Pub Date : 2025-03-01DOI: 10.1016/j.jtha.2024.12.033
Betül Ünlü, Jamie M. O’Sullivan
{"title":"Engulfed in complexity: the role of activated factor VII and protease-activated receptor-2 signaling in regulating macrophage phagocytosis in breast cancer","authors":"Betül Ünlü, Jamie M. O’Sullivan","doi":"10.1016/j.jtha.2024.12.033","DOIUrl":"10.1016/j.jtha.2024.12.033","url":null,"abstract":"","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"23 3","pages":"Pages 820-823"},"PeriodicalIF":5.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143552003","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 : 2025-03-01DOI: 10.1016/j.jtha.2024.11.027
Arnab Ghosh , Avinandan Bhoumick , Subhojit Paul , Akash Chatterjee , Subhasis Mandal , Abhimanyu Basu , Soma Mukhopadhyay , Kaushik Das , Prosenjit Sen
Background
Treatment of breast cancers with immunotherapy has so far achieved limited success. Traditional immunotherapies focusing on cytotoxic T cells have attained modest success, while the approval of phagocytic checkpoint blockers is still pending. Coagulation proteases are crucial to cancer growth and proliferation, but their relevance in altering the immunologic topography in tumors remains largely unknown.
Objectives
In this study, we aimed to examine whether factor VIIa (FVIIa)-driven protease-activated receptor 2 (PAR2) activation and its subsequent signaling pathways assist cancer cells in evading phagocytic macrophages.
Methods
Peripheral blood mononuclear cell- or THP-1-derived macrophages were cocultured with MDA-MB-468 cells that were pretreated with or without FVIIa. The phagocytic activity of macrophages was assessed through flow cytometry and immunofluorescence. Additionally, an allograft model using wild-type and PAR2-deleted 4T1 cells was employed to investigate the impact of PAR2 activation on immune escape from macrophages in vivo.
Results
We found evidence that FVIIa-induced PAR2 cleavage activates downstream signaling cascades and augments cellular levels of microRNA221, which transcriptionally activates both CD47 and stanniocalcein 1 expression, thereby assisting the escape from phagocytosis by macrophages. Stanniocalcein 1 decreases the surface expression of calreticulin, a dominant prophagocytic signal, thereby tilting it in favor of phagocytic evasion. Mouse models using PAR2-depleted cells displayed smaller tumor volumes and corresponding greater phagocytic events when combined with anti-CD47/anti-PD-L1 antibodies.
Conclusion
PAR2 signaling initiates an intrinsic mechanism of immune escape by diminishing phagocytosis of cancer cells.
{"title":"FVIIa-PAR2 signaling facilitates immune escape by reducing phagocytic potential of macrophages in breast cancer","authors":"Arnab Ghosh , Avinandan Bhoumick , Subhojit Paul , Akash Chatterjee , Subhasis Mandal , Abhimanyu Basu , Soma Mukhopadhyay , Kaushik Das , Prosenjit Sen","doi":"10.1016/j.jtha.2024.11.027","DOIUrl":"10.1016/j.jtha.2024.11.027","url":null,"abstract":"<div><h3>Background</h3><div>Treatment of breast cancers with immunotherapy has so far achieved limited success. Traditional immunotherapies focusing on cytotoxic T cells have attained modest success, while the approval of phagocytic checkpoint blockers is still pending. Coagulation proteases are crucial to cancer growth and proliferation, but their relevance in altering the immunologic topography in tumors remains largely unknown.</div></div><div><h3>Objectives</h3><div>In this study, we aimed to examine whether factor VIIa (FVIIa)-driven protease-activated receptor 2 (PAR2) activation and its subsequent signaling pathways assist cancer cells in evading phagocytic macrophages.</div></div><div><h3>Methods</h3><div>Peripheral blood mononuclear cell- or THP-1-derived macrophages were cocultured with MDA-MB-468 cells that were pretreated with or without FVIIa. The phagocytic activity of macrophages was assessed through flow cytometry and immunofluorescence. Additionally, an allograft model using wild-type and PAR2-deleted 4T1 cells was employed to investigate the impact of PAR2 activation on immune escape from macrophages <em>in vivo</em>.</div></div><div><h3>Results</h3><div>We found evidence that FVIIa-induced PAR2 cleavage activates downstream signaling cascades and augments cellular levels of microRNA221, which transcriptionally activates both CD47 and stanniocalcein 1 expression, thereby assisting the escape from phagocytosis by macrophages. Stanniocalcein 1 decreases the surface expression of calreticulin, a dominant prophagocytic signal, thereby tilting it in favor of phagocytic evasion. Mouse models using PAR2-depleted cells displayed smaller tumor volumes and corresponding greater phagocytic events when combined with anti-CD47/anti-PD-L1 antibodies.</div></div><div><h3>Conclusion</h3><div>PAR2 signaling initiates an intrinsic mechanism of immune escape by diminishing phagocytosis of cancer cells.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"23 3","pages":"Pages 903-920"},"PeriodicalIF":5.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142818494","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 : 2025-03-01DOI: 10.1016/j.jtha.2024.12.002
Janneke P. Spiegelenberg , Romy De Laat-Kremers , Mark Roest , Bas de Laat , Marleen M.H.J. van Gelder , Anil M. Tuladhar , Saskia Middeldorp , Frank-Erik de Leeuw , Jenneke Leentjens
Background
Patients with ischemic stroke at a young age (18-50 years) have an increased long-term risk of recurrent ischemic events. Hypercoagulability may contribute to this high risk.
Objectives
To investigate the associations between in vivo and ex vivo hemostatic parameters and recurrent ischemic events after an ischemic stroke or transient ischemic attack (TIA) at a young age.
Methods
We included patients with ischemic stroke or TIA between 1980 and 2010 from the prospective FUTURE cohort. Blood samples were collected in 2010, and patients were followed for recurrent ischemic events from 2010 to 2023. Pro- and anticoagulant markers and thrombin generation assay were measured. Thrombin dynamic analysis was used to study underlying pro- and anticoagulant processes. Hazard ratios (HRs) per standard deviation increase were assessed with cause-specific hazard models.
Results
Of the initial cohort of 581 patients, 332 were eligible. The median time between the index event and 2010 was 7.6 years. During a mean follow-up of 6.5 years, 70 of 332 (21.1%) patients experienced a recurrent ischemic event. Lower antithrombin levels (adjusted HR, 0.77; 95% CI, 0.60-0.98) and higher fibrinogen levels (HR, 1.35; 95% CI, 1.04-1.73) were associated with higher risk of recurrent ischemic events. Plasma thrombin generation was not associated with recurrence. However, the thrombin decay constant (HR, 0.67; 95% CI, 0.51-0.87) was associated with a lower risk of recurrent ischemic events.
Conclusion
After an ischemic stroke or TIA at a young age, the thrombin decay constant, which reflects reduced protection against thrombin (low antithrombin) and decreased potential to inhibit thrombin (high fibrinogen), is associated with recurrent ischemic events.
{"title":"Low thrombin inactivation capacity is associated with an increased risk of recurrent ischemic events after ischemic stroke at a young age","authors":"Janneke P. Spiegelenberg , Romy De Laat-Kremers , Mark Roest , Bas de Laat , Marleen M.H.J. van Gelder , Anil M. Tuladhar , Saskia Middeldorp , Frank-Erik de Leeuw , Jenneke Leentjens","doi":"10.1016/j.jtha.2024.12.002","DOIUrl":"10.1016/j.jtha.2024.12.002","url":null,"abstract":"<div><h3>Background</h3><div>Patients with ischemic stroke at a young age (18-50 years) have an increased long-term risk of recurrent ischemic events. Hypercoagulability may contribute to this high risk.</div></div><div><h3>Objectives</h3><div>To investigate the associations between <em>in vivo</em> and <em>ex vivo</em> hemostatic parameters and recurrent ischemic events after an ischemic stroke or transient ischemic attack (TIA) at a young age.</div></div><div><h3>Methods</h3><div>We included patients with ischemic stroke or TIA between 1980 and 2010 from the prospective FUTURE cohort. Blood samples were collected in 2010, and patients were followed for recurrent ischemic events from 2010 to 2023. Pro- and anticoagulant markers and thrombin generation assay were measured. Thrombin dynamic analysis was used to study underlying pro- and anticoagulant processes. Hazard ratios (HRs) per standard deviation increase were assessed with cause-specific hazard models.</div></div><div><h3>Results</h3><div>Of the initial cohort of 581 patients, 332 were eligible. The median time between the index event and 2010 was 7.6 years. During a mean follow-up of 6.5 years, 70 of 332 (21.1%) patients experienced a recurrent ischemic event. Lower antithrombin levels (adjusted HR, 0.77; 95% CI, 0.60-0.98) and higher fibrinogen levels (HR, 1.35; 95% CI, 1.04-1.73) were associated with higher risk of recurrent ischemic events. Plasma thrombin generation was not associated with recurrence. However, the thrombin decay constant (HR, 0.67; 95% CI, 0.51-0.87) was associated with a lower risk of recurrent ischemic events.</div></div><div><h3>Conclusion</h3><div>After an ischemic stroke or TIA at a young age, the thrombin decay constant, which reflects reduced protection against thrombin (low antithrombin) and decreased potential to inhibit thrombin (high fibrinogen), is associated with recurrent ischemic events.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"23 3","pages":"Pages 978-988"},"PeriodicalIF":5.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142822217","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 : 2025-03-01DOI: 10.1016/j.jtha.2024.12.006
Pierre Suchon , Omar Soukarieh , Clara Bernard , Antoine Mariotti , Vincent Ernest , Marie-Christine Barthet , Noémie Saut , Alexandre Theron , Christine Biron-Andréani , Mélanie Y. Daniel , Judith Catella , Pierre-Simon Rohrlich , Florence Blanc-Jouvan , Véronique Le Cam Duchez , Loubna Dari , David-Alexandre Trégouët , Pierre-Emmanuel Morange
Background
Although heritability of venous thromboembolism (VTE) is high, the thrombophilia screening appears to be positive only in a minority of VTE patients. Adding rare variants screening to identify VTE missing heritability still requires further assessment.
Objectives
We report the results of a panel strategy after 3 years of application.
Methods
We performed the sequencing of 28 genes related to coagulation cascade and/or VTE using high-throughput sequencing in133 unrelated patients with a personal history of VTE and negative thrombophilia screening. Only variants with minor allele frequency <0.1% were classified according to the American College of Medical Genetics recommendations. We recorded class 3, 4, and 5 variants.
Results
We identified class 3, 4, or 5 variants in 46 patients resulting in an identification rate of 35%. Out of the 45 recorded variants, 35 were considered as class 3 (78%), 9 were class 4 (20%), and 1 was class 5 (2%). Four genes accounted for nearly two-thirds (27/45) of the identified variants: SERPINC1, PROS1, F2, and F5. We observed a high rate of recurrent variants in the SERPINC1 and PROS1 genes, including the Cambridge II (SERPINC1 p.A416S), Dublin (SERPINC1 p.V30E), and Heerlen (PROS1 p.S501P) variants. The elevated frequency of these variants in a symptomatic population, compared to their frequency in the general population, provides strong support for their association with VTE risk. We identified 4 (likely) pathogenic variants in F2: p.R596Q (F2 Belgrade), p.R541W, p.P386T, and p.R425L.
Conclusion
The high proportion of class 3 variants emphasizes the need for functional studies to better characterize and classify them.
{"title":"Assessment of a next generation sequencing gene panel strategy in 133 patients with negative thrombophilia screening","authors":"Pierre Suchon , Omar Soukarieh , Clara Bernard , Antoine Mariotti , Vincent Ernest , Marie-Christine Barthet , Noémie Saut , Alexandre Theron , Christine Biron-Andréani , Mélanie Y. Daniel , Judith Catella , Pierre-Simon Rohrlich , Florence Blanc-Jouvan , Véronique Le Cam Duchez , Loubna Dari , David-Alexandre Trégouët , Pierre-Emmanuel Morange","doi":"10.1016/j.jtha.2024.12.006","DOIUrl":"10.1016/j.jtha.2024.12.006","url":null,"abstract":"<div><h3>Background</h3><div>Although heritability of venous thromboembolism (VTE) is high, the thrombophilia screening appears to be positive only in a minority of VTE patients. Adding rare variants screening to identify VTE missing heritability still requires further assessment.</div></div><div><h3>Objectives</h3><div>We report the results of a panel strategy after 3 years of application.</div></div><div><h3>Methods</h3><div>We performed the sequencing of 28 genes related to coagulation cascade and/or VTE using high-throughput sequencing in133 unrelated patients with a personal history of VTE and negative thrombophilia screening. Only variants with minor allele frequency <0.1% were classified according to the American College of Medical Genetics recommendations. We recorded class 3, 4, and 5 variants.</div></div><div><h3>Results</h3><div>We identified class 3, 4, or 5 variants in 46 patients resulting in an identification rate of 35%. Out of the 45 recorded variants, 35 were considered as class 3 (78%), 9 were class 4 (20%), and 1 was class 5 (2%). Four genes accounted for nearly two-thirds (27/45) of the identified variants: <em>SERPINC1</em>, <em>PROS1</em>, <em>F2,</em> and <em>F5</em>. We observed a high rate of recurrent variants in the <em>SERPINC1</em> and <em>PROS1</em> genes, including the Cambridge II (<em>SERPINC1</em> p.A416S), Dublin (<em>SERPINC1</em> p.V30E), and Heerlen (<em>PROS1</em> p.S501P) variants. The elevated frequency of these variants in a symptomatic population, compared to their frequency in the general population, provides strong support for their association with VTE risk. We identified 4 (likely) pathogenic variants in <em>F2</em>: p.R596Q (<em>F2</em> Belgrade), p.R541W, p.P386T, and p.R425L.</div></div><div><h3>Conclusion</h3><div>The high proportion of class 3 variants emphasizes the need for functional studies to better characterize and classify them.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"23 3","pages":"Pages 997-1008"},"PeriodicalIF":5.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142829151","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 : 2025-03-01DOI: 10.1016/j.jtha.2024.12.012
Remy Martins-Gonçalves , Stephane Vicente Rozini , Daniela P. Mendes-de-Almeida , Lohanna Palhinha , Carolina Q. Sacramento , Gean Carlo Pereira-Silva , Mariana M. Campos , Douglas Mathias de Oliveira , Carlos A. Lopes-Cardoso e Souza , Beatriz de Barros Gonçalves de Jesus , Isaclaudia Gomes de Azevedo-Quintanilha , Patricia Mouta Nunes de Oliveira , Renata Saraiva Pedro , Letícia Kegele Lignani , Gabriellen Vitiello Teixeira , Joanna Bokel , Sandra Wagner Cardoso , Brenda Hoagland , Elvira M. Saraiva , Beatriz Grinsztejn , Patricia T. Bozza
Background
Although rare, vaccine-induced thrombotic thrombocytopenia (VITT) following adenoviral vector COVID-19 vaccination is a concerning and often severe adverse effect of vaccination. The generation of high antiplatelet factor 4 antibody titers promotes the formation of immune complexes capable of activating platelets and neutrophils through FcγRIIa.
Objectives
Given that platelet-leukocyte aggregate formation and inflammasome activation are common features of thromboinflammatory diseases, we aimed to evaluate if these are also features of VITT.
Methods
Samples from a cohort of 57 postvaccination thrombosis patients and 28 age- and sex-matched unvaccinated individuals were used for ex vivo investigation of platelet-leukocyte aggregate formation and inflammasome activation.
Results
Patients with clinical features of VITT presented elevated levels of activated caspase-1, interleukin-18, and interleukin-1β in the plasma. We also found that soluble factors in the plasma of VITT patients induce the formation of platelet-neutrophil aggregates but not platelet-monocyte or platelet T-cell aggregates, which are associated with increased caspase-1 activation in neutrophils ex vivo. Platelet-neutrophil aggregate formation was prevented through blockage of FcγRIIa with the neutralizing antibody IV.3 and through blockage of P-selectin or integrin αIIbβ3, also inhibiting caspase-1 activation. Additionally, MCC950, an NLRP3 inflammasome inhibitor, blocked caspase-1 activation.
Conclusion
Taken together, these data show that VITT plasma induces platelet-neutrophil aggregate formation in a FcγRIIa-dependent manner and that platelet-neutrophil interactions may contribute to thromboinflammation in VITT patients by supporting NLRP3 inflammasome activation. These data shed light on novel immunopathological events associated with inflammation and thrombosis in VITT patients.
{"title":"Platelet-neutrophil aggregate formation induces NLRP3 inflammasome activation in vaccine-induced thrombotic thrombocytopenia","authors":"Remy Martins-Gonçalves , Stephane Vicente Rozini , Daniela P. Mendes-de-Almeida , Lohanna Palhinha , Carolina Q. Sacramento , Gean Carlo Pereira-Silva , Mariana M. Campos , Douglas Mathias de Oliveira , Carlos A. Lopes-Cardoso e Souza , Beatriz de Barros Gonçalves de Jesus , Isaclaudia Gomes de Azevedo-Quintanilha , Patricia Mouta Nunes de Oliveira , Renata Saraiva Pedro , Letícia Kegele Lignani , Gabriellen Vitiello Teixeira , Joanna Bokel , Sandra Wagner Cardoso , Brenda Hoagland , Elvira M. Saraiva , Beatriz Grinsztejn , Patricia T. Bozza","doi":"10.1016/j.jtha.2024.12.012","DOIUrl":"10.1016/j.jtha.2024.12.012","url":null,"abstract":"<div><h3>Background</h3><div>Although rare, vaccine-induced thrombotic thrombocytopenia (VITT) following adenoviral vector COVID-19 vaccination is a concerning and often severe adverse effect of vaccination. The generation of high antiplatelet factor 4 antibody titers promotes the formation of immune complexes capable of activating platelets and neutrophils through FcγRIIa.</div></div><div><h3>Objectives</h3><div>Given that platelet-leukocyte aggregate formation and inflammasome activation are common features of thromboinflammatory diseases, we aimed to evaluate if these are also features of VITT.</div></div><div><h3>Methods</h3><div>Samples from a cohort of 57 postvaccination thrombosis patients and 28 age- and sex-matched unvaccinated individuals were used for <em>ex vivo</em> investigation of platelet-leukocyte aggregate formation and inflammasome activation.</div></div><div><h3>Results</h3><div>Patients with clinical features of VITT presented elevated levels of activated caspase-1, interleukin-18, and interleukin-1β in the plasma. We also found that soluble factors in the plasma of VITT patients induce the formation of platelet-neutrophil aggregates but not platelet-monocyte or platelet T-cell aggregates, which are associated with increased caspase-1 activation in neutrophils <em>ex vivo</em>. Platelet-neutrophil aggregate formation was prevented through blockage of FcγRIIa with the neutralizing antibody IV.3 and through blockage of P-selectin or integrin α<sub>IIb</sub>β<sub>3</sub>, also inhibiting caspase-1 activation. Additionally, MCC950, an NLRP3 inflammasome inhibitor, blocked caspase-1 activation.</div></div><div><h3>Conclusion</h3><div>Taken together, these data show that VITT plasma induces platelet-neutrophil aggregate formation in a FcγRIIa-dependent manner and that platelet-neutrophil interactions may contribute to thromboinflammation in VITT patients by supporting NLRP3 inflammasome activation. These data shed light on novel immunopathological events associated with inflammation and thrombosis in VITT patients.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"23 3","pages":"Pages 1034-1042"},"PeriodicalIF":5.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142871244","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 : 2025-03-01DOI: 10.1016/j.jtha.2025.02.001
Ton Lisman , Suzanne C. Cannegieter
{"title":"Interactions","authors":"Ton Lisman , Suzanne C. Cannegieter","doi":"10.1016/j.jtha.2025.02.001","DOIUrl":"10.1016/j.jtha.2025.02.001","url":null,"abstract":"","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"23 3","pages":"Page 759"},"PeriodicalIF":5.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143408905","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 : 2025-03-01DOI: 10.1016/S1538-7836(25)00104-7
{"title":"Annoucements","authors":"","doi":"10.1016/S1538-7836(25)00104-7","DOIUrl":"10.1016/S1538-7836(25)00104-7","url":null,"abstract":"","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"23 3","pages":"Pages 1129-1130"},"PeriodicalIF":5.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143551815","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 : 2025-02-26DOI: 10.1016/j.jtha.2025.02.020
Mouhamed Djahoum Moussa, Osama Abou-Arab, Senna Staessens, Marie Jungling, Julien Labreuche, Antoine Lamer, Christophe Beyls, Natacha Rousse, Antoine Rauch, Valentin Loobuyck, Camille Beaudeux, Adeline Pierache, Delphine Deblauwe, Delphine Corseaux, Martin Dubernet, Mathieu Guilbart, Lise Thellier, Yazine Mahjoub, Francis Juthier, Hervé Dupont, Simon F De Meyer, André Vincentelli, Sophie Susen, Emmanuel Robin
Background: Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is associated with a high rate of thrombotic complications which are prevented using systemic anticoagulation and surface coating technologies. Heparin (Heparin-coating) and phosphorylcholin (PPC-coating) coatings are widely used in clinical practice, but little is known about their effectiveness in VA-ECMO setting.
Objectives: To compare the effects of heparin-coating and PPC-coating on thrombotic complications, bleeding, blood trauma, inflammation, thrombi composition and mortality.
Methods: A retrospective multicenter clinical cohort was studied for clinical endpoints, and a prospective histologic cohort was investigated for thrombi composition. The clinical cohort included adult patients supported by VA-ECMO for cardiogenic shock, without any constitutive or acquired hemostasis disease disorder, from January 2013 to December 2020. Thrombi retrieved from circuit junctions were underwent histochemical and immunochemical analysis for erythrocytes, Von Willebrand factor (VWF), platelets, fibrinogen, and neutrophil extra-cellular traps contents. The clinical cohort was compared using a propensity score overlap weighting (PSOW). A P-value <0.05 was significant.
Results: Compared with PPC-coating, Heparin-coating was associated with a lower incidence of thrombotic complications before and after PSOW [HR=0.67 (95%CI, 0.48; 0.93), P-value =0.015], a lower decrease in hemoglobin, but a greater decrease in platelet count. In the histologic analysis, PPC-coating resulted in a greater content of VWF. The other endpoints were similar among groups.
Conclusion: Compared with PPC-coating, heparin-coating is associated with fewer thrombotic complications during VA-ECMO support. Kinetics of platelet count and hemoglobin, thrombi contents differed according to coating types.
{"title":"Comparison of the effects of Phosphorylcholin versus Heparin-Based Surface Coating on Clinical and Histological Outcomes During Veno-Arterial ECMO Support: A Propensity Score Weighted Analysis.","authors":"Mouhamed Djahoum Moussa, Osama Abou-Arab, Senna Staessens, Marie Jungling, Julien Labreuche, Antoine Lamer, Christophe Beyls, Natacha Rousse, Antoine Rauch, Valentin Loobuyck, Camille Beaudeux, Adeline Pierache, Delphine Deblauwe, Delphine Corseaux, Martin Dubernet, Mathieu Guilbart, Lise Thellier, Yazine Mahjoub, Francis Juthier, Hervé Dupont, Simon F De Meyer, André Vincentelli, Sophie Susen, Emmanuel Robin","doi":"10.1016/j.jtha.2025.02.020","DOIUrl":"https://doi.org/10.1016/j.jtha.2025.02.020","url":null,"abstract":"<p><strong>Background: </strong>Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is associated with a high rate of thrombotic complications which are prevented using systemic anticoagulation and surface coating technologies. Heparin (Heparin-coating) and phosphorylcholin (PPC-coating) coatings are widely used in clinical practice, but little is known about their effectiveness in VA-ECMO setting.</p><p><strong>Objectives: </strong>To compare the effects of heparin-coating and PPC-coating on thrombotic complications, bleeding, blood trauma, inflammation, thrombi composition and mortality.</p><p><strong>Methods: </strong>A retrospective multicenter clinical cohort was studied for clinical endpoints, and a prospective histologic cohort was investigated for thrombi composition. The clinical cohort included adult patients supported by VA-ECMO for cardiogenic shock, without any constitutive or acquired hemostasis disease disorder, from January 2013 to December 2020. Thrombi retrieved from circuit junctions were underwent histochemical and immunochemical analysis for erythrocytes, Von Willebrand factor (VWF), platelets, fibrinogen, and neutrophil extra-cellular traps contents. The clinical cohort was compared using a propensity score overlap weighting (PSOW). A P-value <0.05 was significant.</p><p><strong>Results: </strong>Compared with PPC-coating, Heparin-coating was associated with a lower incidence of thrombotic complications before and after PSOW [HR=0.67 (95%CI, 0.48; 0.93), P-value =0.015], a lower decrease in hemoglobin, but a greater decrease in platelet count. In the histologic analysis, PPC-coating resulted in a greater content of VWF. The other endpoints were similar among groups.</p><p><strong>Conclusion: </strong>Compared with PPC-coating, heparin-coating is associated with fewer thrombotic complications during VA-ECMO support. Kinetics of platelet count and hemoglobin, thrombi contents differed according to coating types.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143531590","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 : 2025-02-25DOI: 10.1016/j.jtha.2025.02.016
Ulrich J Sachs, Michelle Reich, Dan Qiu, Behnaz Bayat, Nina Cooper, Gregor Bein
Background: It is widely accepted that autoantibodies directed against platelet glycoproteins (GP) are a major pathophysiological mechanism in immune thrombocytopenia (ITP), but little clinical data is available demonstrating an association between platelet antibodies and platelet counts.
Objectives: We hypothesized that if platelet antibodies are clinically relevant, number of targeted glycoproteins and antibody concentration should be associated with the extent of thrombocytopenia.
Methods: Platelet antibodies were identified in a direct, GP-specific test that detects antibodies against GP IIb/IIIa and GP Ib/IX. Using laboratory data from 12,335 thrombocytopenic patients with and without GP-specific platelet antibodies, we conducted a large retrospective cohort study.
Results: We identified 1,469 adults with GP-specific platelet antibodies in our database with complete entries. Compared to 10,866 adults without antibodies, patients with antibodies had significantly lower median platelet counts (54 G/l [IQR, 29-89] vs. 85 G/l [IQR, 52-123], P<0.0001). Patients with antibodies against two GPs had significantly lower platelet counts than patients with antibodies against one GP (47 G/l [IQR, 26-81] vs. 62 G/l [IQR, 32-99], P<0.0001 for GP IIb/IIIa and 58 G/l [IQR, 32-99], P=0.0004 for GP Ib/IX). Increasing antibody levels correlated with decreasing platelet counts for anti-GP IIb/IIIa (R2=0.69; rho -0.84), and anti-GP Ib/IX (R2=0.57; rho -0.6).
Conclusion: The presence of autoantibodies against GP IIb/IIIa or GP Ib/IX is associated with lower platelet counts. More glycoproteins targeted by autoantibodies and increasing antibody levels predict lower platelet counts. Platelet antibodies appear to be of clinical relevance.
{"title":"Platelet autoantibodies have an impact on the platelet count in patients.","authors":"Ulrich J Sachs, Michelle Reich, Dan Qiu, Behnaz Bayat, Nina Cooper, Gregor Bein","doi":"10.1016/j.jtha.2025.02.016","DOIUrl":"https://doi.org/10.1016/j.jtha.2025.02.016","url":null,"abstract":"<p><strong>Background: </strong>It is widely accepted that autoantibodies directed against platelet glycoproteins (GP) are a major pathophysiological mechanism in immune thrombocytopenia (ITP), but little clinical data is available demonstrating an association between platelet antibodies and platelet counts.</p><p><strong>Objectives: </strong>We hypothesized that if platelet antibodies are clinically relevant, number of targeted glycoproteins and antibody concentration should be associated with the extent of thrombocytopenia.</p><p><strong>Methods: </strong>Platelet antibodies were identified in a direct, GP-specific test that detects antibodies against GP IIb/IIIa and GP Ib/IX. Using laboratory data from 12,335 thrombocytopenic patients with and without GP-specific platelet antibodies, we conducted a large retrospective cohort study.</p><p><strong>Results: </strong>We identified 1,469 adults with GP-specific platelet antibodies in our database with complete entries. Compared to 10,866 adults without antibodies, patients with antibodies had significantly lower median platelet counts (54 G/l [IQR, 29-89] vs. 85 G/l [IQR, 52-123], P<0.0001). Patients with antibodies against two GPs had significantly lower platelet counts than patients with antibodies against one GP (47 G/l [IQR, 26-81] vs. 62 G/l [IQR, 32-99], P<0.0001 for GP IIb/IIIa and 58 G/l [IQR, 32-99], P=0.0004 for GP Ib/IX). Increasing antibody levels correlated with decreasing platelet counts for anti-GP IIb/IIIa (R<sup>2</sup>=0.69; rho -0.84), and anti-GP Ib/IX (R<sup>2</sup>=0.57; rho -0.6).</p><p><strong>Conclusion: </strong>The presence of autoantibodies against GP IIb/IIIa or GP Ib/IX is associated with lower platelet counts. More glycoproteins targeted by autoantibodies and increasing antibody levels predict lower platelet counts. Platelet antibodies appear to be of clinical relevance.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143523746","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 : 2025-02-24DOI: 10.1016/j.jtha.2025.02.015
Hannah F Bradford, Christophe J Lalaurie, Jayesh Gor, Xin Gao, Charis Pericleous, Stephen J Perkins, Hannah Britt, Konstantinos Thalassinos, Ian Giles, Anisur Rahman, Mihaela Delcea, Paul A Dalby, Thomas C R McDonnell
Beta-2-Glycoprotein I (β2GPI) is the main autoantigenic target of antiphospholipid syndrome (APS) with antibodies leading to clinical manifestations. There are two known structural isomers of β2GPI, a J shape and a circular shaped one. The transition between these structures is incompletely understood, with the functional implications unknown. β2GPI is a substrate of the protease plasmin, which cleaves within the fifth domain of β2GPI leading to altered cellular binding. Very little is currently known regarding the structure and function of this protein variant. We present the first comprehensive structural characterisation plasmin-clipped β2GPI and the associated implications for pathogenic antibody binding to this protein.
Methods: β2GPI was purified using an adapted acid-free process from healthy control plasma and cleaved with plasmin. Cleavage was confirmed by SDS-PAGE. Structural characterisation was undertaken using dynamic light scattering (DLS), small angle X-ray scattering (SAXS), ion mobility mass spectrometry (IMMS) and molecular dynamics simulation (MD). Activity was tested using inhibition of β2GPI ELISAs with patient samples and cleaved β2GPI in the fluid phase and cellular binding by flow cytometry using HUVEC cells.
Results: DLS revealed a significantly smaller hydrodynamic radius for plasmin-clipped β2GPI (p=0.0043). SAXS and MD analysis indicated a novel S-like structure of β2GPI only present in the plasmin-clipped sample whilst IMMS showed a different structure distributions in plasmin clipped compared to non-clipped B2GPI. The increased binding of autoantibodies was shown for plasmin-clipped β2GPI (p=0.056), implying a greater exposure of pathogenic epitopes following cleavage.
Conclusions: Cleavage of β2GPI by plasmin results in the production of a unique S-shaped structural conformation and higher patient antibody binding. This novel structure may increase the production of antibodies and explain the loss of binding to phospholipids described previously for plasmin-clipped β2GPI.
{"title":"Plasmin Cleavage of Beta-2-Glycoprotein I Alters its Structure and Ability to Bind to Pathogenic Antibodies.","authors":"Hannah F Bradford, Christophe J Lalaurie, Jayesh Gor, Xin Gao, Charis Pericleous, Stephen J Perkins, Hannah Britt, Konstantinos Thalassinos, Ian Giles, Anisur Rahman, Mihaela Delcea, Paul A Dalby, Thomas C R McDonnell","doi":"10.1016/j.jtha.2025.02.015","DOIUrl":"https://doi.org/10.1016/j.jtha.2025.02.015","url":null,"abstract":"<p><p>Beta-2-Glycoprotein I (β2GPI) is the main autoantigenic target of antiphospholipid syndrome (APS) with antibodies leading to clinical manifestations. There are two known structural isomers of β2GPI, a J shape and a circular shaped one. The transition between these structures is incompletely understood, with the functional implications unknown. β2GPI is a substrate of the protease plasmin, which cleaves within the fifth domain of β2GPI leading to altered cellular binding. Very little is currently known regarding the structure and function of this protein variant. We present the first comprehensive structural characterisation plasmin-clipped β2GPI and the associated implications for pathogenic antibody binding to this protein.</p><p><strong>Methods: </strong>β2GPI was purified using an adapted acid-free process from healthy control plasma and cleaved with plasmin. Cleavage was confirmed by SDS-PAGE. Structural characterisation was undertaken using dynamic light scattering (DLS), small angle X-ray scattering (SAXS), ion mobility mass spectrometry (IMMS) and molecular dynamics simulation (MD). Activity was tested using inhibition of β2GPI ELISAs with patient samples and cleaved β2GPI in the fluid phase and cellular binding by flow cytometry using HUVEC cells.</p><p><strong>Results: </strong>DLS revealed a significantly smaller hydrodynamic radius for plasmin-clipped β2GPI (p=0.0043). SAXS and MD analysis indicated a novel S-like structure of β2GPI only present in the plasmin-clipped sample whilst IMMS showed a different structure distributions in plasmin clipped compared to non-clipped B2GPI. The increased binding of autoantibodies was shown for plasmin-clipped β2GPI (p=0.056), implying a greater exposure of pathogenic epitopes following cleavage.</p><p><strong>Conclusions: </strong>Cleavage of β2GPI by plasmin results in the production of a unique S-shaped structural conformation and higher patient antibody binding. This novel structure may increase the production of antibodies and explain the loss of binding to phospholipids described previously for plasmin-clipped β2GPI.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143515934","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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