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.2025.09.040
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}
Pub Date : 2026-02-01DOI: 10.1016/j.jtha.2025.10.015
Fatma Işık Üstok, James A. Huntington
Background
Thrombin is generated from its precursor prothrombin by sequential cleavage at Arg320 and Arg271 by the prothrombinase complex, composed of factor (F)Xa and FVa on phospholipid (PL) surfaces. The affinity of human FXa for FVa is low in the absence of PL. However, FXa orthologs from the venom of group D snakes bind to FVa with high affinity, forming an active complex without PL. We previously characterized the properties of the FXa ortholog hopsarin D (HopD) from Hoplocephalus stephensii.
Objectives
In this study, we set out to create a PL-independent human prothrombinase by making mutations to FXa, guided by a model of the prothrombinase complex and the sequence differences between human FXa and HopD.
Methods
We assessed the contribution of individual domains of FXa to its binding to FVa by swapping each with the corresponding domain of HopD. We then chose 3 loops in the serine protease domain predicted to be in contact with FVa to swap to those of HopD. Eventually, 10 residues from the 3 loops in the serine protease domain and 7 from the epidermal growth factor 2 domain were selected for mutation.
Results
The resulting M17 FXa variant bound to FVa with a dissociation constant of 21 nM, similar to HopD, and together efficiently processed prothrombin through the meizothrombin intermediate in the absence of PL.
Conclusion
We conclude that the role of PL membranes in prothrombinase assembly and function is limited to improving the affinity of FXa for FVa and that the M17-FVa complex is likely to be structurally equivalent to human prothrombinase.
背景：凝血酶是由其前体凝血酶原在磷脂（PL）表面上由因子(f) Xa和fVa组成的凝血酶原复合物在Arg320和Arg271处连续切割而产生的。在没有PL的情况下，人类fXa对fVa的亲和力较低。然而，D组蛇毒中的fXa同源物与fVa结合的亲和力很高，形成了一个没有PL的活性复合物。我们之前表征了来自stefan Hoplocephalus的fXa同源物Hopsarin D （HopD）的性质。目的：在这里，我们开始通过对fXa进行突变来创建一个pl独立的人类凝血酶原，在凝血酶原复合物模型和人类fXa和HopD之间的序列差异的指导下。方法：通过与HopD的相应结构域交换，我们评估了fXa的各个结构域对其与fVa结合的贡献。然后，我们选择了三个丝氨酸蛋白酶（SP）结构域中预测与fVa接触的环，以交换到HopD的环。最终，从SP结构域的3个环中选出10个残基，从EGF2结构域选出7个残基进行突变。结果：得到的M17 fXa变体与fVa结合，Kd值为21 nM，与HopD相似，并且在没有PL的情况下通过减数凝血酶中间体有效地加工凝血酶原。结论：我们得出PL膜在凝血酶原组装和功能中的作用仅限于提高fXa对fVa的亲和力，并且M17-fVa复合物可能在结构上与人凝血酶原相当。
{"title":"Engineering a membrane-independent human prothrombinase through parsimonious mutation of factor Xa","authors":"Fatma Işık Üstok, James A. Huntington","doi":"10.1016/j.jtha.2025.10.015","DOIUrl":"10.1016/j.jtha.2025.10.015","url":null,"abstract":"<div><h3>Background</h3><div>Thrombin is generated from its precursor prothrombin by sequential cleavage at Arg320 and Arg271 by the prothrombinase complex, composed of factor (F)Xa and FVa on phospholipid (PL) surfaces. The affinity of human FXa for FVa is low in the absence of PL. However, FXa orthologs from the venom of group D snakes bind to FVa with high affinity, forming an active complex without PL. We previously characterized the properties of the FXa ortholog hopsarin D (HopD) from <em>Hoplocephalus stephensii</em>.</div></div><div><h3>Objectives</h3><div>In this study, we set out to create a PL-independent human prothrombinase by making mutations to FXa, guided by a model of the prothrombinase complex and the sequence differences between human FXa and HopD.</div></div><div><h3>Methods</h3><div>We assessed the contribution of individual domains of FXa to its binding to FVa by swapping each with the corresponding domain of HopD. We then chose 3 loops in the serine protease domain predicted to be in contact with FVa to swap to those of HopD. Eventually, 10 residues from the 3 loops in the serine protease domain and 7 from the epidermal growth factor 2 domain were selected for mutation.</div></div><div><h3>Results</h3><div>The resulting M17 FXa variant bound to FVa with a dissociation constant of 21 nM, similar to HopD, and together efficiently processed prothrombin through the meizothrombin intermediate in the absence of PL.</div></div><div><h3>Conclusion</h3><div>We conclude that the role of PL membranes in prothrombinase assembly and function is limited to improving the affinity of FXa for FVa and that the M17-FVa complex is likely to be structurally equivalent to human prothrombinase.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"24 2","pages":"Pages 458-469"},"PeriodicalIF":5.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145459048","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.2025.10.018
Aaron F.J. Iding , Ruben D. Hupperetz , Rutger J.B. Brans , Hugo ten Cate , Daan J.L. van Twist , Arina J. ten Cate-Hoek
Background
Postthrombotic syndrome (PTS) is a chronic complication of deep vein thrombosis (DVT), with residual venous obstruction (RVO) as a key contributing factor. Oxerutin, a venoactive drug, has the potential to promote DVT resolution, thereby reducing RVO and possibly preventing PTS.
Objectives
This pilot study aimed to estimate the effect of oxerutin therapy on RVO.
Methods
A single-center, patient-unblinded, physician-blinded, assessor-blinded, randomized controlled trial was conducted in adults with acute proximal DVT. Patients were randomized within 48 hours to receive 2-month oxerutin therapy plus standard treatment or standard treatment alone. The primary outcome was RVO at 3 months, defined as a transversal diameter ≥2mm on compressive ultrasound, with sensitivity analysis at ≥4 mm. Secondary outcomes included PTS at 3 months and biomarkers at 5 timepoints. The study was approved by the ethics committee. All patients gave written informed consent.
Results
A total of 44 patients were randomized to oxerutin or standard treatment. At 3 months, the proportion of RVO was lower in the oxerutin group, both for ≥2 mm (42.9% vs 59.1%; odds ratio [OR], 0.34; 95% CI, 0.08-1.28) and ≥4 mm (28.6% vs 54.5%; OR, 0.21; 95% CI, 0.04-0.85), adjusted for DVT extent. A lower proportion of PTS was observed in the oxerutin group (28.6% vs 40.9%; OR, 0.38; 95% CI, 0.08-1.53). Biomarker levels of intercellular adhesion molecule-1 and interleukin-6 were persistently lower in the oxerutin group.
Conclusion
Oxerutin therapy might reduce RVO by promoting DVT resolution. These preliminary findings support further investigation in a large-scale trial to assess the long-term prevention of PTS.
背景：血栓形成后综合征（Post-thrombotic syndrome， PTS）是深静脉血栓形成（deep vein thrombosis， DVT）的一种慢性并发症，其中残余静脉阻塞（residual venous梗阻，RVO）是主要致病因素。Oxerutin是一种静脉活性药物，具有促进DVT消退的潜力，从而降低RVO并可能预防PTS。目的：本初步研究旨在评估奥施罗汀治疗对RVO的影响。方法：对成人急性近端深静脉血栓形成患者进行单中心、非盲法、医师盲法、评估盲法随机对照试验。患者在48小时内随机接受两个月的奥施罗汀治疗加标准治疗或单独标准治疗。主要终点是3个月时的RVO，定义为压缩超声的横径≥2mm，敏感性分析≥4mm。次要终点包括3个月时的PTS和5个时间点的生物标志物。这项研究得到了伦理委员会的批准。所有患者均给予书面知情同意。结果：44例患者随机分为奥施罗汀组和标准组。在3个月时，奥赛芦丁组的RVO比例较低，≥2mm （42.9% vs 59.1%；比值比[OR] 0.34； 95%可信区间[CI] 0.08-1.28）和≥4mm (28.6% vs 54.5%; OR 0.21; 95% CI 0.04-0.85)，根据DVT程度进行调整。奥赛芦丁组PTS发生率较低（28.6% vs 40.9%; OR 0.38; 95% CI 0.08-1.53）。oxerutin组细胞间粘附分子-1和白细胞介素-6的生物标志物水平持续降低。结论：奥施罗汀治疗可能通过促进DVT消退而降低RVO。这些初步发现支持在大规模试验中进一步调查以评估PTS的长期预防。
{"title":"Additional oxerutin therapy to promote deep vein thrombus resolution (RESOLVE-DVT): a randomized controlled pilot trial","authors":"Aaron F.J. Iding , Ruben D. Hupperetz , Rutger J.B. Brans , Hugo ten Cate , Daan J.L. van Twist , Arina J. ten Cate-Hoek","doi":"10.1016/j.jtha.2025.10.018","DOIUrl":"10.1016/j.jtha.2025.10.018","url":null,"abstract":"<div><h3>Background</h3><div>Postthrombotic syndrome (PTS) is a chronic complication of deep vein thrombosis (DVT), with residual venous obstruction (RVO) as a key contributing factor. Oxerutin, a venoactive drug, has the potential to promote DVT resolution, thereby reducing RVO and possibly preventing PTS.</div></div><div><h3>Objectives</h3><div>This pilot study aimed to estimate the effect of oxerutin therapy on RVO.</div></div><div><h3>Methods</h3><div>A single-center, patient-unblinded, physician-blinded, assessor-blinded, randomized controlled trial was conducted in adults with acute proximal DVT. Patients were randomized within 48 hours to receive 2-month oxerutin therapy plus standard treatment or standard treatment alone. The primary outcome was RVO at 3 months, defined as a transversal diameter ≥2mm on compressive ultrasound, with sensitivity analysis at ≥4 mm. Secondary outcomes included PTS at 3 months and biomarkers at 5 timepoints. The study was approved by the ethics committee. All patients gave written informed consent.</div></div><div><h3>Results</h3><div>A total of 44 patients were randomized to oxerutin or standard treatment. At 3 months, the proportion of RVO was lower in the oxerutin group, both for ≥2 mm (42.9% vs 59.1%; odds ratio [OR], 0.34; 95% CI, 0.08-1.28) and ≥4 mm (28.6% vs 54.5%; OR, 0.21; 95% CI, 0.04-0.85), adjusted for DVT extent. A lower proportion of PTS was observed in the oxerutin group (28.6% vs 40.9%; OR, 0.38; 95% CI, 0.08-1.53). Biomarker levels of intercellular adhesion molecule-1 and interleukin-6 were persistently lower in the oxerutin group.</div></div><div><h3>Conclusion</h3><div>Oxerutin therapy might reduce RVO by promoting DVT resolution. These preliminary findings support further investigation in a large-scale trial to assess the long-term prevention of PTS.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"24 2","pages":"Pages 644-653"},"PeriodicalIF":5.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145459059","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.2025.09.032
Ziad Hijazi , Johan Lindbäck , Jonas Oldgren , John H. Alexander , Alexander P. Benz , David D. Berg , Anthony P. Carnicelli , John W. Eikelboom , Robert P. Giugliano , Shinya Goto , Christopher B. Granger , Renato D. Lopes , Christian T. Ruff , Agneta Siegbahn , David A. Morrow , Lars Wallentin
Background
Oral anticoagulation (OAC) reduces stroke in patients with atrial fibrillation (AF), but increases bleeding.
Objectives
This study aimed to evaluate an updated version of the Age, Biomarkers, and Clinical history of bleeding in AF (ABC-AF)-bleeding score (2.0) including consideration of OAC type (direct oral anticoagulant [DOAC] or warfarin) and compare its performance with other bleeding risk scores in 25 962 patients from the COMBINE AF cohort.
Methods
The COMBINE AF biomarker cohort contains individual participant data from patients with AF enrolled in 3 pivotal randomized trials comparing DOACs with warfarin. The biomarkers in the ABC-AF-bleeding score (growth differentiation factor 15, hemoglobin, and troponin-T) were analyzed in baseline samples. The biomarker-based ABC-AF-bleeding score was updated (version 2.0) by incorporating OAC type into the model (DOAC or warfarin). Discrimination was assessed by Harrell C-index and compared with clinically based bleeding scores; HAS-BLED (Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly, Drugs/alcohol), DOAC, and ORBIT (Older age, Reduced haemoglobin/haematocrit or history of anaemia, Bleeding history, Insufficient renal function, Treatment with antiplatelet agents).
Results
During follow-up, 1321 patients (5.1%) had an International Society on Thrombosis and Haemostasis major bleeding event, including 480 gastrointestinal, and 248 intracranial hemorrhages. The ABC-AF-bleeding 2.0 risk score showed better discrimination and calibration than the original version and provided superior discrimination than clinical risk scores for all outcomes. The ABC-AF-bleeding score 2.0 C-indices for major bleeding were 0.69 (95% CI, 0.68-0.71); gastrointestinal bleeding, 0.72 (95% CI, 0.69-0.74); and intracranial bleeding, 0.66 (95% CI, 0.63-0.70). The ABC-AF-bleeding score 2.0 also provided consistent superior discrimination in clinically relevant subgroups.
Conclusion
The updated ABC-AF-bleeding score 2.0 provided better discrimination and calibration for the risk of major bleeding than clinical risk scores, which was consistent across multiple subgroups. These findings support the utility of the ABC-AF-bleeding score for advancing precision medicine in AF.
背景：腹侧抗凝（OAC）可减少房颤（AF）患者的卒中，但会增加出血。本研究旨在评估AF患者年龄、生物标志物和出血的临床史(ABC-AF)-出血评分（2.0）的更新版本，包括OAC类型（直接口服抗凝剂[DOAC]或华法林），并将其与其他出血风险评分进行比较。方法：COMBINE房颤生物标志物队列包含了3项比较DOACs与华法林的关键随机试验中房颤患者的个体参与者数据。在基线样本中分析abc - af出血评分中的生物标志物（生长分化因子15、血红蛋白和肌钙蛋白- t）。通过将OAC类型（DOAC或华法林）纳入模型，更新了基于生物标志物的abc - af出血评分（2.0版）。采用Harrell c指数评估辨别性，并与临床出血评分进行比较；ha -出血（高血压、肾/肝功能异常、中风、出血史或易感、INR不稳定、老年人、药物/酒精）、DOAC和ORBIT（年龄较大、血红蛋白/红细胞压积降低或贫血史、出血史、肾功能不足、抗血小板药物治疗）。结果随访期间，1321例（5.1%）患者发生国际血栓与止血学会大出血事件，其中胃肠道出血480例，颅内出血248例。与原始版本相比，abc - af -出血2.0风险评分具有更好的辨别和校准能力，并且在所有结果上都比临床风险评分具有更好的辨别能力。abc - af -出血评分2.0 c -大出血指数为0.69 (95% CI, 0.68-0.71)；胃肠道出血，0.72 (95% CI, 0.69-0.74)；颅内出血，0.66 （95% CI, 0.63-0.70）。abc - af -出血评分2.0在临床相关亚组中也提供了一致的优势区分。结论更新后的abc - af -出血评分2.0比临床风险评分能更好地区分和校准大出血风险，且在多个亚组中是一致的。这些发现支持abc -AF出血评分在推进房颤精准医学方面的应用。
{"title":"Evaluation of the updated ABC-AF-bleeding score 2.0 in patients with atrial fibrillation treated with a direct oral anticoagulant or warfarin","authors":"Ziad Hijazi , Johan Lindbäck , Jonas Oldgren , John H. Alexander , Alexander P. Benz , David D. Berg , Anthony P. Carnicelli , John W. Eikelboom , Robert P. Giugliano , Shinya Goto , Christopher B. Granger , Renato D. Lopes , Christian T. Ruff , Agneta Siegbahn , David A. Morrow , Lars Wallentin","doi":"10.1016/j.jtha.2025.09.032","DOIUrl":"10.1016/j.jtha.2025.09.032","url":null,"abstract":"<div><h3>Background</h3><div>Oral anticoagulation (OAC) reduces stroke in patients with atrial fibrillation (AF), but increases bleeding.</div></div><div><h3>Objectives</h3><div>This study aimed to evaluate an updated version of the Age, Biomarkers, and Clinical history of bleeding in AF (ABC-AF)-bleeding score (2.0) including consideration of OAC type (direct oral anticoagulant [DOAC] or warfarin) and compare its performance with other bleeding risk scores in 25 962 patients from the COMBINE AF cohort.</div></div><div><h3>Methods</h3><div>The COMBINE AF biomarker cohort contains individual participant data from patients with AF enrolled in 3 pivotal randomized trials comparing DOACs with warfarin. The biomarkers in the ABC-AF-bleeding score (growth differentiation factor 15, hemoglobin, and troponin-T) were analyzed in baseline samples. The biomarker-based ABC-AF-bleeding score was updated (version 2.0) by incorporating OAC type into the model (DOAC or warfarin). Discrimination was assessed by Harrell C-index and compared with clinically based bleeding scores; HAS-BLED (Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly, Drugs/alcohol), DOAC, and ORBIT (Older age, Reduced haemoglobin/haematocrit or history of anaemia, Bleeding history, Insufficient renal function, Treatment with antiplatelet agents).</div></div><div><h3>Results</h3><div>During follow-up, 1321 patients (5.1%) had an International Society on Thrombosis and Haemostasis major bleeding event, including 480 gastrointestinal, and 248 intracranial hemorrhages. The ABC-AF-bleeding 2.0 risk score showed better discrimination and calibration than the original version and provided superior discrimination than clinical risk scores for all outcomes. The ABC-AF-bleeding score 2.0 C-indices for major bleeding were 0.69 (95% CI, 0.68-0.71); gastrointestinal bleeding, 0.72 (95% CI, 0.69-0.74); and intracranial bleeding, 0.66 (95% CI, 0.63-0.70). The ABC-AF-bleeding score 2.0 also provided consistent superior discrimination in clinically relevant subgroups.</div></div><div><h3>Conclusion</h3><div>The updated ABC-AF-bleeding score 2.0 provided better discrimination and calibration for the risk of major bleeding than clinical risk scores, which was consistent across multiple subgroups. These findings support the utility of the ABC-AF-bleeding score for advancing precision medicine in AF.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"24 2","pages":"Pages 399-407"},"PeriodicalIF":5.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146102578","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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