Pub Date : 2026-02-01DOI: 10.1016/j.jtha.2025.10.020
Bram Akerboom , Emily S.L. Martens , Fleur H.J. Kaptein , Tsunenori Kondo , Tom van der Hulle , Erik J. van Gennep , Henri H. Versteeg , Thijs E. van Mens , Frederikus A. .Klok
Background
Patients with renal cell carcinoma (RCC) and tumor thrombus (TT) are at significant risk of venous thromboembolism (VTE).
Objectives
This systematic review aimed to assess the role of anticoagulation in ambulatory patients with RCC and TT.
Methods
Inclusion criteria were diagnosis of RCC with TT, reporting of VTE, major bleeding and/or arterial thromboembolism, as well as exposure to anticoagulation. Studies with <30 patients were excluded. Studies were also excluded if anticoagulation status was not reported per outcome stratum. A comprehensive search was conducted in PubMed and other databases. Risk of bias was assessed in accordance with the Scottish Intercollegiate Guidelines Network bias quality assessment tool.
Results
Six observational studies containing 659 patients were included. All studies had considerable risk of bias. Anticoagulation use ranged from 3.9% to 50%. Two studies reported a lower VTE incidence in anticoagulated patients than in non–anticoagulated patients: 7.3% (1.2–21) vs 20% (6.9–37) after 1 year, and 18% (1.5–49) vs 24% (14–36) after 2 years. In anticoagulated patients, major bleeding incidence was 12% (2.8–27) after 1 year and 33% (8.2–60) after 2 years. For non–anticoagulated patients the incidence was 19% (6.6–36) after 1 year and 12% (5.1–22) after 2 years. Importantly, none of the studies were management studies, and confidence intervals of our outcomes were wide.
Conclusion
Anticoagulation in patients with RCC with TT may lower VTE risk. Bleeding risk is high in both anticoagulated as well as non–anticoagulated patients. Current evidence remains inconclusive due to study heterogeneity and risk of bias.
{"title":"Outcomes of anticoagulation treatment for renal cell carcinoma tumor thrombi: a systematic review","authors":"Bram Akerboom , Emily S.L. Martens , Fleur H.J. Kaptein , Tsunenori Kondo , Tom van der Hulle , Erik J. van Gennep , Henri H. Versteeg , Thijs E. van Mens , Frederikus A. .Klok","doi":"10.1016/j.jtha.2025.10.020","DOIUrl":"10.1016/j.jtha.2025.10.020","url":null,"abstract":"<div><h3>Background</h3><div>Patients with renal cell carcinoma (RCC) and tumor thrombus (TT) are at significant risk of venous thromboembolism (VTE).</div></div><div><h3>Objectives</h3><div>This systematic review aimed to assess the role of anticoagulation in ambulatory patients with RCC and TT.</div></div><div><h3>Methods</h3><div>Inclusion criteria were diagnosis of RCC with TT, reporting of VTE, major bleeding and/or arterial thromboembolism, as well as exposure to anticoagulation. Studies with <30 patients were excluded. Studies were also excluded if anticoagulation status was not reported per outcome stratum. A comprehensive search was conducted in PubMed and other databases. Risk of bias was assessed in accordance with the Scottish Intercollegiate Guidelines Network bias quality assessment tool.</div></div><div><h3>Results</h3><div>Six observational studies containing 659 patients were included. All studies had considerable risk of bias. Anticoagulation use ranged from 3.9% to 50%. Two studies reported a lower VTE incidence in anticoagulated patients than in non–anticoagulated patients: 7.3% (1.2–21) vs 20% (6.9–37) after 1 year, and 18% (1.5–49) vs 24% (14–36) after 2 years. In anticoagulated patients, major bleeding incidence was 12% (2.8–27) after 1 year and 33% (8.2–60) after 2 years. For non–anticoagulated patients the incidence was 19% (6.6–36) after 1 year and 12% (5.1–22) after 2 years. Importantly, none of the studies were management studies, and confidence intervals of our outcomes were wide.</div></div><div><h3>Conclusion</h3><div>Anticoagulation in patients with RCC with TT may lower VTE risk. Bleeding risk is high in both anticoagulated as well as non–anticoagulated patients. Current evidence remains inconclusive due to study heterogeneity and risk of bias.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"24 2","pages":"Pages 654-661"},"PeriodicalIF":5.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145459089","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}
Pub Date : 2026-02-01DOI: 10.1016/j.jtha.2025.10.016
Aizhen Yang , Yaqiong Zhang , Yaowei Sun , Miao Jiang , Yi Lu , Yue Han , Depei Wu , Zhipu Luo , Yi Wu
Background
Protein disulfide isomerases (PDIs) are a family of thiol oxidoreductases that catalyze the oxidation, reduction, and isomerization of disulfide bonds. While some PDIs enhance arterial thrombosis, their roles in coagulation system remain largely unknown.
Methods
The effect of a thiol blocker N-ethylmaleimide and a reducing agent dithiothreitol on factor XII activity was measured by chromogenic assay, activated partial thromboplastin time and thrombin generation assay. Redox states of FXII disulfides were determined by thiol labeling and mass spectrometry. Functional disulfides were evaluated through cysteine mutagenesis of FXII and predicting structural function via molecular dynamics simulations. Thiol modification and kinetic trapping were used to identify ERp46 substrates. The inferior vena cava stenosis model assessed the roles of ERp46 and FXII in venous thrombosis.
Results
N-ethylmaleimide significantly prolonged activated partial thromboplastin time and inhibited FXIIa chromogenic activity, while dithiothreitol inhibited clotting, thrombin generation, and substrate HK cleavage. Of the PDIs tested, only oxidized ERp46 enhanced FXII activity. Screening identified Cys513-Cys529 and Cys540-Cys571 as crucial disulfides for FXII function. Notably, half of Cys540-Cys571 were in partially disulfide-bonded form. ERp46 oxidized Cys540-Cys571 and increased FXII activity. In vivo, ERp46 deficiency reduced venous thrombus growth, with no additive effect observed in mice with combined ERp46 and FXII deficiency. Only wild-type FXII protein, not FXII/C540S-C571S mutant, restored venous thrombus growth in FXII-deficient mice.
Conclusion
These findings reveal a novel redox-regulatory mechanism for FXII activity and identify the critical role of ERp46 in oxidization of Cys540-Cys571 disulfide, facilitating the activation of FXII and intrinsic coagulation pathway.
{"title":"Thiol isomerase ERp46 catalyzes the disulfide formation of coagulation factor XII enhancing its activity","authors":"Aizhen Yang , Yaqiong Zhang , Yaowei Sun , Miao Jiang , Yi Lu , Yue Han , Depei Wu , Zhipu Luo , Yi Wu","doi":"10.1016/j.jtha.2025.10.016","DOIUrl":"10.1016/j.jtha.2025.10.016","url":null,"abstract":"<div><h3>Background</h3><div>Protein disulfide isomerases (PDIs) are a family of thiol oxidoreductases that catalyze the oxidation, reduction, and isomerization of disulfide bonds. While some PDIs enhance arterial thrombosis, their roles in coagulation system remain largely unknown.</div></div><div><h3>Methods</h3><div>The effect of a thiol blocker N-ethylmaleimide and a reducing agent dithiothreitol on factor XII activity was measured by chromogenic assay, activated partial thromboplastin time and thrombin generation assay. Redox states of FXII disulfides were determined by thiol labeling and mass spectrometry. Functional disulfides were evaluated through cysteine mutagenesis of FXII and predicting structural function via molecular dynamics simulations. Thiol modification and kinetic trapping were used to identify ERp46 substrates. The inferior vena cava stenosis model assessed the roles of ERp46 and FXII in venous thrombosis.</div></div><div><h3>Results</h3><div>N-ethylmaleimide significantly prolonged activated partial thromboplastin time and inhibited FXIIa chromogenic activity, while dithiothreitol inhibited clotting, thrombin generation, and substrate HK cleavage. Of the PDIs tested, only oxidized ERp46 enhanced FXII activity. Screening identified Cys513-Cys529 and Cys540-Cys571 as crucial disulfides for FXII function. Notably, half of Cys540-Cys571 were in partially disulfide-bonded form. ERp46 oxidized Cys540-Cys571 and increased FXII activity. <em>In vivo</em>, ERp46 deficiency reduced venous thrombus growth, with no additive effect observed in mice with combined ERp46 and FXII deficiency. Only wild-type FXII protein, not FXII/C540S-C571S mutant, restored venous thrombus growth in FXII-deficient mice.</div></div><div><h3>Conclusion</h3><div>These findings reveal a novel redox-regulatory mechanism for FXII activity and identify the critical role of ERp46 in oxidization of Cys540-Cys571 disulfide, facilitating the activation of FXII and intrinsic coagulation pathway.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"24 2","pages":"Pages 558-572"},"PeriodicalIF":5.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145459112","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}
Pub Date : 2026-02-01DOI: 10.1016/j.jtha.2025.10.022
Timothy Hoberstorfer, Cihan Ay, Julia Riedl
Malignant brain tumors, including both primary brain cancer and metastatic brain cancer, are associated with a markedly increased risk of venous thromboembolism (VTE). Anticoagulation is challenging in this population, as these patients are not only at risk of thrombotic complications but also at high risk of bleeding. In this review, we examine current knowledge on the incidence, risk factors, pathophysiology, and management of brain cancer–associated VTE. In primary brain cancer, particularly in glioblastoma, expression of the procoagulant proteins podoplanin and tissue factor by tumor cells was found to be an important pathophysiological driver of hypercoagulability. Expression of these prothrombotic factors was found to be dependent on the genetic profile of the brain tumor. Clinical data on the treatment of VTE in brain cancer are limited and mostly based on observational studies. The risk of intracranial hemorrhage during anticoagulation remains a key concern. Data from retrospective studies suggest that direct oral anticoagulants may be associated with a lower bleeding risk than low-molecular-weight heparins. Pharmacological thromboprophylaxis in the ambulatory setting is not routinely recommended, largely due to the lack of trial data in this population. Future studies are needed to improve risk prediction, to clarify the underlying mechanisms of brain cancer–associated VTE, and to define safe and effective treatment strategies.
{"title":"Mechanisms and treatment of venous thromboembolism in patients with brain cancer: a narrative review","authors":"Timothy Hoberstorfer, Cihan Ay, Julia Riedl","doi":"10.1016/j.jtha.2025.10.022","DOIUrl":"10.1016/j.jtha.2025.10.022","url":null,"abstract":"<div><div>Malignant brain tumors, including both primary brain cancer and metastatic brain cancer, are associated with a markedly increased risk of venous thromboembolism (VTE). Anticoagulation is challenging in this population, as these patients are not only at risk of thrombotic complications but also at high risk of bleeding. In this review, we examine current knowledge on the incidence, risk factors, pathophysiology, and management of brain cancer–associated VTE. In primary brain cancer, particularly in glioblastoma, expression of the procoagulant proteins podoplanin and tissue factor by tumor cells was found to be an important pathophysiological driver of hypercoagulability. Expression of these prothrombotic factors was found to be dependent on the genetic profile of the brain tumor. Clinical data on the treatment of VTE in brain cancer are limited and mostly based on observational studies. The risk of intracranial hemorrhage during anticoagulation remains a key concern. Data from retrospective studies suggest that direct oral anticoagulants may be associated with a lower bleeding risk than low-molecular-weight heparins. Pharmacological thromboprophylaxis in the ambulatory setting is not routinely recommended, largely due to the lack of trial data in this population. Future studies are needed to improve risk prediction, to clarify the underlying mechanisms of brain cancer–associated VTE, and to define safe and effective treatment strategies.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"24 2","pages":"Pages 343-353"},"PeriodicalIF":5.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145445205","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}
Pub Date : 2026-02-01DOI: 10.1016/j.jtha.2025.11.008
Divyaswathi Citla-Sridhar , Shruti Karanth , Andrea Van Beek , Tara Lech , Bethany Samuelson Bannow
The care of menstruating individuals on anticoagulation is complex and often overlooked in current clinical guidelines. Although existing recommendations address anticoagulant use broadly, they provide little guidance on managing menstrual bleeding, contraception, or reproductive transitions in this population. To address these gaps, we developed a practical clinical toolkit focused on anticoagulation stewardship for individuals who menstruate—from adolescence through menopause. This expert-driven resource outlines the best practices for identifying and managing heavy menstrual bleeding, optimizing contraceptive counseling, and coordinating care during high-risk periods such as pregnancy, surgery, and perimenopause. It also offers guidance for special populations, including adolescents, transgender and gender-diverse individuals, and those with limited access to care. Key topics include medication selection, dose adjustment, screening for anemia, and referral to gynecology when appropriate. The toolkit emphasizes the role of multidisciplinary teams—including hematology, gynecology, primary care, and anticoagulation services—in delivering patient-centered, equitable care. It also highlights practical strategies for integrating menstrual health into routine anticoagulation management, promoting shared decision making, and improving quality of life for affected individuals.
{"title":"Anticoagulation stewardship from menstruation to menopause: a toolkit for clinical management","authors":"Divyaswathi Citla-Sridhar , Shruti Karanth , Andrea Van Beek , Tara Lech , Bethany Samuelson Bannow","doi":"10.1016/j.jtha.2025.11.008","DOIUrl":"10.1016/j.jtha.2025.11.008","url":null,"abstract":"<div><div>The care of menstruating individuals on anticoagulation is complex and often overlooked in current clinical guidelines. Although existing recommendations address anticoagulant use broadly, they provide little guidance on managing menstrual bleeding, contraception, or reproductive transitions in this population. To address these gaps, we developed a practical clinical toolkit focused on anticoagulation stewardship for individuals who menstruate—from adolescence through menopause. This expert-driven resource outlines the best practices for identifying and managing heavy menstrual bleeding, optimizing contraceptive counseling, and coordinating care during high-risk periods such as pregnancy, surgery, and perimenopause. It also offers guidance for special populations, including adolescents, transgender and gender-diverse individuals, and those with limited access to care. Key topics include medication selection, dose adjustment, screening for anemia, and referral to gynecology when appropriate. The toolkit emphasizes the role of multidisciplinary teams—including hematology, gynecology, primary care, and anticoagulation services—in delivering patient-centered, equitable care. It also highlights practical strategies for integrating menstrual health into routine anticoagulation management, promoting shared decision making, and improving quality of life for affected individuals.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"24 2","pages":"Pages 387-398"},"PeriodicalIF":5.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145723875","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}
Pub Date : 2026-02-01DOI: 10.1016/j.jtha.2025.11.012
Cosmo Godino , Riccardo Mazza
{"title":"Plasma levels measurement of the 4 direct oral anticoagulants in patients with atrial fibrillation at the time of acute thromboembolic and bleeding events: reply","authors":"Cosmo Godino , Riccardo Mazza","doi":"10.1016/j.jtha.2025.11.012","DOIUrl":"10.1016/j.jtha.2025.11.012","url":null,"abstract":"","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"24 2","pages":"Page 784"},"PeriodicalIF":5.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146102420","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}
Pub Date : 2026-02-01DOI: 10.1016/j.jtha.2025.09.040
Andrew S. Butler , Susan Cole , Roopen Arya , Jignesh P. Patel
Background
The risk of venous thromboembolism is significantly increased during the perinatal period. The safety of the direct oral anticoagulants, apixaban and rivaroxaban, has not been established in women who breastfeed. Physiologically based pharmacokinetic (PBPK) modeling provides a means to understand drug disposition and is increasingly being used to predict infant exposure to maternal medication via breastmilk.
Objectives
To utilize established PBPK models of apixaban and rivaroxaban to simulate infant exposure to maternal ingestion.
Methods
Existing PBPK models for apixaban and rivaroxaban were adapted to the lactation setting. These models were verified using published reports of apixaban and rivaroxaban from breastfeeding women. A virtual postpartum population was then generated to simulate maternal and infant exposure to rivaroxaban and apixaban at different doses and time points during the postpartum period. Work was conducted on Simcyp Simulator (v23).
Results
The adapted apixaban and rivaroxaban PBPK models captured the published breastfeeding clinical data well. Apixaban transferred into human breastmilk significantly more than rivaroxaban. Steady state infant plasma AUC24-48 to a fully breastfed infant following maternal dose of rivaroxaban 20 mg daily was 242 (±107) ng/mL·h in the immediate postpartum period and for apixaban 5 mg twice a day AUC24-48 was 2041 (±466) ng/mL. Maternal exposure to apixaban and rivaroxaban was lower immediately postdelivery and then normalized by 6 weeks postpartum.
Conclusion
Our work demonstrates that apixaban would not be a suitable agent for breastfeeding women during the postnatal period, while rivaroxaban shows significant promise due to low infant exposure and warrants further investigation.
{"title":"Considerations of safety for women prescribed apixaban or rivaroxaban who breastfeed—a physiologically based pharmacokinetic analysis","authors":"Andrew S. Butler , Susan Cole , Roopen Arya , Jignesh P. Patel","doi":"10.1016/j.jtha.2025.09.040","DOIUrl":"10.1016/j.jtha.2025.09.040","url":null,"abstract":"<div><h3>Background</h3><div>The risk of venous thromboembolism is significantly increased during the perinatal period. The safety of the direct oral anticoagulants, apixaban and rivaroxaban, has not been established in women who breastfeed. Physiologically based pharmacokinetic (PBPK) modeling provides a means to understand drug disposition and is increasingly being used to predict infant exposure to maternal medication via breastmilk.</div></div><div><h3>Objectives</h3><div>To utilize established PBPK models of apixaban and rivaroxaban to simulate infant exposure to maternal ingestion.</div></div><div><h3>Methods</h3><div>Existing PBPK models for apixaban and rivaroxaban were adapted to the lactation setting. These models were verified using published reports of apixaban and rivaroxaban from breastfeeding women. A virtual postpartum population was then generated to simulate maternal and infant exposure to rivaroxaban and apixaban at different doses and time points during the postpartum period. Work was conducted on Simcyp Simulator (v23).</div></div><div><h3>Results</h3><div>The adapted apixaban and rivaroxaban PBPK models captured the published breastfeeding clinical data well. Apixaban transferred into human breastmilk significantly more than rivaroxaban. Steady state infant plasma AUC<sub>24-48</sub> to a fully breastfed infant following maternal dose of rivaroxaban 20 mg daily was 242 (±107) ng/mL·h in the immediate postpartum period and for apixaban 5 mg twice a day AUC<sub>24-48</sub> was 2041 (±466) ng/mL. Maternal exposure to apixaban and rivaroxaban was lower immediately postdelivery and then normalized by 6 weeks postpartum.</div></div><div><h3>Conclusion</h3><div>Our work demonstrates that apixaban would not be a suitable agent for breastfeeding women during the postnatal period, while rivaroxaban shows significant promise due to low infant exposure and warrants further investigation.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"24 2","pages":"Pages 520-529"},"PeriodicalIF":5.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145401298","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}
Pub Date : 2026-02-01DOI: 10.1016/j.jtha.2025.10.004
Vicky Mai , Toshihiko Takada , Noemie Kraaijpoel , Nick van Es , Ranjeeta Mallick , Milou A.M. Stals , Harry R. Büller , D. Mark Courtney , Yonathan Freund , Javier Galipienzo , Waleed Ghanima , Menno V. Huisman , Jeffrey A. Kline , Karel G.M. Moons , Sameer Parpia , Arnaud Perrier , Marc Righini , Helia Robert-Ebadi , Pierre-Marie Roy , Maarten van Smeden , Grégoire Le Gal
Background
The optimal diagnostic management of patients with chronic lung disease (CLD) and suspected pulmonary embolism (PE) is unclear.
Objectives
The aim of this study was to evaluate the performance of PE diagnostic strategies in patients with and without CLD.
Methods
This is a secondary analysis of an individual-patient data meta-analysis (PROSPERO CRD42018089366) of prospective or cross-sectional studies evaluating conventional (Wells or revised Geneva score with fixed or age-adjusted D-dimer) and newer (YEARS and the Pulmonary Embolism Graduated D-dimer Study algorithms) diagnostic strategies. Main outcomes were safety and efficiency. Safety was defined by the failure rate (proportion of patients diagnosed with venous thromboembolism during initial workup or follow-up among those in whom PE was considered ruled out at baseline without imaging). Efficiency was defined as the proportion of patients in whom PE was considered excluded without the need for imaging among all patients.
Results
Twelve studies, representing 16 990 patients (2201 patients with CLD) were included. The safety of each strategy was comparable in patients with and without CLD, whereas efficiency of the strategies was lower in patients with CLD. In patients with CLD, the predicted failure rate varied between 0.58% (95% CI, 0.10%-3.20%) and 1.06% (95% CI, 0.44%-2.53%), and between 2.54% (95% CI, 1.45%-4.39%) and 3.12% (95% CI, 2.04%-4.74%) for conventional and newer diagnostic strategies, respectively. The predicted efficiency was 19.0% to 33.2% and 35.8% to 43.9% for conventional and newer diagnostic strategies, respectively.
Conclusion
In patients with CLD, diagnostic failure rate seemed slightly lower with conventional diagnostic strategies, but more patients would need imaging to rule out PE, compared with newer diagnostic strategies.
{"title":"Safety and efficiency of diagnostic strategies for ruling out pulmonary embolism in patients with chronic lung disease: an individual-patient data meta-analysis","authors":"Vicky Mai , Toshihiko Takada , Noemie Kraaijpoel , Nick van Es , Ranjeeta Mallick , Milou A.M. Stals , Harry R. Büller , D. Mark Courtney , Yonathan Freund , Javier Galipienzo , Waleed Ghanima , Menno V. Huisman , Jeffrey A. Kline , Karel G.M. Moons , Sameer Parpia , Arnaud Perrier , Marc Righini , Helia Robert-Ebadi , Pierre-Marie Roy , Maarten van Smeden , Grégoire Le Gal","doi":"10.1016/j.jtha.2025.10.004","DOIUrl":"10.1016/j.jtha.2025.10.004","url":null,"abstract":"<div><h3>Background</h3><div>The optimal diagnostic management of patients with chronic lung disease (CLD) and suspected pulmonary embolism (PE) is unclear.</div></div><div><h3>Objectives</h3><div>The aim of this study was to evaluate the performance of PE diagnostic strategies in patients with and without CLD.</div></div><div><h3>Methods</h3><div>This is a secondary analysis of an individual-patient data meta-analysis (PROSPERO CRD42018089366) of prospective or cross-sectional studies evaluating conventional (Wells or revised Geneva score with fixed or age-adjusted D-dimer) and newer (YEARS and the Pulmonary Embolism Graduated D-dimer Study algorithms) diagnostic strategies. Main outcomes were safety and efficiency. Safety was defined by the failure rate (proportion of patients diagnosed with venous thromboembolism during initial workup or follow-up among those in whom PE was considered ruled out at baseline without imaging). Efficiency was defined as the proportion of patients in whom PE was considered excluded without the need for imaging among all patients.</div></div><div><h3>Results</h3><div>Twelve studies, representing 16 990 patients (2201 patients with CLD) were included. The safety of each strategy was comparable in patients with and without CLD, whereas efficiency of the strategies was lower in patients with CLD. In patients with CLD, the predicted failure rate varied between 0.58% (95% CI, 0.10%-3.20%) and 1.06% (95% CI, 0.44%-2.53%), and between 2.54% (95% CI, 1.45%-4.39%) and 3.12% (95% CI, 2.04%-4.74%) for conventional and newer diagnostic strategies, respectively. The predicted efficiency was 19.0% to 33.2% and 35.8% to 43.9% for conventional and newer diagnostic strategies, respectively.</div></div><div><h3>Conclusion</h3><div>In patients with CLD, diagnostic failure rate seemed slightly lower with conventional diagnostic strategies, but more patients would need imaging to rule out PE, compared with newer diagnostic strategies.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"24 2","pages":"Pages 598-607"},"PeriodicalIF":5.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145401307","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}
Pub Date : 2026-02-01DOI: 10.1016/j.jtha.2025.10.021
Daniël G. Aynekulu Mersha , Boaz Lopuhaä , Hester A. Gietema , Jim Smit , Anne E. Wind , Anne-Marije Hulshof , Katrijn Daenen , Jessica Khyali , Bas C.T. van Bussel , Matthijs F.M. van Oosterhout , Hazra S. Moeniralam , Eva K. Kempers , Marieke J.H.A. Kruip , Frederikus A. Klok , Virgil A.S.H. Dalm , Henrik Endeman , Eric C.M. Van Gorp , Willem A. Dik , Jan H. von der Thüsen , Nicole P. Juffermans
Background
Pulmonary embolism (PE) is thought to originate from distal thrombosis. However, in hyperinflammatory conditions, such as COVID-19, thrombosis in the lung vasculature may occur independently of peripheral thrombosis, denoted as in situ thrombosis (IST).
Objectives
We hypothesize that IST results from a dysregulated immune response involving both T-helper type 1 (Th1) and non-Th1 cell upregulation and can be distinguished from PE by histologic, serologic, and radiologic features.
Methods
This study included critically ill patients who succumbed to COVID-19 and from whom pulmonary histopathological examination was obtained. Patients were categorized based on histologic characteristics as either IST (thrombus originating from the vessel wall, with a disorganized structure) or PE (centrally in the vessel, with a layered structure) or as controls (without any pulmonary thrombosis). Inflammation, endothelial activity, and hemostasis biomarkers were measured in blood, and computed tomography scans were analyzed.
Results
Of 21 included patients, n = 6 were categorized as IST, n = 8 as PE, and n = 7 as controls (those who did not have pulmonary thrombosis). Radiologic features of IST included irregular filling defects along vessel walls in smaller arteries in areas with infiltrates. Patients with IST had higher levels of interleukin [IL]-17, IL-18 and IL-33 than those with PE and controls, indicating upregulation of both Th1 and non-Th1 cell pathways.
Conclusion
IST and PE are distinct forms of pulmonary thrombosis. IST originates from the pulmonary vessel wall and is characterized by skewing from an effective immune response to upregulation of Th1, Th2, and Th17 cell pathways.
{"title":"In situ pulmonary thrombosis and pulmonary embolus are distinct thrombotic phenotypes in critically ill patients with COVID-19 Acute Respiratory Distress Syndrome","authors":"Daniël G. Aynekulu Mersha , Boaz Lopuhaä , Hester A. Gietema , Jim Smit , Anne E. Wind , Anne-Marije Hulshof , Katrijn Daenen , Jessica Khyali , Bas C.T. van Bussel , Matthijs F.M. van Oosterhout , Hazra S. Moeniralam , Eva K. Kempers , Marieke J.H.A. Kruip , Frederikus A. Klok , Virgil A.S.H. Dalm , Henrik Endeman , Eric C.M. Van Gorp , Willem A. Dik , Jan H. von der Thüsen , Nicole P. Juffermans","doi":"10.1016/j.jtha.2025.10.021","DOIUrl":"10.1016/j.jtha.2025.10.021","url":null,"abstract":"<div><h3>Background</h3><div>Pulmonary embolism (PE) is thought to originate from distal thrombosis. However, in hyperinflammatory conditions, such as COVID-19, thrombosis in the lung vasculature may occur independently of peripheral thrombosis, denoted as <em>in situ</em> thrombosis (IST).</div></div><div><h3>Objectives</h3><div>We hypothesize that IST results from a dysregulated immune response involving both T-helper type 1 (Th1) and non-Th1 cell upregulation and can be distinguished from PE by histologic, serologic, and radiologic features.</div></div><div><h3>Methods</h3><div>This study included critically ill patients who succumbed to COVID-19 and from whom pulmonary histopathological examination was obtained. Patients were categorized based on histologic characteristics as either IST (thrombus originating from the vessel wall, with a disorganized structure) or PE (centrally in the vessel, with a layered structure) or as controls (without any pulmonary thrombosis). Inflammation, endothelial activity, and hemostasis biomarkers were measured in blood, and computed tomography scans were analyzed.</div></div><div><h3>Results</h3><div>Of 21 included patients, <em>n</em> = 6 were categorized as IST, <em>n</em> = 8 as PE, and <em>n</em> = 7 as controls (those who did not have pulmonary thrombosis). Radiologic features of IST included irregular filling defects along vessel walls in smaller arteries in areas with infiltrates. Patients with IST had higher levels of interleukin [IL]-17, IL-18 and IL-33 than those with PE and controls, indicating upregulation of both Th1 and non-Th1 cell pathways.</div></div><div><h3>Conclusion</h3><div>IST and PE are distinct forms of pulmonary thrombosis. IST originates from the pulmonary vessel wall and is characterized by skewing from an effective immune response to upregulation of Th1, Th2, and Th17 cell pathways.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"24 2","pages":"Pages 662-671"},"PeriodicalIF":5.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145452099","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}
Pub Date : 2026-02-01DOI: 10.1016/j.jtha.2025.09.044
Thomas Hilberg , Alexander Schmidt , Andreas C. Strauss , Johannes Oldenburg , Georg Goldmann , Natascha Marquardt , Fabian Tomschi
Background
Pain is a burden for people with hemophilia (PwH) and is often underdiagnosed. Therefore, it is crucial to develop accurate tools for pain assessment.
Objectives
Pain pressure thresholds (PPTs) are valuable in the diagnosis of pain sensitivity. The meaning and influencing factors in PwH were evaluated in this study.
Methods
We investigated PPTs in 327 PwH and 121 healthy controls to compare differences, examine the influence of age on PPT testing, and explore correlations between PPTs and numeric rating scale (NRS) categories or joint status. PPTs were measured bilaterally at hemophilia-specific joints (elbow/knee/ankle) and reference landmarks (sternum/forehead). Joint status was assessed via the Hemophilia Joint Health Score. NRS categories were used to evaluate current, mean, and maximum pain over the last 4 weeks.
Results
PPTs varied significantly across hemophilia-specific joints, such as the knees and ankles, compared with controls (P < .001), but showed no significant differences at the elbows (P ≥ .123) or at reference landmarks (P ≥ .621). Age did not influence PPTs in either group. In contrast, age-related effects were observed across nearly all NRS categories (current/mean/maximum) in both groups. Correlations between PPTs and NRS categories were low (r ≤ −.212), indicating that they measure different dimensions of pain.
Conclusion
This study demonstrates that PPT measurement is an important method of pain assessment in PwH. Joint-specific PPT values are independent of age and correlate with the presence of affected joints, potentially reflecting the local joint condition, while NRS categories likely represent the overall pain status. Therefore, PPT is a useful tool for pain assessment in PwH, particularly for the diagnosis of joint-specific pain sensitivity.
{"title":"Pain diagnostics in people with hemophilia – pain pressure thresholds and influence of age and joint status","authors":"Thomas Hilberg , Alexander Schmidt , Andreas C. Strauss , Johannes Oldenburg , Georg Goldmann , Natascha Marquardt , Fabian Tomschi","doi":"10.1016/j.jtha.2025.09.044","DOIUrl":"10.1016/j.jtha.2025.09.044","url":null,"abstract":"<div><h3>Background</h3><div>Pain is a burden for people with hemophilia (PwH) and is often underdiagnosed. Therefore, it is crucial to develop accurate tools for pain assessment.</div></div><div><h3>Objectives</h3><div>Pain pressure thresholds (PPTs) are valuable in the diagnosis of pain sensitivity. The meaning and influencing factors in PwH were evaluated in this study.</div></div><div><h3>Methods</h3><div>We investigated PPTs in 327 PwH and 121 healthy controls to compare differences, examine the influence of age on PPT testing, and explore correlations between PPTs and numeric rating scale (NRS) categories or joint status. PPTs were measured bilaterally at hemophilia-specific joints (elbow/knee/ankle) and reference landmarks (sternum/forehead). Joint status was assessed via the Hemophilia Joint Health Score. NRS categories were used to evaluate current, mean, and maximum pain over the last 4 weeks.</div></div><div><h3>Results</h3><div>PPTs varied significantly across hemophilia-specific joints, such as the knees and ankles, compared with controls (<em>P</em> < .001), but showed no significant differences at the elbows (<em>P</em> ≥ .123) or at reference landmarks (<em>P</em> ≥ .621). Age did not influence PPTs in either group. In contrast, age-related effects were observed across nearly all NRS categories (current/mean/maximum) in both groups. Correlations between PPTs and NRS categories were low (<em>r</em> ≤ −.212), indicating that they measure different dimensions of pain.</div></div><div><h3>Conclusion</h3><div>This study demonstrates that PPT measurement is an important method of pain assessment in PwH. Joint-specific PPT values are independent of age and correlate with the presence of affected joints, potentially reflecting the local joint condition, while NRS categories likely represent the overall pain status. Therefore, PPT is a useful tool for pain assessment in PwH, particularly for the diagnosis of joint-specific pain sensitivity.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"24 2","pages":"Pages 470-482"},"PeriodicalIF":5.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145459062","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}
Pub Date : 2026-02-01DOI: 10.1016/j.jtha.2025.10.019
Madankumar Ghatge , Gagan D. Flora , Rakesh B. Patel , Manasa K. Nayak , Mariia Kumskova , Tam Nguyen , Yuriy M. Usachev , Anil K. Chauhan
Background
The mitochondrial calcium uniporter (MCU), a selective intracellular calcium (Ca2+) channel, mediates mitochondrial Ca2+ uptake, supporting Ca2+ homeostasis and mitochondrial bioenergetics. While cytosolic Ca2+ flux from the dense tubular system (DTS) and store-operated Ca2+ entry are known to drive platelet activation, the role of mitochondrial Ca2+ handling in platelet function and thrombosis is not well understood.
Objectives
This study examined whether targeting MCU-dependent Ca2+ flux could attenuate platelet activation and arterial thrombosis.
Methods
Susceptibility to arterial thrombosis was assessed using the FeCl3-induced carotid injury model in wild-type and MCU−/− mice. Mitochondrial and cytosolic Ca2+ levels were measured in Rhod-2– and Fura-2–loaded platelets by fluorometry, and platelet bioenergetics were analyzed using a Seahorse extracellular flux analyzer.
Results
Genetic ablation of MCU inhibited agonist-induced platelet functions, including aggregation, fibrinogen binding to integrin αIIbβ3, granule secretion, and spreading on fibrinogen. MCU−/− mice were less susceptible to in vivo arterial thrombosis with unaltered tail bleeding time, suggesting normal hemostasis. Mechanistically, these effects were associated with disruption of Ca2+ homeostasis mediated by reduced mitochondrial Ca2+ uptake, altered release of Ca2+ from dense tubular system, and impaired store-operated Ca2+ entry in agonist-stimulated MCU−/− platelets. Consistent with this, Ca2+-dependent glycoprotein VI signaling events such as phospholipase γ2 and protein kinase C substrate phosphorylation were significantly reduced in collagen-stimulated MCU−/− platelets. Furthermore, disruption of mitochondrial Ca2+ uptake significantly impaired mitochondrial respiration and associated adenosine triphosphate production in agonist-stimulated MCU−/− platelets.
Conclusion
MCU facilitates platelet activation and thrombosis by regulating calcium flux (mitochondrial and cytosolic), thereby establishing its potential as a target for antithrombotic therapeutic intervention.
{"title":"The mitochondrial calcium uniporter regulates calcium dynamics to drive platelet function, bioenergetics, and thrombosis","authors":"Madankumar Ghatge , Gagan D. Flora , Rakesh B. Patel , Manasa K. Nayak , Mariia Kumskova , Tam Nguyen , Yuriy M. Usachev , Anil K. Chauhan","doi":"10.1016/j.jtha.2025.10.019","DOIUrl":"10.1016/j.jtha.2025.10.019","url":null,"abstract":"<div><h3>Background</h3><div>The mitochondrial calcium uniporter (MCU), a selective intracellular calcium (Ca<sup>2+</sup>) channel, mediates mitochondrial Ca<sup>2+</sup> uptake, supporting Ca<sup>2+</sup> homeostasis and mitochondrial bioenergetics. While cytosolic Ca<sup>2+</sup> flux from the dense tubular system (DTS) and store-operated Ca<sup>2+</sup> entry are known to drive platelet activation, the role of mitochondrial Ca<sup>2+</sup> handling in platelet function and thrombosis is not well understood.</div></div><div><h3>Objectives</h3><div>This study examined whether targeting MCU-dependent Ca<sup>2+</sup> flux could attenuate platelet activation and arterial thrombosis.</div></div><div><h3>Methods</h3><div>Susceptibility to arterial thrombosis was assessed using the FeCl<sub>3</sub>-induced carotid injury model in wild-type and MCU<sup>−/−</sup> mice. Mitochondrial and cytosolic Ca<sup>2+</sup> levels were measured in Rhod-2– and Fura-2–loaded platelets by fluorometry, and platelet bioenergetics were analyzed using a Seahorse extracellular flux analyzer.</div></div><div><h3>Results</h3><div>Genetic ablation of MCU inhibited agonist-induced platelet functions, including aggregation, fibrinogen binding to integrin α<sub>IIb</sub>β<sub>3</sub>, granule secretion, and spreading on fibrinogen. MCU<sup>−/−</sup> mice were less susceptible to <em>in vivo</em> arterial thrombosis with unaltered tail bleeding time, suggesting normal hemostasis. Mechanistically, these effects were associated with disruption of Ca<sup>2+</sup> homeostasis mediated by reduced mitochondrial Ca<sup>2+</sup> uptake, altered release of Ca<sup>2+</sup> from dense tubular system, and impaired store-operated Ca<sup>2+</sup> entry in agonist-stimulated MCU<sup>−/−</sup> platelets. Consistent with this, Ca<sup>2+</sup>-dependent glycoprotein VI signaling events such as phospholipase γ2 and protein kinase C substrate phosphorylation were significantly reduced in collagen-stimulated MCU<sup>−/−</sup> platelets. Furthermore, disruption of mitochondrial Ca<sup>2+</sup> uptake significantly impaired mitochondrial respiration and associated adenosine triphosphate production in agonist-stimulated MCU<sup>−/−</sup> platelets.</div></div><div><h3>Conclusion</h3><div>MCU facilitates platelet activation and thrombosis by regulating calcium flux (mitochondrial and cytosolic), thereby establishing its potential as a target for antithrombotic therapeutic intervention.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"24 2","pages":"Pages 716-731"},"PeriodicalIF":5.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145459100","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}
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