The prevalence of arthropathy in patients with moderate hemophilia A (mHA) is highly variable. People with mHA are often under-treated, and this may lead to joint damage and worsen quality of life. The aim of the present study was to evaluate joint status in mHA by means of point-of-care ultrasound (PoC-US) and clinical examination.
Methods
Consecutive mHA patients receiving on-demand replacement treatment underwent a clinical examination of joint status according to HJHS protocol. On the same day, all patients underwent a PoC-US assessment according to the HEAD-US protocol.
Results
A total of 51 subjects were included. The median HJHS score was 2.0(IQR:0-3.0). A 0-1 HJHS score was found in 23 mHA patients (45.1%), between 2 and 3 in 17 (33.3%) and >3 in 11 (21.6%). The median HEAD-US score was 2.0(IQR:1-7) and a statistically significant correlation between HJHS and HEAD-US was found (rho=0.732, p<0.001). Osteochondral damage was found in 21.6% patients, hypertrophic synovium (HS) was found in 29.4%. Among those reporting a 0-1 HJHS score, 13.0% showed HS. The analysis at joint level showed that the most commonly affected joint was the ankle, both for osteochondral damage and for the presence of hypertrophic synovium.
Conclusion
Our study suggests that the prevalence of arthropathy changes in patients with mHA receiving on-demand treatment is not negligible and that PoC-US is able to detect osteochondral damage as well as HS in this clinical setting. A more extensive screening of the joint status could be useful to tailor treatment and improve outcome in mHA.
{"title":"Joint health status in patients with moderate hemophilia A: a cross-sectional multi-center study","authors":"Ilenia Calcaterra , Federico Picasso , Federica Valeri , Erminia Baldacci , Mariasanta Napolitano , Cornelia Guerrino , Ezio Zanon , Cristina Santoro , Sergio Siragusa , Carlo Martinoli , Matteo Nicola Dario Di Minno","doi":"10.1016/j.rpth.2025.102737","DOIUrl":"10.1016/j.rpth.2025.102737","url":null,"abstract":"<div><h3>Background</h3><div>The prevalence of arthropathy in patients with moderate hemophilia A (mHA) is highly variable. People with mHA are often under-treated, and this may lead to joint damage and worsen quality of life. The aim of the present study was to evaluate joint status in mHA by means of point-of-care ultrasound (PoC-US) and clinical examination.</div></div><div><h3>Methods</h3><div>Consecutive mHA patients receiving on-demand replacement treatment underwent a clinical examination of joint status according to HJHS protocol. On the same day, all patients underwent a PoC-US assessment according to the HEAD-US protocol.</div></div><div><h3>Results</h3><div>A total of 51 subjects were included. The median HJHS score was 2.0(IQR:0-3.0). A 0-1 HJHS score was found in 23 mHA patients (45.1%), between 2 and 3 in 17 (33.3%) and >3 in 11 (21.6%). The median HEAD-US score was 2.0(IQR:1-7) and a statistically significant correlation between HJHS and HEAD-US was found (rho=0.732, p<0.001). Osteochondral damage was found in 21.6% patients, hypertrophic synovium (HS) was found in 29.4%. Among those reporting a 0-1 HJHS score, 13.0% showed HS. The analysis at joint level showed that the most commonly affected joint was the ankle, both for osteochondral damage and for the presence of hypertrophic synovium.</div></div><div><h3>Conclusion</h3><div>Our study suggests that the prevalence of arthropathy changes in patients with mHA receiving on-demand treatment is not negligible and that PoC-US is able to detect osteochondral damage as well as HS in this clinical setting. A more extensive screening of the joint status could be useful to tailor treatment and improve outcome in mHA.</div></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"9 2","pages":"Article 102737"},"PeriodicalIF":3.4,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143777615","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}
Pub Date : 2025-03-12DOI: 10.1016/j.rpth.2025.102730
Radha Ramanan , Christine Van Laer , Sarissa Baert , Cyrielle Kint , Chris Van Geet , Quentin Van Thillo , Peter Verhamme , Thomas Vanassche , James D. McFadyen , Andrew C. Perkins , Huyen A. Tran , Veerle Labarque , Kathleen Freson
Introduction
Von Willebrand disease (VWD) is the most prevalent inherited bleeding disorder with a wide spectrum of causative variants. Next-generation sequencing (NGS) analyses the entire VWF gene and provides concomitant assessment of other genes allowing differentiation between genocopies.
Methods
We conducted a single-centre retrospective study of all patients with confirmed or suspected VWD who were screened with panel-based whole-exome sequencing (WES) for inherited bleeding disorders. Pre-sequencing diagnosis was performed using laboratory measures of VWF activity and quantity. Post-sequencing diagnosis was informed by variant curation in combination with laboratory measures. We measured clinically meaningful changes in the pre- vs post-genetic sequencing diagnosis and subtyping.
Results
The study included 108 patients. The population was predominantly composed of paediatric patients < 18 years old (77/108, 71%) and females (66/108, 61%). The largest pre-sequencing subgroup was those with low VWF (n=61, 56%), followed by type 1 VWD (n=21, 19%) and type 2 not otherwise specified (NOS) (n=18, 17%). A clinically meaningful change in management occurred in 19% (20/108) of the study population. The largest effect was seen in the pre-sequencing type 2 group (67%, 16/24). In the type 2 group who could not be accurately subtyped into 2A/B/M/N prior to sequencing (type 2 NOS), 15/18 (83%) were able to be subtyped or given a different diagnosis post sequencing.
Conclusion
Panel-based sequencing for VWD in a well-selected cohort, particularly those with type 2 and type 3 VWD, was clinically relevant in differentiating genocopies, directing therapies and family planning. Sequencing in those with low VWF and type 1 VWD rarely changed management.
{"title":"Clinical utility of panel-based genetic sequencing for von Willebrand disease","authors":"Radha Ramanan , Christine Van Laer , Sarissa Baert , Cyrielle Kint , Chris Van Geet , Quentin Van Thillo , Peter Verhamme , Thomas Vanassche , James D. McFadyen , Andrew C. Perkins , Huyen A. Tran , Veerle Labarque , Kathleen Freson","doi":"10.1016/j.rpth.2025.102730","DOIUrl":"10.1016/j.rpth.2025.102730","url":null,"abstract":"<div><h3>Introduction</h3><div>Von Willebrand disease (VWD) is the most prevalent inherited bleeding disorder with a wide spectrum of causative variants. Next-generation sequencing (NGS) analyses the entire <em>VWF</em> gene and provides concomitant assessment of other genes allowing differentiation between genocopies.</div></div><div><h3>Methods</h3><div>We conducted a single-centre retrospective study of all patients with confirmed or suspected VWD who were screened with panel-based whole-exome sequencing (WES) for inherited bleeding disorders. Pre-sequencing diagnosis was performed using laboratory measures of VWF activity and quantity. Post-sequencing diagnosis was informed by variant curation in combination with laboratory measures. We measured clinically meaningful changes in the pre- vs post-genetic sequencing diagnosis and subtyping.</div></div><div><h3>Results</h3><div>The study included 108 patients. The population was predominantly composed of paediatric patients < 18 years old (77/108, 71%) and females (66/108, 61%). The largest pre-sequencing subgroup was those with low VWF (n=61, 56%), followed by type 1 VWD (n=21, 19%) and type 2 not otherwise specified (NOS) (n=18, 17%). A clinically meaningful change in management occurred in 19% (20/108) of the study population. The largest effect was seen in the pre-sequencing type 2 group (67%, 16/24). In the type 2 group who could not be accurately subtyped into 2A/B/M/N prior to sequencing (type 2 NOS), 15/18 (83%) were able to be subtyped or given a different diagnosis post sequencing.</div></div><div><h3>Conclusion</h3><div>Panel-based sequencing for VWD in a well-selected cohort, particularly those with type 2 and type 3 VWD, was clinically relevant in differentiating genocopies, directing therapies and family planning. Sequencing in those with low VWF and type 1 VWD rarely changed management.</div></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"9 2","pages":"Article 102730"},"PeriodicalIF":3.4,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143777603","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}
Pub Date : 2025-02-01DOI: 10.1016/j.rpth.2025.102706
Chao He , Aizhen Yang , Keyu Lv , Yuxin Zhang , Zhenzhen Zhao , Yi Lu , Chao Fang , Yue Han , Depei Wu , Miao Jiang , Jingyu Zhang , Yi Wu
Background
Thiol isomerases regulate the thiol-disulfide exchange of functional proteins in cells. Using genetically modified mouse models and inhibitors, we and others demonstrated that 7 thiol isomerases (ERp57, protein diisulfide isomerase, ERp72, ERp46, ERp5, TMX4, and TMX1) participate in thrombosis. There are 21 thiol isomerases in mammals, but whether other enzymes of this family also contribute to thrombosis remains unknown.
Objectives
Investigate whether and how ERp18 participates in arterial thrombosis.
Methods
ERp18 knockout mice and arterial thrombosis models were used to determine the role of ERp18 in thrombosis. Platelets from ERp18 knockout mice were used to detect aggregation, activation, spreading, and clot retraction. Finally, flow cytometry and immunoprecipitation were used to detect the binding between ERp18 and αIIbβ3.
Results
The mice lacking ERp18 exhibited a prolonged tail bleeding time and decreased platelet thrombus formation in FeCl3-induced carotid arterial injury and laser-induced cremaster artery injury models. ERp18 deficiency inhibited platelet aggregation, adenosine triphosphate release, integrin αIIbβ3 activation, P-selectin expression, platelet adhesion, as well as clot retraction. Flow cytometry and coimmunoprecipitation analyses revealed that ERp18 binds to the platelet surface via interaction with integrin αIIbβ3. Moreover, the ERp18 protein promoted the binding of integrin αIIbβ3 to fibrinogen and platelet aggregation. Furthermore, the recombinant ERp18 protein exhibited reductase activity and cleaved integrin αIIbβ3 disulfides.
Conclusion
ERp18 participates in platelet activation and thrombosis. Its function is, at least in part, through the regulation of integrin αIIbβ3 function. This finding expands our understanding of the role of thiol isomerases in the redox regulation of thrombosis and platelet function.
{"title":"Thiol isomerase ERp18 enhances platelet activation and arterial thrombosis","authors":"Chao He , Aizhen Yang , Keyu Lv , Yuxin Zhang , Zhenzhen Zhao , Yi Lu , Chao Fang , Yue Han , Depei Wu , Miao Jiang , Jingyu Zhang , Yi Wu","doi":"10.1016/j.rpth.2025.102706","DOIUrl":"10.1016/j.rpth.2025.102706","url":null,"abstract":"<div><h3>Background</h3><div>Thiol isomerases regulate the thiol-disulfide exchange of functional proteins in cells. Using genetically modified mouse models and inhibitors, we and others demonstrated that 7 thiol isomerases (ERp57, protein diisulfide isomerase, ERp72, ERp46, ERp5, TMX4, and TMX1) participate in thrombosis. There are 21 thiol isomerases in mammals, but whether other enzymes of this family also contribute to thrombosis remains unknown.</div></div><div><h3>Objectives</h3><div>Investigate whether and how ERp18 participates in arterial thrombosis.</div></div><div><h3>Methods</h3><div>ERp18 knockout mice and arterial thrombosis models were used to determine the role of ERp18 in thrombosis. Platelets from ERp18 knockout mice were used to detect aggregation, activation, spreading, and clot retraction. Finally, flow cytometry and immunoprecipitation were used to detect the binding between ERp18 and α<sub>IIb</sub>β<sub>3</sub>.</div></div><div><h3>Results</h3><div>The mice lacking ERp18 exhibited a prolonged tail bleeding time and decreased platelet thrombus formation in FeCl<sub>3</sub>-induced carotid arterial injury and laser-induced cremaster artery injury models. ERp18 deficiency inhibited platelet aggregation, adenosine triphosphate release, integrin α<sub>IIb</sub>β<sub>3</sub> activation, P-selectin expression, platelet adhesion, as well as clot retraction. Flow cytometry and coimmunoprecipitation analyses revealed that ERp18 binds to the platelet surface via interaction with integrin α<sub>IIb</sub>β<sub>3</sub>. Moreover, the ERp18 protein promoted the binding of integrin α<sub>IIb</sub>β<sub>3</sub> to fibrinogen and platelet aggregation. Furthermore, the recombinant ERp18 protein exhibited reductase activity and cleaved integrin α<sub>IIb</sub>β<sub>3</sub> disulfides.</div></div><div><h3>Conclusion</h3><div>ERp18 participates in platelet activation and thrombosis. Its function is, at least in part, through the regulation of integrin α<sub>IIb</sub>β<sub>3</sub> function. This finding expands our understanding of the role of thiol isomerases in the redox regulation of thrombosis and platelet function.</div></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"9 2","pages":"Article 102706"},"PeriodicalIF":3.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143683442","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}
Pub Date : 2025-02-01DOI: 10.1016/j.rpth.2025.102710
Craig M. Kessler , Leonard A. Valentino , Courtney D. Thornburg , Carmen Unzu , Mark A. Kay , Flora Peyvandi , Penni Smith , Wolfgang Miesbach , William McKeown , Glenn F. Pierce , Kate Khair , Katarina Starcevic , Monisha Pillai , Micheala Jones , Anil Sindhurakar , Lauren Whyte , Virginie Delwart , Megan Chiao , David E. Gutstein , Ilia Antonino , Steven W. Pipe
Background
Clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 (Cas9)-based targeted gene editing platforms are being developed to treat genetic diseases like hemophilia. Such novel therapy involves complex concepts and terminology that require aligned language to engage key stakeholders in the hemophilia community. Thus, a globally aligned gene editing lexicon – a consistent language to communicate the fundamentals of gene editing in hemophilia, designed to be credible and accessible for people with hemophilia and caregivers while avoiding unnecessary complexity – is required to address this need.
Objectives
To establish an aligned language and communications framework that facilitates informed consent and shared decision-making regarding gene editing and treatment considerations in hemophilia.
Methods
Through an innovative partnership with global experts in hemophilia, gene editing, and biotechnology, initial insights were gathered via interviews, workshops, and analysis of existing language within the hemophilia community. Qualitative research involving lived experience experts (people with hemophilia and caregivers; n = 43) and hematologists (n = 24) informed the lexicon development, which was further validated by a steering committee of global experts in the hemophilia and gene editing fields. Finally, optimized language recommendations were developed for a clear, consistent gene editing lexicon.
Results
Key themes included insights into audience mindsets, guiding language principles, and optimized terminology for key topics like gene editing concepts and posttreatment considerations. Audience mindsets revealed cautious optimism around gene therapy, with more skepticism around gene editing. Guiding language principles indicated a preference for plainspoken over technical language, definitions that link to patient benefits, and explanations that highlight the precise nature of gene editing.
Conclusion
This collaborative approach ensures broad adoption of the lexicon within the hemophilia community and readiness for beta testing.
{"title":"Development of a novel gene editing lexicon for hemophilia: methodology and results","authors":"Craig M. Kessler , Leonard A. Valentino , Courtney D. Thornburg , Carmen Unzu , Mark A. Kay , Flora Peyvandi , Penni Smith , Wolfgang Miesbach , William McKeown , Glenn F. Pierce , Kate Khair , Katarina Starcevic , Monisha Pillai , Micheala Jones , Anil Sindhurakar , Lauren Whyte , Virginie Delwart , Megan Chiao , David E. Gutstein , Ilia Antonino , Steven W. Pipe","doi":"10.1016/j.rpth.2025.102710","DOIUrl":"10.1016/j.rpth.2025.102710","url":null,"abstract":"<div><h3>Background</h3><div>Clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 (Cas9)-based targeted gene editing platforms are being developed to treat genetic diseases like hemophilia. Such novel therapy involves complex concepts and terminology that require aligned language to engage key stakeholders in the hemophilia community. Thus, a globally aligned gene editing lexicon – a consistent language to communicate the fundamentals of gene editing in hemophilia, designed to be credible and accessible for people with hemophilia and caregivers while avoiding unnecessary complexity – is required to address this need.</div></div><div><h3>Objectives</h3><div>To establish an aligned language and communications framework that facilitates informed consent and shared decision-making regarding gene editing and treatment considerations in hemophilia.</div></div><div><h3>Methods</h3><div>Through an innovative partnership with global experts in hemophilia, gene editing, and biotechnology, initial insights were gathered via interviews, workshops, and analysis of existing language within the hemophilia community. Qualitative research involving lived experience experts (people with hemophilia and caregivers; <em>n</em> = 43) and hematologists (<em>n</em> = 24) informed the lexicon development, which was further validated by a steering committee of global experts in the hemophilia and gene editing fields. Finally, optimized language recommendations were developed for a clear, consistent gene editing lexicon.</div></div><div><h3>Results</h3><div>Key themes included insights into audience mindsets, guiding language principles, and optimized terminology for key topics like gene editing concepts and posttreatment considerations. Audience mindsets revealed cautious optimism around gene therapy, with more skepticism around gene editing. Guiding language principles indicated a preference for plainspoken over technical language, definitions that link to patient benefits, and explanations that highlight the precise nature of gene editing.</div></div><div><h3>Conclusion</h3><div>This collaborative approach ensures broad adoption of the lexicon within the hemophilia community and readiness for beta testing.</div></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"9 2","pages":"Article 102710"},"PeriodicalIF":3.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143747392","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}
Pub Date : 2025-02-01DOI: 10.1016/j.rpth.2025.102714
Stacey A. Fedewa , Leonard A. Valentino , Andee Koo , Lorraine Cafuir , Theresa W. Gillespie , Tyler W. Buckner , Duc Q. Tran , Ana Antun , Christine L. Kempton
Background
Drug trials are vital to establish safe and effective treatments for congenital hemophilia, a bleeding disorder that affects about 800,000 males worldwide. The global distribution of hemophilia drug trials (HDTs) and their alignment with hemophilia care is unknown.
Objectives
This study aimed to evaluate the global distribution of HDTs and its association with hemophilia care.
Methods
In this cross-sectional study, HDTs conducted between 2007 and 2022 were selected from the clinicaltrials.gov database. The density of trials per 1000 expected males with hemophilia (eMwH) was assessed according to hemophilia care measures (factor VIII and IX utilization per 1000 eMwH) derived from World Federation of Hemophilia data.
Results
Among 124 trials, 55 countries were represented, with an average of 7.9 countries per trial. Most HDT sites were in high-income (74.4%) or upper middle (20.1%)–income countries. The number of sites in lower-middle–income countries doubled, from 12 in 2007-2011 to 30 in 2017-2022—a nonsignificant increase from 5.8% to 7.0% (P = .53). Factor utilization was substantially reduced in lower-middle (0.4 international units [IUs] per 1000 eMwH) and upper middle (2.8 IUs per 1000 eMwH) compared with high (6.8 IUs per 1000 eMwH) income countries. HDT density was moderately correlated with factor usage (r = 0.436; P ≤ .001).
Conclusion
Most HDT sites were located in high-income countries, although a substantial proportion were in upper middle–income countries. A small but increasing number of trials were conducted in lower-middle–income countries, where factor usage is relatively low. This study provides evidence on the global distribution of HDT and raises questions regarding the generalizability, barriers, opportunities, and ethics of trials for a rare bleeding disorder.
{"title":"Global patterns of hemophilia drug trials, hemophilia care, and health care measures","authors":"Stacey A. Fedewa , Leonard A. Valentino , Andee Koo , Lorraine Cafuir , Theresa W. Gillespie , Tyler W. Buckner , Duc Q. Tran , Ana Antun , Christine L. Kempton","doi":"10.1016/j.rpth.2025.102714","DOIUrl":"10.1016/j.rpth.2025.102714","url":null,"abstract":"<div><h3>Background</h3><div>Drug trials are vital to establish safe and effective treatments for congenital hemophilia, a bleeding disorder that affects about 800,000 males worldwide. The global distribution of hemophilia drug trials (HDTs) and their alignment with hemophilia care is unknown.</div></div><div><h3>Objectives</h3><div>This study aimed to evaluate the global distribution of HDTs and its association with hemophilia care.</div></div><div><h3>Methods</h3><div>In this cross-sectional study, HDTs conducted between 2007 and 2022 were selected from the <span><span>clinicaltrials.gov</span><svg><path></path></svg></span> database. The density of trials per 1000 expected males with hemophilia (eMwH) was assessed according to hemophilia care measures (factor VIII and IX utilization per 1000 eMwH) derived from World Federation of Hemophilia data.</div></div><div><h3>Results</h3><div>Among 124 trials, 55 countries were represented, with an average of 7.9 countries per trial. Most HDT sites were in high-income (74.4%) or upper middle (20.1%)–income countries. The number of sites in lower-middle–income countries doubled, from 12 in 2007-2011 to 30 in 2017-2022—a nonsignificant increase from 5.8% to 7.0% (<em>P</em> = .53). Factor utilization was substantially reduced in lower-middle (0.4 international units [IUs] per 1000 eMwH) and upper middle (2.8 IUs per 1000 eMwH) compared with high (6.8 IUs per 1000 eMwH) income countries. HDT density was moderately correlated with factor usage (<em>r</em> = 0.436; <em>P</em> ≤ .001).</div></div><div><h3>Conclusion</h3><div>Most HDT sites were located in high-income countries, although a substantial proportion were in upper middle–income countries. A small but increasing number of trials were conducted in lower-middle–income countries, where factor usage is relatively low. This study provides evidence on the global distribution of HDT and raises questions regarding the generalizability, barriers, opportunities, and ethics of trials for a rare bleeding disorder.</div></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"9 2","pages":"Article 102714"},"PeriodicalIF":3.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143705392","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}
Pub Date : 2025-02-01DOI: 10.1016/j.rpth.2025.102731
Si Li , Minghui Jiang , Yunlong Guan , Xi Cao , Zhonghe Shao , Jun Deng , Xingjie Hao
Background
The relationship between diet and venous thromboembolism (VTE) remains unclear, and the joint effects of diet patterns and genetic susceptibility on VTE risk are unknown.
Objectives
Investigate the independent and joint effects of Dietary Approaches to Stop Hypertension (DASH) diet adherence and polygenic risk scores (PRS) on VTE risk.
Methods
A total of 411,539 UK Biobank participants were included. DASH scores were calculated using Food Frequency Questionnaires, and PRS quantified genetic risk. Cox proportional hazard models estimated hazard ratios (HRs) for VTE, assessing interactions between the DASH diet and genetic susceptibility.
Results
During a median follow-up of 13.4 years, 10,543 participants were diagnosed with VTE. Higher DASH scores were associated with a lower VTE risk (HR, 0.87; 95% CI, 0.82-0.92). A low-adherent DASH diet combined with high-genetic risk had the highest VTE risk (HR, 2.78; 95% CI, 2.47-3.14). High DASH scores reduced VTE risk in high-genetic-risk individuals (HR, 0.84; 95% CI, 0.76-0.92). Sex-specific associations were detected in the joint effect and interaction of DASH scores and PRS. Notably, high DASH scores can offset moderate genetic risk among men (HR, 0.79; 95% CI, 0.67-0.94). There were additive interactions between DASH scores and high genetic risk in total subjects and men, while not observed in women.
Conclusion
The DASH diet is associated with reduced VTE risk and can partially offset genetic predisposition. Low adherence to the DASH diet increases VTE risk, particularly in high-genetic-risk individuals. The protective effect of high DASH scores against genetic risks for VTE is more pronounced in males. Precision medicine should consider both diet and genetics for VTE prevention.
{"title":"Association between genetic risk and adherence to the Dietary Approaches to Stop Hypertension diet for developing venous thromboembolism","authors":"Si Li , Minghui Jiang , Yunlong Guan , Xi Cao , Zhonghe Shao , Jun Deng , Xingjie Hao","doi":"10.1016/j.rpth.2025.102731","DOIUrl":"10.1016/j.rpth.2025.102731","url":null,"abstract":"<div><h3>Background</h3><div>The relationship between diet and venous thromboembolism (VTE) remains unclear, and the joint effects of diet patterns and genetic susceptibility on VTE risk are unknown.</div></div><div><h3>Objectives</h3><div>Investigate the independent and joint effects of Dietary Approaches to Stop Hypertension (DASH) diet adherence and polygenic risk scores (PRS) on VTE risk.</div></div><div><h3>Methods</h3><div>A total of 411,539 UK Biobank participants were included. DASH scores were calculated using Food Frequency Questionnaires, and PRS quantified genetic risk. Cox proportional hazard models estimated hazard ratios (HRs) for VTE, assessing interactions between the DASH diet and genetic susceptibility.</div></div><div><h3>Results</h3><div>During a median follow-up of 13.4 years, 10,543 participants were diagnosed with VTE. Higher DASH scores were associated with a lower VTE risk (HR, 0.87; 95% CI, 0.82-0.92). A low-adherent DASH diet combined with high-genetic risk had the highest VTE risk (HR, 2.78; 95% CI, 2.47-3.14). High DASH scores reduced VTE risk in high-genetic-risk individuals (HR, 0.84; 95% CI, 0.76-0.92). Sex-specific associations were detected in the joint effect and interaction of DASH scores and PRS. Notably, high DASH scores can offset moderate genetic risk among men (HR, 0.79; 95% CI, 0.67-0.94). There were additive interactions between DASH scores and high genetic risk in total subjects and men, while not observed in women.</div></div><div><h3>Conclusion</h3><div>The DASH diet is associated with reduced VTE risk and can partially offset genetic predisposition. Low adherence to the DASH diet increases VTE risk, particularly in high-genetic-risk individuals. The protective effect of high DASH scores against genetic risks for VTE is more pronounced in males. Precision medicine should consider both diet and genetics for VTE prevention.</div></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"9 2","pages":"Article 102731"},"PeriodicalIF":3.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143759589","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}
Pub Date : 2025-02-01DOI: 10.1016/j.rpth.2025.102702
Lingling Fu , Xi Lin , Zhenping Chen , Zhifa Wang , Yan Liu , Lijuan Wang , Yu Hu , Jingyao Ma , Nan Wang , Xiaoling Cheng , Jie Ma , Runhui Wu
Background
The first second-line international recommendation for children with severe persistent/chronic immune thrombocytopenia is thrombopoietin receptor agonist (TPO-RA)-based treatment; however, <30% can achieve sustained response off-treatment (SRoT), leading to a heavy medical burden.
Objectives
This study aimed to confirm the efficacy of the stepwise response-guided treatment protocol compared with TPO-RA–based second-line therapy for children with severe P/CITP.
Methods
The stepwise response-guided treatment protocol is an individualized stratified immune thrombocytopenia treatment starting with high-dose dexamethasone, then adding rituximab and TPO-RAs in sequential order according to treatment response. A prospective, multicenter clinical cohort study enrolled severe P/CITP children with a 1-year follow-up. We compared the treatment outcome response of platelet count, bleeding control, and treatment-related side effects and cost outcomes (escalation status, SRoT, and treatment costs) between the stepwise group and the TPO-RA–based second-line treatment group (TPO-RA group).
Results
The study enrolled 143 cases of severe P/CITP children with a 12-month follow-up period. There were no differences in baseline characteristics between the stepwise and TPO-RA groups (P > .05). Response/remission rates and bleeding grades showed no differences (P > .05), but there were fewer side effects related to treatment in the stepwise group (9.0%; P < .00). A total of 74% in the stepwise group achieved SRoT while none in the TPO-RA group did. The cost of treatment was significantly lower in the stepwise group compared with the TPO-RA group over the 12-month follow-up period (USD 68.26/kg vs USD 384.76/kg, P < .00).
Conclusion
The stepwise response-guided treatment protocol effectively stratifies children with severe P/CITP based on treatment response, enabling individualized treatment strategies. This protocol achieves comparable efficacy and safety while reducing the treatment burden compared with TPO-RA–based second-line therapy, making it a preferable option for children with severe P/CITP.
{"title":"Stepwise response-guided treatment protocol superior to thrombopoietin receptor agonist-based second-line therapy for severe persistent/chronic immune thrombocytopenia: a multicenter prospective study from China","authors":"Lingling Fu , Xi Lin , Zhenping Chen , Zhifa Wang , Yan Liu , Lijuan Wang , Yu Hu , Jingyao Ma , Nan Wang , Xiaoling Cheng , Jie Ma , Runhui Wu","doi":"10.1016/j.rpth.2025.102702","DOIUrl":"10.1016/j.rpth.2025.102702","url":null,"abstract":"<div><h3>Background</h3><div>The first second-line international recommendation for children with severe persistent/chronic immune thrombocytopenia is thrombopoietin receptor agonist (TPO-RA)-based treatment; however, <30% can achieve sustained response off-treatment (SRoT), leading to a heavy medical burden.</div></div><div><h3>Objectives</h3><div>This study aimed to confirm the efficacy of the stepwise response-guided treatment protocol compared with TPO-RA–based second-line therapy for children with severe P/CITP.</div></div><div><h3>Methods</h3><div>The stepwise response-guided treatment protocol is an individualized stratified immune thrombocytopenia treatment starting with high-dose dexamethasone, then adding rituximab and TPO-RAs in sequential order according to treatment response. A prospective, multicenter clinical cohort study enrolled severe P/CITP children with a 1-year follow-up. We compared the treatment outcome response of platelet count, bleeding control, and treatment-related side effects and cost outcomes (escalation status, SRoT, and treatment costs) between the stepwise group and the TPO-RA–based second-line treatment group (TPO-RA group).</div></div><div><h3>Results</h3><div>The study enrolled 143 cases of severe P/CITP children with a 12-month follow-up period. There were no differences in baseline characteristics between the stepwise and TPO-RA groups (<em>P</em> > .05). Response/remission rates and bleeding grades showed no differences (<em>P</em> > .05), but there were fewer side effects related to treatment in the stepwise group (9.0%; <em>P</em> < .00). A total of 74% in the stepwise group achieved SRoT while none in the TPO-RA group did. The cost of treatment was significantly lower in the stepwise group compared with the TPO-RA group over the 12-month follow-up period (USD 68.26/kg vs USD 384.76/kg, <em>P</em> < .00).</div></div><div><h3>Conclusion</h3><div>The stepwise response-guided treatment protocol effectively stratifies children with severe P/CITP based on treatment response, enabling individualized treatment strategies. This protocol achieves comparable efficacy and safety while reducing the treatment burden compared with TPO-RA–based second-line therapy, making it a preferable option for children with severe P/CITP.</div></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"9 2","pages":"Article 102702"},"PeriodicalIF":3.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143610240","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}
Pub Date : 2025-02-01DOI: 10.1016/j.rpth.2025.102704
David Mutschlechner , Maximilian Tscharre , Patricia Pia Wadowski , Silvia Lee , Joseph Pultar , Constantin Weikert , Simon Panzer , Thomas Gremmel
Background
Aging has recently been associated with increased basal platelet activation and platelet hyperreactivity in response to adenosine diphosphate (ADP) but with decreased platelet response to thrombin receptor stimulation in individuals without antiplatelet therapy.
Objectives
To investigate platelet response to agonist stimulation in elderly patients (≥70 years) on dual antiplatelet therapy with potent P2Y12 inhibitors.
Methods
Platelet aggregation in response to arachidonic acid (AA), ADP, collagen, the protease-activated receptor-1 agonist SFLLRN, and the protease-activated receptor-4 agonist AYPGKF was assessed by multiple electrode aggregometry in 79 prasugrel- and 77 ticagrelor-treated patients 3 days after acute percutaneous coronary intervention.
Results
In the overall study population (N = 156), patients aged ≥70 years (n = 33) had lower platelet aggregation in response to AA, ADP, and SFLLRN than younger patients (all P < .05). In prasugrel-treated patients (n = 79), those aged ≥70 years (n = 13) showed lower platelet aggregation in response to all agonists than younger patients (all P < .05). In contrast, in ticagrelor-treated patients (n = 77), those aged ≥70 years (n = 20) only had lower ADP-inducible platelet aggregation than younger patients (P = .03), whereas platelet aggregation in response to AA, collagen, SFLLRN, and AYPGKF was similar between elderly and younger patients (all P > .05). Among patients aged ≥70 years, prasugrel-treated patients showed lower platelet aggregation in response to AA, collagen, and AYPGKF than those receiving ticagrelor (all P < .05).
Conclusion
Patients aged ≥70 years on potent P2Y12 inhibitors exhibit increased inhibition of ADP-inducible platelet aggregation. In addition, elderly patients on prasugrel show a lower response to AA, collagen, SFLLRN and AYPGKF than younger patients.
{"title":"Elderly patients are hyperresponsive to potent P2Y12 inhibitors","authors":"David Mutschlechner , Maximilian Tscharre , Patricia Pia Wadowski , Silvia Lee , Joseph Pultar , Constantin Weikert , Simon Panzer , Thomas Gremmel","doi":"10.1016/j.rpth.2025.102704","DOIUrl":"10.1016/j.rpth.2025.102704","url":null,"abstract":"<div><h3>Background</h3><div>Aging has recently been associated with increased basal platelet activation and platelet hyperreactivity in response to adenosine diphosphate (ADP) but with decreased platelet response to thrombin receptor stimulation in individuals without antiplatelet therapy.</div></div><div><h3>Objectives</h3><div>To investigate platelet response to agonist stimulation in elderly patients (≥70 years) on dual antiplatelet therapy with potent P2Y12 inhibitors.</div></div><div><h3>Methods</h3><div>Platelet aggregation in response to arachidonic acid (AA), ADP, collagen, the protease-activated receptor-1 agonist SFLLRN, and the protease-activated receptor-4 agonist AYPGKF was assessed by multiple electrode aggregometry in 79 prasugrel- and 77 ticagrelor-treated patients 3 days after acute percutaneous coronary intervention.</div></div><div><h3>Results</h3><div>In the overall study population (<em>N</em> = 156), patients aged ≥70 years (<em>n</em> = 33) had lower platelet aggregation in response to AA, ADP, and SFLLRN than younger patients (all <em>P</em> < .05). In prasugrel-treated patients (<em>n</em> = 79), those aged ≥70 years (<em>n</em> = 13) showed lower platelet aggregation in response to all agonists than younger patients (all <em>P</em> < .05). In contrast, in ticagrelor-treated patients (<em>n</em> = 77), those aged ≥70 years (<em>n</em> = 20) only had lower ADP-inducible platelet aggregation than younger patients (<em>P</em> = .03), whereas platelet aggregation in response to AA, collagen, SFLLRN, and AYPGKF was similar between elderly and younger patients (all <em>P</em> > .05). Among patients aged ≥70 years, prasugrel-treated patients showed lower platelet aggregation in response to AA, collagen, and AYPGKF than those receiving ticagrelor (all <em>P</em> < .05).</div></div><div><h3>Conclusion</h3><div>Patients aged ≥70 years on potent P2Y12 inhibitors exhibit increased inhibition of ADP-inducible platelet aggregation. In addition, elderly patients on prasugrel show a lower response to AA, collagen, SFLLRN and AYPGKF than younger patients.</div></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"9 2","pages":"Article 102704"},"PeriodicalIF":3.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143642970","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}
The risk of recurrent venous thromboembolism (VTE) in patients with isolated distal deep vein thrombosis (IDDVT) is generally low, particularly when IDDVT is asymptomatic. However, cancer patients with IDDVT, even asymptomatic IDDVT, may be at a higher risk of recurrent VTE.
Objectives
To compare the clinical outcomes of cancer patients with asymptomatic and symptomatic IDDVT.
Methods
The ONCO DVT trial is a randomized clinical trial that compared 12-month versus 3-month edoxaban treatment regimens in cancer patients with IDDVT. In this post hoc analysis, 601 patients were categorized into the asymptomatic (n = 479) and symptomatic (n = 122) groups based on IDDVT-related symptoms at diagnosis. The primary outcome was the composite of symptomatic recurrent VTE or VTE-related death at 12 months, while the major secondary outcome was major bleeding at 12 months.
Results
The cumulative 12-month incidence of the primary outcome was lower in the asymptomatic group than that in the symptomatic group (2.9% vs 13.4%; P < .001; hazard ratio, 0.21; 95% CI, 0.10-0.47). Among the 12 patients with symptomatic recurrent VTE in the asymptomatic group, 8 (67%) had recurrent IDDVT, and 11 (92%) experienced recurrence after discontinuing anticoagulation therapy. The cumulative 12-month incidence of major bleeding was lower in the asymptomatic group than that in the symptomatic group (7.8% and 13.2%; P = .048).
Conclusion
The risk of recurrent symptomatic VTE was lower in cancer patients with asymptomatic IDDVT than in those with symptomatic IDDVT. Most recurrent VTE events were recurrent IDDVT, with the majority occurring after discontinuing anticoagulation therapy.
{"title":"Clinical outcomes of cancer-associated isolated distal deep vein thrombosis: a comparison between asymptomatic and symptomatic thrombosis—findings from the ONCO DVT Study","authors":"Yoshito Ogihara , Yugo Yamashita , Takeshi Morimoto , Nao Muraoka , Michihisa Umetsu , Yuji Nishimoto , Takuma Takada , Tatsuya Nishikawa , Nobutaka Ikeda , Kazunori Otsui , Daisuke Sueta , Yukari Tsubata , Masaaki Shoji , Ayumi Shikama , Yutaka Hosoi , Yasuhiro Tanabe , Ryuki Chatani , Kengo Tsukahara , Naohiko Nakanishi , Kitae Kim , Kaoru Dohi","doi":"10.1016/j.rpth.2025.102722","DOIUrl":"10.1016/j.rpth.2025.102722","url":null,"abstract":"<div><h3>Background</h3><div>The risk of recurrent venous thromboembolism (VTE) in patients with isolated distal deep vein thrombosis (IDDVT) is generally low, particularly when IDDVT is asymptomatic. However, cancer patients with IDDVT, even asymptomatic IDDVT, may be at a higher risk of recurrent VTE.</div></div><div><h3>Objectives</h3><div>To compare the clinical outcomes of cancer patients with asymptomatic and symptomatic IDDVT.</div></div><div><h3>Methods</h3><div>The ONCO DVT trial is a randomized clinical trial that compared 12-month versus 3-month edoxaban treatment regimens in cancer patients with IDDVT. In this post hoc analysis, 601 patients were categorized into the asymptomatic (<em>n</em> = 479) and symptomatic (<em>n</em> = 122) groups based on IDDVT-related symptoms at diagnosis. The primary outcome was the composite of symptomatic recurrent VTE or VTE-related death at 12 months, while the major secondary outcome was major bleeding at 12 months.</div></div><div><h3>Results</h3><div>The cumulative 12-month incidence of the primary outcome was lower in the asymptomatic group than that in the symptomatic group (2.9% vs 13.4%; <em>P</em> < .001; hazard ratio, 0.21; 95% CI, 0.10-0.47). Among the 12 patients with symptomatic recurrent VTE in the asymptomatic group, 8 (67%) had recurrent IDDVT, and 11 (92%) experienced recurrence after discontinuing anticoagulation therapy. The cumulative 12-month incidence of major bleeding was lower in the asymptomatic group than that in the symptomatic group (7.8% and 13.2%; <em>P</em> = .048).</div></div><div><h3>Conclusion</h3><div>The risk of recurrent symptomatic VTE was lower in cancer patients with asymptomatic IDDVT than in those with symptomatic IDDVT. Most recurrent VTE events were recurrent IDDVT, with the majority occurring after discontinuing anticoagulation therapy.</div></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"9 2","pages":"Article 102722"},"PeriodicalIF":3.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143705391","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}
Pub Date : 2025-02-01DOI: 10.1016/j.rpth.2025.102725
Tamam Bakchoul, Madhumita Chatterjee
{"title":"Lipid signatures of immunothrombosis: insights from VITT","authors":"Tamam Bakchoul, Madhumita Chatterjee","doi":"10.1016/j.rpth.2025.102725","DOIUrl":"10.1016/j.rpth.2025.102725","url":null,"abstract":"","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"9 2","pages":"Article 102725"},"PeriodicalIF":3.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143705639","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}
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