Thrombosis and haemostasis最新文献

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.

Introduction: Rapidly sorting patients with large vessel occlusion (LVO) ischemic stroke is crucial to ensure efficient transfers to stroke units. Peripheral monocyte subsets (classical-Mon1, intermediate-Mon2, non-classical-Mon3) could be interesting candidate biomarkers in this setting: their profiles in the first hours after stroke symptom onset are unknown.

Aim: To characterize monocyte subsets in patients admitted to emergency units for acute stroke suspicion Methods: BOOST ("Biomarkers-algOrithm-for-strOke-diagnoSis-and-Treatment-resistance-prediction", NCT04726839) is a prospective multicenter cohort. Adult patients with symptoms suggesting acute stroke within the last 24 hours were included. Blood was collected upon admission before brain imaging. Flow-cytometry (FCM) was performed on fresh blood with gating based on CD45/CD14/CD16/CD91 as well as on activation markers (CD62L/CD11b/CD86/HLA-DR/CCR2/ICAM-1/CX3CR1/TF).

Results: Of the 298 consecutive patients tested, mean age 64.0±18.6 years, 64 (21.5%) had LVO stroke vs 234 (78.5%) other diagnosis (non-LVO ischemic stroke, cerebral venous thrombosis, intracranial hemorrhage, transient ischemic attack and stroke mimics). The median time from symptom onset to sampling was 2.3 hours. We found a significantly lower proportion of Mon3 (geometric mean) (-47%, p=0.0093) and a higher proportion of Mon1 (+1.6%, p=0.0296), suggesting earlier Mon1 mobilization and patrolling Mon3 consumption in LVO-patients versus those without. Using linear-mixed-effect model, significant differences in ICAM-1 and HLA-DR expression on monocyte subsets were evidenced between LVO and other patients.

Conclusions: This is the first study to evidence monocyte subset differences in LVO vs non-LVO patients at the time of admission, indicating an acute systemic response in LVO. Whether Mon assessment would add value for LVO-diagnosis remains to be determined.

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.

Background: Epidemiological and experimental studies suggest cocoa flavanols and multivitamin-multimineral (MVM) supplements may confer arterial vascular benefits. However, their effects on clinical venous thromboembolic events have been infrequently examined.

Objective: To evaluate whether cocoa extract (CE) or MVM supplementation reduces the risk of venous thromboembolism (VTE) among older adults.

Methods: We conducted an ancillary study analysis of the COcoa Supplement and Multivitamin Outcomes Study (COSMOS), a completed randomized, double-blind, placebo-controlled, 2-by-2 factorial trial of CE and MVM supplementation for the prevention of cardiovascular disease and cancer among 21,442 older US adults. Our primary outcome was self-reported incident VTE, defined as the first reported deep vein thrombosis (DVT) or pulmonary embolism (PE) event after randomization; secondary outcomes were the individual components.

Results: Over a median follow-up of 3.5 years, 379 participants reported an incident VTE event (including 277 DVT and 165 PE). In intention-to-treat analyses, neither CE (HR: 0.88; 95% CI: 0.72, 1.08) nor MVM (HR: 0.89; 95% CI: 0.73, 1.09) significantly reduced VTE risk, with similar findings for DVT and PE. Exploratory latency and per-protocol analyses suggested potential patterns of benefit that merit further evaluation.

Conclusions: In this large trial of older adults, neither CE nor MVM supplementation significantly reduced the risk of VTE or its component parts in intention-to-treat analyses. Additional research may help clarify whether these supplements influence VTE risk in other contexts or populations.

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.

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Emicizumab is a bispecific monoclonal antibody that mimics the cofactor function of activated factor (F) VIIIa, facilitating the FIXa-catalyzed activation of FX. Emicizumab binds to FIX/IXa and FX with considerably lower affinity than FVIIIa, suggesting that FVIII may outcompete emicizumab when present at higher concentrations. However, the interaction between emicizumab and FVIII at low FVIII concentrations is not well characterized. The current study aimed to assess the pharmacodynamic interaction between emicizumab and FVIII using classical pharmacological concepts of additivity and synergy. Thrombin generation was used as a surrogate marker of hemostatic capacity, providing well-defined quantitative outcome parameters. Tissue factor-triggered thrombin generation was measured in FVIII-deficient plasma supplemented with variable concentrations of emicizumab and recombinant FVIII, alone or in combination. A synergistic interaction between emicizumab and FVIII was observed, resulting in enhanced endogenous thrombin potential and peak thrombin generation beyond the levels expected from either agent alone. This synergistic effect was evident at low FVIII concentrations and was no longer observed once FVIII levels exceeded 20 IU/dl. These findings may provide a pharmacodynamic explanation for the pronounced hemostatic effect of emicizumab at low FVIII levels and offer a conceptual framework for evaluating synergistic interactions between novel non-factor therapies and intrinsic FVIII.

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.