Pub Date : 2025-12-30eCollection Date: 2026-01-01DOI: 10.1016/j.rpth.2025.103324
Annie Borel-Derlon, Agnès Veyradier, Yohann Repessé, Nathalie Itzhar-Baïkan, Dominique Desprez, Fabienne Genre-Volot, Hervé Chambost, Laurent Ardillon, Brigitte Pan-Petesch, Sophie Bayart, Malika Barthez-Toullec, Grégory Marin, Marie Hélène André-Bonnet, Sophie Susen, Sylvia von Mackensen, Jenny Goudemand
Background: Hemorrhagic events in von Willebrand disease (VWD) impair patients' physical health, daily functioning, and psychological/emotional well-being. While few studies have assessed health-related quality of life (HRQoL) in VWD, no prospective evaluation had been conducted in France.
Objectives: The Willebrand study on HRQoL (WiSH-QoL) is an observational and prospective study that addressed this gap. Conducted in 27 French VWD treatment centers, it employed both generic and VWD-specific patient-reported outcome measures (PROs).
Methods: Eligible patients included all ages and VWD types (type 1 restricted to basal von Willebrand factor antigen < 30 IU/dL). PROs (SF-36, VWD-QoL, and VWD-SAT) were assessed at baseline and 24 months.
Results: In total, 224 adult patients were enrolled. Compared with the French general population, participants showed significantly reduced mental/emotional health and social/physical functioning. The VWD-specific PROs confirmed substantial physical impact in severe disease, including limitations in sports, leisure, and work. They also identified social impacts related to self-perception and relationships (family, others, and professionals). Physical and emotional well-being was particularly affected in women. Regardless of VWD type, patients reported mental health impacts, notably concerning future outlook. Social health deteriorated over time.
Conclusion: The Willebrand study on HRQoL, using disease-specific PROs, reveals the real-life physical, emotional, and social burden of VWD, notably in severe forms and among women. By selecting key questions from these tools, clinicians can better assess these impacts across all patients and provide more comprehensive, long-term support for their well-being.
{"title":"Health-related quality of life in adults with von Willebrand disease: results of the French real-life Willebrand study on health-related quality of life.","authors":"Annie Borel-Derlon, Agnès Veyradier, Yohann Repessé, Nathalie Itzhar-Baïkan, Dominique Desprez, Fabienne Genre-Volot, Hervé Chambost, Laurent Ardillon, Brigitte Pan-Petesch, Sophie Bayart, Malika Barthez-Toullec, Grégory Marin, Marie Hélène André-Bonnet, Sophie Susen, Sylvia von Mackensen, Jenny Goudemand","doi":"10.1016/j.rpth.2025.103324","DOIUrl":"https://doi.org/10.1016/j.rpth.2025.103324","url":null,"abstract":"<p><strong>Background: </strong>Hemorrhagic events in von Willebrand disease (VWD) impair patients' physical health, daily functioning, and psychological/emotional well-being. While few studies have assessed health-related quality of life (HRQoL) in VWD, no prospective evaluation had been conducted in France.</p><p><strong>Objectives: </strong>The Willebrand study on HRQoL (WiSH-QoL) is an observational and prospective study that addressed this gap. Conducted in 27 French VWD treatment centers, it employed both generic and VWD-specific patient-reported outcome measures (PROs).</p><p><strong>Methods: </strong>Eligible patients included all ages and VWD types (type 1 restricted to basal von Willebrand factor antigen < 30 IU/dL). PROs (SF-36, VWD-QoL, and VWD-SAT) were assessed at baseline and 24 months.</p><p><strong>Results: </strong>In total, 224 adult patients were enrolled. Compared with the French general population, participants showed significantly reduced mental/emotional health and social/physical functioning. The VWD-specific PROs confirmed substantial physical impact in severe disease, including limitations in sports, leisure, and work. They also identified social impacts related to self-perception and relationships (family, others, and professionals). Physical and emotional well-being was particularly affected in women. Regardless of VWD type, patients reported mental health impacts, notably concerning future outlook. Social health deteriorated over time.</p><p><strong>Conclusion: </strong>The Willebrand study on HRQoL, using disease-specific PROs, reveals the real-life physical, emotional, and social burden of VWD, notably in severe forms and among women. By selecting key questions from these tools, clinicians can better assess these impacts across all patients and provide more comprehensive, long-term support for their well-being.</p>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"10 1","pages":"103324"},"PeriodicalIF":3.4,"publicationDate":"2025-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12887095/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146166469","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Corrigendum to ‘Deep molecular modeling and mechanistic insights into type 2A von Willebrand disease with von Willebrand factor A2 domain mutations’","authors":"Omid Seidizadeh , Luca Mollica , Davide Giana , Luciano Baronciani , Paola Colpani , Lea Sicuro , Andrea Cairo , Flora Peyvandi","doi":"10.1016/j.rpth.2025.103300","DOIUrl":"10.1016/j.rpth.2025.103300","url":null,"abstract":"","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"10 1","pages":"Article 103300"},"PeriodicalIF":3.4,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145789239","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-16DOI: 10.1016/j.rpth.2025.103287
Hossam Elbenawi , Kirsten Lipps , Samuel Heller Jr. , David A. Liedl , Raymond C. Shields , Ana I. Casanegra , Stanislav Henkin , Thom W. Rooke , Paul W. Wennberg , Waldemar E. Wysokinski , Robert D. McBane , Damon E. Houghton
{"title":"Corrigendum to ‘Comparison of direct oral anticoagulants and vitamin K antagonists in the treatment of left ventricular thrombi: a retrospective cohort study","authors":"Hossam Elbenawi , Kirsten Lipps , Samuel Heller Jr. , David A. Liedl , Raymond C. Shields , Ana I. Casanegra , Stanislav Henkin , Thom W. Rooke , Paul W. Wennberg , Waldemar E. Wysokinski , Robert D. McBane , Damon E. Houghton","doi":"10.1016/j.rpth.2025.103287","DOIUrl":"10.1016/j.rpth.2025.103287","url":null,"abstract":"","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"10 1","pages":"Article 103287"},"PeriodicalIF":3.4,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145753859","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-09DOI: 10.1016/j.rpth.2025.103286
Suzanne Maynard , Alexander P. Bye , Michael J.R. Desborough
Antiplatelet drugs are used for treatment of arterial disease, but side effects include an increased risk of bleeding. For patients with intracerebral hemorrhage, traumatic brain injury, and lower gastrointestinal bleeding, mortality rates are higher for patients taking antiplatelet drugs. Reversing the effect of antiplatelet drugs may therefore reduce the risk of mortality and morbidity in these conditions. However, the benefits of any reversal agent must be balanced against the risk of thrombotic complications. Platelet transfusion is often used in clinical practice as a reversal agent, but the only randomized controlled trial in the setting of intracerebral hemorrhage showed an increased risk of death and disability with platelet transfusion compared with standard care. Tranexamic acid is used in a wide range of conditions to reduce bleeding. The risks and benefits of tranexamic acid appear similar in patients taking antiplatelet drugs compared with those not taking antiplatelet drugs. A feasibility trial of desmopressin to reverse the antiplatelet drug effect in intracerebral hemorrhage showed promising results, but definitive efficacy studies are needed. Lastly, unlike other antiplatelet drugs, ticagrelor binds reversibly to platelets. A reversal agent for ticagrelor, bentracimab, has been used in a single-arm clinical trial that demonstrated reversal of the antiplatelet drug effect and good hemostatic outcomes, although without a comparator arm to allow a full assessment of efficacy. This review highlights an unmet need for high-quality studies assessing the efficacy of reversal strategies for drug-induced platelet dysfunction using clinically relevant outcomes.
{"title":"Can drug-induced platelet dysfunction be reversed?","authors":"Suzanne Maynard , Alexander P. Bye , Michael J.R. Desborough","doi":"10.1016/j.rpth.2025.103286","DOIUrl":"10.1016/j.rpth.2025.103286","url":null,"abstract":"<div><div>Antiplatelet drugs are used for treatment of arterial disease, but side effects include an increased risk of bleeding. For patients with intracerebral hemorrhage, traumatic brain injury, and lower gastrointestinal bleeding, mortality rates are higher for patients taking antiplatelet drugs. Reversing the effect of antiplatelet drugs may therefore reduce the risk of mortality and morbidity in these conditions. However, the benefits of any reversal agent must be balanced against the risk of thrombotic complications. Platelet transfusion is often used in clinical practice as a reversal agent, but the only randomized controlled trial in the setting of intracerebral hemorrhage showed an increased risk of death and disability with platelet transfusion compared with standard care. Tranexamic acid is used in a wide range of conditions to reduce bleeding. The risks and benefits of tranexamic acid appear similar in patients taking antiplatelet drugs compared with those not taking antiplatelet drugs. A feasibility trial of desmopressin to reverse the antiplatelet drug effect in intracerebral hemorrhage showed promising results, but definitive efficacy studies are needed. Lastly, unlike other antiplatelet drugs, ticagrelor binds reversibly to platelets. A reversal agent for ticagrelor, bentracimab, has been used in a single-arm clinical trial that demonstrated reversal of the antiplatelet drug effect and good hemostatic outcomes, although without a comparator arm to allow a full assessment of efficacy. This review highlights an unmet need for high-quality studies assessing the efficacy of reversal strategies for drug-induced platelet dysfunction using clinically relevant outcomes.</div></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"10 1","pages":"Article 103286"},"PeriodicalIF":3.4,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145842090","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Von Willebrand disease (VWD) is the most common inherited bleeding disorder in the world. It is characterized by mucocutaneous bleeding, with heavy menstrual bleeding affecting the vast majority of girls and women with this condition. However, while bleeding episodes are the hallmark of VWD, there are marked psychological and socioeconomic ramifications of this chronic disorder, which may impact patients throughout their lifetimes, as well as additional medical issues, which may affect women with VWD preferentially. In this review, we discuss the evidence in support of nonbleeding complications of VWD and the key importance of providing a holistic approach to patient care.
{"title":"Von Willebrand disease: more than just a bleeding disorder","authors":"Dawn Swan , Michelle Sholzberg , Bethany Samuelson Bannow , Jecko Thachil","doi":"10.1016/j.rpth.2025.103276","DOIUrl":"10.1016/j.rpth.2025.103276","url":null,"abstract":"<div><div>Von Willebrand disease (VWD) is the most common inherited bleeding disorder in the world. It is characterized by mucocutaneous bleeding, with heavy menstrual bleeding affecting the vast majority of girls and women with this condition. However, while bleeding episodes are the hallmark of VWD, there are marked psychological and socioeconomic ramifications of this chronic disorder, which may impact patients throughout their lifetimes, as well as additional medical issues, which may affect women with VWD preferentially. In this review, we discuss the evidence in support of nonbleeding complications of VWD and the key importance of providing a holistic approach to patient care.</div></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"10 1","pages":"Article 103276"},"PeriodicalIF":3.4,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145841976","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Bleeding disorders such as hemophilia and von Willebrand disease (VWD) have historically been associated with significant morbidity due to hemarthrosis, surgical bleeding, and transfusion requirements. With advances in hemostatic therapy, surgical outcomes have improved; however, data on renal transplantation in this population remain limited.
Objectives
To assess clinical characteristics and adverse events in renal transplant patients with bleeding diathesis, focusing on primary endpoints: post-transplant bleeding, thrombotic events, and mortality. Secondary endpoints include readmissions, OR takebacks, and renal transplant rejections, including acute cellular rejection and antibody-mediated rejection.
Methods
A retrospective chart review of renal transplant patients with bleeding diathesis across Mayo Clinic.
Results
The cohort included 11 patients: hemophilia A (3/11) and VWD (8/11), with a mean Kidney Donor Profile Index of 37. Among patients with hemophilia A, 2 had congenital disease, and 1 had previously developed a factor VIII inhibitor that had resolved prior to transplantation. Among VWD patients, 6 had acquired VWD and 2 had type 1 VWD. No patients experienced arterial or venous thrombosis within 1 year. Beyond 1 year, 5 thrombotic events occurred in 4 patients (36.4%): 2 myocardial infarctions, 1 ischemic stroke, and 2 deep vein thromboses; no pulmonary emboli occurred. In the immediate postoperative period (days 0-30), 5 patients (45.5%) had bleeding events—4 major (80%) and 1 minor (20%). No bleeding occurred between days 30 and 365. After 1 year, 4 patients (36.4%) had nonallograft-related bleeding, primarily gastrointestinal. Readmission rates were 36.4% (0-30 days), 27.3% (30-90 days), and 9.1% (90-365 days). Surgical reintervention was required in 18.2% of patients. Rejection occurred in 3 patients (27.3%): 2 with acute cellular rejection, 1 with chronic cellular rejection, and 1 with antibody-mediated rejection. Overall mortality was 45%.
Conclusion
Kidney transplant recipients with hemophilia and VWD are at significant perioperative bleeding risk, particularly from perinephric hematomas and intraoperative hemorrhage. The risk decreases after 30 days, but long-term monitoring for both bleeding and thrombosis remains crucial. Rejection rates appear comparable with those of the general transplant population.
{"title":"Characteristics and posttransplant outcomes of patients with congenital and acquired von Willebrand disease and hemophilia A and with renal transplants","authors":"Isabela Wen-Chi Chang , Mia Truman , Claire Yee , Leslie Padrnos","doi":"10.1016/j.rpth.2025.103279","DOIUrl":"10.1016/j.rpth.2025.103279","url":null,"abstract":"<div><h3>Background</h3><div>Bleeding disorders such as hemophilia and von Willebrand disease (VWD) have historically been associated with significant morbidity due to hemarthrosis, surgical bleeding, and transfusion requirements. With advances in hemostatic therapy, surgical outcomes have improved; however, data on renal transplantation in this population remain limited.</div></div><div><h3>Objectives</h3><div>To assess clinical characteristics and adverse events in renal transplant patients with bleeding diathesis, focusing on primary endpoints: post-transplant bleeding, thrombotic events, and mortality. Secondary endpoints include readmissions, OR takebacks, and renal transplant rejections, including acute cellular rejection and antibody-mediated rejection.</div></div><div><h3>Methods</h3><div>A retrospective chart review of renal transplant patients with bleeding diathesis across Mayo Clinic.</div></div><div><h3>Results</h3><div>The cohort included 11 patients: hemophilia A (3/11) and VWD (8/11), with a mean Kidney Donor Profile Index of 37. Among patients with hemophilia A, 2 had congenital disease, and 1 had previously developed a factor VIII inhibitor that had resolved prior to transplantation. Among VWD patients, 6 had acquired VWD and 2 had type 1 VWD. No patients experienced arterial or venous thrombosis within 1 year. Beyond 1 year, 5 thrombotic events occurred in 4 patients (36.4%): 2 myocardial infarctions, 1 ischemic stroke, and 2 deep vein thromboses; no pulmonary emboli occurred. In the immediate postoperative period (days 0-30), 5 patients (45.5%) had bleeding events—4 major (80%) and 1 minor (20%). No bleeding occurred between days 30 and 365. After 1 year, 4 patients (36.4%) had nonallograft-related bleeding, primarily gastrointestinal. Readmission rates were 36.4% (0-30 days), 27.3% (30-90 days), and 9.1% (90-365 days). Surgical reintervention was required in 18.2% of patients. Rejection occurred in 3 patients (27.3%): 2 with acute cellular rejection, 1 with chronic cellular rejection, and 1 with antibody-mediated rejection. Overall mortality was 45%.</div></div><div><h3>Conclusion</h3><div>Kidney transplant recipients with hemophilia and VWD are at significant perioperative bleeding risk, particularly from perinephric hematomas and intraoperative hemorrhage. The risk decreases after 30 days, but long-term monitoring for both bleeding and thrombosis remains crucial. Rejection rates appear comparable with those of the general transplant population.</div></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"10 1","pages":"Article 103279"},"PeriodicalIF":3.4,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145789243","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-02DOI: 10.1016/j.rpth.2025.103280
Omotola O. Olasupo , Emma Iserman , Arun Keepanasseril , Quazi Ibrahim , Zainab Salim Ali Al-Housni , Federico Germini , Jean-Eric Tarride , Lawrence Mbuagbaw , Shannon Jackson , Ingrid Blydt-Hansen , Michelle Bech , Celina Woo , Mark Belletrutti , Alfonso Iorio , Davide Matino
Background
Comparative safety data on hemophilia therapies are scarce.
Objectives
To compare the risk of adverse drug reactions (ADRs) associated with extended-half-life (EHL) and standard-half-life (SHL) clotting factor therapies, bypassing agents, and emicizumab.
Methods and Analysis
We analyzed Canadian Bleeding Disorders Registry data from 2018 to 2022. ADRs were defined as adverse events (AEs) if definitely, possibly, or probably treatment-related. We compared incidence rates of ADRs between therapies to estimate incidence rate ratios and 95% CIs.
Results
We found a total of 183 AEs and 67 ADRs. Reported AEs varied from 6.1 to 14.8 events per 1000 patients per year. Allergic reactions were the most prevalent ADRs. A higher incidence of allergic reactions was associated with emicizumab compared with EHL (IRR 3.59; 95% CI, 1.43-9.00) and SHL (IRR 11.86; 95% CI, 4.73-29.72) clotting factor concentrates. Events reflecting inadequate hemostatic control and other unintended events occurred more often with emicizumab compared with SHL (IRR 6.39, 95% CI, 1.29-31.63) and EHL concentrates (IRR 2.77, 95% CI, 0.56-13.72). No inhibitor development was reported with emicizumab or bypassing agents. Cases of neurological events and thrombosis were reported when emicizumab was used in combination with other hemostatic therapies.
Conclusion
This study highlights the relative safety of therapies approved for the management of hemophilia A and B. While more ADRs were reported with emicizumab, no inhibitor development was observed. However, novelty bias cannot be ruled out. Our estimates are limited by the use of routinely collected data with no adjustment for confounding due to low event rates and missing data.
{"title":"Comparative safety of drug therapies used in hemophilia A and B in Canada: a multi-center, retrospective study","authors":"Omotola O. Olasupo , Emma Iserman , Arun Keepanasseril , Quazi Ibrahim , Zainab Salim Ali Al-Housni , Federico Germini , Jean-Eric Tarride , Lawrence Mbuagbaw , Shannon Jackson , Ingrid Blydt-Hansen , Michelle Bech , Celina Woo , Mark Belletrutti , Alfonso Iorio , Davide Matino","doi":"10.1016/j.rpth.2025.103280","DOIUrl":"10.1016/j.rpth.2025.103280","url":null,"abstract":"<div><h3>Background</h3><div>Comparative safety data on hemophilia therapies are scarce.</div></div><div><h3>Objectives</h3><div>To compare the risk of adverse drug reactions (ADRs) associated with extended-half-life (EHL) and standard-half-life (SHL) clotting factor therapies, bypassing agents, and emicizumab.</div></div><div><h3>Methods and Analysis</h3><div>We analyzed Canadian Bleeding Disorders Registry data from 2018 to 2022. ADRs were defined as adverse events (AEs) if definitely, possibly, or probably treatment-related. We compared incidence rates of ADRs between therapies to estimate incidence rate ratios and 95% CIs.</div></div><div><h3>Results</h3><div>We found a total of 183 AEs and 67 ADRs. Reported AEs varied from 6.1 to 14.8 events per 1000 patients per year. Allergic reactions were the most prevalent ADRs. A higher incidence of allergic reactions was associated with emicizumab compared with EHL (IRR 3.59; 95% CI, 1.43-9.00) and SHL (IRR 11.86; 95% CI, 4.73-29.72) clotting factor concentrates. Events reflecting inadequate hemostatic control and other unintended events occurred more often with emicizumab compared with SHL (IRR 6.39, 95% CI, 1.29-31.63) and EHL concentrates (IRR 2.77, 95% CI, 0.56-13.72). No inhibitor development was reported with emicizumab or bypassing agents. Cases of neurological events and thrombosis were reported when emicizumab was used in combination with other hemostatic therapies.</div></div><div><h3>Conclusion</h3><div>This study highlights the relative safety of therapies approved for the management of hemophilia A and B. While more ADRs were reported with emicizumab, no inhibitor development was observed. However, novelty bias cannot be ruled out. Our estimates are limited by the use of routinely collected data with no adjustment for confounding due to low event rates and missing data.</div></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"10 1","pages":"Article 103280"},"PeriodicalIF":3.4,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145841984","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-02DOI: 10.1016/j.rpth.2025.103274
Naoual Ouazzani Chahdi , Judith J. de Vries , Hande Eyisoylu , Hanke L. Matlung , Chi Hau , Rienk Nieuwland , Moniek P.M. de Maat , Joost C.M. Meijers , Robin van Bruggen
Background
Red blood cells (RBCs) are important constituents of venous clots and contribute to thrombus size and stability. However, it remains unclear whether and how RBCs affect the thrombus. Transglutaminase (TG)2), a protein with similar activity to factor XIIIa, may influence thrombus characteristics.
Objectives
We explored whether RBC-derived TG2 influences thrombus characteristics using a novel approach involving TG2 knockout (KO) RBCs.
Methods
Inhibitors and TG2 KO RBCs were used in clotting assays. In vitro–generated clots were analyzed using advanced microscopy techniques to quantify the fibrin network. Whole blood clotting kinetics were assessed by thrombin generation assay and thromboelastography. Vesiculation was assessed using microparticle flow cytometry.
Results
Our study showed clots formed with TG2 KO RBCs or upon TG2 inhibition displayed fewer and thinner fibrin fibers at the clot surface. Inhibition of TG2 further revealed a redistribution of fibrin away from the clot surface toward deeper regions. Functionally, TG2 inhibition accelerated thrombin generation and clot formation, as shown by shortened lag time in thrombin generation assay and faster kinetics in thromboelastography. A normal fibrin density was observed in clots treated with the TG2 inhibitor after addition of RBC-derived extracellular vesicles (EVs). Moreover, TG2 inhibition increased EV formation, associated with more phosphatidylserine exposure on RBC membranes.
Conclusion
TG2 activity within RBCs plays a specific role in modulating EV formation, which in turn influences the fibrin structure and spatial distribution within blood clots. Absence of TG2 activity leads to more EV formation, promoting faster thrombin generation and clot formation, suggesting a regulatory role for TG2 in coagulation kinetics.
{"title":"Red blood cell–derived transglutaminase 2 influences thrombus formation","authors":"Naoual Ouazzani Chahdi , Judith J. de Vries , Hande Eyisoylu , Hanke L. Matlung , Chi Hau , Rienk Nieuwland , Moniek P.M. de Maat , Joost C.M. Meijers , Robin van Bruggen","doi":"10.1016/j.rpth.2025.103274","DOIUrl":"10.1016/j.rpth.2025.103274","url":null,"abstract":"<div><h3>Background</h3><div>Red blood cells (RBCs) are important constituents of venous clots and contribute to thrombus size and stability. However, it remains unclear whether and how RBCs affect the thrombus. Transglutaminase (TG)2), a protein with similar activity to factor XIIIa, may influence thrombus characteristics.</div></div><div><h3>Objectives</h3><div>We explored whether RBC-derived TG2 influences thrombus characteristics using a novel approach involving TG2 knockout (KO) RBCs.</div></div><div><h3>Methods</h3><div>Inhibitors and TG2 KO RBCs were used in clotting assays. <em>In vitro</em>–generated clots were analyzed using advanced microscopy techniques to quantify the fibrin network. Whole blood clotting kinetics were assessed by thrombin generation assay and thromboelastography. Vesiculation was assessed using microparticle flow cytometry.</div></div><div><h3>Results</h3><div>Our study showed clots formed with TG2 KO RBCs or upon TG2 inhibition displayed fewer and thinner fibrin fibers at the clot surface. Inhibition of TG2 further revealed a redistribution of fibrin away from the clot surface toward deeper regions. Functionally, TG2 inhibition accelerated thrombin generation and clot formation, as shown by shortened lag time in thrombin generation assay and faster kinetics in thromboelastography. A normal fibrin density was observed in clots treated with the TG2 inhibitor after addition of RBC-derived extracellular vesicles (EVs). Moreover, TG2 inhibition increased EV formation, associated with more phosphatidylserine exposure on RBC membranes.</div></div><div><h3>Conclusion</h3><div>TG2 activity within RBCs plays a specific role in modulating EV formation, which in turn influences the fibrin structure and spatial distribution within blood clots. Absence of TG2 activity leads to more EV formation, promoting faster thrombin generation and clot formation, suggesting a regulatory role for TG2 in coagulation kinetics.</div></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"10 1","pages":"Article 103274"},"PeriodicalIF":3.4,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145789241","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-02DOI: 10.1016/j.rpth.2025.103275
Diaz M. Prameyllawati , Caroline M.A. Mussert , Martijn A.H. Oude Voshaar , Hester F. Lingsma , Marjon H. Cnossen , Michiel Coppens , Karina Meijer , Paul R. van der Valk , Frank W.G. Leebeek , Renske M.T. ten Ham
Background
The debate around the cost-effectiveness of gene therapy for hemophilia has largely centered on its price (€1-€3.5 million per individual). While previous studies have explored care organization for gene therapy delivery, none have evaluated the potential resource utilization and associated costs in a real-world setting.
Objectives
This study aimed to estimate the health care resources and costs of delivering gene therapy for hemophilia in clinical practice.
Methods
We conducted a bottom-up microcosting study and constructed a process map outlining each step of care. Data on resource use were obtained from clinical trial protocols and translated to reflect real-world clinical practice through semistructured interviews. Dutch unit costs were assigned to each resource, and mean total costs per individual were calculated for hemophilia A and B. Sensitivity analyses were performed to assess the potential range of consumed resources and costs.
Results
In clinical practice, delivering gene therapy for hemophilia is expected to require resources such as personnel time, hospital visits, laboratory tests, liver function assessments, drugs, hospital facilities, medical consumables, and office equipment. The estimated total cost for an eligible individual without liver function abnormalities, covering screening, pretreatment preparation, administration, and first-year follow-up, is €28,696 (€20,873-€48,973) for hemophilia A and €20,511 (€18,175-€36,310) for hemophilia B.
Conclusion
Delivery of hemophilia gene therapy requires significant resources, incurs substantial costs, and demands additional organizational infrastructure within treatment facilities. These findings may aid stakeholders to better plan implementation of these innovative therapies into clinical practice, as well as inform economic evaluations and reimbursement discussions.
{"title":"Health care resources and costs associated with delivering gene therapy for hemophilia in clinical practice","authors":"Diaz M. Prameyllawati , Caroline M.A. Mussert , Martijn A.H. Oude Voshaar , Hester F. Lingsma , Marjon H. Cnossen , Michiel Coppens , Karina Meijer , Paul R. van der Valk , Frank W.G. Leebeek , Renske M.T. ten Ham","doi":"10.1016/j.rpth.2025.103275","DOIUrl":"10.1016/j.rpth.2025.103275","url":null,"abstract":"<div><h3>Background</h3><div>The debate around the cost-effectiveness of gene therapy for hemophilia has largely centered on its price (€1-€3.5 million per individual). While previous studies have explored care organization for gene therapy delivery, none have evaluated the potential resource utilization and associated costs in a real-world setting.</div></div><div><h3>Objectives</h3><div>This study aimed to estimate the health care resources and costs of delivering gene therapy for hemophilia in clinical practice.</div></div><div><h3>Methods</h3><div>We conducted a bottom-up microcosting study and constructed a process map outlining each step of care. Data on resource use were obtained from clinical trial protocols and translated to reflect real-world clinical practice through semistructured interviews. Dutch unit costs were assigned to each resource, and mean total costs per individual were calculated for hemophilia A and B. Sensitivity analyses were performed to assess the potential range of consumed resources and costs.</div></div><div><h3>Results</h3><div>In clinical practice, delivering gene therapy for hemophilia is expected to require resources such as personnel time, hospital visits, laboratory tests, liver function assessments, drugs, hospital facilities, medical consumables, and office equipment. The estimated total cost for an eligible individual without liver function abnormalities, covering screening, pretreatment preparation, administration, and first-year follow-up, is €28,696 (€20,873-€48,973) for hemophilia A and €20,511 (€18,175-€36,310) for hemophilia B.</div></div><div><h3>Conclusion</h3><div>Delivery of hemophilia gene therapy requires significant resources, incurs substantial costs, and demands additional organizational infrastructure within treatment facilities. These findings may aid stakeholders to better plan implementation of these innovative therapies into clinical practice, as well as inform economic evaluations and reimbursement discussions.</div></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"10 1","pages":"Article 103275"},"PeriodicalIF":3.4,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145841975","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-02DOI: 10.1016/j.rpth.2025.103277
Lara Monica , Olga Oleshko , Lina Aires , Silvio Wuschko , Jonas Füner , Helmut Paul , Paul Schauerte , Ditte Starberg Jespersen , Larisa Belyanskaya , Andreas Tiede , Sonja Werwitzke
Background
Deficiency of coagulation factor (F)VIII is the key characteristic of hemophilia A. The FVIII knockout mouse model is a valuable tool for investigating disease mechanisms and evaluating the pharmacokinetics (PK) and efficacy of therapeutic agents. However, its utility for long-term studies, particularly those focused on prophylaxis, is limited by the development of anti-FVIII antibodies following repeated FVIII administration.
Objectives
To develop a FVIII knockout model that does not generate antibodies against FVIII but is not severely immunosuppressed.
Methods
Established FVIII single-knockout (FVIII-/-; SKO) mice were crossed with the immunoglobulin heavy chain μ (Ighm) knockout strain to generate FVIII/Ighm double-knockout (FVIII-/-/Ighm-/-; DKO) mice. Both SKO and DKO mice received 4 intravenous doses of recombinant human FVIII on days 0, 7, 14, and 21. Peripheral blood, bone marrow, and spleen samples were collected to assess (i) the immune response to FVIII, (ii) FVIII PK after repeated dosing, and (iii) overall immune status.
Results
DKO mice did not develop detectable anti-FVIII antibodies. The formation of FVIII-specific antibody-secreting cells was abrogated, and the presence of FVIII-specific T cells was substantially reduced. PK analysis performed after 3 weeks of FVIII exposure showed variable reductions in FVIII recovery and half-life in SKO mice. In contrast, PK parameters in DKO mice remained consistently within the expected physiological range.
Conclusion
The DKO mouse model can be used for long-term studies of FVIII products and other hemostatic proteins, enabling the evaluation of repeated-dose PK and prophylactic efficacy without interference from inhibitor formation.
{"title":"Characterization of a factor VIII/immunoglobulin heavy chain μ double-knockout mouse model of hemophilia A for long-term exposure to factor VIII proteins","authors":"Lara Monica , Olga Oleshko , Lina Aires , Silvio Wuschko , Jonas Füner , Helmut Paul , Paul Schauerte , Ditte Starberg Jespersen , Larisa Belyanskaya , Andreas Tiede , Sonja Werwitzke","doi":"10.1016/j.rpth.2025.103277","DOIUrl":"10.1016/j.rpth.2025.103277","url":null,"abstract":"<div><h3>Background</h3><div>Deficiency of coagulation factor (F)VIII is the key characteristic of hemophilia A. The FVIII knockout mouse model is a valuable tool for investigating disease mechanisms and evaluating the pharmacokinetics (PK) and efficacy of therapeutic agents. However, its utility for long-term studies, particularly those focused on prophylaxis, is limited by the development of anti-FVIII antibodies following repeated FVIII administration.</div></div><div><h3>Objectives</h3><div>To develop a FVIII knockout model that does not generate antibodies against FVIII but is not severely immunosuppressed.</div></div><div><h3>Methods</h3><div>Established FVIII single-knockout (FVIII<sup>-/-</sup>; SKO) mice were crossed with the immunoglobulin heavy chain μ (Ighm) knockout strain to generate FVIII/Ighm double-knockout (FVIII<sup>-/-</sup>/Ighm<sup>-/-</sup>; DKO) mice. Both SKO and DKO mice received 4 intravenous doses of recombinant human FVIII on days 0, 7, 14, and 21. Peripheral blood, bone marrow, and spleen samples were collected to assess (i) the immune response to FVIII, (ii) FVIII PK after repeated dosing, and (iii) overall immune status.</div></div><div><h3>Results</h3><div>DKO mice did not develop detectable anti-FVIII antibodies. The formation of FVIII-specific antibody-secreting cells was abrogated, and the presence of FVIII-specific T cells was substantially reduced. PK analysis performed after 3 weeks of FVIII exposure showed variable reductions in FVIII recovery and half-life in SKO mice. In contrast, PK parameters in DKO mice remained consistently within the expected physiological range.</div></div><div><h3>Conclusion</h3><div>The DKO mouse model can be used for long-term studies of FVIII products and other hemostatic proteins, enabling the evaluation of repeated-dose PK and prophylactic efficacy without interference from inhibitor formation.</div></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"10 1","pages":"Article 103277"},"PeriodicalIF":3.4,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145789242","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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