Amin Polzin, Marcel Benkhoff, Manuela Thienel, Maike Barcik, Philipp Mourikis, Khrystyna Shchurovska, Carolin Helten, Vincent Ehreiser, Zhang Zhe, Franziska von Wulffen, Alexander Theiss, Sameera Peri, Sophie Cremer, Samantha Ahlbrecht, Saif Zako, Laura Wildeis, Gabrielle Al-Kassis, Daniel Metzen, Amelie Utz, Hao Hu, Lilian Vornholz, Goran Pavic, Enzo Lüsebrink, Jan Strecker, Steffen Tiedt, Mareike Cramer, Michael Gliem, Tobias Ruck, Sven G Meuth, Tobias Zeus, Christoph Mayr, Herbert B Schiller, Lukas Simon, Steffen Massberg, Malte Kelm, Tobias Petzold
{"title":"通过改变血小板蛋白质组，长期抑制 FXa 可减轻急性心肌梗死和中风后的血栓性炎症。","authors":"Amin Polzin, Marcel Benkhoff, Manuela Thienel, Maike Barcik, Philipp Mourikis, Khrystyna Shchurovska, Carolin Helten, Vincent Ehreiser, Zhang Zhe, Franziska von Wulffen, Alexander Theiss, Sameera Peri, Sophie Cremer, Samantha Ahlbrecht, Saif Zako, Laura Wildeis, Gabrielle Al-Kassis, Daniel Metzen, Amelie Utz, Hao Hu, Lilian Vornholz, Goran Pavic, Enzo Lüsebrink, Jan Strecker, Steffen Tiedt, Mareike Cramer, Michael Gliem, Tobias Ruck, Sven G Meuth, Tobias Zeus, Christoph Mayr, Herbert B Schiller, Lukas Simon, Steffen Massberg, Malte Kelm, Tobias Petzold","doi":"10.1016/j.jtha.2024.10.025","DOIUrl":null,"url":null,"abstract":"<p><strong>Background and aims: </strong>Immediate factor Xa (FXa) inhibition exerts direct antiplatelet effects in the context of arterial thrombosis but little is known about the impact of long-term therapy on platelet function in ischemic cardiovascular diseases.</p><p><strong>Methods: </strong>We evaluated the effect of acute versus chronic FXa inhibition on thromboinflammation following acute myocardial infarction (AMI) and stroke in mice in vivo. Mechanistically, we identified changes in platelet gene expression and proteome under chronic FXa NOAC and characterized its functional consequence on platelet physiology. In a prospectively recruited cohort of AMI patients, we determined CMR based cardiac endpoints under FXa NOAC effects on clinical endpoints in a cohort of AMI patients.</p><p><strong>Results: </strong>Chronic but not acute FXa inhibition reduced cerebral and myocardial infarct size and improved cardiac function 24h after AMI in mice. Mechanistically, we identified an attenuated thromboinflammatory response with reduced NET formation in mice and patient samples. Proteome and RNA expression analysis of FXa-inhibitor treated patients revealed a reduction of key regulators within the membrane trafficking and secretion machinery hampering platelet alpha and dense granule release. Subsequent, thromboinflammatory NET density in thrombi isolated from stroke and myocardial infarction patients was reduced. AMI patients treated with FXa inhibitors showed decreased infarct size after myocardial infarction compared to patients without anticoagulation treatment.</p><p><strong>Conclusions: </strong>Long-term FXa inhibition induces anti-thromboinflammatory proteome signatures in platelets, improving infarct size after myocardial infarction and stroke.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5000,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Long-term FXa inhibition attenuates thromboinflammation after acute myocardial infarction and stroke by platelet proteome alteration.\",\"authors\":\"Amin Polzin, Marcel Benkhoff, Manuela Thienel, Maike Barcik, Philipp Mourikis, Khrystyna Shchurovska, Carolin Helten, Vincent Ehreiser, Zhang Zhe, Franziska von Wulffen, Alexander Theiss, Sameera Peri, Sophie Cremer, Samantha Ahlbrecht, Saif Zako, Laura Wildeis, Gabrielle Al-Kassis, Daniel Metzen, Amelie Utz, Hao Hu, Lilian Vornholz, Goran Pavic, Enzo Lüsebrink, Jan Strecker, Steffen Tiedt, Mareike Cramer, Michael Gliem, Tobias Ruck, Sven G Meuth, Tobias Zeus, Christoph Mayr, Herbert B Schiller, Lukas Simon, Steffen Massberg, Malte Kelm, Tobias Petzold\",\"doi\":\"10.1016/j.jtha.2024.10.025\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background and aims: </strong>Immediate factor Xa (FXa) inhibition exerts direct antiplatelet effects in the context of arterial thrombosis but little is known about the impact of long-term therapy on platelet function in ischemic cardiovascular diseases.</p><p><strong>Methods: </strong>We evaluated the effect of acute versus chronic FXa inhibition on thromboinflammation following acute myocardial infarction (AMI) and stroke in mice in vivo. Mechanistically, we identified changes in platelet gene expression and proteome under chronic FXa NOAC and characterized its functional consequence on platelet physiology. In a prospectively recruited cohort of AMI patients, we determined CMR based cardiac endpoints under FXa NOAC effects on clinical endpoints in a cohort of AMI patients.</p><p><strong>Results: </strong>Chronic but not acute FXa inhibition reduced cerebral and myocardial infarct size and improved cardiac function 24h after AMI in mice. Mechanistically, we identified an attenuated thromboinflammatory response with reduced NET formation in mice and patient samples. Proteome and RNA expression analysis of FXa-inhibitor treated patients revealed a reduction of key regulators within the membrane trafficking and secretion machinery hampering platelet alpha and dense granule release. Subsequent, thromboinflammatory NET density in thrombi isolated from stroke and myocardial infarction patients was reduced. AMI patients treated with FXa inhibitors showed decreased infarct size after myocardial infarction compared to patients without anticoagulation treatment.</p><p><strong>Conclusions: </strong>Long-term FXa inhibition induces anti-thromboinflammatory proteome signatures in platelets, improving infarct size after myocardial infarction and stroke.</p>\",\"PeriodicalId\":17326,\"journal\":{\"name\":\"Journal of Thrombosis and Haemostasis\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":5.5000,\"publicationDate\":\"2024-11-15\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Thrombosis and Haemostasis\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.jtha.2024.10.025\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"HEMATOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Thrombosis and Haemostasis","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.jtha.2024.10.025","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"HEMATOLOGY","Score":null,"Total":0}
Long-term FXa inhibition attenuates thromboinflammation after acute myocardial infarction and stroke by platelet proteome alteration.
Background and aims: Immediate factor Xa (FXa) inhibition exerts direct antiplatelet effects in the context of arterial thrombosis but little is known about the impact of long-term therapy on platelet function in ischemic cardiovascular diseases.
Methods: We evaluated the effect of acute versus chronic FXa inhibition on thromboinflammation following acute myocardial infarction (AMI) and stroke in mice in vivo. Mechanistically, we identified changes in platelet gene expression and proteome under chronic FXa NOAC and characterized its functional consequence on platelet physiology. In a prospectively recruited cohort of AMI patients, we determined CMR based cardiac endpoints under FXa NOAC effects on clinical endpoints in a cohort of AMI patients.
Results: Chronic but not acute FXa inhibition reduced cerebral and myocardial infarct size and improved cardiac function 24h after AMI in mice. Mechanistically, we identified an attenuated thromboinflammatory response with reduced NET formation in mice and patient samples. Proteome and RNA expression analysis of FXa-inhibitor treated patients revealed a reduction of key regulators within the membrane trafficking and secretion machinery hampering platelet alpha and dense granule release. Subsequent, thromboinflammatory NET density in thrombi isolated from stroke and myocardial infarction patients was reduced. AMI patients treated with FXa inhibitors showed decreased infarct size after myocardial infarction compared to patients without anticoagulation treatment.
Conclusions: Long-term FXa inhibition induces anti-thromboinflammatory proteome signatures in platelets, improving infarct size after myocardial infarction and stroke.
期刊介绍：
The Journal of Thrombosis and Haemostasis (JTH) serves as the official journal of the International Society on Thrombosis and Haemostasis. It is dedicated to advancing science related to thrombosis, bleeding disorders, and vascular biology through the dissemination and exchange of information and ideas within the global research community.
Types of Publications:
The journal publishes a variety of content, including:
Original research reports
State-of-the-art reviews
Brief reports
Case reports
Invited commentaries on publications in the Journal
Forum articles
Correspondence
Announcements
Scope of Contributions:
Editors invite contributions from both fundamental and clinical domains. These include:
Basic manuscripts on blood coagulation and fibrinolysis
Studies on proteins and reactions related to thrombosis and haemostasis
Research on blood platelets and their interactions with other biological systems, such as the vessel wall, blood cells, and invading organisms
Clinical manuscripts covering various topics including venous thrombosis, arterial disease, hemophilia, bleeding disorders, and platelet diseases
Clinical manuscripts may encompass etiology, diagnostics, prognosis, prevention, and treatment strategies.
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