF variants were identified: 187 missense (84%), 22 null alleles (10%), 5 regulatory (2%), 6 gene conversions (3%), and 2 silent variants (1%). Many variants were recurrent in our cohort, resulting in 114 distinct variants. Of these, 45 (39%) were novel.Our data expands the spectrum of disease-associated variants in VWF, including many newly identified variants. This provides valuable insights for accurate diagnosis and personalized treatment. Additionally, the significant genetic heterogeneity among type 2 patients highlights the challenges in sub-classification.

Complement is activated after trauma, but the activation mechanism is unknown. Plasmin can directly activate C3 and C5, and four distinct fibrinolytic phenotypes have now been recognized after injury-hyperfibrinolysis, fibrinolysis shutdown, hypofibrinolysis, and nonpathologic/physiologic.We set out to investigate whether a relationship between complement activation and fibrinolysis was present in adult trauma patients (n = 56).Rapid and tPA-challenged thromboelastography (TEG) was performed in the emergency department with IRB approval, and plasma obtained for C3a, C4a, C5a, Ba, sC5b-9, Factor I, Factor H, active PAI-1, α-2 antiplasmin (A2AP), plasmin-antiplasmin complex (PAP), and tPA activity measurement via multiplex, ELISA and activity assays. Data were analyzed using ANOVA and Spearman's correlations. Significance was set at p < 0.05.C3a and sC5b-9 were significantly higher in patients with hyperfibrinolysis than with physiologic or hypofibrinolysis (p < 0.05). Elevations in C3a, C4a, and SC5b9, along with depletion of Factors H and I, were significantly associated with massive transfusion within 6 hours and postinjury death. There were significant positive correlations between multiple markers of fibrinolysis and complement activation markers and significant negative correlations with Factors H and I. Significant negative correlations between fibrinolytic inhibitors and complement activation were also observed.Our findings suggest that fibrinolysis may play a direct role in complement activation in trauma through plasmin-mediated cleavage of C3 and C5.

Pulmonary embolism (PE) requires accurate risk assessment. We investigated the prognostic performance of the National Early Warning Score (NEWS) in emergency department patients with PE.We included patients ≥ 18 years from our PE registry (2017 to 2021), excluding patients after cardiac arrest or intubation before admission. The primary outcome was a composite of 30-day all-cause mortality or the need for advanced therapy (i.e., systemic or catheter-directed thrombolysis). We used logistic regression and the Cox proportional hazards models to estimate associations. The Pulmonary Embolism Severity Index (PESI) and the European Society of Cardiology (ESC) classification served as covariates. The overall score performances were quantified using receiver operating characteristic analysis.We included 524 patients. Each increase in NEWS points increased the odds of the primary outcome by 69% (odds ratio: 1.69, 95% confidence interval [CI]: 1.51-1.89, p < 0.001) and 30-day mortality by 44% (hazard ratio: 1.44, 95% CI: 1.30-1.60, p < 0.001). Within the ESC intermediate-high and high-risk group, the 30-day mortality rate was higher in patients with a NEWS ≥ 7 compared with NEWS < 7 (24 vs. 1%, p < 0.001). With a NEWS ≥ 7, 30-day mortality was lower in patients who received advanced therapy (18 vs. 39%) but not significantly. The NEWS predicted the primary outcome better than the PESI (area under the curve: 0.853 vs. 0.752, p < 0.001).The NEWS was associated with 30-day mortality and the need for advanced therapy. Incorporating the NEWS into the ESC classification could help to assess patient outcomes early and thus support timely treatment decisions.

While resting heart rate (RHR) is associated with multiple diseases, conflicting information exists on the association between RHR and venous thromboembolism (VTE). We, therefore, aimed to investigate the association between RHR and risk of VTE in a population-based cohort.Participants (n = 36,395) were followed from inclusion in the Tromsø 4 to 7 surveys (1994-2016) throughout 2020. RHR was measured in beats per minute (bpm) at each survey (repeated measurements for those attending several surveys). All first-time VTEs during follow-up were recorded. Hazard ratios (HR) for VTE with 95% confidence intervals (CIs) according to RHR categories (61-70, 71-80, and >80 bpm) with ≤60 bpm as reference were estimated using Cox regression models, and adjusted for age, sex, body mass index, cardiovascular disease, cancer, and physical activity. We also performed age-stratified analyses (<60 and ≥60 years).During a median of 6.6 years of follow-up, 1,072 participants experienced a VTE. Fully adjusted HRs (95% CI) for overall VTE were 1.12 (0.93-1.35), 1.35 (1.11-1.63), and 1.19 (0.97-1.47) for RHR categories 61 to 70, 71 to 80, and >80 bpm, respectively. Corresponding HRs for unprovoked VTE were 1.56 (1.14-2.14), 1.76 (1.28-2.43), and 1.60 (1.13-2.25), whereas no association was observed for provoked VTE. The association was more consistent in those ≥60 years, with HRs for overall VTE, >80 bpm versus ≤60 bpm of 1.30 (1.02-1.65) and for unprovoked VTE of 1.86 (1.24-2.81).Our findings suggest that higher RHR may be a risk factor for VTE and more consistently so for those ≥60 years. The VTE risk by higher RHR was particularly pronounced for unprovoked events.

F11Receptor/junctional adhesion molecule-A (F11R/JAM-A) is a transmembrane protein expressed in endothelial cells, epithelial cells, and in blood platelets. In blood platelets, F11R/JAM-A participates in adhesion under static conditions, suppresses the activation of the platelet α_IIbβ₃ integrin and was shown to activate blood platelets as soluble form via homophilic interactions.The purpose of presented study was to evaluate whether F11R/JAM-A is involved in platelet adhesion under flow conditions and in thrombus formation.F11R/JAM-A contribution to platelet adhesion under flow conditions was assessed using flow chamber assay. Monoclonal antibodies and recombinant F11R/ JAM-A were used to assess the effects of F11R/JAM-A blockade on platelet aggregation and thrombus formation using total thrombus formation analysis system. Effects of F11R/JAM-A blockade on thrombus formation in vivo were evaluated in murine models of carotid artery injury.F11R/JAM-A was not capable of capturing flowing blood platelets alone but enhanced platelet adhesion to fibrinogen under flow conditions. Blocking of F11R/JAM-A homophilic interactions with specific monoclonal antibodies or with recombinant F11R/JAM-A impaired thrombus formation in vitro in human blood and in vivo in the models of thrombosis in mice.Interactions of F11R/JAM-A located on flowing platelets with its surface-bound counterpart enhance platelet binding to fibrinogen under high shear stress conditions. Blocking of these homophilic interactions compromises thrombus formation. While previously published studies pointed at a significant role of soluble F11R/JAM-A in priming platelets during thrombus formation, our results highlight the role of surface-bound F11R/JAM-A in this process.

Patients with spontaneous intracerebral hemorrhage (ICH) are at high risk of venous thromboembolism (VTE). Recent studies have shown the involvement of neutrophil extracellular traps (NETs) in thrombogenesis.To explore the predictive value of serum MPO-DNA (a NETs surrogate) for VTE and the effect of statins on serum MPO-DNA levels and the VTE incidence in ICH patients.This prospective cohort study enrolled 117 ICH patients and 15 healthy controls. Serum MPO-DNA levels were measured via ELISA. The relationship between serum MPO-DNA levels and VTE risk was analyzed. The predictive value of MPO-DNA was evaluated by ROC curves. Effects of statin on NETs and VTE incidence were evaluated.The median MPO-DNA level in patients with VTE was 0.304 (95% CI: 0.231-0.349), significantly higher than the 0.188 (95% CI: 0.159-0.236) in non-VTE patients. Elevated MPO-DNA levels were associated with an increased VTE risk (OR 7.13, 95% CI 2.58-19.75; P < 0.001), and this association persisted after adjustment. The AUC values for MPO-DNA, CRP, and D-dimer were 0.824 (95% CI: 0.719-0.928), 0.618 (95% CI: 0.481-0.754), and 0.786 (95% CI: 0.683-0.888), respectively. Moreover, statin users exhibited reduced MPO-DNA levels (0.174 vs. 0.218; P = 0.007), though VTE incidence differences (13.8% vs. 19.3%) lacked statistical significance.Serum MPO-DNA serves as a sensitive biomarker for VTE prediction in ICH, highlighting NETs as potential therapeutic targets. Statins could attenuate NETosis, but larger trials are required to validate their clinical efficacy and safety in VTE prevention for ICH patients.

Although direct oral anticoagulants (DOACs) have become a primary treatment choice for cancer-associated venous thromboembolism (CT), the safety and effectiveness of switching from low-molecular-weight heparin (LMWH) to DOACs in current users remains unclear.To evaluate the safety and effectiveness of switching to DOACs in patients with CT currently receiving LMWH therapy, a territory-wide cohort study using linked claims and registry databases in Taiwan was conducted. Between 2013 and 2021, patients with CT were identified and categorized as switchers to DOACs versus persistent LMWH users. Cox regression and Fine-Gray models with inverse probability of treatment weighting were used to estimate hazard ratios (HRs) for recurrent venous thromboembolism (VTE), major bleeding, and all-cause mortality.A total of 3,885 patients with LMWH-treated CT were included, with 2,103 (54.1%) being women and a mean age of 65.6 years at CT diagnosis, of which 2,373 (59.5%) switched to DOAC therapy. Compared with the persistent use of LMWH, switching to DOACs within 6 months was associated with no significant difference in recurrent VTE (HR: 0.86 [95% CI 0.50-1.49]) and major bleeding (HR: 0.89 [95% CI 0.67-1.18]), with a significantly lower risk of all-cause mortality (HR: 0.67 [95% CI 0.52-0.86]).Switching to DOACs is a safe and effective alternative to continuous LMWH in patients with CT. This recommendation applies regardless of the duration of initial LMWH therapy, overall treatment duration, and across various vulnerable patient groups.

Atrial fibrillation (AF) significantly increases the risk of ischemic stroke. This study evaluates whether transmitral atrial flow velocity (MVA), measured non-invasively via transthoracic echocardiography (TTE), predicts stroke risk in AF patients.To assess the independent association between TTE-derived MVA and stroke incidence in paroxysmal AF patients and its value in refining risk stratification, especially in low-risk groups.This cohort study included 10,150 paroxysmal AF patients from 2010 to 2021. The primary outcome was hospitalization for ischemic stroke. Multivariable Cox regression analyses adjusted for CHA₂DS₂-VASc scores evaluated the relationship between MVA and stroke risk.Over a mean follow-up of 4.26 ± 3.52 years, 2,419 (23.8%) patients developed ischemic strokes (5.59% per 100 person-years). In multivariable analysis, adjusting for CHA₂DS₂-VASc score, MVA was independently associated with stroke incidence. Every 10 cm/s reduction in MVA velocity conferred 4% higher stroke risk (adjusted hazard ratio [HR] 0.96 [0.94-0.97], P < 0.001). AF patients with MVA < 50 cm/s had a 39% increase in stroke risk compared to those with MVA ≥ 50 cm/s (adjusted HR 1.39 [1.22-1.58], P < 0.001). In patients with a CHA₂DS₂-VASc score of 0 or 1, the stroke incidence increased from 1.33 to 2.28% when they had MVA < 50 cm/s, which was similar to that of patients with a CHA₂DS₂-VASc score of 2 points (2.51%).TTE-derived MVA independently predicts stroke risk in paroxysmal AF patients. Incorporating MVA enhances risk stratification and guides targeted stroke prevention, particularly in low-risk populations.