Research and Practice in Thrombosis and Haemostasis最新文献

{"title":"Thromboembolic events in severe postpartum hemorrhage treated with recombinant activated factor VII: a systematic literature review and meta-analysis","authors":"Johanna G. van der Bom ,&nbsp;Frédéric J. Mercier ,&nbsp;Damaris Bausch-Fluck ,&nbsp;Mads Nordentoft ,&nbsp;Morten Medici ,&nbsp;Rezan Abdul-Kadir","doi":"10.1016/j.rpth.2024.102533","DOIUrl":"10.1016/j.rpth.2024.102533","url":null,"abstract":"<div><p>Postpartum hemorrhage (PPH) is an obstetric complication with high associated morbidity. Recombinant activated factor VII (rFVIIa) is used to treat severe PPH when uterotonics fail to stop bleeding. However, data on the safety of rFVIIa treatment of severe PPH from adequately powered trials are lacking. We systematically reviewed published data on the incidence of thromboembolic events (TEs) in women with PPH treated or not treated with rFVIIa (PROSPERO CRD42022360736). Databases (Embase, MEDLINE, BIOSIS, Current Contents, and the Cochrane Library) were searched for peer-reviewed publications published between January 1996 and August 2022 and conference abstracts published between January 2017 and August 2022 using search terms related to thromboembolism or infarction and PPH. Data were extracted from all publications reporting on a general population of women with PPH with information on TEs. Descriptive summary statistics and the estimated proportion of TEs were analyzed using a generalized linear mixed model based on the binomial distribution. Quality assessments were based on the checklist by Downs and Black. From 1637 potentially eligible studies, 55 publications were included reporting on 611 women treated and 32,488 women not treated with rFVIIa. The global estimated proportion of TEs was 1.82% (prediction interval [PI], 0.30-10.23) and 0.72% (PI, 0.03-16.47) in women with severe PPH treated and those not treated with rFVIIa, respectively. The estimated proportions of TEs were similarly small, with wide and largely overlapping PIs. Additional well-designed trials are needed to improve understanding of TE incidence in PPH.</p></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"8 5","pages":"Article 102533"},"PeriodicalIF":3.4,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2475037924002280/pdfft?md5=be0da4bab78466826c5464518f53f215&pid=1-s2.0-S2475037924002280-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141849860","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spontaneous bleeding in chronic kidney disease: global coagulation assays may predict bleeding risk","authors":"Rowena Brook ,&nbsp;Julie Wang ,&nbsp;David Barit ,&nbsp;Prahlad Ho ,&nbsp;Hui Yin Lim","doi":"10.1016/j.rpth.2024.102520","DOIUrl":"10.1016/j.rpth.2024.102520","url":null,"abstract":"<div><h3>Background</h3><p>Chronic kidney disease (CKD) is associated with increased bleeding and thrombotic risks. Standard blood tests do not sufficiently quantify these risks. Global coagulation assays (GCAs) provide a more comprehensive assessment of coagulation.</p></div><div><h3>Objectives</h3><p>We aimed to evaluate if GCAs are predictive of spontaneous major bleeding (sMB) in CKD.</p></div><div><h3>Methods</h3><p>Adult patients with CKD (estimated glomerular filtration rate, &lt;30 mL/min/1.73m²) were recruited to this pilot prospective observational study. Testing with GCAs (thromboelastography, overall hemostatic potential, calibrated automated thrombogram, and plasminogen activator inhibitor-1) was performed, and the results were correlated to sMB events.</p></div><div><h3>Results</h3><p>Eighty-seven CKD patients (median age, 67 years; 67.8% male) were included, with median follow-up of 3.1 years. CKD patients demonstrated elevated fibrinogen, factor VIII, and von Willebrand factor antigen levels, while other conventional coagulation test results were within reference intervals. Ten episodes of sMB (11.5%) were captured (3.0/100 person-years), with no significant association demonstrated between sMB and antiplatelet use (<em>P</em> = .36), platelet count (<em>P</em> = .14), or renal function (urea, <em>P</em> = .27; estimated glomerular filtration rate, <em>P</em> = .09). CKD patients with sMB had more hypocoagulable GCA parameters compared with those without sMB. The lowest quartiles of endogenous thrombin potential (subhazard ratio [sHR], 7.11; 95% CI, 1.84-27.45), overall hemostatic potential (sHR, 6.81; 95% CI, 1.77-26.16), and plasminogen activator inhibitor-1 (sHR, 5.26; 95% CI, 1.55-17.91) were associated with sMB.</p></div><div><h3>Conclusion</h3><p>This pilot study demonstrates that GCAs such as thrombin and fibrin generation may predict sMB risk in patients with CKD, which has potential to be practice-changing. Larger studies are required to validate these findings.</p></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"8 5","pages":"Article 102520"},"PeriodicalIF":3.4,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2475037924002152/pdfft?md5=ff2aea45562ef749471de4163fc80ab0&pid=1-s2.0-S2475037924002152-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141851634","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Syndemics in women’s health: poverty, social exclusion, and clustering of thrombotic and hemostasis disorders","authors":"Ellen O’Rourke ,&nbsp;Sarah Kelliher ,&nbsp;Barry Kevane","doi":"10.1016/j.rpth.2024.102481","DOIUrl":"https://doi.org/10.1016/j.rpth.2024.102481","url":null,"abstract":"<div><p>A State of the Art lecture titled “Syndemics in Women’s Health: Poverty, Social Exclusion and Clustering of Thrombotic and Haemostasis Disorders” was presented at the International Society on Thrombosis and Haemostasis (ISTH) Congress in 2023. Syndemics are characterized by the clustering of specific health conditions in vulnerable populations. These populations become vulnerable as a result of large-scale social, political, and economic factors that influence social determinants of health and increase susceptibility to disease. Vulnerable populations at risk of experiencing a syndemic include those who are subjected to social exclusion and gender- or race-based marginalization. Biological sex (assigned at birth based on physical &amp; genetic differences) and gender identity (the personal sense of ones own gender) have been recognized as important determinants of health outcomes in the context of certain syndemic diseases. Potential examples of syndemic biosocial interactions in the field of thrombosis and hemostasis include the effect of social determinants of health in perpetuating the global maternal mortality crisis and the role of poverty and marginalization in influencing thrombosis risk in socially excluded individuals. Initiatives directed at prevention and treatment of syndemic conditions require multilevel interventions directed at the socio-economic as well as the biological determinants of the disease. In the present article, we describe potential syndemic disease interactions in the field of thrombosis and hemostasis, and we summarize some relevant new data relating to the social determinants of health presented during the 2023 ISTH Congress.</p></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"8 5","pages":"Article 102481"},"PeriodicalIF":3.4,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2475037924001705/pdfft?md5=fc674c00a5ee93b88112cb5ebbc04c53&pid=1-s2.0-S2475037924001705-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141604757","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Erratum to ‘Illustrated State-of-the-Art Capsules of the ISTH 2024 Congress’ [Research and Practice in Thrombosis and Haemostasis Volume 8, Issue 4, May 2024, 102432]","authors":"Chris Ward ,&nbsp;Nicola Curry ,&nbsp;Magdy El-Ekiaby ,&nbsp;Kerstin Jurk ,&nbsp;Henri H. Versteeg ,&nbsp;Charithani Keragala ,&nbsp;Tal Burstyn-Cohen ,&nbsp;Silvio Antoniak ,&nbsp;Yuko Suzuki ,&nbsp;Ross I. Baker ,&nbsp;Olivier Christophe ,&nbsp;Shoshana Revel-Vilk ,&nbsp;Alice Hart ,&nbsp;Carsten Deppermann ,&nbsp;Huyen Tran ,&nbsp;Nicola Pozzi ,&nbsp;Walter H.A. Kahr ,&nbsp;Steven P. Grover ,&nbsp;Philip Wenzel ,&nbsp;Ashley C. Brown ,&nbsp;Ana Marín-Quilez","doi":"10.1016/j.rpth.2024.102498","DOIUrl":"https://doi.org/10.1016/j.rpth.2024.102498","url":null,"abstract":"","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"8 5","pages":"Article 102498"},"PeriodicalIF":3.4,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2475037924001936/pdfft?md5=a798afb3bd6f58ff3b81992af90d1d12&pid=1-s2.0-S2475037924001936-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141605149","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interference of lupus anticoagulant causing antiprothrombin and anti–beta-2-glycoprotein I antibodies on international normalized ratio measurements: comparative analysis of international normalized ratio methods","authors":"Rachel Gehlen ,&nbsp;Roxanne G. Moesbergen ,&nbsp;CuiCui Bai ,&nbsp;Philip G. de Groot ,&nbsp;A.J.Gerard Jansen ,&nbsp;Joost C.M. Meijers ,&nbsp;Bas de Laat ,&nbsp;Jasper A. Remijn","doi":"10.1016/j.rpth.2024.102470","DOIUrl":"10.1016/j.rpth.2024.102470","url":null,"abstract":"<div><h3>Background</h3><p>Life-long vitamin K antagonist (VKA) therapy is recommended as a standard of care in antiphospholipid syndrome (APS) patients with thrombosis. Concerns have been raised about the validity of international normalized ratio (INR) measurements in lupus anticoagulant (LA)-positive APS patients because LA may interfere with phospholipid-dependent coagulation tests and could elevate INR measurements.</p></div><div><h3>Objectives</h3><p>Here, we aimed to determine the interference of antigen-specific monoclonal and isolated patient antibodies with LA activity on INR measurements.</p></div><div><h3>Methods</h3><p>Pooled normal plasma and control plasma from patients on VKA (without LA) were incubated with monoclonal and isolated patient immunoglobulin G antiprothrombin and anti–beta-2-glycoprotein I antibodies that express LA activity. INR was determined before and after addition using 3 laboratory assays (Owren STA-Hepato Prest, Quick STA-NeoPTimal, and Quick STA-Neoplastine R) and 1 point-of-care test device (CoaguChek Pro II).</p></div><div><h3>Results</h3><p>Antiprothrombin and anti–beta-2-glycoprotein I antibodies with LA activity interfered with recombinant human thromboplastin reagents (Quick STA-Neoplastine R and CoaguChek Pro II), particularly when added to plasma of VKA-treated controls. This effect was most evident on point-of-care test INR measurements, while the recombinant Quick reagent exhibited a lesser degree of interference. In contrast, tissue-derived thromboplastin reagents (Owren STA-Hepato Prest and Quick STA-NeoPTimal) remained largely unaffected by these antibodies, both in pooled normal plasma and VKA anticoagulated control plasma. Among these reagents, the Owren INR reagent exhibited the lowest sensitivity to the influence of LA antibodies. This observed difference in sensitivity is independent of the plasma dilution factor or the presence of factor V or fibrinogen in Owren reagent.</p></div><div><h3>Conclusion</h3><p>INR reagents that utilize recombinant human thromboplastin are more sensitive to the presence of monoclonal and patient-derived antibodies with LA activity. Consequently, APS patients positive for LA should be monitored using tissue-derived thromboplastin reagents, given its reduced susceptibility to interference by LA-causing antibodies.</p></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"8 5","pages":"Article 102470"},"PeriodicalIF":3.4,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2475037924001596/pdfft?md5=907440664fb64fd45bb59c757e8a972f&pid=1-s2.0-S2475037924001596-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141409482","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Managing surgical relapse risk in acquired thrombotic thrombocytopenic purpura: a systematic review","authors":"Morgana Pinheiro Maux Lessa ,&nbsp;Alexandre Soares Ferreira Junior ,&nbsp;Margaret Graton ,&nbsp;Erin Simon ,&nbsp;Leila Ledbetter ,&nbsp;Oluwatoyosi A. Onwuemene","doi":"10.1016/j.rpth.2024.102478","DOIUrl":"10.1016/j.rpth.2024.102478","url":null,"abstract":"","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"8 5","pages":"Article 102478"},"PeriodicalIF":3.4,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2475037924001675/pdfft?md5=3920f44ea26e27f3ca81846026c365f0&pid=1-s2.0-S2475037924001675-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141630778","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Real-world usage and effectiveness of recombinant factor VIII/factor IX Fc in hemophilia A/B: final data from the 24-month, prospective, noninterventional PREVENT study in Germany","authors":"Christoph Bidlingmaier ,&nbsp;Christine Heller ,&nbsp;Florian Langer ,&nbsp;Wolfgang Miesbach ,&nbsp;Ute Scholz ,&nbsp;Johannes Oldenburg ,&nbsp;Eveline Nüesch ,&nbsp;Helena Palmborg ,&nbsp;Elena Santagostino ,&nbsp;Andreas Tiede","doi":"10.1016/j.rpth.2024.102482","DOIUrl":"10.1016/j.rpth.2024.102482","url":null,"abstract":"<div><h3>Background</h3><p>Real-world experience with efmoroctocog alfa (a recombinant factor [F]VIII Fc fusion protein [rFVIIIFc]) and eftrenonacog alfa (a recombinant factor IX Fc fusion protein [rFIXFc]) is needed to bridge evidence gaps.</p></div><div><h3>Objectives</h3><p>To describe rFVIIIFc/rFIXFc usage and effectiveness over a 24-month prospective period.</p></div><div><h3>Methods</h3><p>PREVENT (NCT03055611), a noninterventional study across 25 German hemophilia treatment centers, enrolled previously treated persons with hemophilia A and B (all ages/severities) on individualized rFVIIIFc/rFIXFc prophylaxis before/at enrollment. Primary endpoints included annualized bleeding rate (ABR), injection frequency (IF), and factor consumption (FC). Additionally, up to 12 months of retrospective FVIII/FIX data were collected. Physician and patient satisfaction, and safety outcomes were also assessed.</p></div><div><h3>Results</h3><p>Overall, 150 patients received ≥1 rFVIIIFc dose and 47 patients received ≥1 rFIXFc dose, with median prospective follow-up of 20.6 and 21.0 months, respectively. rFVIIIFc/rFIXFc demonstrated low median ABR (0.5/1.7), annualized IF (121.8/52.2 injections/y), and FC (4611.7/2423.9 IU/kg) in line with product labels. Compared with previous FVIII/FIX, there was a 56.0% reduction in ABR for rFVIIIFc (rate ratio, 0.44; 95% CI, 0.31-0.64), with no change for rFIXFc (rate ratio, 0.93; 95% CI, 0.66-1.31); rFVIIIFc/rFIXFc reduced annualized IF (rFVIIIFc, mean difference, −31.7; 95% CI, −40.3 to −23.1; rFIXFc, mean difference, −37.3; 95% CI, −46.9 to −27.8), while FC remained stable (rFVIIIFc, +374.1; 95% CI, +46.8 to +701.3; rFIXFc, +503.9; 95% CI, +95.4 to +912.4). Most physicians and patients were satisfied or highly satisfied with rFVIIIFc/rFIXFc. rFVIIIFc/rFIXFc were well tolerated, with no inhibitor development or treatment-related serious adverse events.</p></div><div><h3>Conclusion</h3><p>Real-world PREVENT data complement phase 3 trials and show that individualized rFVIIIFc/rFIXFc prophylaxis provided stable bleed protection with low IF and maintained FC. Compared with previous FVIII, ABR was considerably reduced with rFVIIIFc, with stable annualized FC. For rFIXFc, bleed protection was maintained vs previous FIX while reducing annualized IF.</p></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"8 5","pages":"Article 102482"},"PeriodicalIF":3.4,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2475037924001717/pdfft?md5=d34012183ee4054591d75ab52ad9d95b&pid=1-s2.0-S2475037924001717-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141638879","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bleeding in valvular heart disease: is von Willebrand factor the culprit?","authors":"Shirin Bakhtari,&nbsp;Flavien Vincent,&nbsp;Sophie Susen","doi":"10.1016/j.rpth.2024.102506","DOIUrl":"10.1016/j.rpth.2024.102506","url":null,"abstract":"","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"8 5","pages":"Article 102506"},"PeriodicalIF":3.4,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2475037924002012/pdfft?md5=acd725b13f9cda641fb02327e62bfb3d&pid=1-s2.0-S2475037924002012-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141711684","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In vitro assessment of the risk of ABCB1-mediated drug–drug interaction between rivaroxaban and tacrolimus in human embryonic kidney 293 recombinant cell lines","authors":"Gwenaëlle Mahieu ,&nbsp;Anne-Laure Sennesael ,&nbsp;Lionel Pochet ,&nbsp;Vincent Haufroid ,&nbsp;Françoise Van Bambeke ,&nbsp;Anne Spinewine ,&nbsp;Laure Elens","doi":"10.1016/j.rpth.2024.102521","DOIUrl":"10.1016/j.rpth.2024.102521","url":null,"abstract":"<div><h3>Background</h3><p>In lung transplant patients, direct oral anticoagulants are often taken in combination with immunosuppressive drugs such as tacrolimus. Since tacrolimus is a substrate and inhibitor of the efflux protein ABCB1, also transporting direct oral anticoagulants, a possible drug–drug interaction mediated by competition for this transporter needs to be investigated.</p></div><div><h3>Objectives</h3><p>To determine the <em>in vitro</em> effect of tacrolimus on ABCB1-mediated rivaroxaban transport in order to support clinician practice.</p></div><div><h3>Methods</h3><p>Recombinant cell line models, based on human embryonic kidney 293 cells, were generated by a stable transfection process to overexpress ABCB1 or not (control cells). The impact of tacrolimus on ABCB1-mediated rivaroxaban transport was assessed by accumulation experiments.</p></div><div><h3>Results</h3><p>ABCB1 expression decreased the cellular accumulation of rivaroxaban and tacrolimus at their respective clinically relevant concentrations when compared with control cells. This confirms the involvement of ABCB1 in the active transport of tacrolimus and rivaroxaban. However, tacrolimus had no significant influence on rivaroxaban disposition at those clinically relevant concentrations.</p></div><div><h3>Conclusion</h3><p>Our study does not provide evidence for a possible interaction between tacrolimus and rivaroxaban when used together in practice.</p></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"8 5","pages":"Article 102521"},"PeriodicalIF":3.4,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2475037924002164/pdfft?md5=4bec598e07edbcc379d704c378e999c9&pid=1-s2.0-S2475037924002164-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141851468","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transmembrane thiol isomerase TMX1 counterbalances the effect of ERp46 to inhibit platelet activation and integrin αIIbβ3 function","authors":"Zhenzhen Zhao ,&nbsp;Yixin Cheng ,&nbsp;Yaqiong Zhang ,&nbsp;Meinan Peng ,&nbsp;Yue Han ,&nbsp;Depei Wu ,&nbsp;Aizhen Yang ,&nbsp;Yi Wu","doi":"10.1016/j.rpth.2024.102524","DOIUrl":"10.1016/j.rpth.2024.102524","url":null,"abstract":"<div><h3>Background</h3><p>Previous studies have shown that thiol isomerases such as ERp46 positively regulate platelet function by reducing integrin αIIbβ3 disulfides, and the transmembrane thiol isomerase TMX1 negatively regulates integrin αIIbβ3 activation. However, whether and how the positive and negative thiol isomerases interact with each other and their interactions participate in platelet activation remain unknown.</p></div><div><h3>Objectives</h3><p>To investigate whether and how TMX1 regulates the effect of ERp46 on platelet function.</p></div><div><h3>Methods</h3><p>Using ERp46- and TMX1-deficient platelets, anti-TMX1 antibody, and wild-type TMX1 (TMX1-CPAC, TMX1-SS) and inactive TMX1 (TMX1-SPAS, TMX1-OO) proteins, we studied the antagonistic effect of TMX1 on ERp46 in platelet aggregation, clot retraction, and integrin αIIbβ3 signaling. The underlying mechanisms were further determined using thiol labeling, reductase activity, and other assays.</p></div><div><h3>Results</h3><p>Anti-TMX1 antibody and TMX1-OO reversed the decreased aggregation of ERp46-deficient platelets induced by thrombin, convulxin, and U46619. Anti-TMX1 antibody reversed the attenuated integrin αIIbβ3 function of ERp46-deficient platelets. TMX1 inhibited ERp46 reductase activity in a concentration-dependent manner. TMX1 oxidized thiols of ERp46 and those of integrin αIIbβ3 generated by ERp46. Moreover, TMX1 deficiency increased free thiols of ERp46 in platelets, which was reversed by the addition of wild-type TMX1 protein. Besides, anti-TMX1 antibody increased free thiols of ERp46 in wild-type activated platelets.</p></div><div><h3>Conclusion</h3><p>TMX1 not only oxidizes integrin αIIbβ3 disulfides that are reduced by ERp46 but also directly oxidizes ERp46 to suppress its reduction of integrin αIIbβ3. Thus, TMX1 is critical for maintaining platelets in a quiescent state and counterbalancing the effect of ERp46 to prevent platelet overactivation.</p></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"8 5","pages":"Article 102524"},"PeriodicalIF":3.4,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S247503792400219X/pdfft?md5=a4da5a6aa7accc1bcdd73a13a970f535&pid=1-s2.0-S247503792400219X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141846768","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}