Thrombosis and haemostasis最新文献

Factor XI inhibitors, including antisense oligonucleotides (ASOs), monoclonal antibodies (mAbs), and small-molecule inhibitors, are an emerging class of anticoagulants that offer the potential to prevent and treat thrombosis with a low risk of bleeding. As these agents move toward broader clinical use, it is essential to carefully review perioperative management due to their novel mechanisms and limited real-world experience. Data from clinical trials suggest a reassuring bleeding profile, even among high-risk groups such as patients with end-stage renal disease on hemodialysis and those on concurrent antiplatelet therapy. Many invasive procedures in patients receiving ASOs or mAbs have been reported, with few bleeding complications and little need for hemostatic prophylaxis or anticoagulant interruption. While small-molecule inhibitors may offer more flexibility due to their short half-lives, perioperative outcomes for these agents remain underreported. In emergencies, hemostasis may be achieved with factor XI concentrate for ASOs or bypassing agents for other factor XI inhibitors; however, these options may be limited by availability and potential thrombotic risks. Perioperative management strategies for factor XI inhibitors remain provisional and may require refinement as new evidence becomes available. Further research is needed to identify assays that better measure the anticoagulant effect of factor XI inhibitors, develop tailored protocols for both major and minor surgeries, and create specific reversal agents.

Inherited factor VII deficiency (FVIID) presents a highly variable bleeding phenotype. The weak correlation between plasma FVII levels (FVII:C) and bleeding severity results in diverse management strategies and complicates surgical decision-making.To describe surgical management and bleeding outcomes in patients with FVIID, and to identify key decision-making variables and predictors of surgical bleeding.We conducted a multicenter, retrospective study of 380 surgeries performed in 215 patients with FVIID. Patients were classified by FVII:C levels as mild, moderate, or severe deficiency. Bleeding score (BS) was defined according to ISTH-BAT. Surgeries were categorized as low-moderate risk (LR) or high risk (HR) for bleeding. A decision-tree simulation was performed.Most patients had mild FVIID (76%), and 68% of surgeries were classified as LR. Prophylactic treatment with tranexamic acid (TA) and/or rFVIIa was administered in 42.8% of LR and 62.8% of HR surgeries. Prophylaxis was given to 73.9% of moderate/severe and 41% of mild FVIID patients, especially for HR procedures. FVII:C levels and surgical bleeding risk were key factors that influenced the selection of treatment. The overall bleeding rate was 3.1% (HR: 9%; LR: 0.4%). Most bleeding events occurred in mild FVIID patients with BS ≥3. Our algorithm recommends hemostatic treatment for all moderate/severe, and for mild patients HR surgeries and LR procedures when BS is ≥3.FVII:C levels and surgery type influence prophylactic hemostatic treatment strategies. Patients with mild FVIID, higher BS, and no hemostatic treatment had a greater risk of bleeding. Bleeding score and procedural risk were identified as predictors of surgical bleeding.

The Bleeding Academic Research Consortium (BARC) classification was proposed to standardize bleeding endpoint definitions and reports in cardiovascular clinical trials. However, its prognostic value has not been fully validated in East Asian patients with acute myocardial infarction (AMI) who have a higher bleeding risk than Western populations do.We analyzed bleeding events (types 2 or 3) based on the BARC classification in 13,657 patients with AMI (mean age 64.9 ± 12.7 years) from nationwide prospective registries in Japan and Korea. The primary endpoint was all-cause mortality during the 1-year clinical follow-up.During the 1-year follow-up, BARC type 2 or 3 bleeding occurred in 5.5% of the patients (n = 759). Patients who experienced BARC type 2 or 3 bleeding had a significantly higher risk of mortality compared with those without bleeding (hazard ratio [HR] 4.1, 95% confidence interval [CI] 3.4-4.8, p < 0.001). The risk of mortality was higher in BARC type 3 (HR 6.4, 95% CI 5.1-7.9) than in type 2 bleeding (HR 2.4, 95% CI 1.8-3.1). BARC type 2 or 3 bleeding remained significantly associated with increased mortality after adjustment (adjusted HR 1.9, 95% CI 1.5-2.5, p < 0.001). Similar associations with mortality were observed when each BARC classification (type 2 and 3) was analyzed individually.In East Asian patients with AMI, BARC-defined bleeding events were significantly associated with increased mortality. These findings support the adoption of the BARC classification to predict mortality, particularly in East Asian patients with AMI.

Direct anticoagulants inhibit coagulation serine proteases by reversibly engaging their active site with high affinity. By modifying the S4 active site subpocket of factor (F)Xa, we introduced inhibitor resistance while preserving catalytic activity. Given the homology between FXa and thrombin in active site architecture and direct anticoagulant binding, we have targeted the S4 subsite to introduce inhibitor resistance in (pro)thrombin.Recombinant prothrombin variants were generated in which I174 was substituted or sequence R92-N98 was exchanged with that of human kallikrein-3.Specific prothrombin clotting activity of the variants was 6-fold (intrinsic clotting) to 10-fold (extrinsic clotting) reduced relative to wild-type prothrombin. Further analyses revealed that modification of the S4 subsite hampers fibrinogen and thrombomodulin-mediated protein C conversion by thrombin. Consistent with this, the thrombin variants displayed a reduced catalytic efficiency toward the peptidyl substrate used in thrombin generation assessments. The variants displayed a 2-fold reduced sensitivity for dabigatran relative to wild-type prothrombin, while argatroban inhibition was unaffected. Analyses using a purified component system revealed an up to 24-fold and 4-fold reduced IC₅₀ for inhibition of thrombin by dabigatran and argatroban, respectively. Molecular dynamics (MD) simulations of both dabigatran-bound and unbound (apo) modified thrombin variants indicated these to comprise a larger inhibitor binding pocket relative to wild-type thrombin and display reduced inhibitor binding. As a net effect, (pro)thrombin variants with S4 subsite modifications supported detectable fibrin formation at therapeutic dabigatran concentrations.Our findings provide proof-of-concept for the engineering of thrombin variants that are resistant to direct thrombin inhibitors by modulating the S4 subsite.

Asthma is associated with a prothrombotic state. Plasma factor VIIa-antithrombin complex (FVIIa-AT) concentrations indirectly reflect the interaction of tissue factor (TF) with FVII. Since TF is a key initiator of coagulation in vivo, we hypothesized that FVIIa-AT concentrations are higher in asthma.In 159 clinically stable adult asthma patients and 62 controls, we determined FVIIa-AT in plasma and analyzed their relation to circulating inflammatory and prothrombotic markers together with the total plasma potential for fibrinolysis (clot lysis time, CLT) and thrombin generation. We recorded clinical outcomes, including asthma exacerbations, during 3-year follow-up.Asthma patients were characterized by 38.5% higher FVIIa-AT (p < 0.001), related to bronchial obstruction (FEV₁: r = -0.397, p < 0.001), asthma severity (r = 0.221, p = 0.005), and duration (r = 0.194, p = 0.015) compared to controls. FVIIa-AT showed weak positive associations with C-reactive protein (r = 0.208, p = 0.009), fibrinogen (r = 0.215, p = 0.007), and CLT (r = 0.303, p < 0.001) but not with thrombin generation parameters. In the follow-up (data obtained from 151 patients), we documented 151 severe asthma exacerbations in 51 (33.8%) patients, including 33 (21.9%) with ≥2 such events. Exacerbation-prone asthma phenotype was related to 13.1% higher FVIIa-AT (p = 0.012), along with asthma severity and control (p < 0.003, both). High FVIIa-AT (that is ≥100.1 pmol/L), defined on receiver operating characteristic curves, was linked to exacerbation-prone asthma phenotype (odds ratio 1.85; 95%CI: 1.23-2.80, p = 0.003) and shorter time to first exacerbation (p = 0.023).This study is the first to show that FVIIa-AT concentrations are higher in asthma in relation to its severity and may help identify individuals at risk of the exacerbation-prone asthma phenotype.

Initial thrombin (FIIa) generated via the tissue factor (TF) pathway plays a crucial role in amplifying coagulation. There is growing evidence that the TF pathway might contribute to hypercoagulation in obesity. However, it is unclear if the initial generation of FIIa (TG) is associated with hypercoagulation in obesity due to the lack of appropriate assays. This study aims to evaluate association between TF pathway-driven initial TG and hypercoagulability in obesity.We measured the initial TG levels in plasma from male Tsumura Suzuki obese diabetes (TSOD) mice and overweight subjects using the highly sensitive TG assay. To induce initial TG, TF was added to the plasma and incubated at 37°C for up to 3 minutes. After quenching the TG, we quantified the generated FIIa by kinetically monitoring its amidolytic activity with a fluorogenic substrate.We observed that initial TG levels were significantly higher in TSOD mice (n = 31) compared with non-obese mice (n = 32). Even in the absence of exogenous TF, initial TG levels in obese mice and overweight individuals were elevated when procoagulant phospholipids were added alone. Moreover, the increased initial TG that the inhibitory anti-TF antibody abolished was detectable in reconstituted plasma including pellets prepared by high-speed centrifugation of plasma from obese mice, not in plasma supernatant. We attributed the promotion of the initial TG to the increase in procoagulant TF-bearing microvesicles in circulation. Based on the findings, measuring TF pathway-driven initial TG could be a valuable method for assessing hypercoagulability in obesity.

Dosing guidance for anticoagulation, the mainstay of venous thromboembolism (VTE) treatment, is lacking for obese children. We aimed to compare unfractionated heparin (UFH) and low-molecular-weight heparins (LMWH) dosing requirements and clinical outcomes between obese/overweight and nonobese children.This monocentric retrospective cohort study included patients aged < 18 years old receiving anticoagulation for VTE. The outcomes were: (1) number of dose adjustments to reach therapeutic levels, (2) variation from initial dose, (3) thrombotic progression/recurrence, and (4) clinically relevant bleeding. Characteristics and dosing requirements of obese/overweight and nonobese children were compared using Pearson chi-square, Fisher exact, and Wilcoxon Mann-Whitney tests. Kaplan-Meier estimator compared the cumulative incidence of thrombotic recurrence/progression and clinically relevant bleeding between groups.We included 212 patients (median age: 6.2 years, 23.6% obese/overweight) having 258 anticoagulation encounters (LMWH: 82.6%, UFH: 17.4%). Most children had therapeutic levels following one dosage (66.7% in obese/overweight vs. 51.8% in nonobese, p = 0.201). Dosing requirements significantly differed between obese/overweight and nonobese children (average increase from initial dose: 3.2 vs. 11.3%, p < 0.001). In obese/overweight children, 11.1% of patients required ≥ 10% dose reduction versus 2.1% in nonobese children (p < 0.001). The cumulative incidence of thrombotic progression/recurrence was comparable between groups (obese/overweight: 12.0%, nonobese: 10.5%, p = 0.786). Similarly, clinically significant bleeding was rare for both groups (obese/overweight: 2.0%, nonobese: 3.1%, p = 0.609).In children treated for VTE, obesity/overweight was associated with lower anticoagulation requirements. Further prospective work is urgently needed to explore alternate regimens, such as dose capping, reduced initial dosing, or the use of fat-free mass.