Background As FXI/FXIa inhibitors advance through clinical development, a central challenge is determining how to assess their anticoagulant effects in routine practice. Laboratory Assessment Assays such as the activated partial thromboplastin time (aPTT) and FXI activity tests demonstrate dose-dependent changes with these agents but are limited by reagent variability, poor standardization, and weak correlation with bleeding risk. No FDA-approved or standardized assay currently exists to reliably quantify FXI/FXIa inhibition or guide clinical decision-making. Clinical Implications Available clinical data suggest FXI/FXIa inhibitors provide robust antithrombotic efficacy with low bleeding risk, reducing the need for routine monitoring compared with traditional anticoagulants. However, patients often exhibit markedly prolonged aPTT values that may be misinterpreted in acute settings, especially during surgery or episodes of bleeding. Conventional assays lack reliability for guiding care. Future Directions Developing standardized monitoring strategies and institutional protocols will be critical to support safe integration of these agents, ensure consistency across care settings, and guide management in special clinical situations.

On behalf of the International Society on Thrombosis and Haemostasis (ISTH) Council and Annual Congress Planning Committee (ACPC) As we prepare for the International Society on Thrombosis and Haemostasis (ISTH) 2025 Congress in Washington, D.C., we are reminded of the strength and significance of our global community. The ISTH remains firmly dedicated to advancing science, supporting research and fostering innovation across borders. Now more than ever, we encourage the global ISTH community to come together—not just as individuals or institutions, but as a collective committed to building connections, exchanging knowledge, advancing science and improving patient care.

Background: Milvexian, an oral factor (F)XIa inhibitor, is undergoing phase 3 evaluation for acute coronary syndrome. Such patients often require percutaneous coronary intervention (PCI). The PCI catheters trigger clotting by inducing activation of FXII and FXI. It is unknown whether milvexian blocks this or if adjunctive heparin is needed. Objectives: To (a) compare the effect of FXII depletion or FXI depletion on catheter clotting, (b) investigate catheter-induced FXI activation, and (c) determine the effect of milvexian alone or with heparin on catheter-induced clotting and thrombin generation. Methods: In a 96-well plate assay, catheter-induced clotting and thrombin generation were assessed in recalcified control or depleted plasmas supplemented with control plasma by monitoring absorbance and thrombin substrate hydrolysis, respectively. FXI activation by catheters, FXIIa, or thrombin was evaluated by chromogenic assay. Milvexian, dabigatran, heparin, or milvexian plus heparin were added to control plasma to assess effects. Results: Catheters promoted autoactivation of FXI and augmented FXIIa- and thrombin-mediated FXI activation. Clotting was attenuated in FXII-depleted plasma and abolished in FXI-depleted plasma. Even small amounts of FXI triggered clotting. Milvexian and dabigatran at clinically relevant concentrations did not prevent catheter-induced clotting or thrombin generation. Heparin potentiated milvexian's inhibitory effect on catheter-induced clotting. Conclusion: Catheters promote FXI autoactivation, bypassing FXII, and highlighting the critical role of FXI. The limited capacity of milvexian supports the need for adjunctive heparin in patients treated with milvexian undergoing PCI.

Background The management of recurrent venous thromboembolism (VTE) despite anticoagulant treatment in patients with cancer is uncertain. To address this, we used data from the Hokusai VTE Cancer trial, which compared edoxaban with dalteparin to treat cancer-associated VTE. Objectives To characterize and evaluate anticoagulant treatment strategies during and after on-treatment recurrent VTE, including the type and dose of anticoagulant. Methods In this post hoc analysis, all patients with adjudicated on-treatment recurrent VTE within 12 months after randomization were included. Outcomes were second recurrent VTE and major bleeding within 3 months after the first recurrent VTE. Results A total of 67 patients developed on-treatment recurrent VTE while receiving therapeutic-dose edoxaban (31%), therapeutic-dose low-molecular-weight heparin (LMWH) (34%), maintenance-dose LMWH (21%), or other therapies (14%). After the recurrent event, 28 patients (42%) received an increased dose, 35 (52%) a comparable dose, and 4 (6%) a reduced dose or stopped anticoagulants. Common treatment regimens included supratherapeutic-dose LMWH (21%), therapeutic-dose LMWH (51%), direct oral anticoagulants (16%), or another treatment strategy (12%). In the 3 months after recurrent VTE, 6 (9%) patients had a second recurrence and 7 (10%) had major bleeding. Conclusion Treatment strategies for recurrent VTE in patients with cancer are heterogeneous. The risk of a second recurrence and major bleeding are considerable. More studies are needed to determine the optimal treatment strategy for recurrent cancer-associated thrombosis.

Background: Emerging evidence suggests that antiphospholipid antibodies (aPL) may be associated with an increased cardiovascular risk beyond the thrombotic antiphospholipid syndrome (APS). Among patients with ischemic stroke, the clinical significance of single positive aPL remains ill-defined. We aimed to assess the prevalence of aPL seropositivity in patients with stroke and the association between aPL seropositivity and stroke risk. Methods: This analysis is part of a larger project with PROSPERO ID CRD420251047305. We conducted a systematic search of PubMed and Embase on 5/13/2025 to identify cohort or case-control studies of unselected adult patients (without APS) investigating the association between aPL seropositivity and acute ischemic stroke compared with non-stroke controls. Positivity for aPL was defined as a single positive measurement for lupus anticoagulant in clot-based assays, IgM/IgG anti-β2-glycoprotein I antibody, or IgM/IgG anticardiolipin antibody at the time of stroke. Random-effects models with inverse weights were utilized to calculate pooled odds ratios (OR) with 95% confidence intervals (CIs). Results: Among 3,241 unique records, 43 studies (39 case-control and 4 cohort studies) were included representing a total of 6,374 patients (mean age 59.0 years, 51.1% men). The pooled prevalence of aPL seropositivity among patients with ischemic stroke was 18.1% (95% CI 17.2%-19.0%) (Figure, Panel A). Patients with ischemic stroke, compared with non-stroke controls, had a higher odds for seropositivity for aPL (OR: 2.94, 95% CI 2.31-3.74, I 2 =69%) (Figure, Panel B). In sensitivity analysis following removal of outlier studies, similar findings were demonstrated with overall improvement in model heterogeneity (OR: 2.58, 95% CI, 2.21-3.02, I 2 =20%). Conclusion: In this analysis, seropositivity for aPL were present in nearly one in five patients with ischemic stroke, significantly more than in the general population, and were associated with an increased odds of stroke. Whether seropositivity for aPL at a single time point is a causal risk factor for stroke warrants further investigation in future prospective studies.

Importance:Chronic kidney disease is common in patients with atrial fibrillation (AF) and is associated with higher rates of bleeding with anticoagulation. In the AZALEA-TIMI 71 randomized clinical trial, abelacimab, a novel factor XI inhibitor, reduced rates of major or clinically relevant nonmajor (CRNM) bleeding compared with rivaroxaban in patients with AF. Objective:To examine the safety of abelacimab vs rivaroxaban across a range of kidney function. Design, Setting, and Participants:The AZALEA-TIMI 71 study randomized patients with AF to 1 of 2 abelacimab doses (150 mg or 90 mg monthly) or to rivaroxaban, with stratification by creatinine clearance (CrCl). Patients with CrCl less than 15 mL/min or receiving dialysis were excluded. This secondary analysis of AZALEA-TIMI 71 examines outcomes by randomized treatment and CrCl at randomization. Intervention:Patients randomized to rivaroxaban with a CrCl greater than 50 mL/min received rivaroxaban, 20 mg, daily, and those with a CrCl of 50 mL/min or less received rivaroxaban, 15 mg, daily. Patients randomized to abelacimab received the assigned dose irrespective of CrCl. Main Outcomes and Measure:The primary outcome was major bleeding or CRNM bleeding. Results:Among 1284 patients, median (IQR) age was 74 (69-78) years and 572 patients (44.5%) were female. Median (IQR) CrCl was 71 (54-90) mL/min, with 264 patients (20.6%) having a CrCl of 50 mL/min or less. In the rivaroxaban group, patients with CrCl of 50 mL/min or less experienced higher rates of major or CRNM bleeding compared with those with CrCl greater than 50 mL/min despite dose reduction (incidence rates, 13.6 vs 7.0 per 100 person-years). Abelacimab reduced major or CRNM bleeding vs rivaroxaban irrespective of CrCl (CrCl ≤50 mL/min: hazard ratio [HR], 0.26; 95% CI, 0.12-0.54; >50 mL/min: HR, 0.40; 95% CI, 0.26-0.62; P value for interaction = .33), with absolute risk reductions of 10.1 vs 4.2 per 100 person-years in those with CrCl of 50 mL/min or less vs greater than 50 mL/min, respectively (P value for interaction = .09). This risk reduction was consistent for major bleeding alone and for a broader composite inclusive of major, CRNM, and minor bleeding. Results were similar when comparing the individual abelacimab doses to rivaroxaban. Conclusions and Relevance:In this secondary analysis of the AZALEA-TIMI 71 randomized clinical trial, abelacimab consistently reduced the risk of bleeding relative to rivaroxaban irrespective of kidney function. These findings suggest that abelacimab may offer a particularly favorable safety profile among those with chronic kidney disease; however, larger studies are necessary to characterize the efficacy of abelacimab for stroke prevention in AF.

BACKGROUND:Combining antiplatelet therapy (APT) with conventional anticoagulants increases the risk of bleeding. In the AZALEA-TIMI 71 trial (Safety and Tolerability of Abelacimab [MAA868] vs Rivaroxaban in Patients With Atrial Fibrillation), the novel factor XI inhibitor abelacimab significantly reduced the risk of bleeding compared with rivaroxaban in patients with atrial fibrillation. Whether the safety of combination antithrombotic therapy differs in the context of factor XI inhibition has not been well characterized. METHODS:This prespecified analysis of AZALEA-TIMI 71, which randomized patients between March and December of 2021 to 1 of 2 subcutaneous monthly abelacimab doses (90 or 150 mg) or oral rivaroxaban (20 mg daily, dose reduced to 15 mg in patients with creatinine clearance ≤50 mL/min), stratified patients by planned use of concomitant APT. The primary composite end point of major or clinically relevant nonmajor bleeding and other safety and efficacy outcomes were examined by concomitant APT and randomized treatment. RESULTS:Of 1287 patients (44% female; median age 74 years [interquartile range, 69-78]), 318 (24.7%) were on APT at baseline with planned continuation (15.5% aspirin only, 7.5% P2Y12 inhibitor only, and 1.6% dual APT). In the rivaroxaban arm, the rate of major or clinically relevant nonmajor bleeding was 10.6 per 100 patient-years with concomitant APT versus 7.7 per 100 patient-years without. In the abelacimab arms, the rates were 2.5 and 3.5 per 100 patient-years for the 90-mg and 150-mg doses, respectively, with concomitant APT and 2.7 and 3.1 per 100 patient-years without. Each abelacimab dose significantly reduced major or clinically relevant nonmajor bleeding compared with rivaroxaban, both in those with concomitant APT (adjusted hazard ratio, 0.26 [95% CI, 0.10-0.70] and 0.30 [95% CI, 0.12-0.74] for 90 mg and 150 mg of abelacimab, respectively, versus rivaroxaban) and in those without concomitant APT (adjusted hazard ratio, 0.34 [95% CI, 0.19-0.60] and 0.40 [95% CI, 0.23-0.68] for 90 mg and 150 mg of abelacimab, respectively; Pinteractions=0.56 and 0.60, respectively). Patients with concomitant APT tended to derive greater absolute risk reductions with abelacimab (8.1 and 7.1 for 90 mg and 150 mg of abelacimab, respectively, versus rivaroxaban) than those without concomitant APT (5.0 and 4.6, respectively). CONCLUSIONS:Inhibition of factor XI with abelacimab consistently reduced bleeding compared with rivaroxaban regardless of concomitant APT use, with greater absolute reductions in bleeding in those requiring concomitant APT. These data suggest that factor XI inhibition may be a safe anticoagulant option in patients with atrial fibrillation requiring concomitant APT. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT04755283.

Background With the widespread use of direct oral anticoagulants (DOACs), there is an urgent need for a rapid assay to exclude clinically relevant plasma levels. Accurate and rapid determination of DOAC levels would guide medical decision-making to (1) determine the potential contribution of the DOAC to spontaneous or trauma-induced hemorrhage; (2) identify appropriate candidates for reversal, or (3) optimize the timing of urgent surgery or intervention. Methods and Results The DOAC Dipstick test uses a disposable strip to identify factor Xa- or thrombin inhibitors in a urine sample. Based on the results of a systematic literature search followed by an analysis of a simple pooling of five retrieved clinical studies, the test strip has a high sensitivity and an acceptably high negative predictive value when compared with levels measured with liquid chromatography tandem mass spectrometry or calibrated chromogenic assays to reliably exclude plasma DOAC concentrations ≥30 ng/mL. Conclusion Based on these data, a simple algorithm is proposed to enhance medical decision-making in acute care indications useful primarily in hospitals not having readily available quantitative tests and 24/7. This algorithm not only determines DOAC exposure but also differentiates between factor Xa and thrombin inhibitors to better guide clinical management.

Thrombin is the central mediator of hemostasis, where it converts fibrinogen to fibrin, activates upstream factors to promote coagulation, activates factor XIII and thrombin-activatable fibrinolysis inhibitor to stabilize fibrin, mediates anticoagulation, and modulates cellular activity via cell surface receptors. Thus, regulation of thrombin activity is essential to the hemostatic balance. Thrombin is regulated by positively charged surface domains that surround the active site. These exosites bind substrates, inhibitors, cofactors, and receptors, which coordinate to direct thrombin to the appropriate location and modulate catalytic activity. Thus, the exosites are essential to the activity and regulation of thrombin. In addition to acting as binding sites, the exosites modulate the active site allosterically. Furthermore, the exosites impact each other, whereby the binding of ligands to one exosite impacts the function of the opposing exosite. Given the integral role that exosites play in the regulation of thrombin, they are attractive targets for the regulation of thrombin and for the development of new anticoagulants.

Implant-associated infections remain a significant complication in medicine. often leading to chronic infection, tissue damage, or implant failure. To address this, this work develops a modular, triple-action titanium implant that integrates bacterial repellency, bactericidal activity, and enhanced tissue integration. The implant comprises medical-grade titanium with a co-deposited layer of bacteriophages and collagen stably embedded within a repellent lubricant layer. The collagen layer promotes cell deposition and spreading in vitro. When tested against Pseudomonas aeruginosa, the coating reduces bacterial load by 3.2 logs on the surface and 1.9 logs in the medium, outperforming conventional liquid-infused surfaces. A modified version targeting Staphylococcus aureus achieves 4.1-log and 5.2-log reductions, respectively, after a 6-h incubation. When challenging the coating in a sepsis survival model of Pseudomonas aeruginosa infection, mice with the phage-activated implants exhibit a 100% survival rate and fully recover from the infection. In comparison, those with pathogen-repellent and untreated titanium implants show survival rates of only 30% and 10%, respectively. Furthermore, phage, but no bacteria, are detected in the bloodstream of mice implanted with phage-activated titanium, suggesting that locally implanted phage-biomaterials can distribute systemically to control blood infections. Therefore, the engineered phage-activated, triple-action biomaterials may prevent implant-associated infections locally and systemically.

Background Despite current antiplatelet therapy, patients remain at risk of recurrent ischemic events after acute coronary syndromes (ACS), which may reflect persistently elevated thrombin generation. Factor XIa inhibition reduces thrombin generation and may improve clinical outcomes with minimal bleeding risk. Design Librexia ACS (ClinicalTrials.gov NCT05754957) is a Phase 3, randomized, double-blind, placebo-controlled, event-driven trial to test the efficacy and safety of milvexian, an oral, selective factor XIa inhibitor, in addition to conventional antiplatelet therapy after a recent ACS. Eligibility criteria include symptoms of spontaneous ischemia, a diagnosis of ACS and cardiac biomarker elevation indicative of myonecrosis within 7 days before randomization, along with at least 2 risk-enhancing factors. Participants are randomly assigned to oral milvexian (25 mg twice daily) or a matched placebo. Randomization is stratified according to the planned duration and type of antiplatelet therapy. The primary efficacy endpoint is the time to first occurrence of the composite of cardiovascular death, myocardial infarction (MI), or ischemic stroke that will enroll approximately 16,000 patients with follow-up until 875 events are accrued. The first major secondary endpoint is time to the first occurrence of cardiovascular death, MI, ischemic stroke, major adverse limb events, and symptomatic venous thromboembolism. The principal safety endpoint is Bleeding Academic Research Consortium 3c or 5 bleeding. Summary The Librexia-ACS trial will determine the efficacy and safety of milvexian after ACS and will be the first trial to test whether factor XIa inhibition in addition to standard-of-care antiplatelet therapy reduces major adverse cardiovascular events without an increased risk of significant bleeding.

Importance:Superficial vein thrombosis (SuVT) is characterized by thrombus in the superficial veins, typically in the lower or upper extremities, and has an estimated annual incidence of 64 to 131 per 100 000 person-years. Approximately 10% of patients with SuVT progress to deep vein thrombosis (DVT) or pulmonary embolism (PE). Observations:Endothelial injury (caused by infection or intravenous devices), venous stasis (such as from chronic venous insufficiency or prolonged immobility), and hypercoagulability (due to cancer or pregnancy) are pathophysiologic factors associated with SuVT. Clinical risk factors for lower extremity SuVT are similar to those of DVT and PE and include pregnancy, varicose veins, and active cancer. The incidence of SuVT is greater in females than males (78-167 compared with 49-116 per 100 000 person-years). In contrast with lower extremity SuVT, upper extremity SuVT is primarily caused by indwelling intravenous catheters. Patients typically present with a tender, red, palpable cord under the skin in the upper or lower extremity. D-dimer testing has a sensitivity of approximately 48% to 74.3% and, therefore, is not reliable for excluding SuVT. Approximately 25% of patients with lower extremity SuVT present with concomitant DVT, likely because risk factors for SuVT and DVT are similar and because SuVT can extend into deep veins. In people without classic symptoms and signs of SuVT, ultrasonography can establish the presence and extent of the thrombus. Management may include elastic compression stockings and nonsteroidal anti-inflammatory drugs. For patients with SuVTs that are at least 5 cm long or those with persistent or worsening symptoms despite several days of conservative therapy, treatment includes anticoagulation with fondaparinux 2.5 mg. Alternative anticoagulation treatment includes rivaroxaban 10 mg once daily and low-molecular-weight heparins (eg, enoxaparin 40 mg once daily), which may reduce subsequent venous thromboembolic events. SuVT located within 3 cm of a deep vein should be treated with therapeutic doses of anticoagulation such as direct oral anticoagulants. Conclusions and Relevance:SuVT typically presents as a tender, painful, palpable cord under the skin. Management may include elastic compression stockings, nonsteroidal anti-inflammatory drugs, and systemic anticoagulation with fondaparinux 2.5 mg or rivaroxaban 10 mg. SuVTs within 3 cm of a deep vein should be treated with therapeutic dose anticoagulation.

Background: Asundexian and milvexian are small-molecule factor (F)XIa inhibitors, whereas abelacimab is an antibody that binds FXI and blocks its activation and activity. All 3 FXI inhibitors are currently undergoing phase 3 evaluation. Similar to heparin and dabigatran, asundexian, milvexian, and abelacimab prolong the activated partial thromboplastin time (APTT) in a concentration-dependent manner. DOAC-Stop (DS) is an activated charcoal-based compound that adsorbs direct oral anticoagulants such as dabigatran, but not heparin, from plasma. It is unknown whether DS also neutralizes asundexian and milvexian. Objective: This study aimed to determine whether DS reverses the prolongation of the APTT caused by asundexian or milvexian. Dabigatran was used as a positive control, while abelacimab and heparin served as negative controls. Methods: The APTT in human plasma, with or without asundexian, milvexian, abelacimab, dabigatran, or heparin, was determined before and after DS treatment. Results: As expected, all drugs produced concentration-dependent prolongation of the APTT. DS returned the APTT to baseline values with asundexian, milvexian, and dabigatran, but not with abelacimab or heparin. The APTT was prolonged in a more than additive manner with the combination of 2.5 mu M milvexian and 0.125 U/mL heparin. However, DS reversed only the APTT prolongation induced by milvexian, but not that by heparin. Conclusion: DS reverses the effect of asundexian and milvexian on the APTT and distinguishes between the APTT effects of milvexian and heparin.

Background Abelacimab is a fully human monoclonal antibody that binds to the inactive form of factor XI and blocks its activation. The safety of abelacimab as compared with a direct oral anticoagulant in patients with atrial fibrillation is unknown. Methods Patients with atrial fibrillation and a moderate-to-high risk of stroke were randomly assigned, in a 1:1:1 ratio, to receive subcutaneous injection of abelacimab (150 mg or 90 mg once monthly) administered in a blinded fashion or oral rivaroxaban (20 mg once daily) administered in an open-label fashion. The primary end point was major or clinically relevant nonmajor bleeding. Download a PDF of the Plain Language Summary. Results A total of 1287 patients underwent randomization; the median age was 74 years, and 44% were women. At 3 months, the median reduction in free factor XI levels with abelacimab at a dose of 150 mg was 99% (interquartile range, 98 to 99) and with abelacimab at a dose of 90 mg was 97% (interquartile range, 51 to 99). The trial was stopped early on the recommendation of the independent data monitoring committee because of a greater-than-anticipated reduction in bleeding events with abelacimab. The incidence rate of major or clinically relevant nonmajor bleeding was 3.2 events per 100 person-years with 150-mg abelacimab and 2.6 events per 100 person-years with 90-mg abelacimab, as compared with 8.4 events per 100 person-years with rivaroxaban (hazard ratio for 150-mg abelacimab vs. rivaroxaban, 0.38 [95% confidence interval {CI}, 0.24 to 0.60]; hazard ratio for 90-mg abelacimab vs. rivaroxaban, 0.31 [95% CI, 0.19 to 0.51]; P<0.001 for both comparisons). The incidence and severity of adverse events appeared to be similar in the three groups. Conclusions Among patients with atrial fibrillation who were at moderate-to-high risk for stroke, treatment with abelacimab resulted in markedly lower levels of free factor XI and fewer bleeding events than treatment with rivaroxaban.

BACKGROUND:The association of sex with clinical outcome risk in venous thromboembolism (VTE) is unclear. OBJECTIVE:To investigate sex differences in clinical outcomes and anticoagulation effectiveness in VTE in the GARFIELD-VTE registry. METHODS:Outcomes included all-cause mortality, VTE recurrence, major and any bleeding, myocardial infarction (MI)/acute coronary syndrome (ACS), and stroke/transient ischaemic attack (TIA) over 3 years of follow-up. Hazard ratios were calculated using Cox proportional hazard models with an assessment of sex interactions with parenteral, vitamin K antagonist (VKA), and direct oral anticoagulant (DOAC) therapies. RESULTS:Of 10,650 patients, 5290 (49.7%) were female and 5360 were male. Females and males had comparable ages (median [Q1-Q3]; females: 60.6 [44.0-72.9] years, males: 60.0 [48.0-70.3] years), body mass index (females: 27.6 [23.6-32.7] kg/m2, males: 27.1 [24.4-30.6] kg/m2), and anticoagulant treatment. Females had greater risk of major (adjusted hazard ratio [95% CI (1.25 [1.01-1.55]) and any bleeding (1.32 [1.18-1.47]) than males, but lower risk of recurrent VTE (0.82 [0.72; 0.94]), MI/ACS (0.52 [0.36-0.76]) and stroke/TIA (0.72 [0.52-0.99]). VKA-treated females had greater risk of major (1.69 [1.16-2.48]) and any bleeding (1.43 [1.18-1.73]) than VKA-treated males, while DOAC-treated females had greater risk of any bleeding (1.37 [1.17-1.61]) but not major bleeding (1.22 [0.86-1.72]) than DOAC-treated males. Sensitivity analyses excluding patients with active cancer (N = 9752) yielded similar results. CONCLUSIONS:Compared with males, females with VTE have a greater risk of bleeding, but a lower risk of recurrent VTE, MI/ACS, and stroke/TIA. Sex appears to affect the relationship between VKA and DOAC treatment and bleeding in VTE.