Journal of Thrombosis and Haemostasis最新文献

{"title":"Impaired tolerance in the International Immune Tolerance Induction Study (I-ITI study) due to the presence of very low-titer inhibitors.","authors":"Lars L F G Valke, Charles R M Hay, Donna M DiMichele, Robert Polenewen, Marieke J A Verhagen, Daniëlle Meijer, Sanna R Rijpma, Nicole A M Blijlevens, Saskia E M Schols, Waander L van Heerde","doi":"10.1016/j.jtha.2025.07.005","DOIUrl":"https://doi.org/10.1016/j.jtha.2025.07.005","url":null,"abstract":"<p><strong>Background: </strong>In persons with hemophilia A (pwHA), development of an inhibitor complicates treatment with factor VIII (FVIII) replacement therapy. Immune tolerance induction (ITI) is used to restore tolerance. However, some pwHA do not reach tolerance despite disappearance of the inhibitor detected with the Nijmegen Bethesda Assay (NBA), potentially due to persistent presence of very low-titer inhibitors.</p><p><strong>Aim: </strong>We determined of presence of very low-titer inhibitors with the Nijmegen ultra-sensitive Bethesda Assay (NusBA) in the International-ITI study.</p><p><strong>Methods: </strong>This study included 115 pwHA and inhibitors (pwHAI). In 53 of these participants both NBA and NusBA were determined from the same sample measured in 175 sample time points. Both FVIII half-life and recovery were correlated with NBA and NusBA results and used to plot ROC curves as 50 of these 175 concurrent measurements included a pharmacokinetic analysis.</p><p><strong>Results: </strong>NusBA had a stronger correlation with FVIII half-life (r=-0.56, 95%-CI:-0.80--0.20, p=0.004) than NBA (r=-0.36, 95%-CI:-0.67--0.06, p=0.008). Also, the area under the curve (AUC) of the NusBA (0.79, 95%-CI:0.59-0.98) was higher than the AUC of the NBA (0.64, 95%-CI:0.40-0.87), with FVIII half-life ≥7 hours indicating tolerance. The NBA was unable to detect very low-titer inhibitor levels in pwHAI with a decreased FVIII half-life. Post-ITI, a positive NusBA was detected in 66% of all samples which is in contrast to the 42% NBA positive samples.</p><p><strong>Conclusion: </strong>The NusBA can detect very low-titer inhibitors and correlates with FVIII half-life in the early post-ITI period. The NusBA has added value in pwHAI undergoing ITI to monitor tolerance.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144698941","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Splenectomy for immune thrombotic thrombocytopenic purpura (iTTP): a systematic review and meta-analysis.","authors":"Saarang R Deshpande, Hemza Tarawneh, Jiayi Tong, Ting Zhou, Yong Chen, Adam Cuker","doi":"10.1016/j.jtha.2025.07.012","DOIUrl":"https://doi.org/10.1016/j.jtha.2025.07.012","url":null,"abstract":"<p><strong>Background: </strong>Immune thrombotic thrombocytopenic purpura (iTTP) is a thrombotic microangiopathy caused by autoantibody-mediated ADAMTS13 deficiency. Historically, splenectomy was used for multiply relapsing iTTP in clinical remission to lessen risk of relapse and as treatment for plasma-refractory or plasma-dependent iTTP.</p><p><strong>Methods: </strong>We conducted a systematic review and meta-analysis on two questions related to splenectomy for iTTP: (1) In patients with relapsing iTTP, what is the effect of splenectomy on iTTP relapse rate? (2) In patients with plasma-refractory or plasma-dependent iTTP, what proportion of patients achieve clinical remission after splenectomy? Three electronic databases (Embase, PubMed, Scopus) were searched for keywords related to TTP and splenectomy, and screening was completed following PRISMA guidelines.</p><p><strong>Results: </strong>Twenty-three studies were included, representing 62 patients (205.8 years of follow-up) who underwent splenectomy for relapsing iTTP and 57 patients (173.9 years of follow-up; not reported in 3 studies) who underwent splenectomy for plasma-refractory/dependent iTTP. In patients who underwent splenectomy for relapsing iTTP, there were 1.80 (95% confidence interval [CI], -2.66 - -0.95) fewer iTTP episodes annually after compared to before splenectomy. For patients who underwent splenectomy for plasma-refractory/dependent iTTP, the proportion of patients achieving clinical remission was 0.87 (95% CI, 0.76 - 0.93). Only two studies included any patients who received rituximab.</p><p><strong>Conclusion: </strong>There is low quality evidence to support the use of splenectomy for multiply relapsing iTTP to decrease relapse rate and for plasma-refractory/dependent iTTP to achieve remission, noting that most of the evidence precedes the routine use of rituximab in iTTP.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144675106","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biomarkers of in vivo platelet activation in coronary artery disease: a systematic review and meta-analysis: Communication from the SSC of the ISTH.","authors":"Marta Brambilla, Emma C Josefsson, Sofia Ramstrom, Alessandro Di Minno, Matteo Nicola Dario Di Minno, Pradnya Gangatirkar, Diane Moujalled, Alessia Becchetti, Marie Lordkipanidzé, Marina Camera","doi":"10.1016/j.jtha.2025.07.014","DOIUrl":"https://doi.org/10.1016/j.jtha.2025.07.014","url":null,"abstract":"<p><strong>Background: </strong>Given the role of platelets in coronary artery disease (CAD), assessment of a soluble platelet activation marker may be useful to improve thrombotic risk stratification. Therefore, we performed a meta-analysis investigating the association between levels of 14 such markers with CAD.</p><p><strong>Methods: </strong>PubMed, Web of Science and EMBASE were searched until November 2024. The primary endpoint was the difference in levels of 11-dehydro-thromboxane B₂, 2,3-dinor-TXB₂, β-thromboglobulin, sCD40L, glycocalicin, GPV, GPVI, matrix metalloproteinase-9 (MMP-9) and 2 , Platelet Factor 4 (PF4), sP-selectin, SCUBE1, serotonin and thrombospondin 1(TSP-1) between CAD patients and healthy subjects (HS) in plasma and/or serum. When possible, CAD patients were stratified into acute coronary syndrome (ACS) and chronic coronary disease (CCD). Standardized mean difference (SMD) was calculated.</p><p><strong>Results: </strong>Due to studies' heterogeneity, meta-analysis was performed for sCD40L, sGPV, MMP-9, PF4, sP-selectin, SCUBE1 and TSP-1. All markers but TSP-1 were significantly elevated in CAD patients versus HS. Differences in sCD40L and SCUBE1 were statistically significant only when plasma and serum studies were combined. When compared to HS the differences were bigger in ACS versus CCD for MMP-9 (SMD: 2.49 vs 0.49), PF4 (SMD: 2.01 vs 0.96), and sP-selectin (SMD: 1.81 vs 0.63). Publication bias was identified for sCD40L and in ACS for sP-selectin and PF4.</p><p><strong>Conclusions: </strong>The increased levels of sCD40L, sGPV, MMP-9, PF4, sP-selectin and SCUBE1 in CAD patients compared to HS provide a rationale for designing new studies to address the potential of such molecules as biomarkers for thrombotic risk stratification.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144675104","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Phase 1, Open-Label Study to Assess the Pharmacokinetics, Safety, and Tolerability of a Single Intravenous Injection of Efanesoctocog Alfa in Adults with Type 2N or Type 3 von Willebrand Disease.","authors":"Sophie Susen, Marc Trossaërt, Moshe Zilberstein, Lara Mamikonian, Elena Santagostino, Abhimanyu Yarramaneni, Nancy Wong, Annemieke Willemze, Ekta Seth Chhabra","doi":"10.1016/j.jtha.2025.07.013","DOIUrl":"https://doi.org/10.1016/j.jtha.2025.07.013","url":null,"abstract":"<p><strong>Background: </strong>Efanesoctocog alfa is a high-sustained factor VIII (FVIII) replacement therapy for haemophilia A. The D'D3 domain of efanesoctocog alfa overcomes the von Willebrand factor (VWF)-imposed half-life ceiling and may allow correction of reduced FVIII levels experienced by people with Type 2N or Type 3 von Willebrand disease (VWD).</p><p><strong>Objectives: </strong>To assess the pharmacokinetics, safety, and tolerability of efanesoctocog alfa in Type 2N or Type 3 VWD.</p><p><strong>Patients/methods: </strong>This was a Phase 1, open-label study of efanesoctocog alfa in adults with hereditary Type 2N or Type 3 VWD (NCT04770935). Participants received a single intravenous dose of efanesoctocog alfa (25 IU/kg). The primary endpoint was pharmacokinetic parameters as determined by non-compartmental analysis of efanesoctocog alfa FVIII activity using one-stage assay (OSA) and capture chromogenic (CCS) assay, the latter of which is more relevant in assessing FVIII levels from efanesoctocog alfa among people with VWD. Secondary endpoints included adverse events and FVIII inhibitor development.</p><p><strong>Results: </strong>Six participants were assessed (Type 2N n=2; Type 3 n=4). One dose of efanesoctocog alfa 25 IU/kg maintained FVIII activity levels of >1 IU/dL up to 10 days post-dose. Mean baseline-corrected FVIII activity levels were maintained >40 IU/dL and >10 IU/dL up to 1 day and 4 days post-dose, respectively, per CCS assay. Mean (SD) t_1/2z was 49.0 (10.2) hours. Efanesoctocog alfa was well-tolerated. FVIII inhibitors or antidrug antibodies were not detected.</p><p><strong>Conclusions: </strong>Efanesoctocog alfa is well-tolerated and maintains high FVIII activity levels for a prolonged period in patients with Type 2N or Type 3 VWD.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144675103","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enzymatic modifications of protein S: cause and impact on diagnostics, plasma processing and anticoagulant properties.","authors":"Herm Jan M Brinkman","doi":"10.1016/j.jtha.2025.06.035","DOIUrl":"https://doi.org/10.1016/j.jtha.2025.06.035","url":null,"abstract":"<p><p>Coagulation processes are under critical control of anticoagulation mechanisms. Protein S is a multifunctional natural anticoagulant in plasma that downregulates coagulation at different crucial points in the coagulation process. Protein S is not only cofactor for activated protein C (APC), but also for tissue factor pathway inhibitor alpha (TFPIα). In addition, protein S exhibit so-called direct anticoagulant activity. i.e. inhibition of tenase (Xase, factor IXa/VIIIa) and prothrombinase (IIase, factor Xa/Va) complex assembly and activity. Being a multifunctional anticoagulant, stringent regulation of its functions seems essential. Protein S is susceptible to enzymatic modulation of its anticoagulant properties that includes upregulation by kinases and downregulation by limited proteolysis or even complete degradation. Enzymatic modification of protein S is a largely unrecognized phenomenon that not only may have substantial impact on the diagnostics of protein S deficiencies and on the preparation and clinical utility of pooled plasma products, but it may also provide opportunities for drug development. This review provides historical background, state-of-the-art knowledge and future perspectives on the enzymatic modification of the anticoagulant properties of protein S.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144675105","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development and Validation of Risk Models for Hospital-Acquired Bleeding in Medical Inpatients: The Medical Inpatients Thrombosis and Hemostasis (MITH) Study.","authors":"Neil A Zakai, Katherine Wilkinson, Andrew D Sparks, Ryan T Packer, Nicholas S Roetker, Allen B Repp, Mansour Gergi, Chris Holmes, Mary Cushman, Timothy B Plante, Hanny Al-Samkari, Allyson M Pishko, William A Wood, Camila Masias, Radhika Gangaraju, Ang Li, David Garcia, Kerri L Wiggins, Jordan K Schaefer, Nicholas L Smith, Augusto Ferraris, Karlyn A Martin, Deirdra R Terrell, Leslie A McClure","doi":"10.1016/j.jtha.2025.07.007","DOIUrl":"https://doi.org/10.1016/j.jtha.2025.07.007","url":null,"abstract":"<p><strong>Background: </strong>Hospital-acquired (HA) bleeding in medical inpatients is a serious complication with limited tools to predict risk.</p><p><strong>Objectives: </strong>To develop and validate risk assessment models (RAMs) for anatomic location-specific HA bleeding in medical inpatients using objective and routinely available risk factors.</p><p><strong>Patients/methods: </strong>Patients aged ≥18 years admitted to medical hospital services from 6 health systems and 15 hospitals in the United States between 2016-2020 for at least 1 midnight and without bleeding at admission were eligible for inclusion. Two health systems (10 hospitals) formed the development cohort, and 4 systems (5 hospitals) constituted the validation cohort. Bayesian Least absolute shrinkage and selection operator was used to develop anatomic site-specific risk assessment models (RAMS).</p><p><strong>Results: </strong>Among the development (153,707 admissions) and validation (137,460 admissions) cohorts, 5,999 (3.9%) and 3,282 (2.4%) HA bleeds occurred. RAMs had varied risk factors by anatomic bleeding location; for instance, older age was associated with genitourinary bleeding in men but not women. Different cancer types were associated with different anatomic bleeding locations such as genitourinary cancers associated with genitourinary bleeding and gynecologic bleeding. The RAMs demonstrated good predictive performance for most anatomical bleeding locations; the C-statistic was ≥0.67 for all anatomic location bleeding in the development and validation cohorts, and generally higher in the anatomic-location specific RAMs.</p><p><strong>Conclusions: </strong>These RAMs provide anatomic location- and sex-specific HA bleeding risk stratification, addressing a critical gap in individualized risk assessment. Integration into clinical workflows could enhance patient safety and outcomes. Implementation studies are essential to maximize their clinical utility.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144667838","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of ischemic stroke on the risk of venous thromboembolism in the general population: The Tromsø Study and The Trøndelag Health Study","authors":"Birgitte G Tøndel, Vânia M Morelli, Ellisiv B Mathiesen, Maja-Lisa Løchen, Tom Wilsgaard, Kristian Hveem, John-Bjarne Hansen, Sigrid K Brækkan","doi":"10.1016/j.jtha.2025.07.008","DOIUrl":"10.1016/j.jtha.2025.07.008","url":null,"abstract":"<p><strong>Background: </strong>Data on venous thromboembolism (VTE) after ischemic stroke in the general population is limited. We aimed to explore the impact of ischemic stroke on overall VTE and VTE subtypes and by sex at the population level, and to evaluate whether the risk of stroke-related VTE changed between 1994-2007 and 2008-2019</p><p><strong>Methods: </strong>Participants (n=107,321) were recruited from three surveys of the Tromsø Study (enrolment:1994-2008) and two surveys of the Trøndelag Health Study (enrolment:1995-2008), and followed through 2014 and 2019, respectively. Hazard ratios (HRs) of VTE were calculated using Cox models with stroke as time-varying exposure. Cumulative incidences of VTE were estimated with death as a competing event.</p><p><strong>Results: </strong>Ischemic stroke was diagnosed in 5,974 individuals, of whom 199 developed VTE during follow-up. Within three months post-stroke, the cumulative incidence and HR of VTE was 1.13% and 13.47 (95%CI:9.41-19.27) in women, and 0.76% and 9.50 (95%CI: 6.38-14.14) in men, respectively. Stroke conferred a 19-fold increased risk of provoked VTE (HR 18.67; 95% CI:14.01-24.88) and a 3-fold increased risk of unprovoked VTE (HR 3.05; 95% CI:1.45-6.45) within three months. The risk estimates of VTE after stroke did not change between the two time-periods.</p><p><strong>Conclusion: </strong>Sex-specific risk estimates for VTE were only marginally higher in women than in men. Ischemic stroke was associated with particularly high risk of provoked VTE, emphasizing the potentiating effect of additional risk factors. The risk of VTE after ischemic stroke has not declined over the past decades.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144667843","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Plasma Levels Measurement of the Four Direct Oral Anticoagulants in Patients with Atrial Fibrillation at the Time of Acute Thromboembolic and Bleeding Events.","authors":"Cosmo Godino, Riccardo Mazza, Carlo Gaspardone, Alessia Minerva, Rachele Sena, Gianmarco Cozzani, Anna Salerno, Michela Cera, Massimo Slavich, Leila Anna De Lorenzo, Giulio Leo, Giulia Nemola, Annalisa Fattorini, Luciano Crippa, Patrizia Della Valle, Alberto Margonato, Armando D'Angelo","doi":"10.1016/j.jtha.2025.06.031","DOIUrl":"https://doi.org/10.1016/j.jtha.2025.06.031","url":null,"abstract":"<p><strong>Background: </strong>Direct oral anticoagulants (DOACs) are standard therapy to prevent thromboembolic events in non-valvular atrial fibrillation (NVAF) and are generally used without routine monitoring of plasma anti-Xa or anti-IIa levels.</p><p><strong>Objectives: </strong>To assess whether plasma levels of anti-Xa or anti-IIa at the time of presentation are associated with acute thromboembolic or bleeding events in DOAC-treated NVAF patients.</p><p><strong>Methods: </strong>This prospective case-control study included consecutive long-term DOAC-treated NVAF patients presenting to a European emergency department with acute thromboembolic or bleeding events (cases), or for other medical reasons (controls). DOAC plasma levels were measured using drug-specific chromogenic anti-Xa assays (rivaroxaban, apixaban, edoxaban) or diluted thrombin time (dabigatran), categorized into quartiles, and analyzed according to event type.</p><p><strong>Results: </strong>Among 1,794 patients (mean age 82 years, 49% female), 8% had thromboembolic events, 15% bleeding events, and 77% other presentations. DOAC treatment included apixaban (45%), dabigatran (17%), rivaroxaban (17%), and edoxaban (21%). Thromboembolic events were more common in patients with DOAC plasma levels in the first quartile (Q1: 50% vs. 26%; p<0.001), while bleeding events were more common in the fourth quartile (Q4: 46% vs. 23%; p<0.001). Q1 levels were associated with increased odds of thromboembolic events (OR 2.04, 95% CI: 1.36-3.08), and Q4 levels with bleeding events (OR 2.05, 95% CI: 1.49-2.82).</p><p><strong>Conclusion: </strong>DOAC plasma levels show substantial interindividual variability and are associated with acute thromboembolic and bleeding events. These observations may help generate hypotheses for future studies aimed at better defining the role of DOAC plasma monitoring in clinical practice.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144667842","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of streptozotocin-induced hyperglycemia on the host response to sepsis.","authors":"Sean Carlin, Dhruva J Dwivedi, Erblin Cani, Neha Sharma, Daniel E Venegas-Pino, Manoj Lalu, Asher A Mendelson, Braedon McDonald, Geoff H Werstuck, Patricia C Liaw","doi":"10.1016/j.jtha.2025.07.004","DOIUrl":"10.1016/j.jtha.2025.07.004","url":null,"abstract":"<p><strong>Background: </strong>Diabetes is a common comorbidity in patients with sepsis, yet the influence of baseline glycemic status on sepsis outcomes remains unclear. Clinical studies report conflicting associations between diabetes and sepsis mortality.</p><p><strong>Objectives: </strong>To evaluate how short-term (ie, 4-5 weeks) preinfection hyperglycemia influences the host response to sepsis using a model of fecal-induced peritonitis.</p><p><strong>Methods: </strong>Hyperglycemia was induced in C57BL/6 mice (both sexes) via streptozotocin injections. Hyperglycemic and normoglycemic mice were subjected to fecal-induced peritonitis, with endpoints at 8 hours and 48 hours postinfection. Blood glucose, insulin, advanced glycation end-products, cytokines (interleukins 6 and 10), coagulation markers (thrombin-antithrombin and protein C), cell-free DNA (cfDNA), lung myeloperoxidase, bacterial loads, organ injury, and survival were assessed.</p><p><strong>Results: </strong>Streptozotocin-treated mice exhibited low insulin and elevated blood glucose, advanced glycation end-products, thrombin-antithrombin, and cfDNA compared with normoglycemic mice. Despite these baseline differences, the trajectory of sepsis was similar in both groups. Blood glucose rapidly dropped postinfection, converging at approximately 2 mM within 12 hours in nonsurvivors and partially recovering in survivors. Plasma insulin increased in both groups in response to sepsis, returning to baseline levels by 48 hours in survivors. No significant differences were found between the groups in sepsis-related outcomes, including sepsis scores, body temperature, inflammatory and coagulation responses, cfDNA, lung myeloperoxidase, bacterial burden, organ injury, or survival.</p><p><strong>Conclusion: </strong>Short-term hyperglycemia did not alter the course of sepsis compared with normoglycemic mice. Blood glucose levels partially recovered in surviving mice, suggesting that restoring glucose homeostasis may improve outcomes.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144667840","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mathematical analysis of emicizumab: affinity-driven complex formation and lipid surface reactions.","authors":"Jamie Madrigal, Dougald M Monroe, Suzanne S Sindi, Karin Leiderman","doi":"10.1016/j.jtha.2025.07.002","DOIUrl":"https://doi.org/10.1016/j.jtha.2025.07.002","url":null,"abstract":"<p><strong>Background: </strong>Emicizumab is a bispecific antibody that binds activated Factor IX (FIXa) with one-arm and Factor X (FX) with the other. Binding bridges FIXa and FX, replacing the function of Factor VIII in hemophilia A. Unlike FVIII, emicizumab does not bind directly to lipid surfaces.</p><p><strong>Objectives: </strong>Investigate emicizumab's lipid-surface dependent mechanisms through mathematical modeling and biochemical assays.</p><p><strong>Methods: </strong>We expanded our mathematical model of TF:VIIa activation of FX to incorporate emicizumab and FIXa interactions. We calibrated our model using experimental data.</p><p><strong>Results: </strong>High concentrations of emicizumab inhibit FX activation by TF:VIIa. Our mathematical model explains these observations only when FX bound to emicizumab is partially restricted from binding to lipid surfaces and to TF:VIIa. Lipid enhances FX activation of FIXa in the presence of emicizumab. In our two-arm interaction model, we estimated kinetic rates for emicizumab-dependent activation of FX on the lipid surface. The model successfully predicted FIXa activation of FX with and without emicizumab across many experimental conditions. Ternary complexes (FIXa, FX and emicizumab) in solution decreased when lipid increased while ternary complexes on lipid increased. Sensitivity analysis, which varied lipid, dissociation constants, and catalytic rates, highlighted the impact of binding-arm affinity on reaction velocities.</p><p><strong>Conclusions: </strong>High concentrations of emicizumab decrease TF:VIIa activation of FX by reducing FX binding to both the lipid surface and TF:VIIa. Emicizumab enhances FIXa activation of FX on the lipid surface by preferentially binding to lipid-bound FX and subsequently to lipid-bound FIXa with an enhanced association rate due to colocalization on the lipid surface.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144667841","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}