Research and Practice in Thrombosis and Haemostasis最新文献

{"title":"LAIR-1 and PECAM-1 function via the same signaling pathway to inhibit GPVI-mediated platelet activation","authors":"Christopher W. Smith ,&nbsp;Zoltan Nagy ,&nbsp;Mitchell J. Geer ,&nbsp;Jeremy A. Pike ,&nbsp;Pushpa Patel ,&nbsp;Yotis A. Senis ,&nbsp;Alexandra Mazharian","doi":"10.1016/j.rpth.2024.102557","DOIUrl":"10.1016/j.rpth.2024.102557","url":null,"abstract":"<div><h3>Background</h3><p>Inhibition of platelet responsiveness is important for controlling thrombosis. It is well established that platelet endothelial cell adhesion molecule-1 (PECAM-1) serves as a physiological negative regulator of platelet-collagen interactions. We recently demonstrated that leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1) is a negative regulator of platelet production and reactivity. It is however not known if LAIR-1 and PECAM-1 function in the same or different inhibitory pathways.</p></div><div><h3>Objectives</h3><p>In this study, we investigated the role of LAIR-1 alongside PECAM-1 in megakaryocyte development and platelet production and determined the functional redundancy through characterization of a LAIR-1/PECAM-1 double knockout (DKO) mouse model.</p></div><div><h3>Methods</h3><p>LAIR-1 and PECAM-1 expression in megakaryocytes were evaluated by western blotting. Megakaryocyte ploidy and proplatelet formation were evaluated by flow cytometry and fluorescent microscopy. Platelet function and signalling were compared in wild-type, <em>LAIR-1^{^−/−}</em>, <em>PECAM-1^{^−/−}</em> and DKO mice using aggregometry, flow cytometry and western blotting. Thrombosis was evaluated using the FeCl_₃ carotid artery model.</p></div><div><h3>Results</h3><p>We show that LAIR-1/PECAM-1 DKO mice exhibit a 17% increase in platelet count. Bone marrow-derived megakaryocytes from all 3 mouse models had normal ploidy <em>in vitro</em>, suggesting that neither LAIR-1 nor PECAM-1 regulates megakaryocyte development. Furthermore, relative to wild-type platelets, platelets derived from LAIR-1, PECAM-1, and DKO mice were equally hyperresponsive to collagen <em>in vitro</em>, indicating that LAIR-1 and PECAM-1 participate in the same inhibitory pathway. Interestingly, DKO mice exhibited normal thrombus formation <em>in vivo</em> due to DKO mouse platelets lacking the enhanced Src family kinase activation previously shown in platelets from LAIR-1-deficient mice.</p></div><div><h3>Conclusion</h3><p>Findings from this study reveal that LAIR-1 and PECAM-1 act to inhibit GPVI-mediated platelet activation via the same signaling pathway. Mice lacking LAIR-1 and PECAM-1 do not however exhibit an increase in thrombus formation despite minor increase in platelet count and reactivity to collagen. This study adds to the growing evidence that immunoreceptor tyrosine-based inhibition motif–containing receptors are important regulators of platelet count and function.</p></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"8 6","pages":"Article 102557"},"PeriodicalIF":3.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2475037924002528/pdfft?md5=28e276c6f50262cd61f9ab527bcbe16e&pid=1-s2.0-S2475037924002528-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142242615","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":"A single-center study of patients with rare isolated acquired clotting factor deficiencies other than acquired hemophilia A","authors":"Dandan Yu ,&nbsp;Feng Xue ,&nbsp;Xiaofan Liu ,&nbsp;Yunfei Chen ,&nbsp;Rongfeng Fu ,&nbsp;Ting Sun ,&nbsp;Xinyue Dai ,&nbsp;Mankai Ju ,&nbsp;Huan Dong ,&nbsp;Renchi Yang ,&nbsp;Wei Liu ,&nbsp;Lei Zhang","doi":"10.1016/j.rpth.2024.102554","DOIUrl":"10.1016/j.rpth.2024.102554","url":null,"abstract":"<div><h3>Background</h3><p>Isolated acquired clotting factor deficiencies (ACFDs) are mainly caused by the existence of anti-factor antibodies or adsorption of clotting factors onto substances such as amyloid. Besides acquired factor (F)VIII deficiency (acquired hemophilia A), the remaining factor deficiencies are rare and diverse, posing challenges in both diagnosis and management.</p></div><div><h3>Objectives</h3><p>To describe different features of isolated ACFDs to improve our understanding of these diseases and provide practical recommendations for their management.</p></div><div><h3>Methods</h3><p>Clinical characteristics of patients with isolated acquired FII, FV, FIX, FX, FXI, FXII, FXIII, and von Willebrand factor deficiencies were collected from a single center between July 1997 and December 2021 and analyzed retrospectively.</p></div><div><h3>Results</h3><p>A total of 54 rare isolated ACFD patients were enrolled in our study, mainly including 20 acquired FV deficiency patients and 16 acquired FX deficiency patients. The median age at diagnosis of all rare isolated ACFD patients was 55 years. The median time to diagnose all rare isolated ACFD patients was 60 days. Ten (18.5%) rare isolated ACFD patients had no bleeding and 2 (3.7%) rare isolated ACFD patients showed venous thromboembolism. Hemostatic treatment was applied to 41 (41/54; 75.9%) rare isolated ACFD patients. Thirty-seven (68.5%) rare isolated ACFD patients received immunosuppressive therapy, and 10 (18.5%) rare isolated ACFD patients received chemotherapy targeting primary diseases. Twenty-two (61.9%) rare isolated ACFD patients achieved complete remission, and 9 (21.4%) rare isolated ACFD patients died.</p></div><div><h3>Conclusion</h3><p>Rare isolated ACFDs are underestimated, associated with delayed diagnosis, and lack effective therapy. Clinicians should raise awareness for recognizing and managing rare isolated ACFD patients to avoid morbidity and mortality.</p></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"8 6","pages":"Article 102554"},"PeriodicalIF":3.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2475037924002498/pdfft?md5=091c681de28ee0a16ea80322b5cf3dd5&pid=1-s2.0-S2475037924002498-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142274046","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":"Methods of a cluster-randomized, type II hybrid implementation effectiveness trial to prospectively assess extended-duration thromboprophylaxis for at-risk medical patients being discharged to prevent hospital-associated venous thromboembolism","authors":"Scott C. Woller ,&nbsp;Scott M. Stevens ,&nbsp;Joseph R. Bledsoe ,&nbsp;James Hellewell ,&nbsp;Adam Kraft ,&nbsp;Allison M. Butler ,&nbsp;Masarret Fazili ,&nbsp;James F. Lloyd ,&nbsp;Paige S. Christensen ,&nbsp;Ithan D. Peltan ,&nbsp;Geoffrey D. Barnes ,&nbsp;Benjamin D. Horne","doi":"10.1016/j.rpth.2024.102549","DOIUrl":"10.1016/j.rpth.2024.102549","url":null,"abstract":"<div><h3>Background</h3><div>Venous thromboembolism (VTE) is the third leading cause of preventable hospital-associated (HA) death. Most HA-VTE, including fatal pulmonary emboli, occur among medically ill patients. The rate of symptomatic VTE more than doubles over the first 21 days after hospital discharge. Trials have demonstrated that the burden of HA-VTE may be reduced with postdischarge thromboprophylaxis; however, few patients receive this therapy. We formerly validated the ability of eVTE (eVTE is the abbreviation for a risk assessment tool constituted by 2 calculations: one predicts 90-day VTE and the other predicts 30-day major bleeding derived from only elements of the complete blood count and basic metabolic panel and age) to identify medical patients being discharged with both an elevated risk of VTE and a low risk of bleeding.</div></div><div><h3>Objectives</h3><div>Implement a cluster-randomized, stepped wedge, type II hybrid implementation/effectiveness trial generating an alert among select at-risk patients upon discharge for implementation of thrombosis chemoprophylaxis in a 23-hospital not-for-profit healthcare system.</div></div><div><h3>Methods</h3><div>We use the Reach, Effectiveness, Adoption, Implementation, and Maintenance framework to guide implementation and outcomes reporting.</div></div><div><h3>Results</h3><div>The primary outcome for aim 1 (implementation) is the prescription of rivaroxaban 10 mg daily for 30 days as postdischarge thromboprophylaxis among at-risk patients. The primary efficacy and safety outcomes (effectiveness) are the 90-day composite of symptomatic VTE, myocardial infartcion, nonhemorrhagic stroke, all-cause mortality, and 30-day major bleeding.</div></div><div><h3>Conclusion</h3><div>The eVTE trial will provide high-quality, real-world evidence on the effectiveness and safety of a pragmatic intervention to implement targeted postdischarge thromboprophylaxis using decision support embedded in the electronic health record.</div></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"8 6","pages":"Article 102549"},"PeriodicalIF":3.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142357094","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":"Proportion and risk factors for hospital-acquired venous thromboembolism in children: a systematic review and meta-analysis of data from 20 million individuals in 22 countries","authors":"Jintuo Zhou,&nbsp;Yanting Zhu,&nbsp;Ying Liu,&nbsp;Hairong Zhan,&nbsp;Peiguang Niu,&nbsp;Huajiao Chen,&nbsp;Jinhua Zhang","doi":"10.1016/j.rpth.2024.102541","DOIUrl":"10.1016/j.rpth.2024.102541","url":null,"abstract":"<div><h3>Background</h3><div>Hospital-acquired venous thromboembolism (HA-VTE) in children has been widely regarded.</div></div><div><h3>Objectives</h3><div>We aimed to analyze the proportion and risk factors for HA-VTE in hospitalized children.</div></div><div><h3>Methods</h3><div>We conducted a comprehensive systematic search across 4 databases from 1990 to 2023. Cochran Q test was used to evaluate the heterogeneity of the effect sizes of study, and I² statistic was used to quantify the heterogeneity. Pooled estimates were calculated by the inverse-variance weighted method in a fixed-effect model or a random-effect model when heterogeneity was low (I² &lt; 25%) or high (I² &gt; 25%), respectively.</div></div><div><h3>Results</h3><div>In total, 105 original papers and 20,718,294 patients were included in the study, and the proportion of HA-VTE in children was 4.1% (95% CI, 2.9%-5.2%). Although the proportion of venous thromboembolism increased over the various research periods, the differences were not statistically significant. In the subgroup analysis based on country, the proportion of pediatric HA-VTE was lowest in the United Kingdom and highest in Spain, whereas when based on region, the proportion was lowest in Asia and highest in North America. Multiple HA-VTE risk factors were identified, including central venous catheter use, age of &gt;10 years, surgery, injury, infection, obesity, mechanical ventilation, blood transfusion, malignancy, coagulation and hemorrhagic disorders, and length of hospital stay.</div></div><div><h3>Conclusion</h3><div>In this study, we systematically analyzed the proportion and risk factors of HA-VTE in hospitalized children. Our findings provide valuable insights for the prevention and treatment of HA-VTE in pediatric patients.</div></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"8 6","pages":"Article 102541"},"PeriodicalIF":3.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142319150","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":"The risk of venous thromboembolism in primary central nervous system lymphoma: a systematic review and meta-analysis","authors":"Adam Suleman ,&nbsp;Rachel Wine ,&nbsp;Marc Carrier ,&nbsp;Lisa K. Hicks","doi":"10.1016/j.rpth.2024.102507","DOIUrl":"10.1016/j.rpth.2024.102507","url":null,"abstract":"<div><p>Primary central nervous system lymphoma (PCNSL) is a rare extranodal lymphoma localized to the central nervous system. Small single-center studies have suggested that patients with PCNSL may be at high risk of venous thromboembolism (VTE). This systematic review aimed to estimate the risk of VTE in patients with PCNSL. A systematic review was conducted using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. MEDLINE, Embase, and CINAHL were searched from 1990 to 2022. Prospective and retrospective observational studies as well as clinical trials were included. The primary efficacy outcome was VTE, and the primary safety outcome was major bleeding as defined by the individual studies. After screening 883 studies, 46 studies (3688 patients) with PCNSL were included. Mean age was 62.4 years. Five studies explored the use of thromboprophylaxis (acetyl salicylic acid or anticoagulation [<em>n</em> = 1]) and low-molecular-weight heparin (<em>n</em> = 4). Overall, 420 patients developed VTE (11.4%), including 17 fatal events (4% of all VTE). Two studies that reported on VTE prophylaxis representing 77 patients identified 8 breakthrough VTE events (10.4%). Most studies (<em>n</em> = 34; 74.5%) did not report major bleeding complications. Among studies reporting on bleeding, 174 major bleeding (7.4%) events were reported out of 2361 patients, 3 of which were attributed to thromboprophylaxis. Patients with PCNSL seem to be at high risk of both VTE and bleeding complications. Future clinical trials in this population should routinely collect data on incidence of VTE and bleeding to help clinicians assess the risk-to-benefit ratio of thromboprophylaxis in this high-risk patient population.</p></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"8 6","pages":"Article 102507"},"PeriodicalIF":3.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2475037924002024/pdfft?md5=f1aacc9589f46720801fcbde42f4fb3a&pid=1-s2.0-S2475037924002024-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141706791","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":"Prescription and switching patterns of direct oral anticoagulants in patients with atrial fibrillation","authors":"Tim A.C. de Vries ,&nbsp;Roisin Bavalia ,&nbsp;Gordon Chu ,&nbsp;Helen Xiong ,&nbsp;Kayleigh M. van de Wiel ,&nbsp;Hanne van Ballegooijen ,&nbsp;Menno V. Huisman ,&nbsp;Martin E.W. Hemels ,&nbsp;Saskia Middeldorp ,&nbsp;Joris R. de Groot","doi":"10.1016/j.rpth.2024.102544","DOIUrl":"10.1016/j.rpth.2024.102544","url":null,"abstract":"<div><h3>Background</h3><p>The patterns of direct oral anticoagulant (DOAC) selection and switching to a different oral anticoagulant (OAC) in patients with atrial fibrillation (AF) are unknown.</p></div><div><h3>Objectives</h3><p>To describe temporal patterns in first DOAC prescriptions, estimate the incidence, and identify predictors of switching to a different OAC within 1 year in OAC-naive AF patients.</p></div><div><h3>Methods</h3><p>In this retrospective cohort study, using a near-nationwide prescription registry (IQVIA, the Netherlands), we determined the number of patients per month initiated on each DOAC and identified predictors of switching within 1 year with robust Poisson regression.</p></div><div><h3>Results</h3><p>We included 94,874 patients. From November 2015 to November 2019, the monthly use of apixaban (<em>n</em> = 366 to <em>n</em> = 1066, +191%), rivaroxaban (<em>n</em> = 379 to <em>n</em> = 868, +129%), and edoxaban (<em>n</em> = 2 to <em>n</em> = 305, +15,150%) increased, whereas that of dabigatran decreased (<em>n</em> = 317 to <em>n</em> = 179, −44%). In the 66,090 patients with ≥1 year of available calendar time, 7% switched to a different OAC within 1 year. Strong predictors of switching to a different DOAC were using dabigatran (adjusted risk ratio [aRR], 3.33; 95% CI, 3.02-3.66) or edoxaban (aRR, 1.56; 95% CI, 1.34-1.82) rather than apixaban and using a standard DOAC dose (aRR, 2.54; 95% CI, 2.23-2.88). Strong predictors of switching to a vitamin K antagonist were using rivaroxaban (aRR, 1.36; 95% CI, 1.19-1.54 vs apixaban) and using a standard DOAC dose (aRR, 1.49; 95% CI, 1.26-1.77).</p></div><div><h3>Conclusion</h3><p>In the Netherlands, factor Xa inhibitors are increasingly being selected for OAC-naive AF patients. Seven percent of patients switch to a different OAC within 1 year, and the initial DOAC type and dose are strong predictors of switching.</p></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"8 6","pages":"Article 102544"},"PeriodicalIF":3.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2475037924002395/pdfft?md5=3e676a8fe1eef5cad271dceb451f5210&pid=1-s2.0-S2475037924002395-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142129542","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":"Cross-reacting antiporcine factor VIII inhibitors in patients with acquired hemophilia A","authors":"Maddie Stephen ,&nbsp;Carolyne Elbaz ,&nbsp;Hina Hanif ,&nbsp;Katerina Pavenski ,&nbsp;Jerry Teitel ,&nbsp;Michelle Sholzberg","doi":"10.1016/j.rpth.2024.102553","DOIUrl":"10.1016/j.rpth.2024.102553","url":null,"abstract":"","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"8 6","pages":"Article 102553"},"PeriodicalIF":3.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2475037924002486/pdfft?md5=5cde6793d058b57ee44e1f45bb26b89d&pid=1-s2.0-S2475037924002486-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142167786","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":"G protein–coupled receptor kinase 5 regulates thrombin signaling in platelets","authors":"Chen Li ,&nbsp;Michael Malloy ,&nbsp;Sara K. Ture ,&nbsp;Benjamin Nieves-Lopez ,&nbsp;Florian Thibord ,&nbsp;Andrew D. Johnson ,&nbsp;Craig N. Morrell","doi":"10.1016/j.rpth.2024.102556","DOIUrl":"10.1016/j.rpth.2024.102556","url":null,"abstract":"<div><h3>Background</h3><p>Our prior genome-wide association study of thrombin-induced platelet aggregation identified a G protein–coupled receptor kinase 5 (GRK5) noncoding variant (rs10886430-G) that is strongly associated with increased platelet reactivity to thrombin. This variant predisposes to increased risk of stroke, pulmonary embolism, and venous thromboembolism.</p></div><div><h3>Objectives</h3><p>To determine role of platelet specific GRK5 in platelet responses to agonists and injury.</p></div><div><h3>Methods</h3><p>Platelets from GRK5 mutant mice have been shown to have increased thrombin sensitivity, indicating that GRK5 may be a negative regulator of platelet activation. However, this has not been studied in a platelet-specific manner. We therefore used platelet-specific GRK5 mutant mice and models of thrombosis and pulmonary embolism.</p></div><div><h3>Results</h3><p>We now demonstrate that mice lacking GRK5 specifically in platelets had a mild increase in thrombin responses <em>in vitro</em> and a shortened time to arterial thrombosis <em>in vivo</em>. In addition, platelet GRK5 mutant mice had increased thrombin but not collagen-induced thrombus burden in a mouse model of pulmonary embolism.</p></div><div><h3>Conclusion</h3><p>These data indicate that platelet GRK5 has a significant role in limiting platelet responses to thrombin.</p></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"8 6","pages":"Article 102556"},"PeriodicalIF":3.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2475037924002516/pdfft?md5=5185fefc966689b08d67786f0a393f41&pid=1-s2.0-S2475037924002516-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142171901","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":"Pharmacokinetics and pharmacodynamics of low doses of recombinant tissue plasminogen activator to establish a model for biosimilarity comparisons","authors":"Ulla Derhaschnig ,&nbsp;Nina Buchtele ,&nbsp;Margarete M. Steiner ,&nbsp;Christa Drucker ,&nbsp;Christa Firbas ,&nbsp;Christian Schörgenhofer ,&nbsp;Georg Gelbenegger ,&nbsp;Franz König ,&nbsp;Bernd Jilma ,&nbsp;Katarina D. Kovacevic Miljevic","doi":"10.1016/j.rpth.2024.102518","DOIUrl":"10.1016/j.rpth.2024.102518","url":null,"abstract":"<div><h3>Background</h3><p>Recombinant tissue plasminogen activator (rt-PA) is a thrombolytic agent and essential in emergency medical care. Given recent supply shortages, the availability of biosimilar products is an urgent medical need. However, biosimilarity trials are difficult to perform in critically ill patients.</p></div><div><h3>Objectives</h3><p>The aim of this pilot study was to investigate the pharmacokinetics and pharmacodynamics of low rt-PA doses to establish a model for testing proposed biosimilars in healthy volunteers.</p></div><div><h3>Methods</h3><p>Eight healthy volunteers received 0.02 to 0.05 mg/kg rt-PA on 3 study days; blood samples were obtained every 4 minutes after the end of the bolus infusion to measure rt-PA antigen levels by enzyme immunoassay, and the pharmacodynamics were assessed with rotational thromboelastometry.</p></div><div><h3>Results</h3><p>Bolus infusion of low rt-PA doses was safe and well tolerated. Maximal plasma concentrations and the area under the curve increased dose-dependently. Time-concentration curves were clearly separated between the lower and the higher doses. As expected, the half-live of rt-PA was short (4.5-5 min), and representative for therapeutic doses. The intrasubject coefficient variations were moderate (&lt;25%). Bolus infusion of rt-PA dose-dependently shortened lysis time and lysis onset time in both dose groups and caused maximum clot lysis of 100% in all participants.</p></div><div><h3>Conclusion</h3><p>In conclusion, the pharmacokinetics of rt-PA was dose linear and displayed limited intrasubject variability even at subtherapeutic doses. The half-life and thus clearance of rt-PA was representative of full therapeutic doses. The lysis time was shortened in a dose and time-dependent fashion and was clearly distinguishable between doses. Thus, the model appears to be suitable and sensitive to test biosimilarity.</p></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"8 6","pages":"Article 102518"},"PeriodicalIF":3.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2475037924002139/pdfft?md5=dfff651ba8e76ba6cb98ae530b39fe12&pid=1-s2.0-S2475037924002139-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142048046","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":"Exploratory rivaroxaban trial for isolated calf deep vein thrombosis with a risk factor of thrombosis extension: an open-label, multicenter, randomized controlled trial","authors":"Yoshito Ogihara ,&nbsp;Norikazu Yamada ,&nbsp;Daisuke Izumi ,&nbsp;Yuichi Sato ,&nbsp;Toru Sato ,&nbsp;Hitoshi Nakaya ,&nbsp;Tatsuya Mori ,&nbsp;Satoshi Ota ,&nbsp;Midori Makino ,&nbsp;Toru Ogura ,&nbsp;Satoshi Tamaru ,&nbsp;Yuki Nishimura ,&nbsp;Takashi Tanigawa ,&nbsp;Atsunobu Kasai ,&nbsp;Masakatsu Nishikawa ,&nbsp;Kaoru Dohi ,&nbsp;ISE CALF DVT Study Investigators","doi":"10.1016/j.rpth.2024.102515","DOIUrl":"10.1016/j.rpth.2024.102515","url":null,"abstract":"<div><h3>Background</h3><p>Limited evidence exists regarding the incidence of recurrent venous thromboembolism (VTE) in patients diagnosed with isolated distal deep vein thrombosis (DVT) who are at risk of thrombosis extension whether they receive anticoagulation therapy or not.</p></div><div><h3>Objectives</h3><p>The study aimed to investigate the incidence of recurrent VTE and the impact of rivaroxaban in this patient population.</p></div><div><h3>Methods</h3><p>This open-label, exploratory, and randomized controlled trial was conducted at 7 centers in Japan between April 2019 and April 2022. Adult patients with isolated distal DVT at risk of thrombosis extension received either rivaroxaban combined with physical therapy or physical therapy alone for 90 days. Whole-leg ultrasound was performed at 14 and 90 days. We assessed a composite outcome of symptomatic or asymptomatic proximal DVT or symptomatic pulmonary embolism as the primary outcome until the end of the treatment period using an intention-to-treat analysis. Major bleeding was evaluated as a key secondary outcome.</p></div><div><h3>Results</h3><p>Out of 90 enrolled patients, 3 were excluded due to withdrawal of consent; therefore, we analyzed 87 participants. The rivaroxaban group (<em>n</em> = 42) reported no primary outcomes (0%; 95% CI, 0.0%-8.4%), whereas the physical therapy group (<em>n</em> = 45) had 2 cases of symptomatic proximal DVT (4.4%; 95% CI, 0.5%-15.1%). Major bleeding events occurred in 4 patients in the rivaroxaban group (9.5%; 95% CI, 2.7%-22.6%), whereas no events occurred in the physical therapy group (0%; 95% CI, 0%-7.9%).</p></div><div><h3>Conclusion</h3><p>Preliminary data suggest that rivaroxaban may reduce the risk of VTE recurrence among this patient subset, albeit with an increased incidence of bleeding events.</p></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"8 5","pages":"Article 102515"},"PeriodicalIF":3.4,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2475037924002103/pdfft?md5=08d54b0330e6ca9b0791899a0db535c7&pid=1-s2.0-S2475037924002103-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141690000","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}