Thrombosis and haemostasis最新文献

Edoxaban is a novel oral anticoagulant that directly inhibits factor Xa. The ENGAGE population pharmacokinetic (PopPK) model was established using data from the ENGAGE AF-TIMI 48 trial, which included over 21,000 participants, predominantly (81%) White/Caucasian individuals. However, its applicability to Chinese patients necessitates further evaluation. This study assessed the suitability of the ENGAGE PopPK model for Chinese patients with nonvalvular atrial fibrillation (NVAF).We analyzed 730 pharmacokinetic (PK) plasma samples from 104 Chinese NVAF patients using nonlinear mixed-effects modeling.A two-compartment model with first-order absorption and linear elimination optimally described the PK data of edoxaban in this cohort. Body weight (WT) and creatinine clearance were identified as significant covariates of apparent clearance (CL/F), and positively correlated with CL/F. Model-based simulations demonstrated that, in the 30 mg once-daily (q.d.) dosing group, patients with moderate renal impairment and low WT experienced higher systemic exposure than those with only one of these attributes. Additionally, patients with moderate renal impairment, whether alone or combined with low WT, displayed elevated steady-state trough concentrations (C_min,ss) compared to those receiving the 60 mg q.d. dose.Our PopPK model characterizes the PK profile of edoxaban in Chinese NVAF patients, identifies critical covariates influencing drug exposure, and proposes an evidence-based dosing regimen tailored to this population. This trial was registered at www.clinicaltrials.gov as #NCT05320627.

Inherited primary hemostasis disorders (IPHD) comprise a clinically and genetically heterogeneous spectrum, including inherited platelet disorders (IPD), heritable disorders of connective tissue (HDCT) associated with bleeding, and bleeding disorders of unknown cause (BDUC). Their phenotypic overlap and limited access to specific functional testing make genetic analysis essential for accurate diagnosis. This study aimed to investigate the genetic basis of patients with IPHD through Whole-exome sequencing (WES), providing genotype-phenotype correlations to guide clinical management. A total of 170 probands were included: 114 with IPD (67%), 28 with HDCT (16%), and 28 with BDUC (16%). Definitive genotype-phenotype correlation was achieved in 83 probands (49%), identifying 98 unique candidate variants across 48 genes. Notably, 19 patients carried variants in different genes that can contribute to the phenotype. A partial genotype-phenotype correlation was achieved in 19 probands (11%), while no variants were identified in the remaining 68 (40%), especially in the BDUC group. This multicenter study represents the first integrated analysis using a single workflow for patients with IPHD, encompassing not only IPD and BDUC but also HDCT. The high rate of genotype-phenotype correlations achieved, the identification of 68 previously undescribed variants, and the evidence of a shared and overlapped genetic and phenotypic profile among IPHD patients demonstrate the clinical value of WES. The study advocates for a paradigm shift in the clinical diagnosis of IPHD, from traditional phenotype-driven assesment to genotype-informed strategies, positioning WES as a first-line tool together with basic laboratory tests, allowing faster and more accurate diagnosis and personalized patient care.

Despite restored patency, catheter-directed thrombolysis (CDT) has variable efficacy in preventing post-thrombotic syndrome (PTS); biomarkers may clarify PTS pathophysiology and guide patient selection for CDT.To investigate relationships between biomarkers, patency, popliteal reflux, and PTS.This prespecified CAVA trial subanalysis included patients with first acute iliofemoral deep vein thrombosis (DVT), randomized to standard treatment (ST) or ultrasound accelerated CDT (UACDT). Baseline blood samples were analyzed for fibrinogen, CRP, IL-6, IL-10, VEGF-A, P-selectin, E-selectin, ICAM-1, VCAM-1, MMP-2, MMP-9, and adiponectin. Patency and reflux (duplex ultrasound), and PTS (Villalta score) were assessed at 1-year and long-term follow-up (LT).Among 108 patients (51 UACDT, 57 ST), absence of patency at 1-year was associated with higher baseline CRP and fibrinogen in both groups, and elevated IL-6 and VEGF-A in the ST group. Reflux at LT was associated with lower IL-6 and adiponectin in the UACDT group. (Moderate-to-severe) PTS at LT was associated with higher baseline MMP-2 and lower IL-10 in the UACDT group, and lower baseline VCAM-1 and adiponectin in the ST group.Pro-inflammatory processes are linked to reduced patency, with UACDT improving patency in patients with enhanced inflammatory responses. LT reflux is associated with impaired vasoprotective properties. PTS involves impaired anti-inflammatory responses and tissue remodelling both not modifiable by UACDT. Therefore, biomarker-guided treatment selection may potentially improve treatment outcome.

Rule-based natural language processing (NLP) tools can identify pulmonary embolism (PE) via radiology reports. However, their external validity remains uncertain.In this cross-sectional study, 1,712 hospitalized patients (with and without PE) at Mass General Brigham (MGB) hospitals (2016-2021) were analyzed. Two previously published NLP algorithms were applied to radiology reports to identify PE. Chart review by two physicians was the reference standard. We tested three approaches: (A) NLP applied to all patients; (B) NLP limited to radiology reports of patients with principal or secondary International Classification of Diseases 10th revision (ICD-10) PE discharge codes; and (C) NLP applied to patients with PE discharge codes or a Present-on-Admission (POA) indicator ("Y") for PE. All others were assumed PE-negative in Approaches B and C to minimize NLP false positives. Weighted estimates were derived from the MGB hospitalized cohort (n = 381,642) to calculate F1 scores (as the harmonic mean of sensitivity and positive predictive value [PPV]).In Approach A, both NLP tools showed high sensitivity (82.5%, 93.0%) and specificity (98.9%, 98.7%) but low PPV (60.3%, 59.6%). Approach B improved PPV (95.2%, 94.9%) but reduced sensitivity (74.1%, 76.2%), while Approach C preserved both high sensitivity (82.5%, 93.0%) and PPV (95.6%, 95.8%). Approach C demonstrated the best performance, yielding significantly higher F1 scores for both NLP tools (88.6%, 94.4%) compared with Approach A (69.7%, 72.6%) and Approach B (83.3%, 84.5%) (P < 0.001).The accuracy of PE detection improves when rule-based NLP algorithms are operationalized using administrative claims data in addition to radiology reports.

Thrombosis drives substantial global mortality across atrial fibrillation, venous thromboembolism, and atherosclerosis. However, clinical scores treat risk as a static variable and omit evolving comorbidities, functional biomarkers, anatomy, and treatment exposure, leading to misclassification and preventable events. This statement advances a unified scientific agenda for patient-specific digital twins that dynamically integrate multimodal longitudinal data with mechanistic insight to predict thrombogenesis risks. We position these digital twins as hybrid models anchored in physics and data-driven algorithms that can simulate disease progression and therapy. The goal of this approach is to refine stroke and bleeding estimation beyond current clinical rules. Continuous updating from imaging data, laboratory test results, wearables, and electronic health records supports dynamic risk trajectories and adaptive care pathways, facilitating continuous risk reassessment. This statement analyzes gaps in data quality, calibration, validation, and uncertainty quantification that presently limit the clinical translation of this technology. Research priorities are then proposed for multiscale thrombosis modelling, physics-informed learning, probabilistic forecasting, and regulatory-compliant data stewardship. Finally, we outline translation to in silico trials, regulatory alignment, and hospital workflows that link predictions to decisions. By articulating shared challenges across thrombosis-driven diseases and reframing risk as a time-varying measurable quantity, this statement lays a foundation for developing digital twin approaches that support a shift from population heuristics towards precise, timely thrombosis care. These advances are essential for translating digital twin technology from research to clinical practice, enabling dynamic risk prediction and personalized anticoagulation therapy.

Left ventricular thrombus (LVT) commonly complicates ST-segment elevation myocardial infarction (MI), and up to 30% of LVT may persist despite anticoagulation. Data linking post-MI LVT and inherited thrombophilias are sparse.A total of 148 consecutive MI patients with LVT at a mean age of 63.9 (6.9) years were referred for further workup. After 3 months of oral anticoagulation, screening for factor V Leiden (FVL) and prothrombin G20210A variant, protein S, protein C, and antithrombin deficiency was performed. Subjects with antiphospholipid syndrome were not eligible. Thrombus persistence was assessed after 3 and 6 months of anticoagulation.Inherited thrombophilias were identified in 34 (23%) patients, including 18 (52.9%) with FVL, 9 (26.5%) with prothrombin G20210A variant, 3 (8.8%) with protein C deficiency, and 4 (11.8%) with protein S deficiency. Carriers of thrombophilias were similar to non-thrombophilic subjects, except for higher fibrinogen in the former group. Inherited thrombophilias were associated with LVT persistence after 3 and 6 months post MI (25 [73.5%] vs. 50 [43.9%], p = 0.002 and 20 [58.8%] vs. 24 [21.1%], p < 0.001, respectively). Inherited thrombophilias were independently associated with an increased risk of persistent LVT 3 and 6 months post MI (OR 2.75, 95% CI 1.13-6.74, p = 0.026 and OR 4.06, 95% CI 1.57-10.51, p = 0.004, respectively).Our findings suggest that inherited thrombophilias may predispose to LVT persistence despite anticoagulation in MI survivors. Thrombophilia screening may help identify a subgroup likely to benefit from prolonged anticoagulation.

Once released into human blood, Shiga toxins (Stx) interact with platelets and leukocytes, stimulating them to form aggregates and to release pathogenic extracellular vesicles (EV) containing Stx. These EV are considered the trigger driving the transition from bloody diarrhea to the life-threatening hemolytic uremic syndrome (HUS) during human infections by Stx-producing Escherichia coli (STEC). In children, HUS is characterized by hemolytic anemia, thrombocytopenia and acute renal failure. The risk of any STEC-infected patient of developing HUS varies significantly depending on the Stx type produced by the bacteria, i.e. it is negligible for Shiga toxin 1 (Stx1), relevant for Shiga toxin 2 (Stx2) and considerably reduced when both toxins are present. To mimic what happens in the bloodstream of patients, human blood was challenged with Stx2a, Stx1a or both toxins and the formation of leukocyte/platelet aggregates was evaluated by direct-flow cytometric analysis. Pathogenic blood cell-derived EV were then isolated, their number and size determined by nanoparticle tracking analysis and their proteins characterized by capillary Western blotting. We found that the presence of Stx1a during Stx2a challenge significantly reduced the formation of pathogenic EV, particularly the large (>300 nm) EV population causing HUS development. Notably, the amount of Stx2a significantly decreased in Stx1a+Stx2a-triggered EV with respect to Stx2a-induced EV. Our findings suggest that in STEC-infected children the presence of Stx1 in association with Stx2 reduces the risk of developing HUS by lowering the release of Stx2-containing blood cell-derived EV which are considered the main culprits for HUS onset.

Hemophilia B is a rare inherited bleeding disorder resulting from mutations in the coagulation factor IX (factor IX) gene. While mutations in factor IX catalytic domains directly compromise clotting activity, mutations in the signal peptide and propeptide domains contribute to disease pathogenesis through more complex and indirect mechanisms. Despite not participating directly in enzymatic catalysis, the signal peptide and propeptide domains are indispensable for proper factor IX biosynthesis, structural maturation, and post-translational modifications. Research on these regions remains limited, and the precise molecular mechanisms linking mutations in the signal peptide and propeptide domains to clinical manifestations are not yet fully elucidated. In this review, we systematically catalog pathogenic mutations identified in factor IX's signal peptide and propeptide domains, organizing them by mutation types and functional consequences. We highlight how these mutations disrupt domain integrity, compromise factor IX stability, and interfere with its physiological processing. Furthermore, we discuss additional modifiers of disease severity, such as vitamin K availability, hypersensitivity to anticoagulant therapies, and inhibitor development. By integrating genetic, biochemical, and clinical perspectives, this review highlights the crucial role of factor IX's signal peptide and propeptide domains in the pathogenesis of hemophilia B and provides a foundational mechanistic framework that may inform future therapeutic development and help elucidate the molecular basis of disease heterogeneity.

Risk of venous thromboembolism (VTE) is increased in pregnancy and postpartum, and 40% of VTEs in pregnancy (Caucasians) are associated with heterozygous factor V Leiden mutation (FVL). Thrombin generation is increased in individuals with FVL and in pregnant women, and thrombin amplifies both platelet and coagulation activation. Although both contribute to VTE pathophysiology, the mechanisms of platelet activation in pregnant women, particularly with heterozygous FVL, remain poorly understood.To describe the physiological course of the platelet activation marker plasma soluble P-selectin (sP-selectin), whole blood platelet aggregation, and thromboelastography (TEG) parameters throughout pregnancy and postpartum, and assess differences between women with and without heterozygous FVL.A total of 22 pregnant women with heterozygous FVL and 22 without were enrolled. Blood samples were collected at multiple time points during and after pregnancy. Platelet activation and aggregation were evaluated using sP-selectin, multiple electrode aggregometry (MEA) with adenosine diphosphate, arachidonic acid, thrombin receptor-activating peptide-6 as agonists, and TEG.sP-selectin levels increased significantly during pregnancy, while platelet aggregation decreased in response to all agonists (P < 0.005). TEG maximum amplitude (MA) increased throughout pregnancy. No significant differences were observed between women with and without FVL.In late pregnancy, decreased platelet aggregation responses were observed alongside increased sP-selectin levels, with no differences in levels between women with and without heterozygous FVL. These findings indicate that the presence of heterozygous FVL does not significantly influence platelet function during pregnancy. The cause of the unexpected, reduced platelet aggregation remains unclear and warrants further investigation.

Platelets are among the most abundant cells in the body and play important roles in coagulation and immunity. Platelets are formed when hematopoietic stem cells proliferate and differentiate into megakaryocytes via the regulation of various cytokines. After the megakaryocytes mature in the bone marrow cavity, proplatelets are released into the blood circulation where they eventually remodel into mature platelets. Given that the production and functions of platelets involve the regulation of many factors-such as hematopoietic stem cells, the hematopoietic microenvironment, and cytokines-the causes and mechanisms of platelet-related diseases are diverse, often involving platelet production, clearance, and distribution. In this review, we examined the regulation of platelet production and summarized common disorders affecting platelet quantity, namely, thrombocytopenia and thrombocytosis. In addition, we reviewed previous clinical studies and summarized the medication strategies commonly used for the treatment of different platelet disorders in different clinical scenarios.