Background: Platelet C-type lectin-like receptor 2 (CLEC-2) induces platelet activation and aggregation after clustering by its ligand podoplanin (PDPN). PDPN, which is not normally expressed in cells in contact with blood flow, is induced in inflammatory immune cells and some malignant tumor cells, thereby increasing the risk of venous thromboembolism (VTE) and tumor metastasis. Therefore, small-molecule compounds that can interfere with the PDPN-CLEC-2 axis have the potential to become selective antiplatelet agents.
Methods and results: Using molecular docking analysis of CLEC-2 and a PDPN-CLEC-2 binding-inhibition assay, we identified a group of diphenyl-tetrazol-propanamide derivatives as novel CLEC-2 inhibitors. A total of 12 hit compounds also inhibited PDPN-induced platelet aggregation in humans and mice. Unexpectedly, these compounds also fit the collagen-binding pocket of the glycoprotein VI molecule, thereby inhibiting collagen interaction. These compounds also inhibited collagen-induced platelet aggregation, and one compound ameliorated collagen-induced thrombocytopenia in mice. For clinical use, these compounds will require a degree of chemical modification to decrease albumin binding.
Conclusion: Nonetheless, as dual activation of platelets by collagen and PDPN-positive cells is expected to occur after the rupture of atherosclerotic plaques, these dual antagonists could represent a promising pharmacophore, particularly for arterial thrombosis, in addition to VTE and metastasis.
{"title":"Diphenyl-tetrazol-propanamide Derivatives Act as Dual-Specific Antagonists of Platelet CLEC-2 and Glycoprotein VI.","authors":"Nobuo Watanabe, Yoshiko Shinozaki, Sanae Ogiwara, Riko Miyagasako, Ayumi Sasaki, Junko Kato, Yusuke Suzuki, Natsuko Fukunishi, Yoshinori Okada, Takeshi Saito, Yumi Iida, Misaki Higashiseto, Haruchika Masuda, Eiichiro Nagata, Kazuhito Gotoh, Mari Amino, Tomoatsu Tsuji, Seiji Morita, Yoshihide Nakagawa, Noriaki Hirayama, Sadaki Inokuchi","doi":"10.1055/a-2211-5202","DOIUrl":"10.1055/a-2211-5202","url":null,"abstract":"<p><strong>Background: </strong> Platelet C-type lectin-like receptor 2 (CLEC-2) induces platelet activation and aggregation after clustering by its ligand podoplanin (PDPN). PDPN, which is not normally expressed in cells in contact with blood flow, is induced in inflammatory immune cells and some malignant tumor cells, thereby increasing the risk of venous thromboembolism (VTE) and tumor metastasis. Therefore, small-molecule compounds that can interfere with the PDPN-CLEC-2 axis have the potential to become selective antiplatelet agents.</p><p><strong>Methods and results: </strong> Using molecular docking analysis of CLEC-2 and a PDPN-CLEC-2 binding-inhibition assay, we identified a group of diphenyl-tetrazol-propanamide derivatives as novel CLEC-2 inhibitors. A total of 12 hit compounds also inhibited PDPN-induced platelet aggregation in humans and mice. Unexpectedly, these compounds also fit the collagen-binding pocket of the glycoprotein VI molecule, thereby inhibiting collagen interaction. These compounds also inhibited collagen-induced platelet aggregation, and one compound ameliorated collagen-induced thrombocytopenia in mice. For clinical use, these compounds will require a degree of chemical modification to decrease albumin binding.</p><p><strong>Conclusion: </strong> Nonetheless, as dual activation of platelets by collagen and PDPN-positive cells is expected to occur after the rupture of atherosclerotic plaques, these dual antagonists could represent a promising pharmacophore, particularly for arterial thrombosis, in addition to VTE and metastasis.</p>","PeriodicalId":23036,"journal":{"name":"Thrombosis and haemostasis","volume":null,"pages":null},"PeriodicalIF":6.7,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134649771","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}
Background: The Caprini risk assessment model (RAM) is the most commonly used tool for evaluating venous thromboembolism (VTE) risk, a high score for arthroplasty can result in patients being classified as high risk for VTE. Therefore, its value in post-arthroplasty has been subject to debate.
Methods: Retrospective data were collected from patients who underwent arthroplasty between August 2015 and December 2021. The study cohort included 3,807 patients, all of whom underwent a thorough evaluation using Caprini RAM and vascular Doppler ultrasonography preoperatively.
Results: A total of 432 individuals (11.35%) developed VTE, while 3,375 did not. Furthermore, 32 (0.84%) presented with symptomatic VTE, while 400 (10.51%) were detected as asymptomatic. Additionally, 368 (9.67%) VTE events occurred during the hospitalization period, and 64 (1.68%) cases were detected during postdischarge follow-up. Statistical analysis revealed significant differences between the VTE and non-VTE groups in terms of ages, blood loss, D-dimer, body mass index >25, visible varicose veins, swollen legs, smoking, history of blood clots, broken hip, percent of female, hypertension, and knee joint arthroplasty (p < 0.05). The Caprini score was found to be significantly higher in the VTE group (10.10 ± 2.23) compared with the non-VTE group (9.35 ± 2.14) (p < 0.001). Furthermore, there was a significant correlation between the incidence of VTE and the Caprini score (r = 0.775, p = 0.003). Patients with a score ≥9 are at a high-risk threshold for postoperative VTE.
Conclusion: The Caprini RAM shows a significant correlation with the occurrence of VTE. A higher score indicates a greater likelihood of developing VTE. The score ≥9 is at particularly high risk of developing VTE.
{"title":"The Validation and Modification of the Caprini Risk Assessment Model for Evaluating Venous Thromboembolism after Joint Arthroplasty.","authors":"Liang Qiao, Yao Yao, Dengxian Wu, Ruijuan Xu, Honggang Cai, Ying Shen, Zhihong Xu, Qing Jiang","doi":"10.1055/a-2122-7780","DOIUrl":"10.1055/a-2122-7780","url":null,"abstract":"<p><strong>Background: </strong> The Caprini risk assessment model (RAM) is the most commonly used tool for evaluating venous thromboembolism (VTE) risk, a high score for arthroplasty can result in patients being classified as high risk for VTE. Therefore, its value in post-arthroplasty has been subject to debate.</p><p><strong>Methods: </strong> Retrospective data were collected from patients who underwent arthroplasty between August 2015 and December 2021. The study cohort included 3,807 patients, all of whom underwent a thorough evaluation using Caprini RAM and vascular Doppler ultrasonography preoperatively.</p><p><strong>Results: </strong> A total of 432 individuals (11.35%) developed VTE, while 3,375 did not. Furthermore, 32 (0.84%) presented with symptomatic VTE, while 400 (10.51%) were detected as asymptomatic. Additionally, 368 (9.67%) VTE events occurred during the hospitalization period, and 64 (1.68%) cases were detected during postdischarge follow-up. Statistical analysis revealed significant differences between the VTE and non-VTE groups in terms of ages, blood loss, D-dimer, body mass index >25, visible varicose veins, swollen legs, smoking, history of blood clots, broken hip, percent of female, hypertension, and knee joint arthroplasty (<i>p</i> < 0.05). The Caprini score was found to be significantly higher in the VTE group (10.10 ± 2.23) compared with the non-VTE group (9.35 ± 2.14) (<i>p</i> < 0.001). Furthermore, there was a significant correlation between the incidence of VTE and the Caprini score (<i>r</i> = 0.775, <i>p</i> = 0.003). Patients with a score ≥9 are at a high-risk threshold for postoperative VTE.</p><p><strong>Conclusion: </strong> The Caprini RAM shows a significant correlation with the occurrence of VTE. A higher score indicates a greater likelihood of developing VTE. The score ≥9 is at particularly high risk of developing VTE.</p>","PeriodicalId":23036,"journal":{"name":"Thrombosis and haemostasis","volume":null,"pages":null},"PeriodicalIF":6.7,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10890911/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9931628","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 : 2024-03-01Epub Date: 2023-09-30DOI: 10.1055/a-2184-7506
Chuan-Tsai Tsai, Yi-Hsin Chan, Jo-Nan Liao, Tzeng-Ji Chen, Gregory Y H Lip, Shih-Ann Chen, Tze-Fan Chao
Background: Dementia and atrial fibrillation (AF) have many shared risk factors. Besides, patients with dementia are under-represented in randomized trials, and even if AF is present, oral anticoagulants (OACs) are not prescribed frequently. This study aimed to report the incidence of newly diagnosed AF in dementia patients, and the impacts of use of vitamin K antagonist (VKA; e.g., warfarin) and non-VKA OAC (NOACs) on stroke and bleeding outcomes.
Methods: Our study utilized the Taiwan National Health Insurance Research Database. A total of 554,074 patients with dementia were compared with 554,074 age- and sex-matched patients without dementia regarding the risk of incident AF. Among patients with dementia who experienced incident AF, the risks of clinical events of patients treated with warfarin or NOACs were compared with those without OACs (reference group).
Results: The risk of incident AF was greater for patients with dementia compared with those without (adjusted hazard ratio [aHR]: 1.054; 95% confidence interval [CI]: 1.040-1.068 for all types of dementia, aHR: 1.035; 95% CI: 1.020-1.051 for presenile/senile dementia, and aHR: 1.125; 95% CI: 1.091-1.159 for vascular dementia). Among patients with dementia and experienced incident AF, warfarin use was associated with a higher risk of ischemic stroke (aHR: 1.290; 95% CI: 1.156-1.440), intracranial hemorrhage (ICH; aHR: 1.678; 95% CI: 1.346-2.090), and major bleeding (aHR: 1.192; 95% CI: 1.073-1.323) compared with non-OACs. NOAC use was associated with a lower risk of ischemic stroke (aHR: 0.421; 95% CI: 0.352-0.503) and composite risk of ischemic stroke or major bleeding (aHR: 0.544; 95% CI: 0.487-0.608) compared with non-OACs. These results were consistent among the patients after the propensity matching.
Conclusion: In this large nationwide cohort, the risk of newly diagnosed AF was higher in patients with dementia (all dementia, presenile/senile dementia, and vascular dementia) compared with those without dementia. For patients with dementia who experienced incident AF, NOAC use was associated with a better clinical outcome compared with non-OAC. Patients with dementia require a holistic approach to their care and management, including the use of NOACs to reduce the risks of clinical events.
{"title":"Risk of Incident Atrial Fibrillation and Subsequent Use of Oral Anticoagulants in Patients with Dementia.","authors":"Chuan-Tsai Tsai, Yi-Hsin Chan, Jo-Nan Liao, Tzeng-Ji Chen, Gregory Y H Lip, Shih-Ann Chen, Tze-Fan Chao","doi":"10.1055/a-2184-7506","DOIUrl":"10.1055/a-2184-7506","url":null,"abstract":"<p><strong>Background: </strong> Dementia and atrial fibrillation (AF) have many shared risk factors. Besides, patients with dementia are under-represented in randomized trials, and even if AF is present, oral anticoagulants (OACs) are not prescribed frequently. This study aimed to report the incidence of newly diagnosed AF in dementia patients, and the impacts of use of vitamin K antagonist (VKA; e.g., warfarin) and non-VKA OAC (NOACs) on stroke and bleeding outcomes.</p><p><strong>Methods: </strong> Our study utilized the Taiwan National Health Insurance Research Database. A total of 554,074 patients with dementia were compared with 554,074 age- and sex-matched patients without dementia regarding the risk of incident AF. Among patients with dementia who experienced incident AF, the risks of clinical events of patients treated with warfarin or NOACs were compared with those without OACs (reference group).</p><p><strong>Results: </strong> The risk of incident AF was greater for patients with dementia compared with those without (adjusted hazard ratio [aHR]: 1.054; 95% confidence interval [CI]: 1.040-1.068 for all types of dementia, aHR: 1.035; 95% CI: 1.020-1.051 for presenile/senile dementia, and aHR: 1.125; 95% CI: 1.091-1.159 for vascular dementia). Among patients with dementia and experienced incident AF, warfarin use was associated with a higher risk of ischemic stroke (aHR: 1.290; 95% CI: 1.156-1.440), intracranial hemorrhage (ICH; aHR: 1.678; 95% CI: 1.346-2.090), and major bleeding (aHR: 1.192; 95% CI: 1.073-1.323) compared with non-OACs. NOAC use was associated with a lower risk of ischemic stroke (aHR: 0.421; 95% CI: 0.352-0.503) and composite risk of ischemic stroke or major bleeding (aHR: 0.544; 95% CI: 0.487-0.608) compared with non-OACs. These results were consistent among the patients after the propensity matching.</p><p><strong>Conclusion: </strong> In this large nationwide cohort, the risk of newly diagnosed AF was higher in patients with dementia (all dementia, presenile/senile dementia, and vascular dementia) compared with those without dementia. For patients with dementia who experienced incident AF, NOAC use was associated with a better clinical outcome compared with non-OAC. Patients with dementia require a holistic approach to their care and management, including the use of NOACs to reduce the risks of clinical events.</p>","PeriodicalId":23036,"journal":{"name":"Thrombosis and haemostasis","volume":null,"pages":null},"PeriodicalIF":6.7,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41141385","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 : 2024-03-01Epub Date: 2023-09-12DOI: 10.1055/a-2174-0963
Joseph A Caprini, Maryanne Cronin, Nancy Dengler, Eugene Krauss
{"title":"A New Chapter Regarding Thrombosis Risk Assessment in Total Joint Replacement Patients.","authors":"Joseph A Caprini, Maryanne Cronin, Nancy Dengler, Eugene Krauss","doi":"10.1055/a-2174-0963","DOIUrl":"10.1055/a-2174-0963","url":null,"abstract":"","PeriodicalId":23036,"journal":{"name":"Thrombosis and haemostasis","volume":null,"pages":null},"PeriodicalIF":6.7,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10277635","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 : 2024-03-01Epub Date: 2023-09-12DOI: 10.1055/a-2174-0844
Lasse M Obel, Jes S Lindholt, Axel C Diederichsen, Christian Kring, Lars M Rasmussen, Anne B Alnor, Pernille J Vinholt
{"title":"Platelet Aggregation Is Not Altered in Men with Aortic Aneurysms.","authors":"Lasse M Obel, Jes S Lindholt, Axel C Diederichsen, Christian Kring, Lars M Rasmussen, Anne B Alnor, Pernille J Vinholt","doi":"10.1055/a-2174-0844","DOIUrl":"10.1055/a-2174-0844","url":null,"abstract":"","PeriodicalId":23036,"journal":{"name":"Thrombosis and haemostasis","volume":null,"pages":null},"PeriodicalIF":6.7,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10277636","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 : 2024-03-01Epub Date: 2023-10-16DOI: 10.1055/s-0043-1776305
Oliver Buchhave Pedersen, Anne-Mette Hvas, Leonardo Pasalic, Steen Dalby Kristensen, Erik Lerkevang Grove, Peter H Nissen
Background: Reduced effect of antiplatelet therapy has been reported in patients with ST-segment elevation myocardial infarction (STEMI). MicroRNAs (miRs) may influence platelet function and maturity, and subsequently the effect of antiplatelet therapy.
Objectives: We aimed to explore the association between miR expression and platelet function and maturity in patients with acute STEMI and healthy individuals.
Methods: We performed an observational study of STEMI patients admitted directly to primary percutaneous coronary intervention. Patients were treated with antiplatelet therapy according to guidelines. Within 24 hours after admission, blood samples were obtained to measure: the expression of 10 candidate miRs, platelet function markers using advanced flow cytometry, platelet aggregation, serum thromboxane B2, and platelet maturity markers. Furthermore, blood samples from healthy individuals were obtained to determine the normal variation.
Results: In total, 61 STEMI patients and 50 healthy individuals were included. STEMI patients had higher expression of miR-21-5p, miR-26b-5p, and miR-223-3p and lower expression of miR-150-5p, miR423-5p, and miR-1180-3p than healthy individuals. In STEMI patients, the expression of miR-26b-5p showed the most consistent association with platelet function (all p-values <0.05, Spearman's rho ranging from 0.27 to 0.41), while the expression of miR-150-5p and miR-223-3p showed negative associations with platelet function. No association between miR expression and platelet maturity markers was observed.
Conclusion: In patients with STEMI, the expression of six miRs was significantly different from healthy individuals. The expression of miR-26b-5p may affect platelet function in acute STEMI patients and potentially influence the effect of antiplatelet therapy.
{"title":"Platelet Function and Maturity and Related microRNA Expression in Whole Blood in Patients with ST-Segment Elevation Myocardial Infarction.","authors":"Oliver Buchhave Pedersen, Anne-Mette Hvas, Leonardo Pasalic, Steen Dalby Kristensen, Erik Lerkevang Grove, Peter H Nissen","doi":"10.1055/s-0043-1776305","DOIUrl":"10.1055/s-0043-1776305","url":null,"abstract":"<p><strong>Background: </strong> Reduced effect of antiplatelet therapy has been reported in patients with ST-segment elevation myocardial infarction (STEMI). MicroRNAs (miRs) may influence platelet function and maturity, and subsequently the effect of antiplatelet therapy.</p><p><strong>Objectives: </strong> We aimed to explore the association between miR expression and platelet function and maturity in patients with acute STEMI and healthy individuals.</p><p><strong>Methods: </strong> We performed an observational study of STEMI patients admitted directly to primary percutaneous coronary intervention. Patients were treated with antiplatelet therapy according to guidelines. Within 24 hours after admission, blood samples were obtained to measure: the expression of 10 candidate miRs, platelet function markers using advanced flow cytometry, platelet aggregation, serum thromboxane B<sub>2</sub>, and platelet maturity markers. Furthermore, blood samples from healthy individuals were obtained to determine the normal variation.</p><p><strong>Results: </strong> In total, 61 STEMI patients and 50 healthy individuals were included. STEMI patients had higher expression of miR-21-5p, miR-26b-5p, and miR-223-3p and lower expression of miR-150-5p, miR423-5p, and miR-1180-3p than healthy individuals. In STEMI patients, the expression of miR-26b-5p showed the most consistent association with platelet function (all <i>p</i>-values <0.05, Spearman's rho ranging from 0.27 to 0.41), while the expression of miR-150-5p and miR-223-3p showed negative associations with platelet function. No association between miR expression and platelet maturity markers was observed.</p><p><strong>Conclusion: </strong> In patients with STEMI, the expression of six miRs was significantly different from healthy individuals. The expression of miR-26b-5p may affect platelet function in acute STEMI patients and potentially influence the effect of antiplatelet therapy.</p>","PeriodicalId":23036,"journal":{"name":"Thrombosis and haemostasis","volume":null,"pages":null},"PeriodicalIF":6.7,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41238653","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 : 2024-03-01Epub Date: 2023-10-09DOI: 10.1055/s-0043-1776010
Karlyn A Martin, Neil A Zakai
{"title":"Venous Thromboembolism and Obesity: Moving Toward a Better Understanding of the Population-Attributable Risk.","authors":"Karlyn A Martin, Neil A Zakai","doi":"10.1055/s-0043-1776010","DOIUrl":"10.1055/s-0043-1776010","url":null,"abstract":"","PeriodicalId":23036,"journal":{"name":"Thrombosis and haemostasis","volume":null,"pages":null},"PeriodicalIF":6.7,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41183656","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}
Hong-Cheng Du, Yun-Fei Zheng, Meng-Qi Shen, Bai-Yang Deng
Background: Given the current debate in clinical research about the relationship between tobacco smoking and the risk of venous thromboembolism (VTE), a Mendelian randomization (MR) study was conducted aimed at elucidating the causal associations of current and past tobacco smoking with the risk of VTE, from the perspective of genetics.
Methods: Two-sample univariate and multivariable MR analyses were designed, using summary-level data from large genome-wide association studies involving European individuals. Causality was primarily assessed using multiplicative fixed-effects or random-effects model and inverse variance weighting, supplemented by MR-Egger regression, MR-PRESSO, Cochran's Q test, and leave-one-out for sensitivity analysis to test the reliability of the results.
Results: In the univariate MR analysis, no significant causal effects were found between current tobacco smoking and the risk of VTE, deep vein thrombosis (DVT), and pulmonary embolism (PE). Similarly, no significant causal effects were found between past smoking and VTE, DVT, and PE. As for the multivariable MR analysis, results were consistent with univariate MR analysis, with no significant causal effect of either current or past tobacco smoking on the risk of VTE, DVT, and PE.
Conclusion: Evidence from both univariate and multivariable MR analyses demonstrated no significant causal relationships between current and past tobacco smoking and VTE, DVT, and PE. This contradicts positive correlations reported in some previous observational studies, which may be explained by other confounding factors. This provided genetic evidence for the conclusion reported in other observational studies that smoking did not affect VTE risk.
研究背景鉴于目前临床研究中关于吸烟与静脉血栓栓塞症(VTE)风险之间关系的争论,我们开展了一项孟德尔随机化(MR)研究,旨在从遗传学的角度阐明当前和过去吸烟与 VTE 风险之间的因果关系:方法:利用涉及欧洲人的大型全基因组关联研究的汇总数据,设计了双样本单变量和多变量 MR 分析。因果关系主要通过乘法固定效应或随机效应模型和反方差加权进行评估,并辅以MR-Egger回归、MR-PRESSO、Cochran's Q检验和leave-one-out进行敏感性分析,以检验结果的可靠性:在单变量MR分析中,未发现当前吸烟与VTE、深静脉血栓(DVT)和肺栓塞(PE)风险之间存在显著的因果关系。同样,既往吸烟与 VTE、DVT 和 PE 之间也没有发现明显的因果关系。至于多变量磁共振分析,结果与单变量磁共振分析一致,当前或既往吸烟对VTE、DVT和PE的风险均无明显的因果关系:单变量和多变量磁共振分析的证据表明,当前和既往吸烟与 VTE、DVT 和 PE 之间没有明显的因果关系。这与之前一些观察性研究中报告的正相关性相矛盾,后者可能是由其他混杂因素造成的。这为其他观察性研究中报告的吸烟不影响 VTE 风险的结论提供了遗传学证据。
{"title":"No Genetic Causality between Tobacco Smoking and Venous Thromboembolism: A Two-Sample Mendelian Randomization Study.","authors":"Hong-Cheng Du, Yun-Fei Zheng, Meng-Qi Shen, Bai-Yang Deng","doi":"10.1055/s-0044-1781425","DOIUrl":"https://doi.org/10.1055/s-0044-1781425","url":null,"abstract":"<p><strong>Background: </strong> Given the current debate in clinical research about the relationship between tobacco smoking and the risk of venous thromboembolism (VTE), a Mendelian randomization (MR) study was conducted aimed at elucidating the causal associations of current and past tobacco smoking with the risk of VTE, from the perspective of genetics.</p><p><strong>Methods: </strong> Two-sample univariate and multivariable MR analyses were designed, using summary-level data from large genome-wide association studies involving European individuals. Causality was primarily assessed using multiplicative fixed-effects or random-effects model and inverse variance weighting, supplemented by MR-Egger regression, MR-PRESSO, Cochran's Q test, and leave-one-out for sensitivity analysis to test the reliability of the results.</p><p><strong>Results: </strong> In the univariate MR analysis, no significant causal effects were found between current tobacco smoking and the risk of VTE, deep vein thrombosis (DVT), and pulmonary embolism (PE). Similarly, no significant causal effects were found between past smoking and VTE, DVT, and PE. As for the multivariable MR analysis, results were consistent with univariate MR analysis, with no significant causal effect of either current or past tobacco smoking on the risk of VTE, DVT, and PE.</p><p><strong>Conclusion: </strong> Evidence from both univariate and multivariable MR analyses demonstrated no significant causal relationships between current and past tobacco smoking and VTE, DVT, and PE. This contradicts positive correlations reported in some previous observational studies, which may be explained by other confounding factors. This provided genetic evidence for the conclusion reported in other observational studies that smoking did not affect VTE risk.</p>","PeriodicalId":23036,"journal":{"name":"Thrombosis and haemostasis","volume":null,"pages":null},"PeriodicalIF":6.7,"publicationDate":"2024-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139933023","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}
Background: Vascular injury results in uncontrollable hemorrhage in hemorrhagic diseases and excessive antithrombotic therapy. Safe and efficient hemostatic agents which can be orally administered are urgently needed. Platelets play indispensable roles in hemostasis, but there is no drug exerting hemostatic effects through enhancing platelet function.
Methods: The regulatory effects of icaritin, a natural compound isolated from Herba Epimedii, on the dense granule release, thromboxane A2 (TxA2) synthesis, α-granule release, activation of integrin αIIbβ3, and aggregation of platelets induced by multiple agonists were investigated. The effects of icaritin on tail vein bleeding times of warfarin-treated mice were also evaluated. Furthermore, we investigated the underlying mechanisms by which icaritin exerted its pharmacological effects.
Results: Icaritin alone did not activate platelets, but significantly potentiated the dense granule release, α-granule release, activation of integrin αIIbβ3, and aggregation of platelets induced by thrombin and U46619. Icaritin also shortened tail vein bleeding times of mice treated with warfarin. In addition, phosphorylated proteome analysis, immunoblotting analysis, and pharmacological research revealed that icaritin sensitized the activation of phospholipase Cγ2 (PLCγ2)-protein kinase C (PKC) signaling pathways, which play important roles in platelet activation.
Conclusion: Icaritin can sensitize platelet activation induced by thrombin and TxA2 through enhancing the activation of PLCγ2-PKC signaling pathways and promote hemostasis, and has potential to be developed into a novel orally deliverable therapeutic agent for hemorrhages.
{"title":"Icaritin Sensitizes Thrombin- and TxA2-Induced Platelet Activation and Promotes Hemostasis via Enhancing PLCγ2-PKC Signaling Pathways.","authors":"Zhixiang Zhu, Yanggan Luo, Hanjing Liao, Ran Guo, Doudou Hao, Zihan Lu, Manjing Huang, Chenghong Sun, Jingchun Yao, Ning Wei, Kewu Zeng, Pengfei Tu, Guimin Zhang","doi":"10.1055/a-2245-8457","DOIUrl":"10.1055/a-2245-8457","url":null,"abstract":"<p><strong>Background: </strong> Vascular injury results in uncontrollable hemorrhage in hemorrhagic diseases and excessive antithrombotic therapy. Safe and efficient hemostatic agents which can be orally administered are urgently needed. Platelets play indispensable roles in hemostasis, but there is no drug exerting hemostatic effects through enhancing platelet function.</p><p><strong>Methods: </strong> The regulatory effects of icaritin, a natural compound isolated from <i>Herba Epimedii</i>, on the dense granule release, thromboxane A<sub>2</sub> (TxA<sub>2</sub>) synthesis, α-granule release, activation of integrin αIIbβ3, and aggregation of platelets induced by multiple agonists were investigated. The effects of icaritin on tail vein bleeding times of warfarin-treated mice were also evaluated. Furthermore, we investigated the underlying mechanisms by which icaritin exerted its pharmacological effects.</p><p><strong>Results: </strong> Icaritin alone did not activate platelets, but significantly potentiated the dense granule release, α-granule release, activation of integrin αIIbβ3, and aggregation of platelets induced by thrombin and U46619. Icaritin also shortened tail vein bleeding times of mice treated with warfarin. In addition, phosphorylated proteome analysis, immunoblotting analysis, and pharmacological research revealed that icaritin sensitized the activation of phospholipase Cγ2 (PLCγ2)-protein kinase C (PKC) signaling pathways, which play important roles in platelet activation.</p><p><strong>Conclusion: </strong> Icaritin can sensitize platelet activation induced by thrombin and TxA<sub>2</sub> through enhancing the activation of PLCγ2-PKC signaling pathways and promote hemostasis, and has potential to be developed into a novel orally deliverable therapeutic agent for hemorrhages.</p>","PeriodicalId":23036,"journal":{"name":"Thrombosis and haemostasis","volume":null,"pages":null},"PeriodicalIF":6.7,"publicationDate":"2024-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139472898","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}