Pub Date : 2024-06-01Epub Date: 2024-03-19DOI: 10.1055/s-0044-1782161
Luis Ortega-Paz, Francesco Franchi, Dominick J Angiolillo
{"title":"The Lipid-Platelet Interplay: Unraveling the Effects of PCSK9 Inhibition on Platelet Reactivity.","authors":"Luis Ortega-Paz, Francesco Franchi, Dominick J Angiolillo","doi":"10.1055/s-0044-1782161","DOIUrl":"10.1055/s-0044-1782161","url":null,"abstract":"","PeriodicalId":23036,"journal":{"name":"Thrombosis and haemostasis","volume":null,"pages":null},"PeriodicalIF":6.7,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140176597","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: Intra-plaque hemorrhage (IPH) leads to rapid plaque progression and instability through upregulation of matrix metalloproteinases (MMPs) and collagen degradation. Hemoglobin-derived hemin during IPH promotes plaque instability. We investigated whether hemin affects MMP overexpression in macrophages and explored the underlying mechanisms.
Material and methods: In vivo, hemorrhagic plaque models were established in rabbits and ApoE-/- mice. Ferrostatin-1 was used to inhibit ferroptosis. Plaque size, collagen, and MMP2/9 levels were evaluated using immunohistochemistry, H&E, Sirius Red, and Masson staining. In vitro, mouse peritoneal macrophages were extracted. Western blot and ELISA were used to measure MMP2/9 levels. Bioinformatics analysis investigated the association between MMPs and ferroptosis pathway genes. Macrophage ferroptosis was assessed by evaluating cell viability, lipid reactive oxygen species, mitochondrial ultrastructure, iron content, and COX2 levels after pretreatment with cell death inhibitors. Hemin's impact on ferroptosis and MMP expression was studied using Ferrostatin-1 and SB202190.
Results: In the rabbit hemorrhagic plaques, hemin deposition and overexpression of MMP2/9 were observed, particularly in macrophage-enriched regions. In vitro, hemin induced ferroptosis and MMP2/9 expression in macrophages. Ferrostatin-1 and SB202190 inhibited hemin-induced MMP2/9 overexpression. Ferrostatin-1 inhibited p38 phosphorylation in macrophages. Ferostatin-1 inhibits macrophage ferroptosis, reduces MMP2/9 levels in plaques, and stabilizes the hemorrhagic plaques.
Conclusion: Our results suggested that hemin-induced macrophage ferroptosis promotes p38 pathway activation and MMP2/9 overexpression, which may play a crucial role in increasing hemorrhagic plaque vulnerability. These findings provide insights into the pathogenesis of hemorrhagic plaques and suggest that targeting macrophage ferroptosis may be a promising strategy for stabilizing vulnerable plaque.
{"title":"Macrophage Ferroptosis Promotes MMP2/9 Overexpression Induced by Hemin in Hemorrhagic Plaque.","authors":"Bicheng Li, Minqiao Lu, Hui Wang, Siqi Sheng, Shuyuan Guo, Jia Li, Ye Tian","doi":"10.1055/a-2173-3602","DOIUrl":"10.1055/a-2173-3602","url":null,"abstract":"<p><strong>Background: </strong> Intra-plaque hemorrhage (IPH) leads to rapid plaque progression and instability through upregulation of matrix metalloproteinases (MMPs) and collagen degradation. Hemoglobin-derived hemin during IPH promotes plaque instability. We investigated whether hemin affects MMP overexpression in macrophages and explored the underlying mechanisms.</p><p><strong>Material and methods: </strong> In vivo, hemorrhagic plaque models were established in rabbits and ApoE<sup>-/-</sup> mice. Ferrostatin-1 was used to inhibit ferroptosis. Plaque size, collagen, and MMP2/9 levels were evaluated using immunohistochemistry, H&E, Sirius Red, and Masson staining. In vitro, mouse peritoneal macrophages were extracted. Western blot and ELISA were used to measure MMP2/9 levels. Bioinformatics analysis investigated the association between MMPs and ferroptosis pathway genes. Macrophage ferroptosis was assessed by evaluating cell viability, lipid reactive oxygen species, mitochondrial ultrastructure, iron content, and COX2 levels after pretreatment with cell death inhibitors. Hemin's impact on ferroptosis and MMP expression was studied using Ferrostatin-1 and SB202190.</p><p><strong>Results: </strong> In the rabbit hemorrhagic plaques, hemin deposition and overexpression of MMP2/9 were observed, particularly in macrophage-enriched regions. In vitro, hemin induced ferroptosis and MMP2/9 expression in macrophages. Ferrostatin-1 and SB202190 inhibited hemin-induced MMP2/9 overexpression. Ferrostatin-1 inhibited p38 phosphorylation in macrophages. Ferostatin-1 inhibits macrophage ferroptosis, reduces MMP2/9 levels in plaques, and stabilizes the hemorrhagic plaques.</p><p><strong>Conclusion: </strong> Our results suggested that hemin-induced macrophage ferroptosis promotes p38 pathway activation and MMP2/9 overexpression, which may play a crucial role in increasing hemorrhagic plaque vulnerability. These findings provide insights into the pathogenesis of hemorrhagic plaques and suggest that targeting macrophage ferroptosis may be a promising strategy for stabilizing vulnerable plaque.</p>","PeriodicalId":23036,"journal":{"name":"Thrombosis and haemostasis","volume":null,"pages":null},"PeriodicalIF":6.7,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10203614","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 : 2024-06-01Epub Date: 2023-11-22DOI: 10.1055/a-2216-5263
Marco Cattaneo, Alessandro Squizzato, Simone Birocchi, Gian Marco Podda
{"title":"Guided Anti-P2Y12 Therapy in Patients Undergoing Percutaneous Coronary Intervention.","authors":"Marco Cattaneo, Alessandro Squizzato, Simone Birocchi, Gian Marco Podda","doi":"10.1055/a-2216-5263","DOIUrl":"10.1055/a-2216-5263","url":null,"abstract":"","PeriodicalId":23036,"journal":{"name":"Thrombosis and haemostasis","volume":null,"pages":null},"PeriodicalIF":6.7,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138296040","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 : 2024-06-01Epub Date: 2024-01-09DOI: 10.1055/s-0043-1778071
Graeme I Lancaster, Pooranee K Morgan, Andrew J Murphy
{"title":"Iron Macrophages: Dance of Death and MMP Release in Intraplaque Hemorrhage.","authors":"Graeme I Lancaster, Pooranee K Morgan, Andrew J Murphy","doi":"10.1055/s-0043-1778071","DOIUrl":"10.1055/s-0043-1778071","url":null,"abstract":"","PeriodicalId":23036,"journal":{"name":"Thrombosis and haemostasis","volume":null,"pages":null},"PeriodicalIF":6.7,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139404503","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: Real-world data on clinical characteristics and outcomes related to the use of different direct oral anticoagulants (DOACs) for cancer-associated venous thromboembolism (VTE) is lacking.
Methods: The COMMAND VTE Registry-2 is a multicenter registry enrolling 5,197 consecutive patients with acute symptomatic VTE from 31 centers in Japan from January 2015 to August 2020. Our study population comprised 1,197 patients with active cancer who were divided into the edoxaban (N = 643, 54%), rivaroxaban (N = 297, 25%), and apixaban (N = 257, 22%) groups.
Results: The cumulative 5-year incidence of recurrent VTE (9.3, 10.2, and 8.5%, respectively, p = 0.82) and all-cause death (67.5, 66.8, and 63.8%, respectively, p = 0.22) did not differ among the groups. Despite adjusting for confounders, the risks of recurrent VTE and all-cause death did not differ significantly among the groups. The cumulative 5-year incidence of major and clinically relevant bleeding was significantly lower in the rivaroxaban group than those in the other groups (22.6, 14.0, and 22.8%, p = 0.04; and 37.6, 26.8, and 38.3%, p = 0.01, respectively). After adjusting for confounders, in the rivaroxaban group, the risk for major bleeding was numerically lower (hazard ratio [HR]: 0.65, 95% confidence interval [CI]: 0.40-1.01) and that of clinically relevant all bleeding was significantly lower (HR: 0.67, 95% CI: 0.48-0.92) than those in the edoxaban group.
Conclusion: The risks of recurrent VTE and all-cause death did not differ significantly among the different DOACs ; however, the risk of bleeding events could differ, with a potentially lower risk of bleeding with rivaroxaban.
{"title":"Edoxaban, Rivaroxaban, or Apixaban for Cancer-Associated Venous Thromboembolism in the Real World: Insights from the COMMAND VTE Registry-2.","authors":"Daisuke Sueta, Yugo Yamashita, Takeshi Morimoto, Ryuki Chatani, Yuji Nishimoto, Kazuhisa Kaneda, Nobutaka Ikeda, Yohei Kobayashi, Satoshi Ikeda, Kitae Kim, Moriaki Inoko, Toru Takase, Shuhei Tsuji, Maki Oi, Takuma Takada, Kazunori Otsui, Jiro Sakamoto, Yoshito Ogihara, Takeshi Inoue, Shunsuke Usami, Po-Min Chen, Kiyonori Togi, Norimichi Koitabashi, Seiichi Hiramori, Kosuke Doi, Hiroshi Mabuchi, Yoshiaki Tsuyuki, Koichiro Murata, Kensuke Takabayashi, Hisato Nakai, Wataru Shioyama, Tomohiro Dohke, Ryusuke Nishikawa, Takeshi Kimura, Kenichi Tsujita","doi":"10.1055/a-2316-5269","DOIUrl":"10.1055/a-2316-5269","url":null,"abstract":"<p><strong>Background: </strong> Real-world data on clinical characteristics and outcomes related to the use of different direct oral anticoagulants (DOACs) for cancer-associated venous thromboembolism (VTE) is lacking.</p><p><strong>Methods: </strong> The COMMAND VTE Registry-2 is a multicenter registry enrolling 5,197 consecutive patients with acute symptomatic VTE from 31 centers in Japan from January 2015 to August 2020. Our study population comprised 1,197 patients with active cancer who were divided into the edoxaban (<i>N</i> = 643, 54%), rivaroxaban (<i>N</i> = 297, 25%), and apixaban (<i>N</i> = 257, 22%) groups.</p><p><strong>Results: </strong> The cumulative 5-year incidence of recurrent VTE (9.3, 10.2, and 8.5%, respectively, <i>p</i> = 0.82) and all-cause death (67.5, 66.8, and 63.8%, respectively, <i>p</i> = 0.22) did not differ among the groups. Despite adjusting for confounders, the risks of recurrent VTE and all-cause death did not differ significantly among the groups. The cumulative 5-year incidence of major and clinically relevant bleeding was significantly lower in the rivaroxaban group than those in the other groups (22.6, 14.0, and 22.8%, <i>p</i> = 0.04; and 37.6, 26.8, and 38.3%, <i>p</i> = 0.01, respectively). After adjusting for confounders, in the rivaroxaban group, the risk for major bleeding was numerically lower (hazard ratio [HR]: 0.65, 95% confidence interval [CI]: 0.40-1.01) and that of clinically relevant all bleeding was significantly lower (HR: 0.67, 95% CI: 0.48-0.92) than those in the edoxaban group.</p><p><strong>Conclusion: </strong> The risks of recurrent VTE and all-cause death did not differ significantly among the different DOACs ; however, the risk of bleeding events could differ, with a potentially lower risk of bleeding with rivaroxaban.</p>","PeriodicalId":23036,"journal":{"name":"Thrombosis and haemostasis","volume":null,"pages":null},"PeriodicalIF":6.7,"publicationDate":"2024-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140869391","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}
Bihui Zhang, Rui He, Ziping Yao, Pengyu Li, Guochen Niu, Ziguang Yan, Yinghua Zou, Xiaoqiang Tong, Min Yang
Background: Thromboangiitis obliterans (TAO) is a vascular condition characterized by poor prognosis and an unclear etiology. This study employs Mendelian randomization (MR) to investigate the causal impact of circulating inflammatory proteins on TAO.
Methods: In this MR analysis, summary statistics from a genome-wide association study meta-analysis of 91 inflammation-related proteins were integrated with independently sourced TAO data from the FinnGen consortium's R10 release. Methods such as inverse variance weighting, MR-Egger regression, weighted median approaches, MR-PRESSO, and multivariable MR (MVMR) analysis were utilized.
Results: The analysis indicated an association between higher levels of C-C motif chemokine 4 and a reduced risk of TAO, with an odds ratio (OR) of 0.44 (95% confidence interval [CI]: 0.29-0.67; p = 1.4 × 10-4; adjusted p = 0.013). Similarly, glial cell line-derived neurotrophic factor exhibited a suggestively protective effect against TAO (OR: 0.43, 95% CI: 0.22-0.81; p = 0.010; adjusted p = 0.218). Conversely, higher levels of C-C motif chemokine 23 were suggestively linked to an increased risk of TAO (OR: 1.88, 95% CI: 1.21-2.93; p = 0.005; adjusted p = 0.218). The sensitivity analysis and MVMR revealed no evidence of heterogeneity or pleiotropy.
Conclusion: This study identifies C-C motif chemokine 4 and glial cell line-derived neurotrophic factor as potential protective biomarkers for TAO, whereas C-C motif chemokine 23 emerges as a suggestive risk marker. These findings elucidate potential causal relationships and highlight the significance of these proteins in the pathogenesis and prospective therapeutic strategies for TAO.
背景:血栓闭塞性脉管炎(TAO血栓闭塞性脉管炎(TAO)是一种预后不良、病因不明的血管疾病。本研究采用孟德尔随机分析法(MR)研究循环炎症蛋白对血栓闭塞性脉管炎的因果影响:在这项MR分析中,来自91种炎症相关蛋白的全基因组关联研究荟萃分析的汇总统计数据与FinnGen联盟R10版本中独立来源的TAO数据进行了整合。采用的方法包括反方差加权法、MR-Egger回归法、加权中值法、MR-PRESSO和多变量MR(MVMR)分析:分析表明,C-C 矩阵趋化因子 4 水平越高,患 TAO 的风险就越低,几率比(OR)为 0.44(95% 置信区间[CI]:0.29-0.67;P = 1.4 × 10-4;调整后 P = 0.013)。同样,神经胶质细胞系源性神经营养因子对TAO也有提示性保护作用(OR:0.43,95% CI:0.22-0.81;P = 0.010;调整后P = 0.218)。相反,C-C 矩阵趋化因子 23 水平越高,TAO 风险越高(OR:1.88,95% CI:1.21-2.93;p = 0.005;调整后 p = 0.218)。敏感性分析和 MVMR 没有发现异质性或多义性的证据:本研究发现 C-C motif 趋化因子 4 和胶质细胞系衍生神经营养因子是 TAO 的潜在保护性生物标志物,而 C-C motif 趋化因子 23 则是一个提示性风险标志物。这些发现阐明了潜在的因果关系,并强调了这些蛋白质在 TAO 发病机制和前瞻性治疗策略中的重要作用。
{"title":"Exploring Causal Relationships between Circulating Inflammatory Proteins and Thromboangiitis Obliterans: A Mendelian Randomization Study.","authors":"Bihui Zhang, Rui He, Ziping Yao, Pengyu Li, Guochen Niu, Ziguang Yan, Yinghua Zou, Xiaoqiang Tong, Min Yang","doi":"10.1055/s-0044-1786809","DOIUrl":"https://doi.org/10.1055/s-0044-1786809","url":null,"abstract":"<p><strong>Background: </strong> Thromboangiitis obliterans (TAO) is a vascular condition characterized by poor prognosis and an unclear etiology. This study employs Mendelian randomization (MR) to investigate the causal impact of circulating inflammatory proteins on TAO.</p><p><strong>Methods: </strong> In this MR analysis, summary statistics from a genome-wide association study meta-analysis of 91 inflammation-related proteins were integrated with independently sourced TAO data from the FinnGen consortium's R10 release. Methods such as inverse variance weighting, MR-Egger regression, weighted median approaches, MR-PRESSO, and multivariable MR (MVMR) analysis were utilized.</p><p><strong>Results: </strong> The analysis indicated an association between higher levels of C-C motif chemokine 4 and a reduced risk of TAO, with an odds ratio (OR) of 0.44 (95% confidence interval [CI]: 0.29-0.67; <i>p</i> = 1.4 × 10<sup>-4</sup>; adjusted <i>p</i> = 0.013). Similarly, glial cell line-derived neurotrophic factor exhibited a suggestively protective effect against TAO (OR: 0.43, 95% CI: 0.22-0.81; <i>p</i> = 0.010; adjusted <i>p</i> = 0.218). Conversely, higher levels of C-C motif chemokine 23 were suggestively linked to an increased risk of TAO (OR: 1.88, 95% CI: 1.21-2.93; <i>p</i> = 0.005; adjusted <i>p</i> = 0.218). The sensitivity analysis and MVMR revealed no evidence of heterogeneity or pleiotropy.</p><p><strong>Conclusion: </strong> This study identifies C-C motif chemokine 4 and glial cell line-derived neurotrophic factor as potential protective biomarkers for TAO, whereas C-C motif chemokine 23 emerges as a suggestive risk marker. These findings elucidate potential causal relationships and highlight the significance of these proteins in the pathogenesis and prospective therapeutic strategies for TAO.</p>","PeriodicalId":23036,"journal":{"name":"Thrombosis and haemostasis","volume":null,"pages":null},"PeriodicalIF":6.7,"publicationDate":"2024-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141094260","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}
Sayhaan R Goraya, Connor O'Hare, Kelsey A Grace, William J Schaeffer, S Nabeel Hyder, Geoffrey D Barnes, Colin F Greineder
Background: High-sensitivity troponin T (HS-TnT) may improve risk-stratification in hemodynamically stable acute pulmonary embolism (PE), but an optimal strategy for combining this biomarker with clinical risk-stratification tools has not been determined.
Study hypothesis: We hypothesized that different HS-TnT cutoff values may be optimal for identifying (1) low-risk patients who may be eligible for outpatient management and (2) patients at increased risk of clinical deterioration who might benefit from advanced PE therapies.
Methods: Retrospective analysis of hemodynamically stable patients in the University of Michigan acute ED-PE registry with available HS-TnT values. Primary and secondary outcomes were 30-day mortality and need for intensive care unit-level care. Receiver operating characteristic curves were used to determine optimal HS-TnT cutoffs in the entire cohort, and for those at higher risk based on the simplified Pulmonary Embolism Severity Index (PESI) or imaging findings.
Results: The optimal HS-TnT cutoff in the full cohort, 12 pg/mL, was significantly associated with 30-day mortality (odds ratio [OR]: 3.94, 95% confidence interval [CI]: 1.48-10.50) and remained a significant predictor after adjusting for the simplified PESI (sPESI) score and serum creatinine (adjusted OR: 3.05, 95% CI: 1.11-8.38). A HS-TnT cutoff of 87 pg/mL was associated with 30-day mortality (OR: 5.01, 95% CI: 2.08-12.06) in patients with sPESI ≥1 or right ventricular dysfunction.
Conclusion: In this retrospective, single-center study of acute PE patients, we identified distinct optimal HS-TnT values for different clinical uses-a lower cutoff, which identified low-risk patients even in the absence of other risk-stratification methods, and a higher cutoff, which was strongly associated with adverse outcomes in patients at increased risk.
{"title":"Optimizing Use of High-Sensitivity Troponin for Risk-Stratification of Acute Pulmonary Embolism.","authors":"Sayhaan R Goraya, Connor O'Hare, Kelsey A Grace, William J Schaeffer, S Nabeel Hyder, Geoffrey D Barnes, Colin F Greineder","doi":"10.1055/s-0044-1786820","DOIUrl":"10.1055/s-0044-1786820","url":null,"abstract":"<p><strong>Background: </strong> High-sensitivity troponin T (HS-TnT) may improve risk-stratification in hemodynamically stable acute pulmonary embolism (PE), but an optimal strategy for combining this biomarker with clinical risk-stratification tools has not been determined.</p><p><strong>Study hypothesis: </strong> We hypothesized that different HS-TnT cutoff values may be optimal for identifying (1) low-risk patients who may be eligible for outpatient management and (2) patients at increased risk of clinical deterioration who might benefit from advanced PE therapies.</p><p><strong>Methods: </strong> Retrospective analysis of hemodynamically stable patients in the University of Michigan acute ED-PE registry with available HS-TnT values. Primary and secondary outcomes were 30-day mortality and need for intensive care unit-level care. Receiver operating characteristic curves were used to determine optimal HS-TnT cutoffs in the entire cohort, and for those at higher risk based on the simplified Pulmonary Embolism Severity Index (PESI) or imaging findings.</p><p><strong>Results: </strong> The optimal HS-TnT cutoff in the full cohort, 12 pg/mL, was significantly associated with 30-day mortality (odds ratio [OR]: 3.94, 95% confidence interval [CI]: 1.48-10.50) and remained a significant predictor after adjusting for the simplified PESI (sPESI) score and serum creatinine (adjusted OR: 3.05, 95% CI: 1.11-8.38). A HS-TnT cutoff of 87 pg/mL was associated with 30-day mortality (OR: 5.01, 95% CI: 2.08-12.06) in patients with sPESI ≥1 or right ventricular dysfunction.</p><p><strong>Conclusion: </strong> In this retrospective, single-center study of acute PE patients, we identified distinct optimal HS-TnT values for different clinical uses-a lower cutoff, which identified low-risk patients even in the absence of other risk-stratification methods, and a higher cutoff, which was strongly associated with adverse outcomes in patients at increased risk.</p>","PeriodicalId":23036,"journal":{"name":"Thrombosis and haemostasis","volume":null,"pages":null},"PeriodicalIF":6.7,"publicationDate":"2024-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141094205","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}
Objective: Platelet plays a key role in thrombosis formation, especially that the alteration of platelet function may influence the thrombosis development. This study aimed to investigate platelet function alterations in the formation of portal vein thrombosis (PVT) in cirrhosis.
Methods: Cirrhotic patients admitted to The First Affiliated Hospital of Soochow University between October 2021 and April 2023 were recruited and divided into PVT and non-PVT groups according to radiological results. Clinical parameters and prognosis were also collected and assessed to identify potential risk factors. Flow cytometry was used to detect the expression of CD62p, CD63, monocyte-platelet aggregates (MPAs), neutrophil-platelet aggregates (NPAs), and von Willebrand factor antigen (vWF-Ag) to evaluate platelet activation and adhesion function.
Results: A total of 145 subjects were enrolled in our study including 60 cirrhotic PVT patients, 60 cirrhotic non-PVT patients, and 25 healthy volunteers. Multivariate analysis suggested that esophageal gastric varices, splenectomy, and D-dimer were independent risk factors for PVT pathogenesis in cirrhosis. The vWF-Ag expression level was reduced in the PVT group compared with the non-PVT group (p = 0.046) but was not an independent risk factor for PVT formation pathogenesis. The expression of CD41+CD62p+ and CD41+CD63+ platelets in the PVT group was significantly elevated compared with that in the non-PVT group (p < 0.05). There were no significant differences in MPAs and NPAs between the two cirrhotic groups. Subgroup analysis showed that the mean fluorescence intensity (MFI) of CD62p and CD63 was associated with portal hypertension-related complications (p = 0.008, p < 0.001), and CD63 MFI was significantly associated with thrombosis burden (p = 0.019). CD41+CD62p+ and CD41+CD63+ platelets as well as MPAs and NPAs were highly expressed in the splenectomy group compared with those in the nonsplenectomy group in cirrhotic patients (p < 0.05). Positive correlations were found between CD62p MFI and CD63 MFI, MPAs and NPAs (r = 0.642, p < 0.001; r = 0.378, p = 0.003; r = 0.430, p < 0.001). In addition, platelet counts were also correlated with MPAs (r = 0.556, p < 0.001) and NPAs (r = 0.467, p < 0.001). Cirrhotic patients with PVT had higher mortality and were more likely to experience portal hypertension-related complications in the prognostic analysis (p < 0.05).
Conclusion: Highly activated platelet function exists in patients with cirrhosis, and platelet activation was elevated during PVT formation, suggesting that activated platelets may participate in the formation of PVT in patients with cirrhosis.
{"title":"Platelet Activation Is Upregulated in Cirrhotic Patients with Portal Vein Thrombosis.","authors":"Fazhi Zhao, Jingnuo Ding, Juanjuan Cui, Mingqing Zhu, Weifeng Zhao","doi":"10.1055/a-2190-8705","DOIUrl":"10.1055/a-2190-8705","url":null,"abstract":"<p><strong>Objective: </strong> Platelet plays a key role in thrombosis formation, especially that the alteration of platelet function may influence the thrombosis development. This study aimed to investigate platelet function alterations in the formation of portal vein thrombosis (PVT) in cirrhosis.</p><p><strong>Methods: </strong> Cirrhotic patients admitted to The First Affiliated Hospital of Soochow University between October 2021 and April 2023 were recruited and divided into PVT and non-PVT groups according to radiological results. Clinical parameters and prognosis were also collected and assessed to identify potential risk factors. Flow cytometry was used to detect the expression of CD62p, CD63, monocyte-platelet aggregates (MPAs), neutrophil-platelet aggregates (NPAs), and von Willebrand factor antigen (vWF-Ag) to evaluate platelet activation and adhesion function.</p><p><strong>Results: </strong> A total of 145 subjects were enrolled in our study including 60 cirrhotic PVT patients, 60 cirrhotic non-PVT patients, and 25 healthy volunteers. Multivariate analysis suggested that esophageal gastric varices, splenectomy, and D-dimer were independent risk factors for PVT pathogenesis in cirrhosis. The vWF-Ag expression level was reduced in the PVT group compared with the non-PVT group (<i>p</i> = 0.046) but was not an independent risk factor for PVT formation pathogenesis. The expression of CD41<sup>+</sup>CD62p<sup>+</sup> and CD41<sup>+</sup>CD63<sup>+</sup> platelets in the PVT group was significantly elevated compared with that in the non-PVT group (<i>p</i> < 0.05). There were no significant differences in MPAs and NPAs between the two cirrhotic groups. Subgroup analysis showed that the mean fluorescence intensity (MFI) of CD62p and CD63 was associated with portal hypertension-related complications (<i>p</i> = 0.008, <i>p</i> < 0.001), and CD63 MFI was significantly associated with thrombosis burden (<i>p</i> = 0.019). CD41<sup>+</sup>CD62p<sup>+</sup> and CD41<sup>+</sup>CD63<sup>+</sup> platelets as well as MPAs and NPAs were highly expressed in the splenectomy group compared with those in the nonsplenectomy group in cirrhotic patients (<i>p</i> < 0.05). Positive correlations were found between CD62p MFI and CD63 MFI, MPAs and NPAs (<i>r</i> = 0.642, <i>p <</i> 0.001; <i>r</i> = 0.378, <i>p</i> = 0.003; <i>r</i> = 0.430, <i>p <</i> 0.001). In addition, platelet counts were also correlated with MPAs (<i>r</i> = 0.556, <i>p <</i> 0.001) and NPAs (<i>r</i> = 0.467, <i>p <</i> 0.001). Cirrhotic patients with PVT had higher mortality and were more likely to experience portal hypertension-related complications in the prognostic analysis (<i>p</i> < 0.05).</p><p><strong>Conclusion: </strong> Highly activated platelet function exists in patients with cirrhosis, and platelet activation was elevated during PVT formation, suggesting that activated platelets may participate in the formation of PVT in patients with cirrhosis.</p>","PeriodicalId":23036,"journal":{"name":"Thrombosis and haemostasis","volume":null,"pages":null},"PeriodicalIF":6.7,"publicationDate":"2024-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41213697","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Lack of Formyl-peptide Receptor 1 Mitigates Atherosclerosis in Hyperlipidemic Mice.","authors":"Yvonne Döring, Alexander Bender, Oliver Soehnlein","doi":"10.1055/s-0044-1787264","DOIUrl":"https://doi.org/10.1055/s-0044-1787264","url":null,"abstract":"","PeriodicalId":23036,"journal":{"name":"Thrombosis and haemostasis","volume":null,"pages":null},"PeriodicalIF":6.7,"publicationDate":"2024-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141087793","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}
B. Guillet, Maxime Pawlowski, Pierre Boisseau, Y. Repesse, Philippe Beurrier, Sophie Bayart, X. Delavenne, Marc Trossaërt, Peter J Lenting
Desmopressin (DDAVP) is used in patients with moderate/mild hemophilia A (PWMH) to increase their factor VIII (FVIII) level and, if possible, normalize it. However, its effectiveness varies between individuals. The GIDEMHA study aims to investigate the influence of F8 gene variants. The study collected the evolution of FVIII levels from therapeutic intravenous DDAVP tests in 4 French hemophilia treatment centers. A pharmacological analysis was performed associated with efficacy scores according to F8 variants: absolute and relative responses, as well as new scores: absolute duration (based on duration with FVIII ≥0.50 IU.mL-1) and relative duration (based on half-life). From enrolled 439 PWMH, 327 had a hot-spot F8 variant (with ≥5 PWMH). For these, the median (min-max) basal and peak FVIII were 0.20 (0.02-0.040) and 0.74 (0.14-2.18) IU.mL-1 respectively, with FVIII recovery being 3.80 IU.ml-1 (1.15-14.75). The median FVIII half-life was 3.9h (0.7-15.9h). FVIII was normalized (≥0.50 IU.mL-1) in 224/327 PWMH (69%) and the median time with normalized FVIII was 3.9h (0.0-54.1h). Following the response profiles to DDAVP defined by the 4 efficacy scores, 4 groups of F8 variants were isolated then compared into survival curves with normalized FVIII (p<0.0001): "long lastingly effective" [p.(Glu739Lys), p.(Ser2030Asn), p.(Arg2178His), p.(Gln2208Glu) and T-stretch deletion in intron 13]; "moderately effective" [p.(Ser112Phe), p.(Ala219Thr), p.(Thr2105Ile), p.Phe2146Ser) and p.(Asp2150Asn)]; "moderately ineffective" [p.Ala81Asp), p.(Gln324Pro), p.(Tyr492His), p.(Arg612Cys), p.(Met701Val), p.(Val2035Asn) and p.(Arg2178Cys)]; and "frequently ineffective" [c.-219C>T, p.(Cys2040Tyr), p.(Tyr2169His), p.(Pro2319Leu) and p.(Arg2326Gln)]. In view of our data, we propose indications for DDAVP-use in PWMH based on F8 variants for minor and major invasive procedures.
{"title":"Genotype-dependent response to desmopressin in hemophilia A and proposal of a predictive response score.","authors":"B. Guillet, Maxime Pawlowski, Pierre Boisseau, Y. Repesse, Philippe Beurrier, Sophie Bayart, X. Delavenne, Marc Trossaërt, Peter J Lenting","doi":"10.1055/a-2329-3375","DOIUrl":"https://doi.org/10.1055/a-2329-3375","url":null,"abstract":"Desmopressin (DDAVP) is used in patients with moderate/mild hemophilia A (PWMH) to increase their factor VIII (FVIII) level and, if possible, normalize it. However, its effectiveness varies between individuals. The GIDEMHA study aims to investigate the influence of F8 gene variants. The study collected the evolution of FVIII levels from therapeutic intravenous DDAVP tests in 4 French hemophilia treatment centers. A pharmacological analysis was performed associated with efficacy scores according to F8 variants: absolute and relative responses, as well as new scores: absolute duration (based on duration with FVIII ≥0.50 IU.mL-1) and relative duration (based on half-life). From enrolled 439 PWMH, 327 had a hot-spot F8 variant (with ≥5 PWMH). For these, the median (min-max) basal and peak FVIII were 0.20 (0.02-0.040) and 0.74 (0.14-2.18) IU.mL-1 respectively, with FVIII recovery being 3.80 IU.ml-1 (1.15-14.75). The median FVIII half-life was 3.9h (0.7-15.9h). FVIII was normalized (≥0.50 IU.mL-1) in 224/327 PWMH (69%) and the median time with normalized FVIII was 3.9h (0.0-54.1h). Following the response profiles to DDAVP defined by the 4 efficacy scores, 4 groups of F8 variants were isolated then compared into survival curves with normalized FVIII (p<0.0001): \"long lastingly effective\" [p.(Glu739Lys), p.(Ser2030Asn), p.(Arg2178His), p.(Gln2208Glu) and T-stretch deletion in intron 13]; \"moderately effective\" [p.(Ser112Phe), p.(Ala219Thr), p.(Thr2105Ile), p.Phe2146Ser) and p.(Asp2150Asn)]; \"moderately ineffective\" [p.Ala81Asp), p.(Gln324Pro), p.(Tyr492His), p.(Arg612Cys), p.(Met701Val), p.(Val2035Asn) and p.(Arg2178Cys)]; and \"frequently ineffective\" [c.-219C>T, p.(Cys2040Tyr), p.(Tyr2169His), p.(Pro2319Leu) and p.(Arg2326Gln)]. In view of our data, we propose indications for DDAVP-use in PWMH based on F8 variants for minor and major invasive procedures.","PeriodicalId":23036,"journal":{"name":"Thrombosis and haemostasis","volume":null,"pages":null},"PeriodicalIF":6.7,"publicationDate":"2024-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140964661","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}