Journal of Thrombosis and Haemostasis最新文献

{"title":"Persistent splenic-derived IgMs preferentially recognize factor VIII A2 and C2 domain epitopes but do not alter antibody production","authors":"Elizabeth S. York ,&nbsp;Benjamin D. Dratch ,&nbsp;Jasmine Ito ,&nbsp;Samantha M. Horwitz ,&nbsp;Sahand Emamian ,&nbsp;Joseph A. Ambarian ,&nbsp;Surinder Gill ,&nbsp;Jayre Jones ,&nbsp;Satheesh Chonat ,&nbsp;Pete Lollar ,&nbsp;Shannon L. Meeks ,&nbsp;Katherine M. Davis ,&nbsp;Glaivy Batsuli","doi":"10.1016/j.jtha.2024.10.017","DOIUrl":"10.1016/j.jtha.2024.10.017","url":null,"abstract":"<div><h3>Background</h3><div>The most significant treatment complication for patients with hemophilia A is the development of neutralizing immunoglobins (Igs) G, termed inhibitors, against factor VIII (FVIII), which prevent FVIII replacement therapy. Low titers of FVIII-specific IgMs have been identified in hemophilia A patients with and without inhibitors, as well as in healthy individuals. However, the duration and influence of IgMs on the immune response to FVIII remains unclear.</div></div><div><h3>Objectives</h3><div>To characterize the binding interactions of persistently secreted FVIII-specific IgMs in hemophilia A mice and assess their effect on IgG antibody development.</div></div><div><h3>Methods</h3><div>Splenic-derived monoclonal antibodies (mAbs) from immunized FVIII knockout mice were isolated and purified using hybridoma technology. Binding interactions were assessed utilizing a novel fluid-phase enzyme-linked immunosorbent assay and computational modeling with High Ambiguity-Driven protein-protein DOCKing to account for weak IgM binding.</div></div><div><h3>Results</h3><div>Sixteen porcine cross-reactive and noninhibitory FVIII-specific IgM mAbs were identified. RNA sequencing of FVIII-specific IgMs revealed 13 unique variable, diversity, and joining (VDJ)/variable and joining (VJ) sequences indicating derivation from 13 unique B cell clones. The IgMs demonstrated polyclonal and polyreactive binding to FVIII <em>in vitro</em> and <em>in silico</em>. Molecular docking studies with reconstructed IgM variable, diversity, and joining/variable and joining regions identified frequent IgM interactions with amino acid residues K376, T381, K437, R2215, or K2249 within the FVIII A2 and C2 domains. Injections of individual IgMs prior to FVIII exposure and co-injection of FVIII/IgM immune complexes did not affect <em>de novo</em> FVIII antibody production.</div></div><div><h3>Conclusion</h3><div>Persistent FVIII-specific IgMs are polyclonal but preferentially bind the A2 and C2 domains. FVIII/IgM immune complex formation does not significantly alter inhibitor development.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"23 2","pages":"Pages 440-457"},"PeriodicalIF":5.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142546158","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":"Validating International Classification of Diseases Code 10th Revision algorithms for accurate identification of pulmonary embolism","authors":"Behnood Bikdeli ,&nbsp;Candrika D. Khairani ,&nbsp;Antoine Bejjani ,&nbsp;Ying-Chih Lo ,&nbsp;Shiwani Mahajan ,&nbsp;César Caraballo ,&nbsp;Jose Victor Jimenez ,&nbsp;Darsiya Krishnathasan ,&nbsp;Mehrdad Zarghami ,&nbsp;Sina Rashedi ,&nbsp;David Jimenez ,&nbsp;Stefano Barco ,&nbsp;Eric A. Secemsky ,&nbsp;Frederikus A. Klok ,&nbsp;Andetta R. Hunsaker ,&nbsp;Ayaz Aghayev ,&nbsp;Alfonso Muriel ,&nbsp;Mohamad A. Hussain ,&nbsp;Abena Appah-Sampong ,&nbsp;Yuan Lu ,&nbsp;Harlan M. Krumholz","doi":"10.1016/j.jtha.2024.10.013","DOIUrl":"10.1016/j.jtha.2024.10.013","url":null,"abstract":"<div><h3>Background</h3><div>Many research investigations for pulmonary embolism (PE) rely on the International Classification of Diseases 10th Revision (ICD-10) codes for analyses of electronic databases. The validity of ICD-10 codes in identifying PE remains uncertain.</div></div><div><h3>Objectives</h3><div>The objective of this study was to validate an algorithm to efficiently identify pulmonary embolism using ICD-10 codes.</div></div><div><h3>Methods</h3><div>Using a prespecified protocol, patients in the Mass General-Brigham hospitals (2016-2021) with ICD-10 principal discharge codes for PE, those with secondary codes for PE, and those without PE codes were identified (<em>n</em> = 578 from each group). Weighting was applied to represent each group proportionate to their true prevalence. The accuracy of ICD-10 codes for identifying PE was compared with adjudication by independent physicians. The F1 score, which incorporates sensitivity and positive predictive value (PPV), was assessed. Subset validation was performed at Yale-New Haven Health System.</div></div><div><h3>Results</h3><div>A total of 1712 patients were included (age: 60.6 years; 52.3% female). ICD-10 PE codes in the principal discharge position had sensitivity and PPV of 58.3% and 92.1%, respectively. Adding secondary discharge codes to the principal discharge codes improved the sensitivity to 83.2%, but the PPV was reduced to 79.1%. Using a combination of ICD-10 PE principal discharge codes or secondary codes plus imaging codes for PE led to sensitivity and PPV of 81.6% and 84.7%, respectively, and the highest F1 score (83.1%; <em>P &lt;</em> .001 compared with other methods). Validation yielded largely similar results.</div></div><div><h3>Conclusion</h3><div>Although the principal discharge codes for PE show excellent PPV, they miss 40% of acute PEs. A combination of principal discharge codes and secondary codes plus PE imaging codes led to improved sensitivity without severe reduction in PPV.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"23 2","pages":"Pages 556-564"},"PeriodicalIF":5.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142591030","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":"Catheter-related thrombosis in adults with cancer: a secondary analysis of a prospective randomized controlled trial","authors":"Greg Hapgood ,&nbsp;Kate Hill ,&nbsp;Satomi Okano ,&nbsp;Emad Abro ,&nbsp;David Looke ,&nbsp;Glen Kennedy ,&nbsp;Gilbert Pavilion ,&nbsp;Rosita Van Kuilenburg ,&nbsp;Alanna Geary ,&nbsp;Warren Joubert ,&nbsp;Melissa Eastgate ,&nbsp;Mark Jones ,&nbsp;Peter Mollee","doi":"10.1016/j.jtha.2024.11.002","DOIUrl":"10.1016/j.jtha.2024.11.002","url":null,"abstract":"<div><h3>Background</h3><div>Catheter-related thrombosis (CRT) is a complication of central venous access devices (CVADs). Evidence is variable regarding the significance of the side of catheter insertion. The role of the patient’s hand dominance in predisposition to CRT remains uncertain.</div></div><div><h3>Objectives</h3><div>In a prospective randomized controlled trial, adult cancer patients were randomly allocated to either dominant or nondominant side CVAD insertion. The primary endpoint of this trial examined the incidence of catheter-associated bloodstream infection. Here, we report the secondary endpoint of the incidence of CRT.</div></div><div><h3>Methods</h3><div>Six hundred forty CVADs were randomized to the dominant (<em>n</em> = 322) or nondominant (<em>n</em> = 318) side of insertion. Only symptomatic patients underwent ultrasound imaging to evaluate for CRT.</div></div><div><h3>Results</h3><div>The median patient age was 58 years, 60% of patients had hematologic malignancies and 40% had solid tumors. CVADs used were peripherally-inserted central catheter line (67%), tunneled CVAD (23%), or nontunneled CVAD (10%). The CRT incidence rate was 0.65 versus 0.82 per 1000 line days in the dominant versus nondominant group (hazard ratio [HR], 1.2; 95% CI, 0.58-2.48; <em>P</em> = .63). There was no significant difference in CRT incidence rate between left- and right-sided insertions (HR, 0.63; 95% CI, 0.30-1.32; <em>P</em> = .22). The CRT incidence rate was lower in right-handed versus left-handed line inserters (HR, 0.29; 95% CI, 0.12-0.71; <em>P</em> = .007).</div></div><div><h3>Conclusion</h3><div>The rate of CRT was not associated with whether CVAD insertion was on the patient’s dominant or nondominant side or the side of insertion. The role of inserter hand dominance requires further investigation.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"23 2","pages":"Pages 627-634"},"PeriodicalIF":5.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142644063","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":"Long-term FXa inhibition attenuates thromboinflammation after acute myocardial infarction and stroke by platelet proteome alteration","authors":"Amin Polzin ,&nbsp;Marcel Benkhoff ,&nbsp;Manuela Thienel ,&nbsp;Maike Barcik ,&nbsp;Philipp Mourikis ,&nbsp;Khrystyna Shchurovska ,&nbsp;Carolin Helten ,&nbsp;Vincent Ehreiser ,&nbsp;Zhang Zhe ,&nbsp;Franziska von Wulffen ,&nbsp;Alexander Theiss ,&nbsp;Sameera Peri ,&nbsp;Sophie Cremer ,&nbsp;Samantha Ahlbrecht ,&nbsp;Saif Zako ,&nbsp;Laura Wildeis ,&nbsp;Gabrielle Al-Kassis ,&nbsp;Daniel Metzen ,&nbsp;Amelie Utz ,&nbsp;Hao Hu ,&nbsp;Tobias Petzold","doi":"10.1016/j.jtha.2024.10.025","DOIUrl":"10.1016/j.jtha.2024.10.025","url":null,"abstract":"<div><h3>Background</h3><div>Immediate activated factor (F)X (FXa) inhibition exerts direct antiplatelet effects in the context of arterial thrombosis but little is known about the impact of long-term therapy on platelet function in ischemic cardiovascular diseases.</div></div><div><h3>Objectives</h3><div>Therefore, we analyzed platelet-derived effects of long-term FXa inhibition in the setting of acute myocardial infarction (AMI) and stroke.</div></div><div><h3>Methods</h3><div>We evaluated the effect of acute versus chronic FXa inhibition on thromboinflammation following AMI and stroke in mice <em>in vivo</em>. Mechanistically, we identified changes in platelet gene expression and proteome under chronic FXa nonvitamin K antagonist oral anticoagulant treatment and characterized its functional consequence on platelet physiology. In a prospectively recruited cohort of patients with AMI, we determined cardiovascular magnetic resonance based cardiac endpoints under FXa nonvitamin K antagonist oral anticoagulant effects on clinical endpoints in a cohort of patients with AMI.</div></div><div><h3>Results</h3><div>Chronic but not acute FXa inhibition reduced cerebral and myocardial infarct size and improved cardiac function 24 hours after AMI in mice. Mechanistically, we identified an attenuated thromboinflammatory response with reduced neutrophil extracellular trap formation in mice and patient samples. Proteome and RNA expression analysis of FXa inhibitor treated patients revealed a reduction of key regulators within the membrane trafficking and secretion machinery hampering platelet α and dense granule release. Subsequent, thromboinflammatory neutrophil extracellular trap density in thrombi isolated from stroke and myocardial infarction patients was reduced. Patients with AMI treated with FXa inhibitors showed decreased infarct size after myocardial infarction compared to patients without anticoagulation treatment.</div></div><div><h3>Conclusion</h3><div>Long-term FXa inhibition induces antithromboinflammatory proteome signatures in platelets, improving infarct size after myocardial infarction and stroke.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"23 2","pages":"Pages 668-683"},"PeriodicalIF":5.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142648392","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}

{"title":"Reuse, recycle, repurpose: pazopanib for bleeding in hereditary hemorrhagic telangiectasia","authors":"Hanny Al-Samkari","doi":"10.1016/j.jtha.2024.11.025","DOIUrl":"10.1016/j.jtha.2024.11.025","url":null,"abstract":"","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"23 2","pages":"Pages 394-396"},"PeriodicalIF":5.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074771","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":"Comparative effectiveness and safety of rivaroxaban with other oral anticoagulants in older adults with nonvalvular atrial fibrillation: population-based analysis in response to updated Beers Criteria","authors":"Ghadeer K. Dawwas ,&nbsp;Adam Cuker","doi":"10.1016/j.jtha.2024.10.009","DOIUrl":"10.1016/j.jtha.2024.10.009","url":null,"abstract":"<div><h3>Background</h3><div>Concerns have been raised regarding the updated Beers Criteria that recommended avoiding rivaroxaban use for long-term treatment of older adults with nonvalvular atrial fibrillation (AF).</div></div><div><h3>Objectives</h3><div>We sought to compare the effectiveness and safety of rivaroxaban with oral anticoagulants in older adults with nonvalvular AF.</div></div><div><h3>Methods</h3><div>We used an administrative healthcare database and included adults with AF aged ≥65 years who were new users of rivaroxaban or the comparators. We created 3 pairwise comparisons: rivaroxaban vs warfarin; rivaroxaban vs dabigatran; and rivaroxaban vs apixaban. Study outcomes included stroke or systemic embolism (effectiveness) and gastrointestinal or intracranial bleeding (safety). In the propensity score–matched sample, we used Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% CIs.</div></div><div><h3>Results</h3><div>In the matched cohorts, use of rivaroxaban (vs warfarin) increased risk of bleeding (HR, 1.13; 95% CI, 1.03-1.23) with no difference in ischemic stroke or systemic embolism (HR, 0.90; 95% CI, 0.79-1.02); use of rivaroxaban (vs dabigatran) increased risk of bleeding (HR, 1.18; 95% CI, 1.03-1.35) with no difference in ischemic stroke and systemic embolism (HR, 1.00; 95% CI, 0.83-1.22); and use of rivaroxaban (vs apixaban) increased risk of stroke and systemic embolism (HR, 1.23; 95% CI, 1.08-1.40) and bleeding (HR, 1.60; 95% CI, 1.45-1.76).</div></div><div><h3>Conclusion</h3><div>In this comparative effectiveness and safety study of older adults with nonvalvular AF, use of rivaroxaban was associated with a significantly increased risk of ischemic stroke and systemic embolism compared with apixaban and bleeding compared with warfarin, dabigatran, and apixaban. Our findings may inform anticoagulant selection in older adults with nonvalvular AF.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"23 2","pages":"Pages 546-555"},"PeriodicalIF":5.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142502851","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}

{"title":"“Identification of hemodynamically stable patients with acute pulmonary embolism at high risk for death: external validation of different models”: comment","authors":"Carlo Bova","doi":"10.1016/j.jtha.2024.11.026","DOIUrl":"10.1016/j.jtha.2024.11.026","url":null,"abstract":"","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"23 2","pages":"Page 753"},"PeriodicalIF":5.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074747","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":"Real-world safety and efficacy of rADAMTS13 in the treatment of congenital thrombotic thrombocytopenic purpura in pediatric patients in Poland","authors":"Pawel Laguna ,&nbsp;Maria Szczepanska ,&nbsp;Magdalena Wojdalska ,&nbsp;Halina Bobrowska ,&nbsp;Joanna Kulik ,&nbsp;Danuta Pietrys ,&nbsp;Walentyna Balwierz ,&nbsp;Elzbieta Trembecka-Dubel ,&nbsp;Wojciech Mlynarski ,&nbsp;Aleksandra Laguna","doi":"10.1016/j.jtha.2024.11.008","DOIUrl":"10.1016/j.jtha.2024.11.008","url":null,"abstract":"<div><h3>Background</h3><div>Congenital thrombotic thrombocytopenic purpura (cTTP) is an ultrarare microvascular disease caused by the deficiency of the metalloprotease ADAMTS13 (a disintegrin and metalloprotease with thrombospondin motifs 13). Approximately half of all cases remain undiagnosed until a triggering event in adulthood; therefore, the prevalence rates may be underestimated. The current standard of care is based on regular transfusions of fresh frozen plasma, which often lead to allergic reactions in patients. Recombinant ADAMTS13 (rADAMTS13) is a novel treatment for cTTP, which has been approved for use in the USA, Europe, and Japan.</div></div><div><h3>Objectives</h3><div>The primary objective of this real-world data collection was to comprehensively analyze the clinical data of pediatric patients with cTTP and to provide real-world evidence of the effectiveness of rADAMTS13 treatment in the pediatric population.</div></div><div><h3>Methods</h3><div>Nine pediatric patients with cTTP were treated with an intravenous infusion of rADAMTS13 every 2 weeks.</div></div><div><h3>Results</h3><div>The results showed an increase in platelet count and a decrease in lactate dehydrogenase levels compared with baseline. None of the patients experienced any adverse events or complications as a result of treatment. Patients reported an improved quality of life due to fewer hospital visits and a reduced number of recurrent episodes of cTTP.</div></div><div><h3>Conclusion</h3><div>Treatment with rADAMTS13 resulted in the normalization of laboratory parameters in all pediatric patients with cTTP.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"23 2","pages":"Pages 635-640"},"PeriodicalIF":5.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142739803","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}

{"title":"Risk assessment and management strategies in older patients with acute pulmonary embolism","authors":"Dieuwke Luijten ,&nbsp;Denise Abbel ,&nbsp;Suzanne C. Cannegieter ,&nbsp;Jeroen Eikenboom ,&nbsp;Paul L. den Exter ,&nbsp;Jacobijn Gussekloo ,&nbsp;Menno V. Huisman ,&nbsp;Thijs E. van Mens ,&nbsp;Lara Tahir ,&nbsp;Stella Trompet ,&nbsp;Simon P. Mooijaart ,&nbsp;Frederikus A. Klok","doi":"10.1016/j.jtha.2024.10.015","DOIUrl":"10.1016/j.jtha.2024.10.015","url":null,"abstract":"<div><h3>Background</h3><div>Managing older patients with acute pulmonary embolism (PE) is challenging due to their underrepresentation in clinical trials, comorbidities, and increased complication risk.</div></div><div><h3>Objectives</h3><div>To evaluate risk assessment and management outcomes in older patients with PE focusing on home and reperfusion treatment.</div></div><div><h3>Methods</h3><div>A retrospective analysis was conducted on patients aged 70 years or older diagnosed with acute PE at an academic medical center (2015-2022).</div></div><div><h3>Results</h3><div>In total, 242 patients with a mean age of 77 years were included. All 59 patients with negative Hestia criteria were discharged ≤24 hours, and in total, 81 patients (35%) received home treatment. Among these 14-day mortality and recurrent venous thromboembolism were 0% and major bleeding occurred in 1.3% (1 patient, 95% CI: 0.11-6.1). European Society of Cardiology risk classification showed 9 low-risk (3.9%), 199 intermediate-risk (87%), and 20 high-risk (8.8) patients with PE. In 5 of the 20 high-risk patients, hypotension was mainly caused by another condition, that is, sepsis. Eight high-risk patients received reperfusion therapy. The 14-day mortality rate was 51% in high-risk patients (95% CI: 27-71); 5 of 8 patients receiving reperfusion treatment died within 5 days. Patients with an Acute Presenting Older Patient score of ≥45% had higher 14-day mortality (28%; 95% CI: 12-46) compared with &lt;45% (3.2%; 95% CI: 0.85-8.3; hazard ratios: 10.2; 95% CI: 2.6-39).</div></div><div><h3>Conclusion</h3><div>Selecting for home treatment using Hestia criteria was safe for older patients with PE in our cohort. Mortality in the high-risk group was high also when receiving reperfusion treatment. The European Society of Cardiology risk classification and Acute Presenting Older Patient score identified patients at higher mortality risk, suggesting their potential utility in clinical decision-making.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"23 2","pages":"Pages 588-599"},"PeriodicalIF":5.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142502861","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}

{"title":"The severe von Willebrand disease variant p.M771V leads to impaired anterograde trafficking of von Willebrand factor in patient-derived and base-edited endothelial colony-forming cells","authors":"Isabel Bär ,&nbsp;Alastair Barraclough ,&nbsp;Petra E. Bürgisser ,&nbsp;Calvin van Kwawegen ,&nbsp;Karin Fijnvandraat ,&nbsp;Jeroen C.J. Eikenboom ,&nbsp;Frank W.G. Leebeek ,&nbsp;Jan Voorberg ,&nbsp;Ruben Bierings","doi":"10.1016/j.jtha.2024.10.023","DOIUrl":"10.1016/j.jtha.2024.10.023","url":null,"abstract":"<div><h3>Background</h3><div>von Willebrand disease (VWD) is the most common inherited bleeding disorder caused by quantitative or qualitative defects in von Willebrand factor (VWF). The p.M771V VWF variant leads to a severe bleeding phenotype in homozygous patients. However, the exact molecular mechanism remains unclear, which prevents personalized treatment of those VWD patients.</div></div><div><h3>Objectives</h3><div>This study aimed to characterize the underlying molecular mechanisms of the p.M771V variant in multiple representative <em>ex vivo</em> cell models.</div></div><div><h3>Methods</h3><div>Endothelial colony-forming cells (ECFCs) were isolated from venous blood of VWD patients from the Willebrand in the Netherlands cohort carrying homozygous and heterozygous p.M771V VWF variants. The p.M771V variant was also introduced in cord blood-derived ECFCs (CB-ECFCs) through adenine base editing and was overexpressed in HEK293 cells. Biosynthesis, storage, and secretion of VWF was studied using biochemical methods and confocal microscopy.</div></div><div><h3>Results</h3><div>Two unrelated homozygous p.M771V patients presented with very low VWF activity and antigen levels in plasma. Patient ECFCs showed impaired uncleaved VWF processing into mature VWF, with secreted VWF being severely reduced when compared to ECFCs of healthy donors. Multimer analysis of p.M771V ECFCs showed a deficiency of high molecular weight VWF multimers. Immunofluorescent staining revealed VWF retention in the endoplasmic reticulum; this was confirmed in various populations of base-edited CB-ECFCs harboring the p.M771V variant.</div></div><div><h3>Conclusion</h3><div>The severe endothelial phenotype observed in patient-derived p.M771V ECFCs, HEK293 cells, and an original base-edited CB-ECFC modeling system show that endoplasmic reticulum retention of VWF and failure to undergo subsequent proteolytic processing underpins the severe bleeding phenotype of patients with homozygous variants at M771.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"23 2","pages":"Pages 466-479"},"PeriodicalIF":5.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142605179","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}