Thrombosis and haemostasis最新文献_第10页

Long-Term Safety of a Four-Factor Prothrombin Complex Concentrate (Kcentra®/Beriplex® P/N): An Updated Pharmacovigilance Review. 四因子凝血酶原复合物浓缩物（Kcentra®/Beriplex® P/N）的长期安全性：最新药物警戒回顾。

IF 5 2区医学

Thrombosis and haemostasis Pub Date : 2025-01-01 Epub Date: 2024-07-29 DOI: 10.1055/s-0044-1788305

Truman J Milling, Anna Voronov, Dirk S Schmidt, Edelgard Lindhoff-Last

{"title":"Long-Term Safety of a Four-Factor Prothrombin Complex Concentrate (Kcentra®/Beriplex® P/N): An Updated Pharmacovigilance Review.","authors":"Truman J Milling, Anna Voronov, Dirk S Schmidt, Edelgard Lindhoff-Last","doi":"10.1055/s-0044-1788305","DOIUrl":"10.1055/s-0044-1788305","url":null,"abstract":"Introduction: Four-factor prothrombin complex concentrate (4F-PCC) is recommended for vitamin K antagonist reversal in patients with major bleeding or in need of surgery. The most important risk associated with the use of 4F-PCC is the occurrence of thromboembolic events (TEEs). In this review, we aim to evaluate the safety profile of a 4F-PCC (Kcentra®/Beriplex® P/N; CSL Behring, Marburg, Germany) by reviewing pharmacovigilance data.Methods: A retrospective analysis of postmarketing pharmacovigilance data of Kcentra®/Beriplex® P/N from February 1996 to April 2022 was performed and complemented by a review of clinical studies published between January 2012 and April 2022.Results: A total of 2,321,443 standard infusions of Kcentra®/Beriplex® P/N were administered during the evaluation period. Adverse drug reactions (ADRs) were reported in 614 cases (∼1 per 3,781 standard infusions) and 233 of these cases (37.9%) experienced suspected TEEs related to 4F-PCC (∼1 per 9,963 standard infusions); most of these cases had pre-existing or concomitant conditions likely to be significant risk factors for thrombosis. TEE rates were similar when 4F-PCC was used on-label or off-label for direct oral anticoagulant-associated bleeding. Thirty-six cases (5.9%) reported hypersensitivity type reactions (∼1 per 64,485 standard infusions). No confirmed case of viral transmission related to 4F-PCC use was reported. The published literature also revealed a favorable safety profile of 4F-PCC.Conclusion: Analysis of postmarketing pharmacovigilance safety reports demonstrated that treatment with 4F-PCC was associated with few ADRs and a low rate of TEEs across multiple indications and settings, thus confirming a positive safety profile of 4F-PCC.","PeriodicalId":23036,"journal":{"name":"Thrombosis and haemostasis","volume":" ","pages":"46-57"},"PeriodicalIF":5.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11698618/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141793580","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}

引用次数: 0

Welcoming 2025-A Year of Collaboration and Progress. 欢迎2025年——合作进步之年。

IF 5 2区医学

Thrombosis and haemostasis Pub Date : 2025-01-01 Epub Date: 2025-01-03 DOI: 10.1055/a-2495-2105

Gregory Y H Lip, Anne Rigby, Christian Weber

引用次数: 0

Risk of Major Bleeding with Antiplatelet and/or Anticoagulation Therapy in Inherited Factor XI Deficiency: Insights from Real-World Observations. 遗传性因子 XI 缺乏症患者接受抗聚集和/或抗凝治疗后发生大出血的风险：来自真实世界观察的启示。

IF 5 2区医学

Thrombosis and haemostasis Pub Date : 2025-01-01 Epub Date: 2024-06-18 DOI: 10.1055/a-2347-4338

Shanni Vaismann, Nili Stein, Liat Dizengoff, Amir Warwar, Shoshan Perek, Ibraheem Zoabi, Walid Saliba, Meir Preis

引用次数: 0

Neutrophil Extracellular Traps, Platelets and Endothelial Cells Cooperatively Contribute to Hypercoagulability in Non-Small Cell Lung Cancer. 中性粒细胞胞外陷阱，血小板和内皮细胞共同促进非小细胞肺癌的高凝性。

IF 5 2区医学

Thrombosis and haemostasis Pub Date : 2024-12-27 DOI: 10.1055/a-2493-2499

Dongxia Tong, Yuan Gao, Weihua Sun, Jie Yang, Yang Liu, Jihe Li, Yan Zhang

{"title":"Neutrophil Extracellular Traps, Platelets and Endothelial Cells Cooperatively Contribute to Hypercoagulability in Non-Small Cell Lung Cancer.","authors":"Dongxia Tong, Yuan Gao, Weihua Sun, Jie Yang, Yang Liu, Jihe Li, Yan Zhang","doi":"10.1055/a-2493-2499","DOIUrl":"10.1055/a-2493-2499","url":null,"abstract":"Background: Thromboembolism is the second leading cause of death among patients with non-small cell lung cancer (NSCLC), but the precise mechanisms of thrombogenesis in NSCLC remain largely unknown. Our objectives were to evaluate the definitive role of neutrophil extracellular traps (NETs) in the hypercoagulability in NSCLC and to explore its interactions with platelets and endothelial cells (ECs).Methods: The levels of NET markers in samples from 100 NSCLC patients and 30 healthy controls were measured by ELISA. NET formation was detected using immunofluorescence. Procoagulant activity was assessed based on purified coagulation complex, thrombin, clotting time, and fibrin formation assays.Results: The plasma levels of NETs were increased in a stage-dependent manner in NSCLC patients and were markedly higher than those in controls. Neutrophils from NSCLC patients were more prone to form NETs, resulting in shortened coagulation time, significantly increased thrombin-antithrombin complexes and fibrin compared to controls. Moreover, NETs generation was mediated by High Mobility Group Box 1 from activated platelets in NSCLC patients. Conversely, NETs from NSCLC patients also induce phosphatidylserine exposure on platelets, leading to markedly enhanced procoagulant activity (PCA). Furthermore, NETs can damage endothelial cells and convert them to a procoagulant phenotype. The administration of NETs inhibitors (DNase I/activated protein C) could markedly diminish the PCA of NETs, activated platelets, and ECs.Conclusion: Our results suggest that NETs contribute to hypercoagulability and may represent a potential therapeutic target to prevent cancer-associated thrombosis in NSCLC patients.","PeriodicalId":23036,"journal":{"name":"Thrombosis and haemostasis","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142755484","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}

引用次数: 0

C-reactive Protein, Genetic Susceptibility, and the Long-Term Risk of Venous Thromboembolism in Patients with Past Cancer. c反应蛋白、遗传易感性和既往癌症患者静脉血栓栓塞的长期风险

IF 5 2区医学

Thrombosis and haemostasis Pub Date : 2024-12-27 DOI: 10.1055/a-2495-1350

Yunlong Guan, Zeyu Gan, Si Li, Xi Cao, Ao Zeng, Jing Li, Wei Gong, Jun Deng, Xingjie Hao

{"title":"C-reactive Protein, Genetic Susceptibility, and the Long-Term Risk of Venous Thromboembolism in Patients with Past Cancer.","authors":"Yunlong Guan, Zeyu Gan, Si Li, Xi Cao, Ao Zeng, Jing Li, Wei Gong, Jun Deng, Xingjie Hao","doi":"10.1055/a-2495-1350","DOIUrl":"10.1055/a-2495-1350","url":null,"abstract":"Background: Several studies have indicated that C-reactive protein (CRP) level is associated with the risk of venous thromboembolism (VTE) in the general population. However, CRP appears to be unrelated to VTE events in patients newly diagnosed with cancer. As the survival time of cancer patients increases, the effect of CRP on the long-term risk of VTE may change. We aimed to investigate the association between CRP and VTE in cancer survivors and further assess the modification effect of genetic susceptibility.Methods: The Cox proportional hazards model was used to evaluate the association between CRP levels and VTE risk as well as to investigate the joint effect of CRP and genetic susceptibility. The Kaplan-Meier curve and restricted cubic spline were used to visualize the relationship between CRP and VTE.Results: This study included 27,806 participants with cancer diagnosis at baseline in the UK Biobank. Over a follow-up period of 344,636 person-years, a total of 1,151 VTE events were recorded. Participants were divided into four groups based on CRP level quartiles. The adjusted hazard ratios (95% CIs) of Q1, Q2, Q3, and Q4 were 1.00, 1.20 (0.99-1.44), 1.25 (1.04-1.50), and 1.51 (1.25-1.82), respectively. For those with high genetic risk of VTE, high CRP had an additional increased risk for VTE.Conclusion: CRP can be used as a predictive biomarker for VTE risk in cancer survivors, especially in those with high genetic risk. Future research can explore whether prevention and treatment strategies for VTE can be developed based on CRP for cancer survivors.","PeriodicalId":23036,"journal":{"name":"Thrombosis and haemostasis","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142772623","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}

引用次数: 0

Dabigatran Attenuates the Binding of Thrombin to Platelets-A Novel Mechanism of Action. 达比加群能减弱凝血酶与血小板的结合--这是一种新的作用机制。

IF 5 2区医学

Thrombosis and haemostasis Pub Date : 2024-12-19 DOI: 10.1055/a-2483-0107

Tomas L Lindahl, Aishwarya Prasanna Kumar, Teresia Hallström, Ahmed Al-Hashimi, Anna du Rietz, Elena Arlaman, Kajsa Uvdal, Ankit S Macwan

{"title":"Dabigatran Attenuates the Binding of Thrombin to Platelets-A Novel Mechanism of Action.","authors":"Tomas L Lindahl, Aishwarya Prasanna Kumar, Teresia Hallström, Ahmed Al-Hashimi, Anna du Rietz, Elena Arlaman, Kajsa Uvdal, Ankit S Macwan","doi":"10.1055/a-2483-0107","DOIUrl":"10.1055/a-2483-0107","url":null,"abstract":"Background: Thrombin is a multifunctional regulatory enzyme of the haemostasis and has both pro- and anticoagulant roles. It has, therefore, been a main target for drug discovery over many decades. Thrombin is a serine protease and possesses two positively charged regions called exosites, through which it is known to bind to many substrates. Dabigatran is a thrombin inhibitor and is widely used as an oral anticoagulant for the antithrombotic treatment of atrial fibrillation and venous thromboembolism. The mechanism by which dabigatran inhibits thrombin is the blockage of the active site, however, its effect on thrombin binding to its substrates has not been studied thoroughly and is thus poorly understood.Material and methods: The effect of dabigatran on thrombin binding to platelets was evaluated by flow cytometry using fluorescently labelled thrombin and washed platelets. Further, to confirm the results we utilized modern techniques for biomolecular binding studies, microscale thermophoresis (MST) and surface plasmon resonance (SPR), which validated the results.Results: Dabigatran inhibited thrombin binding to platelets as analysed by flow cytometry. The inhibition was dose dependent with IC50 of 118 nM which was slightly lower than for inhibition of platelet activation and is close to the clinically relevant plasma concentration of dabigatran. MST and SPR also confirmed inhibitory effect of dabigatran on thrombin binding to platelets.Conclusion: Apart from blocking the active site, dabigatran also inhibits thrombin binding to platelets. Since thrombin has numerous functions beyond the cardiovascular system, this finding may have important implications.","PeriodicalId":23036,"journal":{"name":"Thrombosis and haemostasis","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142717070","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}

引用次数: 0

Venous Thromboembolism at Low Risk of Recurrence in Young Women: Stress and Violence Associated with Recurrence. An International Case-Control Study. 年轻女性静脉血栓栓塞复发风险低：压力和暴力与复发相关。一项国际病例对照研究

IF 5 2区医学

Thrombosis and haemostasis Pub Date : 2024-12-18 DOI: 10.1055/a-2484-0923

Victoria Bitsadze, Mariya Gennadevna Nikolaeva, Ève Mousty, Jamilya Khizroeva, Jérémy Laurent, Sylvie Ripart, Ekaterina Kudryavtseva, Lorris Le Collen, Anastasia Shatilina, Salim Allal, Elizaveta Lyadnova, Mathieu Fortier, Sylvie Bouvier, Mathias Chea, Marina Sabirovna Zainulina, Antonia Perez-Martin, Alexander Makatsariya, Jean-Christophe Gris

{"title":"Venous Thromboembolism at Low Risk of Recurrence in Young Women: Stress and Violence Associated with Recurrence. An International Case-Control Study.","authors":"Victoria Bitsadze, Mariya Gennadevna Nikolaeva, Ève Mousty, Jamilya Khizroeva, Jérémy Laurent, Sylvie Ripart, Ekaterina Kudryavtseva, Lorris Le Collen, Anastasia Shatilina, Salim Allal, Elizaveta Lyadnova, Mathieu Fortier, Sylvie Bouvier, Mathias Chea, Marina Sabirovna Zainulina, Antonia Perez-Martin, Alexander Makatsariya, Jean-Christophe Gris","doi":"10.1055/a-2484-0923","DOIUrl":"https://doi.org/10.1055/a-2484-0923","url":null,"abstract":"Background: In young women with venous thromboembolism (VTE) related to weak transient risk factors, it remains unknown whether stress levels and intimate partner violence (IPV) are associated with recurrence. The VTE-WEAK study aims to investigate the association between perceived stress and IPV with a recurrence of VTE in women with a first episode of VTE due to combined oral contraceptives, pregnancy-puerperium, minor trauma/fracture, brief surgery, infection or brief immobility, and not using antithrombotic prophylaxis.Material and methods: We performed a multicenter, international, observational, retrospective study on women referred for thrombophilia screening who were subsequently monitored. Patients were aged 18 to 55 years old and free of high-risk thrombophilia. When a recurrence of VTE was suspected for the first time, the perceived stress level and IPV were evaluated using self-administrated PSS-10 and Woman Abuse Screening Tool (WAST) questionnaires.Results: We monitored 7,754 women over 43,880 patients-years. A first suspected recurrence occurred in 4,772 women, among whom 1,316 had an objectively confirmed recurrence. The perceived stress level and an IPV situation were both independent risk factors for recurrence: moderate stress: adjusted odds ratio (aOR) 1.630 (1.415-2.468); high perceived stress: aOR 10.03 (7.528-13.36); IPV: 1.953 (1.546-2.468), p < 0.0001.Conclusion: The perceived level of stress and IPV are associated with a recurrence of VTE when suspected. The mechanisms and clinical consequences of a possible stress coagulopathy require investigation.","PeriodicalId":23036,"journal":{"name":"Thrombosis and haemostasis","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142855537","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}

引用次数: 0

Circulating Levels of Low-Density Granulocytes and Cell-Free DNA as Predictors of Cardiovascular Disease and Bone Deterioration in SLE Patients. 作为系统性红斑狼疮患者心血管疾病和骨质恶化预测因子的低密度粒细胞和游离 DNA 循环水平。

IF 5 2区医学

Thrombosis and haemostasis Pub Date : 2024-12-18 DOI: 10.1055/a-2467-6826

Ana Suárez, Uxía Tobío-Parada, Javier Rodríguez-Carrio, Aleida Martínez-Zapico, Ángel I Pérez-Álvarez, Silvia Suárez-Díaz, Luis Caminal-Montero, Patricia López

{"title":"Circulating Levels of Low-Density Granulocytes and Cell-Free DNA as Predictors of Cardiovascular Disease and Bone Deterioration in SLE Patients.","authors":"Ana Suárez, Uxía Tobío-Parada, Javier Rodríguez-Carrio, Aleida Martínez-Zapico, Ángel I Pérez-Álvarez, Silvia Suárez-Díaz, Luis Caminal-Montero, Patricia López","doi":"10.1055/a-2467-6826","DOIUrl":"10.1055/a-2467-6826","url":null,"abstract":"Objective: The present work evaluates the predictive value of low-density granulocytes (LDGs) for the development of cardiovascular disease (CVD) and/or bone deterioration (BD) in a 6-year prospective study in systemic lupus erythematosus (SLE). Considering the high SLE-LDG capacity to form neutrophil extracellular traps (NETs), circulating levels of total cell-free DNA (cirDNA) and relative amounts of mitochondrial and nuclear DNA (mtDNA and nDNA, respectively) were tested as LDG-associated biomarkers to identify SLE patients at risk of CVD and BD.Material and methods: The frequency of total blood LDGs, as well as the CD16negCD14neg (nLDG) and CD16posCD14low (pLDG) subsets, was quantified by flow cytometry in 33 controls and 144 SLE patients. Total cirDNA and relative amounts of mitochondrial (mtDNA) and nuclear (nDNA) cell-free DNA were measured by fluorometry or qPCR in plasma from a subgroup of 117 patients and 23 controls at enrolment.Results and conclusion: Our findings showed increased blood levels of SLE-nLDGs at enrolment associated with prospective CVD development (pCVD) and the presence of BD, thus revealing LDG expansion as a predictor of both comorbidities in SLE progression. The amounts of the different types of circulating DNA analyzed were increased in patients, especially those presenting with traditional CV risk factors or subclinical atheromatosis. Similar to nLDGs, the nDNA concentration could predict the development of pCVD in SLE, supporting the quantification of cirDNA levels as a surrogate marker of LDGs in clinical practice.","PeriodicalId":23036,"journal":{"name":"Thrombosis and haemostasis","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142627478","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}

引用次数: 0

The Plasma Proteome and Risk of Future Venous Thromboembolism-Results from the HUNT Study. 血浆蛋白质组与未来静脉血栓栓塞风险--HUNT 研究的结果。

IF 5 2区医学

Thrombosis and haemostasis Pub Date : 2024-12-18 DOI: 10.1055/a-2484-0836

Sigrid K Brækkan, Asbjørn L Onsaker, Therese H Nøst, Weihong Tang, Kristian D Hindberg, Vania M Morelli, Weihua Guan, Christian Jonasson, Aaron R Folsom, Kristian Hveem, John-Bjarne Hansen

{"title":"The Plasma Proteome and Risk of Future Venous Thromboembolism-Results from the HUNT Study.","authors":"Sigrid K Brækkan, Asbjørn L Onsaker, Therese H Nøst, Weihong Tang, Kristian D Hindberg, Vania M Morelli, Weihua Guan, Christian Jonasson, Aaron R Folsom, Kristian Hveem, John-Bjarne Hansen","doi":"10.1055/a-2484-0836","DOIUrl":"10.1055/a-2484-0836","url":null,"abstract":"Background: This study aimed to identify novel plasma proteins associated with first-lifetime venous thromboembolism (VTE) and molecular pathways involved in VTE pathogenesis.Methods: A case-cohort comprising incident VTE cases (n = 294) and a randomly sampled age- and sex-weighted subcohort (n = 1,066) was derived from the Trøndelag Health Study (HUNT3, n = 50,800). Blood samples were collected and stored at cohort inclusion (2006-2008), and participants were followed up to 5 years. Proteome-wide analyses was performed using the 7k SomaScan® proteomics platform, and weighted Cox-regression models adjusted for age, sex, and sample batch were conducted, with the Bonferroni method applied to account for multiple testing. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were applied on the top-ranked 200 proteins associated with VTE.Results: Out of 7,288 human proteins, 7 proteins were significantly associated with higher VTE risk with p-value <6.9 × 10-6 (hazard ratios per 1 standard deviation increase in protein levels ranging from 1.39 to 1.86). Except for coagulation factor VIII and tumor necrosis factor soluble receptor II, these proteins were novel associations and included collagen alpha-3(VI):BPTI/Kunitz inhibitor, histo-blood group ABO system transferase, peroxidasin, human epididymis protein 4, and regulator of G protein signaling 3. KEGG analyses of the top-ranked 200 proteins revealed significant pathway enrichment of nine proteins in the complement (mainly lectin pathway) and coagulation (mainly intrinsic pathway) cascades.Conclusion: Our proteome-wide analysis led to discovery of five novel protein candidates associated with 5-year risk of future VTE. KEGG analyses supported an interplay between the complement and coagulation pathways in the pathogenesis of VTE.","PeriodicalId":23036,"journal":{"name":"Thrombosis and haemostasis","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142717178","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}

引用次数: 0

Roles of ROCK/Myosin Pathway in Macrothrombocytopenia in Bernard-Soulier Syndrome. ROCK/Myosin通路在Bernard-Soulier综合征大血小板减少症中的作用。

IF 5 2区医学

Thrombosis and haemostasis Pub Date : 2024-12-18 DOI: 10.1055/a-2474-5644

Ponthip Mekchay, Praewphan Ingrungruanglert, Netchanok Leela-Adisorn, Noppacharn Uaprasert, Nipan Israsena, Ponlapat Rojnuckarin

{"title":"Roles of ROCK/Myosin Pathway in Macrothrombocytopenia in Bernard-Soulier Syndrome.","authors":"Ponthip Mekchay, Praewphan Ingrungruanglert, Netchanok Leela-Adisorn, Noppacharn Uaprasert, Nipan Israsena, Ponlapat Rojnuckarin","doi":"10.1055/a-2474-5644","DOIUrl":"https://doi.org/10.1055/a-2474-5644","url":null,"abstract":"Background: Megakaryocytes (MK) from Bernard-Soulier syndrome (BSS) induced pluripotent stem cells (iPSCs) yielded reduced numbers but increased sizes of platelets. The molecular mechanisms remain unclear. This study aims to determine roles of signaling molecules involved in this process.Material and methods: Wild-type (WT) iPSCs and iPSCs from BSS patients with GP1BA (BSS-A) or GP1BB (BSS-B) mutations were differentiated into MKs and platelets with or without myosin II inhibitor (blebbistatin), ROCK inhibitor (Y27632), and procaspase-3 activator (PAC-1). Proplatelet and platelet numbers and sizes were characterized. The iPSC lines containing tubulin-green fluorescent protein (GFP) reporters were constructed to observe proplatelet formation under time-lapse microscopy.Result: BSS-derived MKs (BSS-MKs) yielded fewer but larger platelets compared with the WT. In the presence of blebbistatin, ROCK inhibitor, or PAC-1, WT, BSS-A, and BSS-B MKs could generate more platelets with decreased sizes, but PAC-1 caused CD42 loss on WT platelets. The proportions of proplatelet formation from MKs carrying tubulin-GFP were not different between WT and BSS-MKs, as well as among inhibitors. Notably, initially thick cytoplasmic processes were transformed into thin branching proplatelets over the observation time. The proplatelet shafts of BSS-MK became thinner in the presence of blebbistatin or ROCK inhibitor, but not of PAC-1, which displayed uneven F-actin distribution.Conclusion: Inhibition of the ROCK/myosin pathway, downstream of GpIb, could restore normal morphology of proplatelets in BSS-MKs. Procaspase-3 activation could increase platelet yields, but with abnormal proplatelet and platelet structures. Our model can be used for therapeutic drug screening and a disease model for platelet production in the future.","PeriodicalId":23036,"journal":{"name":"Thrombosis and haemostasis","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142855536","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}

引用次数: 0