Pub Date : 2026-01-01DOI: 10.1016/j.rpth.2025.103322
Jie Huang , Jinlong Liu , Yaxin Liu , Yichen Cao , Wei Sun , Yanrong Dong , Yuwei Li , Jing Li , Qian Wu , Xiaoyan Yang , Shuang Yang , Chuanpin Chen , Guoping Yang
Background
KN060 is a humanized dual-domain antibody targeting coagulation factor XI (FXI) and factor XIa (FXIa) and is currently being developed for the prevention of thromboembolic diseases.
Objectives
This study aims to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of a single intravenous administration of KN060 in healthy Chinese subjects.
Methods
This single-center, randomized, double-blind, placebo-controlled clinical study was conducted in 38 healthy Chinese subjects. The study included 6 dose groups (0.1, 0.3, 1.0, 2.5, 5.0, and 10.0 mg/kg), with KN060 administered via a single ascending-dose regimen.
Results
KN060 demonstrates good tolerability and safety, with no significant treatment-emergent adverse events. A single intravenous infusion of KN060, ranging from 0.1 to 10.0 mg/kg, resulted in an average Tmax ranging from 1.02 to 3.34 hours. For a dose range of 0.3 to 10.0 mg/kg, the average half-life ranged from 122.96 to 146.47 hours. Pharmacokinetic and pharmacodynamic analyses revealed that within the dose range of 0.1 to 10.0 mg/kg, drug concentration was positively correlated with activated partial thromboplastin time and negatively correlated with factor (F)XI activity and free FXI content. Immunogenicity analysis showed that all subjects were negative for antidrug antibodies.
Conclusion
The study results demonstrated that KN060 was well tolerated and safe. Based on pharmacokinetic and pharmacodynamic data, KN060 is a promising humanized dual-domain antibody simultaneously targeting FXI/FXIa for the prevention of thromboembolic diseases.
{"title":"Safety, tolerability, pharmacokinetics, and pharmacodynamics of KN060, a humanized anti-FXI/FXIa dual-domain antibody, following single ascending doses in healthy Chinese subjects","authors":"Jie Huang , Jinlong Liu , Yaxin Liu , Yichen Cao , Wei Sun , Yanrong Dong , Yuwei Li , Jing Li , Qian Wu , Xiaoyan Yang , Shuang Yang , Chuanpin Chen , Guoping Yang","doi":"10.1016/j.rpth.2025.103322","DOIUrl":"10.1016/j.rpth.2025.103322","url":null,"abstract":"<div><h3>Background</h3><div>KN060 is a humanized dual-domain antibody targeting coagulation factor XI (FXI) and factor XIa (FXIa) and is currently being developed for the prevention of thromboembolic diseases.</div></div><div><h3>Objectives</h3><div>This study aims to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of a single intravenous administration of KN060 in healthy Chinese subjects.</div></div><div><h3>Methods</h3><div>This single-center, randomized, double-blind, placebo-controlled clinical study was conducted in 38 healthy Chinese subjects. The study included 6 dose groups (0.1, 0.3, 1.0, 2.5, 5.0, and 10.0 mg/kg), with KN060 administered via a single ascending-dose regimen.</div></div><div><h3>Results</h3><div>KN060 demonstrates good tolerability and safety, with no significant treatment-emergent adverse events. A single intravenous infusion of KN060, ranging from 0.1 to 10.0 mg/kg, resulted in an average <em>T</em><sub>max</sub> ranging from 1.02 to 3.34 hours. For a dose range of 0.3 to 10.0 mg/kg, the average half-life ranged from 122.96 to 146.47 hours. Pharmacokinetic and pharmacodynamic analyses revealed that within the dose range of 0.1 to 10.0 mg/kg, drug concentration was positively correlated with activated partial thromboplastin time and negatively correlated with factor (F)XI activity and free FXI content. Immunogenicity analysis showed that all subjects were negative for antidrug antibodies.</div></div><div><h3>Conclusion</h3><div>The study results demonstrated that KN060 was well tolerated and safe. Based on pharmacokinetic and pharmacodynamic data, KN060 is a promising humanized dual-domain antibody simultaneously targeting FXI/FXIa for the prevention of thromboembolic diseases.</div></div><div><h3>Trial Registration</h3><div><span><span>https://www.chictr.org.cn</span><svg><path></path></svg></span>, identifier: ChiCTR2200056926; <span><span>http://www.chinadrugtrials.org.cn</span><svg><path></path></svg></span>, identifier: CTR20222339.</div></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"10 1","pages":"Article 103322"},"PeriodicalIF":3.4,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146078261","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01DOI: 10.1016/j.rpth.2025.103301
Olga Gavín Sebastián , Javier Trujillo-Santos , María del Carmen Díaz-Pedroche , Pablo Demelo-Rodríguez , Sonia Otálora , Benjamin Brenner , José María Pedrajas , Alessandra Bura-Riviere , Luis Hernández-Blasco , Manuel Monreal
Background
The risk of recurrent venous thromboembolism (VTE) and bleeding during anticoagulation may vary by the cancer type.
Objectives
We assessed outcomes during anticoagulation in women with breast, ovarian, or uterine cancer and VTE.
Methods
We analyzed data from the Registro Informatizado Enfermedad TromboEmbólica registry on 4721 women with active breast (n = 2929), ovarian (n = 886), or uterine (n = 906) cancer and acute VTE. We assessed VTE recurrences, bleeding, and mortality according to cancer type and anticoagulant type. Multivariate Cox models were adjusted for age, metastases, anemia, renal function, and treatment at VTE onset.
Results
Uterine cancer patients had the highest rates of major bleeding (11.1 per 100 patient-years) and fatal bleeding (1.07 per 100 patient-years), while ovarian cancer patients had the highest rate of VTE recurrences (7.29 per 100 patient-years). In contrast, breast cancer patients had the lowest event rates overall. Among low-molecular-weight heparin–treated patients, major bleeding was higher in uterine (6.37 per 100 patient-years) and ovarian (4.62 per 100 patient-years) cancer than breast cancer patients (1.89 per 100 patient-years). Direct oral anticoagulant use was associated with low recurrence rates in breast cancer (0.58 per 100 patient-years), but outcomes in uterine cancer remained less favorable. Multivariable models confirmed cancer-specific risks.
Conclusions
VTE outcomes vary significantly by cancer type. Patients with uterine cancer face an elevated bleeding risk, potentially impacting anticoagulant continuity and contributing to VTE recurrence. These findings support the need for cancer-specific risk assessment and individualized anticoagulation strategies adapted to the specific cancer type.
{"title":"Venous thromboembolism in patients with breast, ovarian, and uterine cancer. A comparative analysis from the Registro Informatizado Enfermedad TromboEmbólica registry","authors":"Olga Gavín Sebastián , Javier Trujillo-Santos , María del Carmen Díaz-Pedroche , Pablo Demelo-Rodríguez , Sonia Otálora , Benjamin Brenner , José María Pedrajas , Alessandra Bura-Riviere , Luis Hernández-Blasco , Manuel Monreal","doi":"10.1016/j.rpth.2025.103301","DOIUrl":"10.1016/j.rpth.2025.103301","url":null,"abstract":"<div><h3>Background</h3><div>The risk of recurrent venous thromboembolism (VTE) and bleeding during anticoagulation may vary by the cancer type.</div></div><div><h3>Objectives</h3><div>We assessed outcomes during anticoagulation in women with breast, ovarian, or uterine cancer and VTE.</div></div><div><h3>Methods</h3><div>We analyzed data from the Registro Informatizado Enfermedad TromboEmbólica registry on 4721 women with active breast (<em>n</em> = 2929), ovarian (<em>n</em> = 886), or uterine (<em>n</em> = 906) cancer and acute VTE. We assessed VTE recurrences, bleeding, and mortality according to cancer type and anticoagulant type. Multivariate Cox models were adjusted for age, metastases, anemia, renal function, and treatment at VTE onset.</div></div><div><h3>Results</h3><div>Uterine cancer patients had the highest rates of major bleeding (11.1 per 100 patient-years) and fatal bleeding (1.07 per 100 patient-years), while ovarian cancer patients had the highest rate of VTE recurrences (7.29 per 100 patient-years). In contrast, breast cancer patients had the lowest event rates overall. Among low-molecular-weight heparin–treated patients, major bleeding was higher in uterine (6.37 per 100 patient-years) and ovarian (4.62 per 100 patient-years) cancer than breast cancer patients (1.89 per 100 patient-years). Direct oral anticoagulant use was associated with low recurrence rates in breast cancer (0.58 per 100 patient-years), but outcomes in uterine cancer remained less favorable. Multivariable models confirmed cancer-specific risks.</div></div><div><h3>Conclusions</h3><div>VTE outcomes vary significantly by cancer type. Patients with uterine cancer face an elevated bleeding risk, potentially impacting anticoagulant continuity and contributing to VTE recurrence. These findings support the need for cancer-specific risk assessment and individualized anticoagulation strategies adapted to the specific cancer type.</div></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"10 1","pages":"Article 103301"},"PeriodicalIF":3.4,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146078265","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01DOI: 10.1016/j.rpth.2025.103323
Gerard Gurumurthy , Juditha Gurumurthy , Samantha Gurumurthy , Lianna Reynolds , Dawn Swan , Jecko Thachil
Platelets play a central role in the pathogenesis of tropical infectious diseases. Infections such as malaria, dengue, and leptospirosis are often accompanied by thrombocytopenia. While the platelet count is typically monitored as a measure of thrombocytopenia, other platelet indices may better determine bleeding severity. Platelet dysfunction in these conditions requires a nuanced approach to management. Prophylactic platelet transfusions have shown limited efficacy in preventing hemorrhagic complications and carry additional risks. These include transfusion-transmitted infections, logistical challenges, and the high cost of platelet concentrates. Herein, we review current insights into platelet biology in major tropical infections, examine the varied mechanisms underlying thrombocytopenia in these conditions, and discuss the latest evidence on transfusion guidelines. We also propose evidence-based approaches to thrombocytopenia management and platelet transfusion. We aim to summarize approaches that may improve care for populations disproportionately affected by tropical infectious diseases in resource-limited settings.
{"title":"Clinical characteristics of thrombocytopenia in tropical diseases and management in resource-limited settings","authors":"Gerard Gurumurthy , Juditha Gurumurthy , Samantha Gurumurthy , Lianna Reynolds , Dawn Swan , Jecko Thachil","doi":"10.1016/j.rpth.2025.103323","DOIUrl":"10.1016/j.rpth.2025.103323","url":null,"abstract":"<div><div>Platelets play a central role in the pathogenesis of tropical infectious diseases. Infections such as malaria, dengue, and leptospirosis are often accompanied by thrombocytopenia. While the platelet count is typically monitored as a measure of thrombocytopenia, other platelet indices may better determine bleeding severity. Platelet dysfunction in these conditions requires a nuanced approach to management. Prophylactic platelet transfusions have shown limited efficacy in preventing hemorrhagic complications and carry additional risks. These include transfusion-transmitted infections, logistical challenges, and the high cost of platelet concentrates. Herein, we review current insights into platelet biology in major tropical infections, examine the varied mechanisms underlying thrombocytopenia in these conditions, and discuss the latest evidence on transfusion guidelines. We also propose evidence-based approaches to thrombocytopenia management and platelet transfusion. We aim to summarize approaches that may improve care for populations disproportionately affected by tropical infectious diseases in resource-limited settings.</div></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"10 1","pages":"Article 103323"},"PeriodicalIF":3.4,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146022849","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Rap1 is critical for platelet activation, functioning as a key node of the platelet activation pathways.
Objectives
This study aimed to develop VHH-Fc (minibodies) against Rap1 for the purpose to quantify active Rap1 levels in platelets.
Methods
We have produced the first generation of VHHs against active Rap1 through a series of negative and positive screenings of a synthetic phage display library, utilizing both inactive and active Rap1B. We performed random mutagenesis, followed by yeast 2-hybrid screening to optimize variants.
Results
Among 122 VHH clones, 2 with the highest redundancy were subcloned as VHH-Fc. Both selectively detected active Rap1B G12V in HeLa cells but failed to recognize the inactive Rap1B S17N isoform. They successfully captured Rap1 from platelet lysates incubated with GTPγS and from thrombin receptor activator peptide 6–stimulated platelets. Further optimization yielded 2 superbinder VHH clones: VHH-Fc B89 and VHH-Fc B14. VHH-Fc B89 exhibited a KD of 4.4 nM and showed enhanced capacity to capture active GTP-bound Rap1 compared with the original VHH-Fc. Additionally, it was able to detect overexpressed active Rap1B G12V in HeLa cells. An ELISA setup combining VHH-Fc B14 and a commercial monoclonal antibody targeting total Rap1 was highly effective in detecting both GTPγS-bound Rap1 and endogenous active Rap1 in platelets.
Conclusion
This study identifies, that accurately capture active Rap1 in platelets, thereby establishing them as promising tools for future research. We also developed a reliable ELISA test that can facilitate clinical studies to monitor platelet Rap1 activation in various medical contexts.
背景：drap1对血小板激活至关重要，是血小板激活途径的关键节点。目的建立抗Rap1的VHH-Fc（小体），定量测定血小板中Rap1的活性水平。方法利用非活性和活性Rap1B，通过一系列合成噬菌体展示文库的阴性和阳性筛选，制备了第一代抗活性Rap1的vhs。我们进行了随机诱变，然后进行酵母2杂交筛选以优化变异。结果122个VHH克隆中，2个冗余度最高的克隆为VHH- fc。这两种方法都能在HeLa细胞中选择性地检测到活性Rap1B G12V，但无法识别非活性Rap1B S17N亚型。他们成功地从与gtp - γ s孵育的血小板裂解液和凝血酶受体激活肽6刺激的血小板中捕获Rap1。进一步优化得到2个超粘结剂VHH克隆：VHH- fc B89和VHH- fc B14。与原始VHH-Fc相比，VHH-Fc B89的KD值为4.4 nM，具有更强的捕获活性gtp结合Rap1的能力。此外，它能够检测HeLa细胞中过表达的活性Rap1B G12V。结合vhs - fc B14和一种靶向总Rap1的商业单克隆抗体建立的ELISA试剂盒在检测血小板中gtp - γ - s结合的Rap1和内源性活性Rap1中都是非常有效的。本研究确定了准确捕获血小板中活性Rap1的方法，从而将其作为未来研究的有前途的工具。我们还开发了一种可靠的ELISA测试，可以促进临床研究，以监测血小板Rap1在各种医学背景下的激活。
{"title":"Selection and optimization strategy for Rap1-targeting single-domain antibodies as platelet activation markers","authors":"Marie-Christine Alessi , Maxime Moulard , Daniele Boulay-Moine , Cyril Pons , Marielle Margier , Cléa Vessière , Marjorie Poggi , Theo Pigaglio , Francoise Dignat-George , Alain Roussel , Stéphane Burtey , Laurent Bonello , Patrick Chames , Remi Bonjean , Franck Peiretti","doi":"10.1016/j.rpth.2025.103294","DOIUrl":"10.1016/j.rpth.2025.103294","url":null,"abstract":"<div><h3>Background</h3><div>Rap1 is critical for platelet activation, functioning as a key node of the platelet activation pathways.</div></div><div><h3>Objectives</h3><div>This study aimed to develop VHH-Fc (minibodies) against Rap1 for the purpose to quantify active Rap1 levels in platelets.</div></div><div><h3>Methods</h3><div>We have produced the first generation of VHHs against active Rap1 through a series of negative and positive screenings of a synthetic phage display library, utilizing both inactive and active Rap1B. We performed random mutagenesis, followed by yeast 2-hybrid screening to optimize variants.</div></div><div><h3>Results</h3><div>Among 122 VHH clones, 2 with the highest redundancy were subcloned as VHH-Fc. Both selectively detected active Rap1B G12V in HeLa cells but failed to recognize the inactive Rap1B S17N isoform. They successfully captured Rap1 from platelet lysates incubated with GTPγS and from thrombin receptor activator peptide 6–stimulated platelets. Further optimization yielded 2 superbinder VHH clones: VHH-Fc B89 and VHH-Fc B14. VHH-Fc B89 exhibited a <em>K</em><sub>D</sub> of 4.4 nM and showed enhanced capacity to capture active GTP-bound Rap1 compared with the original VHH-Fc. Additionally, it was able to detect overexpressed active Rap1B G12V in HeLa cells. An ELISA setup combining VHH-Fc B14 and a commercial monoclonal antibody targeting total Rap1 was highly effective in detecting both GTPγS-bound Rap1 and endogenous active Rap1 in platelets.</div></div><div><h3>Conclusion</h3><div>This study identifies, that accurately capture active Rap1 in platelets, thereby establishing them as promising tools for future research. We also developed a reliable ELISA test that can facilitate clinical studies to monitor platelet Rap1 activation in various medical contexts.</div></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"10 1","pages":"Article 103294"},"PeriodicalIF":3.4,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146022850","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01DOI: 10.1016/j.rpth.2025.103334
Rick Timmerije , Saskia E.M. Schols , Daniëlle Meijer , Wideke Barteling , An K. Stroobants , Sanna R. Rijpma
Background
Direct oral anticoagulants (DOACs) interfere with clot-based assays, including factor (F)VIII testing and the Nijmegen–Bethesda assay, potentially leading to false-positive results for FVIII inhibitors. Misinterpretation of these results carries serious clinical consequences. Activated charcoal-based products, such as DOAC Remove, may restore assay accuracy, but data supporting their use in FVIII inhibitor assays are limited.
Objectives
In this study, we aim to determine DOAC interference in FVIII inhibitor testing and evaluate effectivity of DOAC removal to restore assay reliability.
Methods
Normal pooled plasma was spiked with therapeutic and supratherapeutic concentrations of apixaban, edoxaban, rivaroxaban, and dabigatran. Plasma pools from persons with acquired hemophilia A were spiked with DOACs and retested with and without DOAC removal treatment to evaluate workflow performance. FVIII inhibitor activity was measured with and without activated charcoal-based DOAC removal to establish DOAC interference and removal efficacy.
Results
Spiking experiments with DOACs caused concentration-dependent false-positive FVIII inhibitor results (>0.6 Nijmegen Bethesda Units/mL), with dabigatran showing the strongest interference and apixaban the weakest. DOAC removal substantially reduced or eliminated interference across all drugs. Post-removal FVIII inhibitor values closely matched baseline concentrations in both spiked normal pooled plasma and pooled patient plasma, with most results within ±20% of the assay variability.
Conclusion
DOACs significantly interfere with FVIII inhibitor assays, potentially causing clinically significant false-positive results. Activated charcoal-based DOAC removal treatment provides a practical solution to restore assay reliability. These findings support the integration of DOAC removal into anti-FVIII testing protocols for patients on anticoagulant therapy.
{"title":"Direct oral anticoagulant interference and removal in the factor VIII inhibitor assay","authors":"Rick Timmerije , Saskia E.M. Schols , Daniëlle Meijer , Wideke Barteling , An K. Stroobants , Sanna R. Rijpma","doi":"10.1016/j.rpth.2025.103334","DOIUrl":"10.1016/j.rpth.2025.103334","url":null,"abstract":"<div><h3>Background</h3><div>Direct oral anticoagulants (DOACs) interfere with clot-based assays, including factor (F)VIII testing and the Nijmegen–Bethesda assay, potentially leading to false-positive results for FVIII inhibitors. Misinterpretation of these results carries serious clinical consequences. Activated charcoal-based products, such as DOAC Remove, may restore assay accuracy, but data supporting their use in FVIII inhibitor assays are limited.</div></div><div><h3>Objectives</h3><div>In this study, we aim to determine DOAC interference in FVIII inhibitor testing and evaluate effectivity of DOAC removal to restore assay reliability.</div></div><div><h3>Methods</h3><div>Normal pooled plasma was spiked with therapeutic and supratherapeutic concentrations of apixaban, edoxaban, rivaroxaban, and dabigatran. Plasma pools from persons with acquired hemophilia A were spiked with DOACs and retested with and without DOAC removal treatment to evaluate workflow performance. FVIII inhibitor activity was measured with and without activated charcoal-based DOAC removal to establish DOAC interference and removal efficacy.</div></div><div><h3>Results</h3><div>Spiking experiments with DOACs caused concentration-dependent false-positive FVIII inhibitor results (>0.6 Nijmegen Bethesda Units/mL), with dabigatran showing the strongest interference and apixaban the weakest. DOAC removal substantially reduced or eliminated interference across all drugs. Post-removal FVIII inhibitor values closely matched baseline concentrations in both spiked normal pooled plasma and pooled patient plasma, with most results within ±20% of the assay variability.</div></div><div><h3>Conclusion</h3><div>DOACs significantly interfere with FVIII inhibitor assays, potentially causing clinically significant false-positive results. Activated charcoal-based DOAC removal treatment provides a practical solution to restore assay reliability. These findings support the integration of DOAC removal into anti-FVIII testing protocols for patients on anticoagulant therapy.</div></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"10 1","pages":"Article 103334"},"PeriodicalIF":3.4,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146022853","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01DOI: 10.1016/j.rpth.2025.103341
David Hesselbarth , Michelle D’Orazio , Giovanni Ciccarone , Diona Gjermeni , Carina Jülch , Philipp Breitbart , Philipp Ruile , Manuel Hein , Marius Wessinger , Mariya Maslarska , Jonathan Rilinger , Christopher Schlett , Fabian Bamberg , Klaus Kaier , Daniel Duerschmied , Torben Pottgiesser , Constantin von zur Mühlen , Dirk Westermann , Christoph B. Olivier
Background
Patients after transcatheter aortic valve replacement (TAVR) have a high incidence of hypoattenuating leaflet thickening (HALT). However, data on biomarkers related to HALT remain limited.
Objectives
To identify hemostatic markers associated with HALT following TAVR.
Methods
This prospective single-center cohort study assessed hemostatic profiles of patients undergoing TAVR between November 2020 and June 2022 using thrombelastography, light transmission aggregometry, and conventional laboratory markers. The primary outcome was moderate-to-severe HALT (grade 3/4) or reduced leaflet motion (grade 2/3) detected by computed tomography angiography at 6 months post-TAVR.
Results
Of the 107 patients included, 68 had interpretable computed tomography angiography at 6 months. The primary outcome occurred in 14 (20%) patients. Biomarkers were measured at a median of 4 days (IQR, 3-6) after TAVR. Shortened clot formation time (R-time with heparin neutralization) indicated an association with HALT at 6 months (odds ratio [OR], 1.12 [95% CI, 1.00; 1.25]; P = .05) and demonstrated moderate discriminatory ability, with an optimal cutoff of 4.9 minutes (sensitivity 79%; specificity 74%; area under the curve, 0.74 [95% CI, 0.60; 0.89]; P = .005). Increased platelet count (OR, 1.08 [95% CI, 1.01; 1.15]; P = .03), elevated protein S (OR, 1.21 [95% CI, 1.01; 1.44]; P = .04), and higher C-reactive protein levels (OR, 1.19 [95% CI, 1.00; 1.41]; P = .05) also demonstrated associations with HALT. However, after adjustment for multiple testing using the Benjamini–Hochberg procedure, none of these associations was statistically significant.
Conclusion
This exploratory study identified associations between HALT and biomarkers of hypercoagulability and inflammation, which did not persist after correction for multiple testing. These findings should be regarded as hypothesis-generating and warrant confirmation in future studies.
背景：经导管主动脉瓣置换术（TAVR）后患者低衰减小叶增厚（HALT）的发生率很高。然而，与HALT相关的生物标志物数据仍然有限。目的探讨TAVR术后与HALT相关的止血标志物。方法本前瞻性单中心队列研究评估了2020年11月至2022年6月期间接受TAVR的患者的止血情况，采用血栓造影、光透射聚集术和常规实验室标志物。主要结局是tavr后6个月通过计算机断层血管造影检测到中度至重度HALT（3/4级）或小叶运动减少（2/3级）。结果在纳入的107例患者中，68例在6个月时进行了可解释的计算机断层血管造影。主要结局发生在14例（20%）患者中。TAVR后中位4天（IQR, 3-6）测量生物标志物。缩短凝块形成时间（肝素中和后的R-time）表明与6个月时的HALT相关（优势比[OR]， 1.12 [95% CI, 1.00; 1.25]; P = 0.05），并表现出中等的区分能力，最佳截止时间为4.9分钟（灵敏度79%；特异性74%；曲线下面积0.74 [95% CI, 0.60; 0.89]; P = 0.005）。血小板计数增加（OR, 1.08 [95% CI, 1.01; 1.15]; P = 0.03）、蛋白S升高（OR, 1.21 [95% CI, 1.01; 1.44]; P = 0.04）和c反应蛋白水平升高（OR, 1.19 [95% CI, 1.00; 1.41]; P = 0.05）也显示与HALT相关。然而，在使用Benjamini-Hochberg程序对多重检验进行调整后，这些关联都没有统计学意义。结论：本探索性研究确定了HALT与高凝性和炎症生物标志物之间的关联，这种关联在多次校正后并不持续存在。这些发现应该被视为假设的产生，并在未来的研究中得到证实。
{"title":"Associations of biomarkers with hypoattenuated leaflet thickening after transcatheter aortic valve replacement","authors":"David Hesselbarth , Michelle D’Orazio , Giovanni Ciccarone , Diona Gjermeni , Carina Jülch , Philipp Breitbart , Philipp Ruile , Manuel Hein , Marius Wessinger , Mariya Maslarska , Jonathan Rilinger , Christopher Schlett , Fabian Bamberg , Klaus Kaier , Daniel Duerschmied , Torben Pottgiesser , Constantin von zur Mühlen , Dirk Westermann , Christoph B. Olivier","doi":"10.1016/j.rpth.2025.103341","DOIUrl":"10.1016/j.rpth.2025.103341","url":null,"abstract":"<div><h3>Background</h3><div>Patients after transcatheter aortic valve replacement (TAVR) have a high incidence of hypoattenuating leaflet thickening (HALT). However, data on biomarkers related to HALT remain limited.</div></div><div><h3>Objectives</h3><div>To identify hemostatic markers associated with HALT following TAVR.</div></div><div><h3>Methods</h3><div>This prospective single-center cohort study assessed hemostatic profiles of patients undergoing TAVR between November 2020 and June 2022 using thrombelastography, light transmission aggregometry, and conventional laboratory markers. The primary outcome was moderate-to-severe HALT (grade 3/4) or reduced leaflet motion (grade 2/3) detected by computed tomography angiography at 6 months post-TAVR.</div></div><div><h3>Results</h3><div>Of the 107 patients included, 68 had interpretable computed tomography angiography at 6 months. The primary outcome occurred in 14 (20%) patients. Biomarkers were measured at a median of 4 days (IQR, 3-6) after TAVR. Shortened clot formation time (R-time with heparin neutralization) indicated an association with HALT at 6 months (odds ratio [OR], 1.12 [95% CI, 1.00; 1.25]; <em>P</em> = .05) and demonstrated moderate discriminatory ability, with an optimal cutoff of 4.9 minutes (sensitivity 79%; specificity 74%; area under the curve, 0.74 [95% CI, 0.60; 0.89]; <em>P</em> = .005). Increased platelet count (OR, 1.08 [95% CI, 1.01; 1.15]; <em>P</em> = .03), elevated protein S (OR, 1.21 [95% CI, 1.01; 1.44]; <em>P</em> = .04), and higher C-reactive protein levels (OR, 1.19 [95% CI, 1.00; 1.41]; <em>P</em> = .05) also demonstrated associations with HALT. However, after adjustment for multiple testing using the Benjamini–Hochberg procedure, none of these associations was statistically significant.</div></div><div><h3>Conclusion</h3><div>This exploratory study identified associations between HALT and biomarkers of hypercoagulability and inflammation, which did not persist after correction for multiple testing. These findings should be regarded as hypothesis-generating and warrant confirmation in future studies.</div></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"10 1","pages":"Article 103341"},"PeriodicalIF":3.4,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146022856","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01DOI: 10.1016/j.rpth.2025.103291
Jamilla Goedegebuur , Elena Butera , Qingui Chen , Behnood Bikdeli , Walter Ageno , Roberto Pola , Angelo Porfidia , Stefano Barco , Thijs E. van Mens , Joost R. van der Vorst , Suzanne C. Cannegieter , Frederikus A. Klok
Background
Antithrombotic therapy (ATT) is recommended for patients with symptomatic lower extremity peripheral arterial disease (PAD). Optimal management of “breakthrough” venous thromboembolic events (VTEs) in these patients remains unclear. This study aims to describe current ATT prescription patterns in PAD patients before, during, and after VTE (treatment) and subsequent clinical outcomes.
Methods
Using Dutch nationwide data, this cohort study identified patients with a reimbursement code for PAD between 2013 and 2021. Within this source population, patients with an International Classification of Diseases-10 code for VTE were identified and followed from VTE date until end-of-study date or death, whichever occurred first. ATT prescriptions, determined from pharmacy records, were mapped in 3 timeframes: 3 months before VTE, during VTE treatment, and 4 to 12 months after VTE.
Results
Patients with PAD (N = 1866) and a concurrent VTE were included, with a mean age of 71.7 years and a median survival of 3.8 years. Before the VTE, 64% used antiplatelet therapy only, in contrast to 12% after VTE treatment. During the VTE treatment period, direct oral anticoagulants were the most frequently dispensed ATT type (40%), whereas 27% received anticoagulation plus antiplatelet therapy during this time. The one-year cumulative incidences of arterial thromboembolic events and clinically relevant bleedings were 6.1% (95% CI: 4.9-7.3) and 1.8% (95% CI, 1.2-2.4), respectively.
Conclusion
Immediate treatment of VTE and long-term ATT use in PAD patients were heterogeneous in our cohort. A substantial proportion of patients had prescriptions for both antiplatelet therapy and anticoagulation during the VTE treatment period. Our findings highlight the need for consensus on this complex clinical dilemma.
{"title":"Antithrombotic therapy in lower extremity peripheral artery disease patients with venous thromboembolism: a nationwide cohort study","authors":"Jamilla Goedegebuur , Elena Butera , Qingui Chen , Behnood Bikdeli , Walter Ageno , Roberto Pola , Angelo Porfidia , Stefano Barco , Thijs E. van Mens , Joost R. van der Vorst , Suzanne C. Cannegieter , Frederikus A. Klok","doi":"10.1016/j.rpth.2025.103291","DOIUrl":"10.1016/j.rpth.2025.103291","url":null,"abstract":"<div><h3>Background</h3><div>Antithrombotic therapy (ATT) is recommended for patients with symptomatic lower extremity peripheral arterial disease (PAD). Optimal management of “breakthrough” venous thromboembolic events (VTEs) in these patients remains unclear. This study aims to describe current ATT prescription patterns in PAD patients before, during, and after VTE (treatment) and subsequent clinical outcomes.</div></div><div><h3>Methods</h3><div>Using Dutch nationwide data, this cohort study identified patients with a reimbursement code for PAD between 2013 and 2021. Within this source population, patients with an International Classification of Diseases-10 code for VTE were identified and followed from VTE date until end-of-study date or death, whichever occurred first. ATT prescriptions, determined from pharmacy records, were mapped in 3 timeframes: 3 months before VTE, during VTE treatment, and 4 to 12 months after VTE.</div></div><div><h3>Results</h3><div>Patients with PAD (<em>N</em> = 1866) and a concurrent VTE were included, with a mean age of 71.7 years and a median survival of 3.8 years. Before the VTE, 64% used antiplatelet therapy only, in contrast to 12% after VTE treatment. During the VTE treatment period, direct oral anticoagulants were the most frequently dispensed ATT type (40%), whereas 27% received anticoagulation plus antiplatelet therapy during this time. The one-year cumulative incidences of arterial thromboembolic events and clinically relevant bleedings were 6.1% (95% CI: 4.9-7.3) and 1.8% (95% CI, 1.2-2.4), respectively.</div></div><div><h3>Conclusion</h3><div>Immediate treatment of VTE and long-term ATT use in PAD patients were heterogeneous in our cohort. A substantial proportion of patients had prescriptions for both antiplatelet therapy and anticoagulation during the VTE treatment period. Our findings highlight the need for consensus on this complex clinical dilemma.</div></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"10 1","pages":"Article 103291"},"PeriodicalIF":3.4,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145927166","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01DOI: 10.1016/j.rpth.2025.103338
Vânia M. Morelli
{"title":"Mortality trends in patients with coexisting pulmonary embolism and obesity: a major public health concern","authors":"Vânia M. Morelli","doi":"10.1016/j.rpth.2025.103338","DOIUrl":"10.1016/j.rpth.2025.103338","url":null,"abstract":"","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"10 1","pages":"Article 103338"},"PeriodicalIF":3.4,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145978192","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01DOI: 10.1016/j.rpth.2025.103326
Yuan Liu , Bo Liu , Shan-Shan Fang , Run-Sheng Zhao , Lin Li , Hui-Xiong Qi , Quan Li
Based on real-world research, we aimed to systematically evaluate the efficacy and safety of hetrombopag for the treatment of chemotherapy-induced thrombocytopenia (CIT) in patients with solid tumors. Patients with solid tumors who developed CIT (platelet count < 100 × 109/L) and were treated with hetrombopag in a single hospital between February 2022 and September 2023 were included in the study. The primary outcome was complete response rate within 14 days, defined as the proportion of patients with platelet counts of ≥100 × 109/L or platelet counts increased by at least 50 × 109/L from baseline. Response rate within 21 days, the incidence of chemotherapy intensity reduction, the median time of response, and adverse events were reported. A total of 73 patients met the inclusion criteria and were subsequently included in the analysis. The complete response rate within 14 days was 79.5%. Within 21 days, the complete response rate was 91.8%. The incidence of chemotherapy intensity reduction was 21.9%. The median time to platelet response was 9.0 days (95% CI, 8.3-9.7 days). The baseline platelet count of ≥ 50 × 109/L and the treatment regimen of hetrombopag combined with rhTPO/rhIL-11 were identified as independent favorable prognostic factors for platelet response time. Subgroup analyses demonstrated that patients receiving combination regimen exhibited a significantly reduced median time to platelet response with baseline platelet counts of ≥50 × 109/L. Safety profile showed good tolerability of hetrombopag (monotherapy or combined with rhTPO/rhIL-11) in patients. Hetrombopag may be an effective and well-tolerated treatment option for CIT in patients with solid tumors.
{"title":"Hetrombopag for the treatment of chemotherapy-induced thrombocytopenia in patients with solid tumors","authors":"Yuan Liu , Bo Liu , Shan-Shan Fang , Run-Sheng Zhao , Lin Li , Hui-Xiong Qi , Quan Li","doi":"10.1016/j.rpth.2025.103326","DOIUrl":"10.1016/j.rpth.2025.103326","url":null,"abstract":"<div><div>Based on real-world research, we aimed to systematically evaluate the efficacy and safety of hetrombopag for the treatment of chemotherapy-induced thrombocytopenia (CIT) in patients with solid tumors. Patients with solid tumors who developed CIT (platelet count < 100 × 10<sup>9</sup>/L) and were treated with hetrombopag in a single hospital between February 2022 and September 2023 were included in the study. The primary outcome was complete response rate within 14 days, defined as the proportion of patients with platelet counts of ≥100 × 10<sup>9</sup>/L or platelet counts increased by at least 50 × 10<sup>9</sup>/L from baseline. Response rate within 21 days, the incidence of chemotherapy intensity reduction, the median time of response, and adverse events were reported. A total of 73 patients met the inclusion criteria and were subsequently included in the analysis. The complete response rate within 14 days was 79.5%. Within 21 days, the complete response rate was 91.8%. The incidence of chemotherapy intensity reduction was 21.9%. The median time to platelet response was 9.0 days (95% CI, 8.3-9.7 days). The baseline platelet count of ≥ 50 × 10<sup>9</sup>/L and the treatment regimen of hetrombopag combined with rhTPO/rhIL-11 were identified as independent favorable prognostic factors for platelet response time. Subgroup analyses demonstrated that patients receiving combination regimen exhibited a significantly reduced median time to platelet response with baseline platelet counts of ≥50 × 10<sup>9</sup>/L. Safety profile showed good tolerability of hetrombopag (monotherapy or combined with rhTPO/rhIL-11) in patients. Hetrombopag may be an effective and well-tolerated treatment option for CIT in patients with solid tumors.</div></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"10 1","pages":"Article 103326"},"PeriodicalIF":3.4,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146022848","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01DOI: 10.1016/j.rpth.2025.103336
Megan V. Perkins , Sierra J. Archibald , Ana T.A. Sachetto , Nigel Mackman
Background
Tissue factor (TF) is a receptor for factor (F)VII/FVIIa and is essential for hemostasis. TF is expressed in a tissue-specific manner, with differing TF levels across tissues. TF expression is increased in a variety of diseases, so accurate measurement of TF protein levels is important.
Objectives
The goal of this study was to evaluate the ability of 4 commercial antibodies to measure TF in various mouse tissues using western blotting.
Methods
We used the goat anti-mouse TF polyclonal antibody AF3178 (R&D Systems), the rabbit anti-mouse TF monoclonal antibody ab189483 (Abcam), the rabbit anti-mouse TF monoclonal antibody 44861 (Cell Signaling Technology), and the mouse anti-mouse TF monoclonal antibody H9 (Santa Cruz Biotechnology) to measure TF in the mouse pancreatic cancer cell line KPC2 wild-type and KPC2 TF knockout cell lysates, as well as various tissues from wild-type and low TF mice (no mouse TF expression) using western blotting.
Results
All 4 antibodies detected TF in KPC2 wild-type cells but not in KPC2 TF knockout cells. All 4 antibodies detected TF in the brain, lung, heart, kidney, and spleen. The relative amounts of TF in these tissues were consistent with the tissue distribution of TF mRNA reported in previous studies. Nonspecific bands were detected in various tissues with the different antibodies.
Conclusion
Our study demonstrated that the Abcam and Cell Signaling Technology anti-mouse TF monoclonal antibodies gave the strongest signal for TF in mouse tissues. However, researchers should be aware that all 4 antibodies also detect nonspecific bands in some tissues.
{"title":"Tissue factor detection in mouse tissues by western blotting using commercial antibodies","authors":"Megan V. Perkins , Sierra J. Archibald , Ana T.A. Sachetto , Nigel Mackman","doi":"10.1016/j.rpth.2025.103336","DOIUrl":"10.1016/j.rpth.2025.103336","url":null,"abstract":"<div><h3>Background</h3><div>Tissue factor (TF) is a receptor for factor (F)VII/FVIIa and is essential for hemostasis. TF is expressed in a tissue-specific manner, with differing TF levels across tissues. TF expression is increased in a variety of diseases, so accurate measurement of TF protein levels is important.</div></div><div><h3>Objectives</h3><div>The goal of this study was to evaluate the ability of 4 commercial antibodies to measure TF in various mouse tissues using western blotting.</div></div><div><h3>Methods</h3><div>We used the goat anti-mouse TF polyclonal antibody AF3178 (R&D Systems), the rabbit anti-mouse TF monoclonal antibody ab189483 (Abcam), the rabbit anti-mouse TF monoclonal antibody 44861 (Cell Signaling Technology), and the mouse anti-mouse TF monoclonal antibody H9 (Santa Cruz Biotechnology) to measure TF in the mouse pancreatic cancer cell line KPC2 wild-type and KPC2 TF knockout cell lysates, as well as various tissues from wild-type and low TF mice (no mouse TF expression) using western blotting.</div></div><div><h3>Results</h3><div>All 4 antibodies detected TF in KPC2 wild-type cells but not in KPC2 TF knockout cells. All 4 antibodies detected TF in the brain, lung, heart, kidney, and spleen. The relative amounts of TF in these tissues were consistent with the tissue distribution of TF mRNA reported in previous studies. Nonspecific bands were detected in various tissues with the different antibodies.</div></div><div><h3>Conclusion</h3><div>Our study demonstrated that the Abcam and Cell Signaling Technology anti-mouse TF monoclonal antibodies gave the strongest signal for TF in mouse tissues. However, researchers should be aware that all 4 antibodies also detect nonspecific bands in some tissues.</div></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"10 1","pages":"Article 103336"},"PeriodicalIF":3.4,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146022851","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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