Journal of Thrombosis and Haemostasis最新文献

{"title":"Mice with Reduced PAR4 Reactivity show Decreased Venous Thrombosis and Platelet Procoagulant Activity.","authors":"Elizabeth A Knauss, Johana Guci, Norman Luc, Dante Disharoon, Grace H Huang, Anirban Sen Gupta, Marvin T Nieman","doi":"10.1016/j.jtha.2024.12.031","DOIUrl":"10.1016/j.jtha.2024.12.031","url":null,"abstract":"<p><strong>Background: </strong>Hypercoagulation and thrombin generation are major risk factors for venous thrombosis. Sustained thrombin signaling through PAR4 promotes platelet activation, phosphatidylserine exposure, and subsequent thrombin generation. A single-nucleotide polymorphism in PAR4 (rs2227376) changes proline to leucine extracellular loop 3 (P310L), which decreases PAR4 reactivity and is associated with a lower risk for venous thromboembolism (VTE) in a GWAS meta-analysis.</p><p><strong>Objective: </strong>The goal of this study is to determine the mechanism for the association of rs2227376 with reduced risk for VTE in using mice with a homologous mutation (PAR4-P322L).</p><p><strong>Methods: </strong>Venous thrombosis was examined using our recently generated PAR4-P322L mice in the inferior vena cava stasis and stenosis models. Coagulation and clot stability was measured using rotational thromboelastometry (ROTEM). Thrombin generating potential was measured in platelet-rich plasma. Phosphatidylserine surface expression and platelet-neutrophil aggregates were analyzed using flow cytometry.</p><p><strong>Results: </strong>PAR4^P/L and PAR4^L/L had reduced size of venous clots at 48 hours. PAR4^P/L and PAR4^L/L platelets had progressively decreased phosphatidylserine in response to thrombin and convulxin, in addition to decreased thrombin generation and decreased PAR4-mediated platelet-neutrophil aggregation.</p><p><strong>Conclusions: </strong>The leucine allele in extracellular loop 3, PAR4-322L leads to fewer procoagulant platelets, decreased endogenous thrombin potential and reduced platelet-neutrophil aggregation. This decreased ability to generate thrombin and bind to neutrophils offers a mechanism for PAR4's role in VTE highlighting a key role for PAR4 signaling.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142971363","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}

{"title":"Peak and Trough Concentrations of Apixaban and Rivaroxaban in Adult Patients: A Systematic Review and Meta-Analysis.","authors":"Christian Andrew Almalbis, Adyani Md Redzuan, Chester Paul Andrada, Nicole Ann Gonzaga, Shamin Mohd Saffian","doi":"10.1016/j.jtha.2024.12.032","DOIUrl":"https://doi.org/10.1016/j.jtha.2024.12.032","url":null,"abstract":"<p><strong>Background: </strong>Apixaban and rivaroxaban are factor Xa inhibitors commonly used for treatment of venous thromboembolism and stroke prevention in patients with atrial fibrillation. While routine monitoring of their concentrations is not recommended, but it may be beneficial in certain situations. Expected peak and trough concentrations remain poorly understood, with most data derived from small studies OBJECTIVES: To establish the average peak and trough concentrations of apixaban and rivaroxaban from real-world studies.</p><p><strong>Methods: </strong>PubMed, Scopus, and Web of Science were searched until October 2023 for observational studies reporting apixaban and rivaroxaban concentrations. Meta-regression was used to examine factors influencing these concentrations.</p><p><strong>Results: </strong>Sixteen studies involving 1054 apixaban and 1321 rivaroxaban patients were pooled using random-effects model. Mean apixaban peak concentrations were 157 ng/mL (95% CI, 127-187) for 2.5 mg and 228 ng/mL (95% CI, 204-252) for 5 mg, with trough concentrations of 77 ng/mL (95% CI, 56-98) and 113 ng/mL (95% CI, 101-124), respectively. Mean rivaroxaban peak concentrations were 168 ng/mL (95% CI, 104-232) for 10 mg, 225 ng/mL (95% CI, 192-257) for 15 mg, and 229 ng/mL (95% CI, 193-264) for 20 mg, with trough concentrations of 23 ng/mL (95% CI, 13-32), 31 ng/mL (95% CI, 26-36), and 36 ng/mL (95% CI, 25-47), respectively. Meta-regression revealed age and creatinine clearance correlated with apixaban peak concentrations. Creatinine clearance correlated with apixaban and rivaroxaban trough concentrations.</p><p><strong>Conclusions: </strong>The pooled mean concentrations align with expected concentration ranges reported in different pharmacokinetic studies.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142971441","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}

{"title":"A mutant complement factor H (W1183R) enhances proteolytic cleavage of von Willebrand factor by ADAMTS-13 under shear.","authors":"Wenjing Cao, Yi Liu, X Frank Zhang, X Long Zheng","doi":"10.1016/j.jtha.2024.11.031","DOIUrl":"10.1016/j.jtha.2024.11.031","url":null,"abstract":"<p><strong>Background: </strong>A loss-of-functional mutation (W1183R) in human complement factor H (CFH) is associated with complement-associated hemolytic uremic syndrome; mice carrying a similar mutation (W1206R) in CFH also develop thrombotic microangiopathy but its plasma von Willebrand factor (VWF) multimer sizes were dramatically reduced. The mechanism underlying such a dramatic change in plasma VWF multimer distribution in these mice is not fully understood.</p><p><strong>Objectives: </strong>To determine the VWF and CFH interaction and how CFH proteins affect VWF multimer distribution.</p><p><strong>Methods: </strong>We employed recombinant protein expression, purification, and various biochemical and biophysical tools.</p><p><strong>Results: </strong>Purified recombinant W1183R-CFH but not wild-type (WT) CFH protein enhanced the proteolytic cleavage of both peptidyl and multimeric VWF substrates by recombinant ADAMTS-13 in a concentration-dependent manner. Microscale thermophoresis assay demonstrated that both W1183R-CFH and WT-CFH proteins bound various VWF fragments (eg, AIM-A1, A1-A2-A3, D'D3, D'D3-A1, and D'D3-A1-A2) with high affinities. Optical tweezer experiments further showed a concentration-dependent alteration in the contour length (L_c) and the persistent length (L_p) following pulling VWF-A2 domain in the presence of W1183R-CFH or WT-CFH protein. AlphaFold experiments revealed conformational changes in the VWF-A2, particularly the central region where the cleavage bond resides following addition of W1183R-CFH or WT-CFH protein.</p><p><strong>Conclusion: </strong>These results demonstrate for the first time that W1183R-CFH but not WT-CFH protein enhances the proteolytic cleavage of VWF by ADAMTS-13 under shear. This may be achieved by mechanic-induced conformational changes of the central A2 domain, leading to an enhanced cleavage of Tyr¹⁶⁰⁵-Met¹⁶⁰⁶ bond by ADAMTS-13 under pathophysiological conditions.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142971360","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}

{"title":"Accurate evaluation of factor VIII activity of efanesoctocog alfa in the presence of emicizumab.","authors":"Christophe Nougier, Steven W Pipe, Ingrid Pabinger, Claire Pouplard, Roger E G Schutgens, Cedric Hermans, Guy Young, Edison Sexton, Peter Quehenberger, Eve-Anne Guery, Albert Huisman, Marie-Astrid Van Dievoet, Elizabeth Marquez, Yesim Dargaud","doi":"10.1016/j.jtha.2024.12.034","DOIUrl":"10.1016/j.jtha.2024.12.034","url":null,"abstract":"<p><strong>Background: </strong>Efanesoctocog is a B-domain-deleted, Fc-fusion factor (F)VIII linked to the D'D3 domain of von Willebrand factor and 2 XTEN polypeptides, designed for an ultra-extended half-life for prophylaxis in hemophilia A, but also aiding in managing acute bleeding or surgery in patients on long-term emicizumab. However, no current laboratory method accurately measures FVIII levels in the presence of emicizumab.</p><p><strong>Objectives: </strong>To test whether the bovine chromogenic FVIII assay, specifically calibrated for efanesoctocog, could provide an accurate assessment of efanesoctocog activity.</p><p><strong>Methods: </strong>Seven centers across 5 countries received 12 plasma samples to measure in triplicate using 2 calibration methods across 3 independent days. Samples (n = 6) contained either only efanesoctocog (FVIII activity [FVIII:C]= 5 to 150 IU/dL), or efanesoctocog (FVIII:C = 5 to 150 IU/dL) in combination with emicizumab (50 μg/mL; n = 5). One sample contained efanesoctocog (FVIII:C = 50 IU/dL) and a high dose of emicizumab (80 μg/mL); another sample contained efanesoctocog (FVIII:C = 50 IU/dL) with a low dose of emicizumab (20 μg/mL). Each center used its own analyzers, along with their usual reagents.</p><p><strong>Results: </strong>Chromogenic assay (CSA) calibrated with standard calibrators highly overestimates FVIII:C. However, specific calibration with efanesoctocog enabled accurate measurement of FVIII:C, with low inter- and intra-laboratory variability, and no interference from emicizumab. All CSA reagents used in the study demonstrated low variability across different laboratories (interlaboratory coefficient of variation ranges between 9% and 20%).</p><p><strong>Conclusion: </strong>Specific calibration of the FVIII CSA using efanesoctocog and bovine reagents allows for accurate measurement of FVIII:C in patients receiving efanesoctocog, even in the presence of emicizumab.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142971411","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}

{"title":"Systematic Analysis of the Design, Methodology and Patient Population Characteristics of the Pediatric Direct Oral Anticoagulant (DOAC) Trials of Venous Thromboembolism Treatment.","authors":"Marisol Betensky, Manuela Albisetti, Tina Biss, Rukhmi V Bhat, Leonardo R Brandão, Thomas Diacovo, Paul Monagle, Leslie Raffini, Shoshana Revel-Vilk, C Heleen van Ommen, Hilary Whitworth, Neil A Goldenberg, Christoph Male","doi":"10.1016/j.jtha.2024.12.035","DOIUrl":"https://doi.org/10.1016/j.jtha.2024.12.035","url":null,"abstract":"<p><strong>Introduction: </strong>The pediatric direct oral anticoagulation (DOAC) trials provide an opportunity to evaluate and characterize challenges in their design and execution to inform future antithrombotic trials.</p><p><strong>Objective: </strong>To perform a systematic review of pediatric DOAC trials for the treatment of venous thromboembolism to critically appraise their methodology and understand the feasibility and challenges.</p><p><strong>Methods: </strong>Systematic search of MEDLINE, EMBASE, the Cochrane Library and ClinicalTrials.gov (January 2002 to December 2022). Studies reporting the results of interventional trials of a DOAC for the treatment of acute VTE in children, and their respective design papers were included. Trial registration information was reviewed in clinicaltrials.gov. Discrepancies in study design, targeted populations, sample size and analyses between planned and actual trial conduct were examined qualitatively.</p><p><strong>Results: </strong>Five published studies, and unpublished data for two additional trials were included. All trials had modifications to their design or methodology, and discrepancies between the trial's registration and the final published study, suggesting feasibility challenges. Modifications to the eligibility criteria, changes in sample size, challenges with recruitment of younger patients, and enrolled population not matching the clinical target population were identified for all trials. Discrepancies in outcome reporting, particularly for secondary endpoints, were also common.</p><p><strong>Conclusions: </strong>DOAC trials experienced feasibility challenges that led to design or methodology modifications. Future pediatric antithrombotic trials will need to be adaptive in their design, prioritize enrollment of younger children and input from clinicians providing care to target populations, ensure that enrolled populations match the clinical population, and select clinically meaningful endpoints.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142971503","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}

{"title":"Risk of ischemic stroke after cancer diagnosis: a population-based matched cohort study.","authors":"Deborah M Siegal, Joshua O Cerasuolo, Marc Carrier, Peter L Gross, Moira K Kapral, David Kirkwood, Ronda Lun, Michel Shamy, Rinku Sutradhar","doi":"10.1016/j.jtha.2024.12.029","DOIUrl":"https://doi.org/10.1016/j.jtha.2024.12.029","url":null,"abstract":"<p><strong>Background: </strong>There are limited data regarding the association between cancer and ischemic stroke, particularly among individuals with previous stroke. Our objective was to measure and compare the risk of ischemic stroke in individuals with and without cancer.</p><p><strong>Methods: </strong>Population-based matched cohort study in Ontario, Canada. Participants ≥18 years with a new diagnosis of cancer were matched (1:1) to cancer-free controls by age and sex in two separate matched cohorts based on the absence (Matched Cohort 1) or presence (Matched Cohort 2) of prior ischemic stroke. The primary outcome was the incidence of ischemic stroke. We calculated sub-distribution adjusted hazard ratios (aHR) and 95% confidence intervals (CI) for ischemic stroke (death as a competing event).</p><p><strong>Results: </strong>In Matched Cohort 1, the rate and risk of ischemic stroke were higher among 620,647 cancer patients versus 620,647 controls at 1.5 years (4.6/1000 person-years [95%CI 4.5-4.7] vs 3.5/1000 person-years [95%CI 3.4-3.6], aHR 1.40, 95%CI 1.34-1.47). In Matched Cohort 2, the rate and risk of ischemic stroke were similar among 13,924 cancer patients and 13,924 controls at 1.5 years (26.9/1000 person-years [95%CI 25.1-28.9] vs 22.0 /1000 person-years [95/%CI 20.7-23.4]; aHR 1.00, 95%CI 0.88-1.14). In both cohorts, the risk of ischemic stroke was lower in cancer patients versus controls from 1.5 to 5 years (aHR 0.72, 95%CI 0.69-0.74 and aHR 0.53, 95%CI 0.46-0.62).</p><p><strong>Conclusions: </strong>Compared to cancer-free controls, the rate and risk of ischemic stroke were higher 1.5 years after cancer diagnosis in individuals without prior stroke and varied according to cancer site and stage.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142971489","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}

{"title":"Gut microbiome dysbiosis is not associated with portal vein thrombosis in patients with end-stage liver disease: a cross-sectional study.","authors":"Rali R Aleksandrova, Lianne M Nieuwenhuis, Naomi Karmi, Shuyan Zhang, J Casper Swarte, Johannes R Björk, Ranko Gacesa, Hans Blokzijl, Margery A Connelly, Rinse K Weersma, Ton Lisman, Eleonora A M Festen, Vincent E de Meijer","doi":"10.1016/j.jtha.2024.12.036","DOIUrl":"https://doi.org/10.1016/j.jtha.2024.12.036","url":null,"abstract":"<p><strong>Background: </strong>Portal vein thrombosis (PVT) is a common complication in patients with end-stage liver disease (ESLD). The portal vein in ESLD patients is proposedly an inflammatory vascular bed due to translocation of endotoxins and cytokines from the gut. We hypothesized that a pro-inflammatory gut microbiome and elevated trimethylamine N-oxide (TMAO), a driver of thrombosis, may contribute to PVT development.</p><p><strong>Objectives: </strong>We investigated whether gut microbiome diversity, bacterial species, metabolic pathways, and TMAO levels are associated with PVT in ESLD patients.</p><p><strong>Methods: </strong>Fecal samples, plasma samples and data from ESLD patients and healthy controls were collected through the TransplantLines Biobank and Cohort Study. PVT was defined as a thrombus in the portal vein within a year prior to or after fecal sample collection. Fecal samples were analyzed using Shotgun Metagenomic Sequencing, and TMAO levels were measured in plasma using a Vantera® Clinical Analyzer.</p><p><strong>Results: </strong>102 ESLD patients, of which 23 with PVT, and 246 healthy controls were included. No significant difference in gut microbiome diversity was found between patients with PVT and without PVT (P=0.18). Both ESLD groups had significantly lower alpha-diversity compared with controls. Bacteroides fragilis and three Clostridiales species were increased in patients with PVT compared to without PVT. TMAO levels between the three groups were not significantly different.</p><p><strong>Conclusion: </strong>We observed profound differences in gut microbiota between ESLD patients and controls, but minimal differences between ESLD patients with or without PVT. In our cohort, a gut-derived pro-inflammatory state was not associated with presence of PVT in ESLD patients.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142971436","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}

{"title":"Replacement of a single residue changes the primary specificity of thrombin.","authors":"Alessia Dei Rossi, Samantha Deavila, Bassem M Mohammed, Sergey Korolev, Enrico Di Cera","doi":"10.1016/j.jtha.2024.12.024","DOIUrl":"10.1016/j.jtha.2024.12.024","url":null,"abstract":"<p><strong>Background: </strong>Thrombin prefers substrates carrying Arg at the site of cleavage (P1) because of the presence of D189 in the primary specificity (S1) pocket but can also cleave substrates carrying Phe at P1. The structural basis of this property is unknown.</p><p><strong>Objectives: </strong>Solve the X-ray structure of thrombin bound to a ligand carrying Phe at P1 and investigate the effects of replacing D189.</p><p><strong>Methods: </strong>X-ray crystallography is used to solve the structure of thrombin bound to the irreversible inhibitor H-D-Phe-Pro-Phe-CH₂Cl (PPPCK). Residue D189 is mutated to Ala, Lys, Phe, and Ser.</p><p><strong>Results: </strong>The X-ray structure of the thrombin-PPPCK complex is solved at 2.5 Å resolution and compared to the structure of thrombin bound to H-D-Phe-Pro-Arg-CH₂Cl (PPACK). PPPCK binds to thrombin in a conformation similar to that of PPACK, but Phe at P1 makes no contacts with D189. Replacement of D189 with Ala, Lys, Phe, or Ser reverses both substrate preference and stability enhancement from Arg to Phe.</p><p><strong>Conclusion: </strong>D189 in the S1 pocket confers thrombin \"trypsin-like\" specificity for Arg at P1. However, the S1 pocket is wide enough to also enable \"chymotrypsin-like\" specificity for Phe at P1. Consistent with these structural features, a single amino acid replacement (D189A) switches thrombin specificity from trypsin-like to chymotrypsin-like, converting the substrate preference from H-D-Phe-Pro-Arg-p-nitroanilide to H-D-Phe-Pro-Phe-p-nitroanilide and preferential stability enhancement from PPACK to PPPCK. The observation that thrombin specificity is controlled mainly by a single residue establishes a new paradigm in the field of trypsin-like proteases.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142932191","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}

{"title":"Therapeutic potential of roxadustat in immune thrombocytopenia: A Mendelian randomization analysis.","authors":"Jingyao Ma, Yu Hu, Shuyue Dong, Jinxi Meng, Zhifa Wang, Juntao Ouyang, Zheyan Lin, Xiaoling Cheng, Zhenping Chen, Runhui Wu","doi":"10.1016/j.jtha.2024.12.028","DOIUrl":"https://doi.org/10.1016/j.jtha.2024.12.028","url":null,"abstract":"<p><strong>Background: </strong>Immune thrombocytopenia (ITP) is characterized by immune-mediated platelet destruction and impaired megakaryocyte maturation. Hypoxia-inducible factor-1 alpha (HIF-1α), pivotal in the development of megakaryocytes and immune regulation, is downregulated in ITP. Roxadustat, which stabilizes HIF-1α, has emerged as a potential therapeutic drug for ITP that acts by enhancing HIF-1α-mediated megakaryocyte development and modulating immune responses.</p><p><strong>Objectives: </strong>This study evaluates the safety profile of roxadustat and its therapeutic efficacy for ITP treatment using Mendelian randomization (MR) analysis.</p><p><strong>Methods: </strong>We used expression Quantitative Trait Loci (eQTLs) data for roxadustat's target genes (EGLN1, EGLN2, EGLN3) and genetic associations with ITP, and adverse outcomes from the Open Genome-Wide Association Study (OpenGWAS) project. MR analysis included IVW, MR-Egger regression, weighted median, and MR pleiotropy residual sum and outlier (MR-PRESSO) methods to evaluate pleiotropy. Heterogeneity was assessed using Cochran's Q statistic and I² measure, with sensitivity analyses. A meta-analysis was performed to integrate effect sizes from multiple literature sources.</p><p><strong>Results: </strong>MR analysis revealed a significant association between roxadustat and reduced ITP risk (odds ratio [OR] 0.79, 95% confidence interval [CI] 0.66-0.95, P=0.01) with no evidence of horizontal pleiotropy. Meta-analysis confirmed the protective effect of roxadustat on ITP. Utilizing eQTLs of roxadustat's target gene EGLN1 as instrumental variables, an MR analysis of 39 potential adverse reactions revealed no significant increase, suggesting a favorable safety profile for roxadustat.</p><p><strong>Conclusion: </strong>Roxadustat demonstrates a potential protective effect against ITP without increasing the risk of adverse outcomes, suggesting its promise as a therapeutic option for ITP and warranting further investigation.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142932195","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}

{"title":"Structure-resolved dynamics of type 2M von Willebrand disease.","authors":"Alexander Tischer, Laurie Moon-Tasson, Matthew Auton","doi":"10.1016/j.jtha.2024.12.026","DOIUrl":"10.1016/j.jtha.2024.12.026","url":null,"abstract":"<p><strong>Background: </strong>Genetically determined amino acid substitutions in the platelet adhesive A1 domain alter von Willebrand factor's (VWF) platelet agglutination competence, resulting in both gain- (type 2B) and loss-of-function (type 2M) phenotypes of von Willebrand disease. Prior studies of variants in both phenotypes revealed defects in secondary structure that altered stability and folding of the domain. An intriguing observation was that loss of function arose from both misfolding of A1 and, in a few cases, hyperstabilization of the native structure.</p><p><strong>Objectives: </strong>To fully understand the 2M phenotype, we thoroughly investigated the structure/function relationships of 15 additional type 2M variants and 2 polymorphisms in the A1 domain.</p><p><strong>Methods: </strong>These variants were characterized using circular dichroism, fluorescence, calorimetry, hydrogen-deuterium exchange mass spectrometry, surface plasmon resonance, and platelet adhesion under shear flow.</p><p><strong>Results: </strong>Six variants were natively folded, with 4 being hyperstabilized. Nine variants disordered A1, causing a loss in α-helical structure and unfolding enthalpy. GPIbα binding affinity and platelet adhesion dynamics were highly correlated to helical structure. Hydrogen-deuterium exchange resolved specific C-terminal secondary structure elements that differentially diminish the GPIbα binding affinity of A1. These localized structural perturbations were highly correlated to GPIbα binding affinity and shear-dependent platelet adhesion.</p><p><strong>Conclusion: </strong>While hyperstabilized dynamics in A1 do impair stable platelet attachment to VWF under flow, variant-induced localized disorder in specific regions of the domain misfolds A1 and abrogates platelet adhesion. These 2 opposing conformational properties represent 2 structural classes of VWF that drive the loss-of-function phenotype that is type 2M von Willebrand disease.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142932193","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}