Pub Date : 2025-02-03DOI: 10.1016/j.jtha.2025.01.007
Rock Bum Kim, Justine H Ryu, Danielle Guffey, Emily Zhou, Mrinal Ranjan, Shengling Ma, Jennifer La, Nathanael R Fillmore, Ang Li
Background: The incidence of and risk factors for arterial thromboembolism (ATE) in patients with cancer, particularly in those with low socioeconomic status, remains understudied.
Objective: We aim to report the association between cancer-related and cardiovascular (CV) risk factors and the development of ATE.
Methods: We performed a retrospective cohort study for patients with newly diagnosed invasive cancer from 2011 to 2021 at a safety-net hospital system. We ascertained ATE outcomes using validated inpatient billing diagnosis codes for myocardial infarction (MI) and ischemic stroke (iCVD). We examined the incidence of ATE after cancer diagnosis using the cumulative incidence competing risk method to account for early mortality and estimated sub-distribution hazard ratios for ATE using multivariable Fine-Gray models.
Results: Among 17,236 patients (45.4% male, median 56 years), the ATE incidence was 1.5% (1.3%-1.6%) at 1-year and 2.8% (2.5%-3.0%) at 5-year after cancer diagnosis. In unadjusted analysis, the 5-year ATE incidence was highest in hematologic malignancies such as multiple myeloma (8.6%) and acute leukemia (7.8%), among patients receiving immune checkpoint inhibitors (8.3% vs 2.7%), those with poor Eastern Cooperative Oncology Group performance status (PS) (5.4% PS 4 vs 2.2% PS 0), and advanced stage (3.1% IV vs 1.9% I). After multivariable adjustment, only cancer type remained significantly associated with ATE along with known CV risk factors including advanced age, smoking, diabetes, hypertension, history of MI, and history of iCVD.
Conclusions: Both cancer type and traditional CV risk factors are independently associated with the development of ATE in patients with cancer.
{"title":"Incidence and risk of arterial thromboembolism in cancer patients from a safety-net healthcare system.","authors":"Rock Bum Kim, Justine H Ryu, Danielle Guffey, Emily Zhou, Mrinal Ranjan, Shengling Ma, Jennifer La, Nathanael R Fillmore, Ang Li","doi":"10.1016/j.jtha.2025.01.007","DOIUrl":"https://doi.org/10.1016/j.jtha.2025.01.007","url":null,"abstract":"<p><strong>Background: </strong>The incidence of and risk factors for arterial thromboembolism (ATE) in patients with cancer, particularly in those with low socioeconomic status, remains understudied.</p><p><strong>Objective: </strong>We aim to report the association between cancer-related and cardiovascular (CV) risk factors and the development of ATE.</p><p><strong>Methods: </strong>We performed a retrospective cohort study for patients with newly diagnosed invasive cancer from 2011 to 2021 at a safety-net hospital system. We ascertained ATE outcomes using validated inpatient billing diagnosis codes for myocardial infarction (MI) and ischemic stroke (iCVD). We examined the incidence of ATE after cancer diagnosis using the cumulative incidence competing risk method to account for early mortality and estimated sub-distribution hazard ratios for ATE using multivariable Fine-Gray models.</p><p><strong>Results: </strong>Among 17,236 patients (45.4% male, median 56 years), the ATE incidence was 1.5% (1.3%-1.6%) at 1-year and 2.8% (2.5%-3.0%) at 5-year after cancer diagnosis. In unadjusted analysis, the 5-year ATE incidence was highest in hematologic malignancies such as multiple myeloma (8.6%) and acute leukemia (7.8%), among patients receiving immune checkpoint inhibitors (8.3% vs 2.7%), those with poor Eastern Cooperative Oncology Group performance status (PS) (5.4% PS 4 vs 2.2% PS 0), and advanced stage (3.1% IV vs 1.9% I). After multivariable adjustment, only cancer type remained significantly associated with ATE along with known CV risk factors including advanced age, smoking, diabetes, hypertension, history of MI, and history of iCVD.</p><p><strong>Conclusions: </strong>Both cancer type and traditional CV risk factors are independently associated with the development of ATE in patients with cancer.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143256232","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 : 2025-02-01DOI: 10.1016/j.jtha.2024.11.023
Cecilia Becattini, Maria Cristina Vedovati
{"title":"Identification of hemodynamically stable patients with acute pulmonary embolism at high risk for death: external validation of different models","authors":"Cecilia Becattini, Maria Cristina Vedovati","doi":"10.1016/j.jtha.2024.11.023","DOIUrl":"10.1016/j.jtha.2024.11.023","url":null,"abstract":"","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"23 2","pages":"Pages 754-755"},"PeriodicalIF":5.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074769","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 : 2025-02-01DOI: 10.1016/j.jtha.2024.09.038
Neil A. Goldenberg , Sam Schulman , John M. Kittelson , Thomas C. Abshire , James F. Casella , Rita Dale , Jonathan L. Halperin , Jade Hanson , Craig M. Kessler , Marilyn J. Manco-Johnson , Laurel McDevitt , Robert F. Sidonio , Alex C. Spyropoulos , P. Gabriel Steg , Marc P. Bonaca
Background
The Multicenter Evaluation of the Duration of Therapy for Thrombosis in Children multinational, randomized clinical trial revealed noninferiority of a 6-week vs 3-month duration of anticoagulation for the treatment of provoked venous thromboembolism (VTE) in patients <21 years old in regard to net clinical benefit at 1 year.
Objectives
To evaluate noninferiority at 2 years.
Methods
Patients whose repeat imaging 6 weeks after VTE diagnosis did not show complete veno-occlusion were randomized to discontinue anticoagulation vs receive a total 3-month course and followed for 2 years for the occurrence of symptomatic recurrent VTE (efficacy outcome) and clinically relevant bleeding (safety outcome). Outcomes were centrally adjudicated, and net clinical benefit was compared between treatment arms via a prespecified bivariate noninferiority boundary, using 95% CIs in absolute risk differences between treatment arms.
Results
Kaplan–Meier estimates of 2-year cumulative incidences in the 6-week and 3-month arms of the intention-to-treat population (n = 417) were 1.7% (95% CI, 0%, 3.7%) and 2.9% (95% CI, 0.3%, 5.4%), respectively, for symptomatic recurrent VTE and 1.1% (95% CI, 0%, 2.5%) and 3.2% (95% CI, 0.6%, 5.7%), respectively, for clinically relevant bleeding. Bivariate analysis of the absolute risk differences in the intention-to-treat population demonstrated that a 6-week anticoagulation duration was noninferior to a 3-month course.
Conclusion
These findings support durability of the Kids-DOTT randomized clinical trial findings of net clinical benefit at 2 years.
{"title":"Duration of anticoagulation for venous thromboembolism in pediatric patients: Evaluation of the Duration of Therapy for Thrombosis in Children (Kids-DOTT) trial outcomes at 2 years","authors":"Neil A. Goldenberg , Sam Schulman , John M. Kittelson , Thomas C. Abshire , James F. Casella , Rita Dale , Jonathan L. Halperin , Jade Hanson , Craig M. Kessler , Marilyn J. Manco-Johnson , Laurel McDevitt , Robert F. Sidonio , Alex C. Spyropoulos , P. Gabriel Steg , Marc P. Bonaca","doi":"10.1016/j.jtha.2024.09.038","DOIUrl":"10.1016/j.jtha.2024.09.038","url":null,"abstract":"<div><h3>Background</h3><div>The Multicenter Evaluation of the Duration of Therapy for Thrombosis in Children multinational, randomized clinical trial revealed noninferiority of a 6-week vs 3-month duration of anticoagulation for the treatment of provoked venous thromboembolism (VTE) in patients <21 years old in regard to net clinical benefit at 1 year.</div></div><div><h3>Objectives</h3><div>To evaluate noninferiority at 2 years.</div></div><div><h3>Methods</h3><div>Patients whose repeat imaging 6 weeks after VTE diagnosis did not show complete veno-occlusion were randomized to discontinue anticoagulation vs receive a total 3-month course and followed for 2 years for the occurrence of symptomatic recurrent VTE (efficacy outcome) and clinically relevant bleeding (safety outcome). Outcomes were centrally adjudicated, and net clinical benefit was compared between treatment arms via a prespecified bivariate noninferiority boundary, using 95% CIs in absolute risk differences between treatment arms.</div></div><div><h3>Results</h3><div>Kaplan–Meier estimates of 2-year cumulative incidences in the 6-week and 3-month arms of the intention-to-treat population (<em>n</em> = 417) were 1.7% (95% CI, 0%, 3.7%) and 2.9% (95% CI, 0.3%, 5.4%), respectively, for symptomatic recurrent VTE and 1.1% (95% CI, 0%, 2.5%) and 3.2% (95% CI, 0.6%, 5.7%), respectively, for clinically relevant bleeding. Bivariate analysis of the absolute risk differences in the intention-to-treat population demonstrated that a 6-week anticoagulation duration was noninferior to a 3-month course.</div></div><div><h3>Conclusion</h3><div>These findings support durability of the Kids-DOTT randomized clinical trial findings of net clinical benefit at 2 years.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"23 2","pages":"Pages 651-656"},"PeriodicalIF":5.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142502853","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 : 2025-02-01DOI: 10.1016/j.jtha.2024.09.037
Leslie Skeith , Paula James , Peter Kouides , Kelsey Uminski , Lisa Duffett , Shannon Jackson , Michelle Sholzberg , Margaret V. Ragni , Adam Cuker , Maeve O’Beirne , Julia Hews-Girard , Natalia Rydz , Dawn M. Goodyear , Jill Baxter , Andra James , David Garcia , Sara K. Vesely , Man-Chiu Poon , VWD Pregnancy Loss Study Group
Background
While bleeding around pregnancy is well described in von Willebrand disease (VWD), the risk of pregnancy loss is less certain.
Objectives
We aimed to describe the frequency of pregnancy loss in females with VWD compared with those with a similar mucocutaneous bleeding phenotype and no VWD or compared with nonbleeding disorder controls.
Methods
Female patients were consecutively approached in 8 specialty bleeding disorder clinics between 2014 and 2023. The VWD group was defined as having von Willebrand factor (VWF) antigen and VWF activity levels, each <0.50 IU/mL on ≥2 occasions, and a condensed MCMDM-1 score of ≥4. The non-VWD mucocutaneous bleeding disorder group had VWF levels ≥ 0.50 IU/mL on ≥2 occasions and an MCMDM-1 score ≥ 4. A nonbleeding disorder control group was recruited in pregnancy from a low-risk maternity clinic.
Results
There were 150 females in the VWD group, 145 in the non-VWD mucocutaneous bleeding disorder group, and 137 in the control group. There was a similar frequency of individuals with ≥1 loss in the VWD group (45.3%, 68/150), the non-VWD group (56.6%; 82/145; −11.2%; 97.5% CI, −24.2%, 1.8%), and the nonbleeding disorder control group (37.2%; 51/137; 8.1%; 97.5% CI, −4.9%, 21.1%). Using a logistic regression, the odds ratio of pregnancy losses in the VWD group vs the non-VWD group was 0.94 (95% CI 0.65, 1.36). All groups experienced more recurrent losses compared with the literature.
Conclusion
There was no statistically significant difference in risk of pregnancy loss between females with VWD, females with a similar mucocutaneous bleeding phenotype, and nonbleeding disorder controls.
背景：von-Willebrand病（VWD）患者妊娠期出血的情况已得到充分描述，但妊娠失败的风险却不太确定。我们旨在描述 VWD 女性患者的妊娠损失频率，并与具有相似粘膜出血表型但无 VWD 的女性患者进行比较，或与非出血性疾病对照组进行比较：2014-2023年间，8家出血性疾病专科门诊连续接诊了女性患者。VWD组被定义为具有VWF:抗原（Ag）和VWF:活性（Act）水平的患者：VWD组有150名女性，非VWD粘膜出血性疾病组有145名女性，对照组有137名女性。在 VWD 组（45.3%，68/150）、非 VWD 组（56.6%，82/145）（-11.2%，97.5% CI -24.2，1.8%）和非出血性疾病对照组（37.2%，51/137）（8.1%，97.5% CI -4.9%，21.1%）中，≥1 项损失的人数频率相似。通过逻辑回归，VWD 组与非 VWD 组的妊娠损失几率比为 0.94（95% CI 0.65，1.36）。与文献相比，所有组别都经历了更多的复发性流产：患有 VWD 的女性、具有相似粘膜出血表型的女性以及非出血障碍对照组的女性在妊娠损失风险方面没有明显的统计学差异。
{"title":"Pregnancy loss in individuals with von Willebrand disease and unspecified mucocutaneous bleeding disorders: a multicenter cohort study","authors":"Leslie Skeith , Paula James , Peter Kouides , Kelsey Uminski , Lisa Duffett , Shannon Jackson , Michelle Sholzberg , Margaret V. Ragni , Adam Cuker , Maeve O’Beirne , Julia Hews-Girard , Natalia Rydz , Dawn M. Goodyear , Jill Baxter , Andra James , David Garcia , Sara K. Vesely , Man-Chiu Poon , VWD Pregnancy Loss Study Group","doi":"10.1016/j.jtha.2024.09.037","DOIUrl":"10.1016/j.jtha.2024.09.037","url":null,"abstract":"<div><h3>Background</h3><div>While bleeding around pregnancy is well described in von Willebrand disease (VWD), the risk of pregnancy loss is less certain.</div></div><div><h3>Objectives</h3><div>We aimed to describe the frequency of pregnancy loss in females with VWD compared with those with a similar mucocutaneous bleeding phenotype and no VWD or compared with nonbleeding disorder controls.</div></div><div><h3>Methods</h3><div>Female patients were consecutively approached in 8 specialty bleeding disorder clinics between 2014 and 2023. The VWD group was defined as having von Willebrand factor (VWF) antigen and VWF activity levels, each <0.50 IU/mL on ≥2 occasions, and a condensed MCMDM-1 score of ≥4. The non-VWD mucocutaneous bleeding disorder group had VWF levels ≥ 0.50 IU/mL on ≥2 occasions and an MCMDM-1 score ≥ 4. A nonbleeding disorder control group was recruited in pregnancy from a low-risk maternity clinic.</div></div><div><h3>Results</h3><div>There were 150 females in the VWD group, 145 in the non-VWD mucocutaneous bleeding disorder group, and 137 in the control group. There was a similar frequency of individuals with ≥1 loss in the VWD group (45.3%, 68/150), the non-VWD group (56.6%; 82/145; −11.2%; 97.5% CI, −24.2%, 1.8%), and the nonbleeding disorder control group (37.2%; 51/137; 8.1%; 97.5% CI, −4.9%, 21.1%). Using a logistic regression, the odds ratio of pregnancy losses in the VWD group vs the non-VWD group was 0.94 (95% CI 0.65, 1.36). All groups experienced more recurrent losses compared with the literature.</div></div><div><h3>Conclusion</h3><div>There was no statistically significant difference in risk of pregnancy loss between females with VWD, females with a similar mucocutaneous bleeding phenotype, and nonbleeding disorder controls.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"23 2","pages":"Pages 429-439"},"PeriodicalIF":5.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142502860","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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.jtha.2024.11.004
Stanislav Henkin , Gregory Piazza
{"title":"Love for lysis in the time of catheters: is it time to resurrect an old standby?","authors":"Stanislav Henkin , Gregory Piazza","doi":"10.1016/j.jtha.2024.11.004","DOIUrl":"10.1016/j.jtha.2024.11.004","url":null,"abstract":"","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"23 2","pages":"Pages 401-403"},"PeriodicalIF":5.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074770","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 : 2025-02-01DOI: 10.1016/j.jtha.2024.09.030
Luisa Weiss , Aideen O’Doherty , Wido Uhrig , Paulina B. Szklanna , Molly Hong-Minh , Kieran Wynne , Alfonso Blanco , Jan Zivny , Valeria Lima Passos , Barry Kevane , Seán Murphy , Fionnuala Ní Áinle , Martin O’Donnell , Patricia B. Maguire
Background
Despite secondary prevention with aspirin, patients with stable cardiovascular disease (CVD) remain at elevated long-term risk of major adverse cardiovascular events. The Cardiovascular Outcomes in People Using Anticoagulant Strategies (COMPASS) double-blind, randomized clinical trial demonstrated that aspirin plus low-dose rivaroxaban (COMPASS regime) significantly decreased the incidence of major adverse cardiovascular events by 24% compared with aspirin alone. However, the mechanisms underlying these potential synergistic/nonantithrombotic effects remain elusive. Extracellular vesicles (EVs) are crucial messengers regulating a myriad of biological/pathological processes and are highly implicated in CVD.
Objectives
We hypothesized that circulating EV profiles reflect the cardioprotective properties of the COMPASS regime.
Methods
A cohort of stable CVD patients (N = 40) who participated in the COMPASS trial and were previously randomized to receive aspirin were prospectively recruited and assigned a revised regimen of open-label aspirin plus rivaroxaban. Blood samples were obtained at baseline (aspirin only) and 6-month follow-up. Plasma EV concentration, size, and origin were analyzed by nanoparticle tracking analysis and flow cytometry. EVs were enriched by ultracentrifugation for proteomic analysis.
Results
The COMPASS regime fundamentally altered small (<200 nm) and large (200-1000 nm) EV concentration and size compared with aspirin alone. Crucially, levels of platelet-derived and myeloperoxidase-positive EVs became significantly decreased at follow-up. Comparative proteomic characterization further revealed a significant decrease in highly proinflammatory protein expression at follow-up.
Conclusion
The observed changes in EV subpopulations, together with the differential protein expression profiles, suggest amelioration of an underlying proinflammatory and prothrombotic state upon dual therapy, which may be of clinical relevance toward understanding the fundamental mechanism underlying the reported superior cardiovascular outcomes associated with this antithrombotic regimen.
背景：尽管使用了阿司匹林进行二级预防，但病情稳定的心血管疾病（CVD）患者发生重大心血管事件（MACE）的长期风险仍然很高。COMPASS 双盲随机临床试验表明，与单用阿司匹林相比，阿司匹林加小剂量利伐沙班（COMPASS 方案）可将 MACE 发生率显著降低 24%。然而，这些潜在的协同/非抗血栓作用的机制仍然难以捉摸。细胞外囊泡（EVs）是调节无数生物/病理过程的重要信使，与心血管疾病有很大关系。我们假设循环中的EV能反映COMPASS疗法的心脏保护特性：我们前瞻性地招募了一批参与 COMPASS 试验的稳定型心血管疾病患者（40 人），这些患者之前被随机分配接受阿司匹林治疗，现在他们又被分配接受了开放标签阿司匹林加利伐沙班的修订治疗方案。在基线（仅服用阿司匹林）和6个月随访时采集血样。通过 NTA 和流式细胞术分析血浆 EV 的浓度、大小和来源。通过超速离心法富集 EVs 进行蛋白质组分析：结果：COMPASS 方案从根本上改变了小EV（结论：观察到的 EV 亚群的变化以及不同的蛋白质表达谱表明，双重疗法改善了潜在的促炎症和促血栓形成状态，这可能与临床相关，有助于理解与这种抗血栓治疗方案相关的卓越心血管疗效的基本机制。
{"title":"Rivaroxaban, in combination with low-dose aspirin, is associated with a reduction in proinflammatory and prothrombotic circulating vesicle signatures in patients with cardiovascular disease","authors":"Luisa Weiss , Aideen O’Doherty , Wido Uhrig , Paulina B. Szklanna , Molly Hong-Minh , Kieran Wynne , Alfonso Blanco , Jan Zivny , Valeria Lima Passos , Barry Kevane , Seán Murphy , Fionnuala Ní Áinle , Martin O’Donnell , Patricia B. Maguire","doi":"10.1016/j.jtha.2024.09.030","DOIUrl":"10.1016/j.jtha.2024.09.030","url":null,"abstract":"<div><h3>Background</h3><div>Despite secondary prevention with aspirin, patients with stable cardiovascular disease (CVD) remain at elevated long-term risk of major adverse cardiovascular events. The Cardiovascular Outcomes in People Using Anticoagulant Strategies (COMPASS) double-blind, randomized clinical trial demonstrated that aspirin plus low-dose rivaroxaban (COMPASS regime) significantly decreased the incidence of major adverse cardiovascular events by 24% compared with aspirin alone. However, the mechanisms underlying these potential synergistic/nonantithrombotic effects remain elusive. Extracellular vesicles (EVs) are crucial messengers regulating a myriad of biological/pathological processes and are highly implicated in CVD.</div></div><div><h3>Objectives</h3><div>We hypothesized that circulating EV profiles reflect the cardioprotective properties of the COMPASS regime.</div></div><div><h3>Methods</h3><div>A cohort of stable CVD patients (<em>N</em> = 40) who participated in the COMPASS trial and were previously randomized to receive aspirin were prospectively recruited and assigned a revised regimen of open-label aspirin plus rivaroxaban. Blood samples were obtained at baseline (aspirin only) and 6-month follow-up. Plasma EV concentration, size, and origin were analyzed by nanoparticle tracking analysis and flow cytometry. EVs were enriched by ultracentrifugation for proteomic analysis.</div></div><div><h3>Results</h3><div>The COMPASS regime fundamentally altered small (<200 nm) and large (200-1000 nm) EV concentration and size compared with aspirin alone. Crucially, levels of platelet-derived and myeloperoxidase-positive EVs became significantly decreased at follow-up. Comparative proteomic characterization further revealed a significant decrease in highly proinflammatory protein expression at follow-up.</div></div><div><h3>Conclusion</h3><div>The observed changes in EV subpopulations, together with the differential protein expression profiles, suggest amelioration of an underlying proinflammatory and prothrombotic state upon dual therapy, which may be of clinical relevance toward understanding the fundamental mechanism underlying the reported superior cardiovascular outcomes associated with this antithrombotic regimen.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"23 2","pages":"Pages 531-545"},"PeriodicalIF":5.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142468678","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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.jtha.2024.09.036
Nathan Ponzar , Mathivanan Chinnaraj , Anna Pagotto , Vincenzo De Filippis , Robert Flaumenhaft , Nicola Pozzi
Background
Protein disulfide isomerase (PDI) is a promising target for combating thrombosis. Extensive research over the past decade has identified numerous PDI-targeting compounds. However, limited information exists regarding how these compounds control PDI activity, which complicates further development.
Objectives
To define the mechanism of action of 2 allosteric antithrombotic compounds of therapeutic interest, quercetin-3-O-rutinoside and bepristat-2a.
Methods
A multipronged approach that integrates single-molecule spectroscopy, steady-state kinetics, single-turnover kinetics, and site-specific mutagenesis.
Results
PDI is a thiol isomerase consisting of 2 catalytic a domains and 2 inactive b domains arranged in the order a-b-b'-a'. The active sites CGHC are located in the a and a' domains. The binding site of quercetin-3-O-rutinoside and bepristat-2a is in the b' domain. Using a library of 9 Förster resonance energy transfer sensors, we showed that quercetin-3-O-rutinoside and bepristat-2a globally alter PDI structure and dynamics, leading to ligand-specific modifications of its shape and reorientation of the active sites. Combined with enzyme kinetics and mutagenesis of the active sites, Förster resonance energy transfer data reveal that binding of quercetin-3-O-rutinoside results in a twisted enzyme with reduced affinity for the substrate. In contrast, bepristat-2a promotes a more compact conformation of PDI, in which a greater enzymatic activity is achieved by accelerating the nucleophilic step of the a domain, leading to faster formation of the covalent enzyme–substrate complex.
Conclusion
This work reveals the mechanistic basis underlying PDI regulation by antithrombotic compounds quercetin-3-O-rutinoside and bepristat-2a and points to novel strategies for furthering the development of PDI-targeting compounds into drugs.
{"title":"Mechanistic basis of activation and inhibition of protein disulfide isomerase by allosteric antithrombotic compounds","authors":"Nathan Ponzar , Mathivanan Chinnaraj , Anna Pagotto , Vincenzo De Filippis , Robert Flaumenhaft , Nicola Pozzi","doi":"10.1016/j.jtha.2024.09.036","DOIUrl":"10.1016/j.jtha.2024.09.036","url":null,"abstract":"<div><h3>Background</h3><div>Protein disulfide isomerase (PDI) is a promising target for combating thrombosis. Extensive research over the past decade has identified numerous PDI-targeting compounds. However, limited information exists regarding how these compounds control PDI activity, which complicates further development.</div></div><div><h3>Objectives</h3><div>To define the mechanism of action of 2 allosteric antithrombotic compounds of therapeutic interest, quercetin-3-O-rutinoside and bepristat-2a.</div></div><div><h3>Methods</h3><div>A multipronged approach that integrates single-molecule spectroscopy, steady-state kinetics, single-turnover kinetics, and site-specific mutagenesis.</div></div><div><h3>Results</h3><div>PDI is a thiol isomerase consisting of 2 catalytic <strong>a</strong> domains and 2 inactive <strong>b</strong> domains arranged in the order <strong>a-b-b'-a'</strong>. The active sites CGHC are located in the <strong>a</strong> and <strong>a'</strong> domains. The binding site of quercetin-3-O-rutinoside and bepristat-2a is in the <strong>b'</strong> domain. Using a library of 9 Förster resonance energy transfer sensors, we showed that quercetin-3-O-rutinoside and bepristat-2a globally alter PDI structure and dynamics, leading to ligand-specific modifications of its shape and reorientation of the active sites. Combined with enzyme kinetics and mutagenesis of the active sites, Förster resonance energy transfer data reveal that binding of quercetin-3-O-rutinoside results in a twisted enzyme with reduced affinity for the substrate. In contrast, bepristat-2a promotes a more compact conformation of PDI, in which a greater enzymatic activity is achieved by accelerating the nucleophilic step of the <strong>a</strong> domain, leading to faster formation of the covalent enzyme–substrate complex.</div></div><div><h3>Conclusion</h3><div>This work reveals the mechanistic basis underlying PDI regulation by antithrombotic compounds quercetin-3-O-rutinoside and bepristat-2a and points to novel strategies for furthering the development of PDI-targeting compounds into drugs.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"23 2","pages":"Pages 577-587"},"PeriodicalIF":5.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142502857","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 : 2025-02-01DOI: 10.1016/j.jtha.2024.10.032
Jin Mao , Jingyu Zhao , Hong Pan , Zhen Gao , Lele Zhang , Weiwang Li , Liwei Fang , Cuicui Liu , Pei Su , Hongtao Wang , Jiaxi Zhou , Jun Shi
Background
Aplastic anemia (AA) is a bone marrow failure disease for which the means of assessing and predicting the therapeutic effectiveness are still relatively limited. Thrombocytopenia is often the earliest and most severe symptom in patients newly diagnosed with AA. While clinical consideration is usually given to the quantitative changes in platelets during treatment, there is little focus on the resolution of the molecular characteristics of platelets in AA.
Objectives
To investigate the changes in platelet molecular characteristics throughout the treatment process of AA, and to explore the use of transcriptomics for monitoring and predicting treatment outcomes.
Methods
We comprehensively analyzed platelet transcriptomic changes in patients with AA at initial diagnosis and different stages of treatment effectiveness using bulk transcriptome sequencing.
Results
Genes associated with cell proliferation, erythroid function, and amino acid transport were elevated in newly diagnosed AA. Conversely, genes linked to histones, thrombopoiesis, mitochondrial energy metabolism, and signaling pathways were significantly downregulated. Additionally, 60.6% of the differentially expressed genes were substantially restored following complete remission. Furthermore, through the examination of longitudinal samples, we identified recovery ascending genes that could serve as viable biomarkers for assessing treatment effectiveness in AA. Besides, we observed that higher expression levels of recovery ascending genes may predict superior long-term platelet counts recovery 6 months in advance in patients with partial response.
Conclusion
The platelet transcriptome undergoes profound changes and can serve as a potential indicator for assessing treatment effectiveness and predicting long-term platelet counts recovery in AA.
背景：再生障碍性贫血（AA）是一种骨髓衰竭疾病：再生障碍性贫血（AA）是一种骨髓衰竭疾病，其治疗效果的评估和预测手段仍然相对有限。血小板减少通常是新诊断为再生障碍性贫血（Dx-AA）的患者最早出现且最严重的症状。临床上通常考虑治疗过程中血小板的数量变化，但很少关注 AA 患者血小板分子特征的变化：研究AA治疗过程中血小板分子特征的变化，并探索利用转录组学监测和预测治疗结果：方法：我们利用批量转录组测序技术全面分析了AA患者在最初诊断和不同治疗效果阶段的血小板转录组变化：结果：与细胞增殖、红细胞功能和氨基酸转运相关的基因在Dx-AA中升高。相反，与组蛋白、血栓形成、线粒体能量代谢和信号通路相关的基因则明显下调。完全缓解后，60.6%的差异表达基因得到了大幅恢复。此外，通过对纵向样本的研究，我们发现了可作为评估 AA 治疗效果的生物标志物的恢复上升基因（RAG）。此外，我们还观察到，较高的 RAG 表达水平可提前 6 个月预示部分反应患者的血小板计数会有较好的长期恢复：血小板转录组发生了深刻变化，可作为评估治疗效果和预测 AA 患者血小板计数长期恢复的潜在指标。
{"title":"Application of platelet transcriptomics for assessing treatment effectiveness and predicting long-term platelet counts recovery in aplastic anemia","authors":"Jin Mao , Jingyu Zhao , Hong Pan , Zhen Gao , Lele Zhang , Weiwang Li , Liwei Fang , Cuicui Liu , Pei Su , Hongtao Wang , Jiaxi Zhou , Jun Shi","doi":"10.1016/j.jtha.2024.10.032","DOIUrl":"10.1016/j.jtha.2024.10.032","url":null,"abstract":"<div><h3>Background</h3><div>Aplastic anemia (AA) is a bone marrow failure disease for which the means of assessing and predicting the therapeutic effectiveness are still relatively limited. Thrombocytopenia is often the earliest and most severe symptom in patients newly diagnosed with AA. While clinical consideration is usually given to the quantitative changes in platelets during treatment, there is little focus on the resolution of the molecular characteristics of platelets in AA.</div></div><div><h3>Objectives</h3><div>To investigate the changes in platelet molecular characteristics throughout the treatment process of AA, and to explore the use of transcriptomics for monitoring and predicting treatment outcomes.</div></div><div><h3>Methods</h3><div>We comprehensively analyzed platelet transcriptomic changes in patients with AA at initial diagnosis and different stages of treatment effectiveness using bulk transcriptome sequencing.</div></div><div><h3>Results</h3><div>Genes associated with cell proliferation, erythroid function, and amino acid transport were elevated in newly diagnosed AA. Conversely, genes linked to histones, thrombopoiesis, mitochondrial energy metabolism, and signaling pathways were significantly downregulated. Additionally, 60.6% of the differentially expressed genes were substantially restored following complete remission. Furthermore, through the examination of longitudinal samples, we identified recovery ascending genes that could serve as viable biomarkers for assessing treatment effectiveness in AA. Besides, we observed that higher expression levels of recovery ascending genes may predict superior long-term platelet counts recovery 6 months in advance in patients with partial response.</div></div><div><h3>Conclusion</h3><div>The platelet transcriptome undergoes profound changes and can serve as a potential indicator for assessing treatment effectiveness and predicting long-term platelet counts recovery in AA.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"23 2","pages":"Pages 692-703"},"PeriodicalIF":5.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142639195","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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.jtha.2024.10.034
Juri Alessandro Giannotta , Andrea Artoni , Ilaria Mancini , Pasquale Agosti , Monica Carpenedo , Addolorata Truma , Syna Miri , Barbara Ferrari , Pasqualina De Leo , Prassede Salutari , Giorgia Mancini , Alfredo Molteni , Ermina Rinaldi , Monica Bocchia , Mariasanta Napolitano , Lucia Prezioso , Annarosa Cuccaro , Elisabetta Scarpa , Annalisa Condorelli , Daniele Grimaldi , Flora Peyvandi
Background
Immune-mediated thrombotic thrombocytopenic purpura (iTTP) patients are not responsive to standard rituximab in approximately 10% to 15% of cases, and oral immunosuppressants showed controversial results with significant toxicity. Targeting plasma cells with bortezomib appears promising, but the available evidence is scarce and stems only from isolated reports in the precaplacizumab era.
Objectives
To evaluate the safety and efficacy of bortezomib in rituximab-refractory iTTP patients.
Methods
We conducted a retrospective observational multicenter study among 13 Italian iTTP treating centers, collecting data from May 2017 to May 2023 (caplacizumab was licensed in Italy in January 2020).
Results
Bortezomib was effective in 10/17 patients (59%). Eleven were treated in the acute phase (9/11 responders, 82%, allowing discontinuation of caplacizumab in 5/6 treated patients), and 7 during clinical remission (2/7 responders, 28%). Responses occurred at a median time of 30 days, but 3 patients responded after 4 months. The median duration of response was 22 months (IQR, 10-38), still ongoing in 6 patients at the time of data cutoff. Responders had fewer previous acute iTTP episodes than nonresponders (median [IQR], 1 [1,2] vs 5.5 [[2], [3], [4], [5], [6], [7]]; P = .03). Eight subjects (47%) reported toxicities, mostly in those treated with ≥2 cycles.
Conclusion
Durable responses to bortezomib were registered in about 60% of multirefractory iTTP patients with mild to moderate toxicities. The occurrence of late responses (ie, after 30 days) suggests a “watchful waiting” approach after bortezomib treatment.
{"title":"Bortezomib for rituximab-refractory immune-mediated thrombotic thrombocytopenic purpura in the caplacizumab era: an Italian multicenter study","authors":"Juri Alessandro Giannotta , Andrea Artoni , Ilaria Mancini , Pasquale Agosti , Monica Carpenedo , Addolorata Truma , Syna Miri , Barbara Ferrari , Pasqualina De Leo , Prassede Salutari , Giorgia Mancini , Alfredo Molteni , Ermina Rinaldi , Monica Bocchia , Mariasanta Napolitano , Lucia Prezioso , Annarosa Cuccaro , Elisabetta Scarpa , Annalisa Condorelli , Daniele Grimaldi , Flora Peyvandi","doi":"10.1016/j.jtha.2024.10.034","DOIUrl":"10.1016/j.jtha.2024.10.034","url":null,"abstract":"<div><h3>Background</h3><div>Immune-mediated thrombotic thrombocytopenic purpura (iTTP) patients are not responsive to standard rituximab in approximately 10% to 15% of cases, and oral immunosuppressants showed controversial results with significant toxicity. Targeting plasma cells with bortezomib appears promising, but the available evidence is scarce and stems only from isolated reports in the precaplacizumab era.</div></div><div><h3>Objectives</h3><div>To evaluate the safety and efficacy of bortezomib in rituximab-refractory iTTP patients.</div></div><div><h3>Methods</h3><div>We conducted a retrospective observational multicenter study among 13 Italian iTTP treating centers, collecting data from May 2017 to May 2023 (caplacizumab was licensed in Italy in January 2020).</div></div><div><h3>Results</h3><div>Bortezomib was effective in 10/17 patients (59%). Eleven were treated in the acute phase (9/11 responders, 82%, allowing discontinuation of caplacizumab in 5/6 treated patients), and 7 during clinical remission (2/7 responders, 28%). Responses occurred at a median time of 30 days, but 3 patients responded after 4 months. The median duration of response was 22 months (IQR, 10-38), still ongoing in 6 patients at the time of data cutoff. Responders had fewer previous acute iTTP episodes than nonresponders (median [IQR], 1 [<span><span>1</span></span>,<span><span>2</span></span>] vs 5.5 [<span><span>[2]</span></span>, <span><span>[3]</span></span>, <span><span>[4]</span></span>, <span><span>[5]</span></span>, <span><span>[6]</span></span>, <span><span>[7]</span></span>]; <em>P</em> = .03). Eight subjects (47%) reported toxicities, mostly in those treated with ≥2 cycles.</div></div><div><h3>Conclusion</h3><div>Durable responses to bortezomib were registered in about 60% of multirefractory iTTP patients with mild to moderate toxicities. The occurrence of late responses (ie, after 30 days) suggests a “watchful waiting” approach after bortezomib treatment.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"23 2","pages":"Pages 704-716"},"PeriodicalIF":5.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142644076","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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.jtha.2024.11.006
Fionnuala Ní Áinle , Saskia Middeldorp , Andrea Hickman , Cary Clark , Walter Ageno , Patricia Casais , Jean M. Connors , Sabine Eichinger , Damon Houghton , Tadashi Matsushita , Joost C.M. Meijers , Angela C. Weyand , James Douketis , International Society on Thrombosis and Haemostasis (ISTH) Guidelines and Guidance Committee
{"title":"Guidelines and guidance: what is the path forward for the ISTH?","authors":"Fionnuala Ní Áinle , Saskia Middeldorp , Andrea Hickman , Cary Clark , Walter Ageno , Patricia Casais , Jean M. Connors , Sabine Eichinger , Damon Houghton , Tadashi Matsushita , Joost C.M. Meijers , Angela C. Weyand , James Douketis , International Society on Thrombosis and Haemostasis (ISTH) Guidelines and Guidance Committee","doi":"10.1016/j.jtha.2024.11.006","DOIUrl":"10.1016/j.jtha.2024.11.006","url":null,"abstract":"","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"23 2","pages":"Pages 361-367"},"PeriodicalIF":5.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142739860","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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