JAK2V617F相关骨髓增殖性肿瘤中的纤维蛋白溶解功能受损。

IF 5.5 2区 医学 Q1 HEMATOLOGY Journal of Thrombosis and Haemostasis Pub Date : 2024-09-12 DOI:10.1016/j.jtha.2024.07.031
Marie-Charlotte Bourrienne , Stéphane Loyau , Dorothée Faille , Juliette Gay , Séléna Akhenak , Carine Farkh , Véronique Ollivier , Mialitiana Solonomenjanahary , Sébastien Dupont , Christine Choqueux , Jean-Luc Villeval , Isabelle Plo , Valérie Edmond , Benoît Ho-Tin-Noé , Nadine Ajzenberg , Mikaël Mazighi
{"title":"JAK2V617F相关骨髓增殖性肿瘤中的纤维蛋白溶解功能受损。","authors":"Marie-Charlotte Bourrienne ,&nbsp;Stéphane Loyau ,&nbsp;Dorothée Faille ,&nbsp;Juliette Gay ,&nbsp;Séléna Akhenak ,&nbsp;Carine Farkh ,&nbsp;Véronique Ollivier ,&nbsp;Mialitiana Solonomenjanahary ,&nbsp;Sébastien Dupont ,&nbsp;Christine Choqueux ,&nbsp;Jean-Luc Villeval ,&nbsp;Isabelle Plo ,&nbsp;Valérie Edmond ,&nbsp;Benoît Ho-Tin-Noé ,&nbsp;Nadine Ajzenberg ,&nbsp;Mikaël Mazighi","doi":"10.1016/j.jtha.2024.07.031","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><div>Myeloproliferative neoplasms (MPNs) are characterized by a high rate of thrombotic complications that contribute to morbidity and mortality. MPN-related thrombogenesis is assumed to be multifactorial, involving both procoagulant and proinflammatory processes. Whether impaired fibrinolysis also participates in the prothrombotic phenotype of MPN has been poorly investigated.</div></div><div><h3>Objectives</h3><div>We determined whether MPN, particularly <em>JAK2</em>V617F-positive MPN, is associated with fibrinolytic changes.</div></div><div><h3>Methods</h3><div>Tissue-type plasminogen activator (tPA)–mediated fibrinolysis was evaluated both in whole blood and plasma from mice with a hematopoietic-restricted Jak2<sup>V617F</sup> expression compared with wild-type (WT) mice (Jak2<sup>WT</sup>) using (1) halo clot lysis, (2) front lysis, and (3) plasmin generation assays. tPA clot lysis assay was performed in the plasma from 65 MPN patients (<em>JAK2</em>V617F mutation, <em>n</em> = 50; <em>CALR</em> mutations, <em>n</em> = 9) compared with 28 healthy controls.</div></div><div><h3>Results</h3><div>In whole blood from Jak2<sup>V617F</sup> mice, we observed a decreased fibrinolysis characterized by a significantly lower halo clot lysis rate compared with Jak2<sup>WT</sup> (95 ± 22 vs 147 ± 39 AU/min; <em>P</em> &lt; .05). Similar results were observed in plasma (halo clot lysis rate, 130 ± 27 vs 186 ± 29 AU/min; front lysis rate, 2.8 ± 1.6 vs 6.1 ± 1.2 μm.min<sup>−1</sup>; <em>P</em> &lt; .05). Plasmin generation was significantly decreased both in plasma clots and standardized fibrin clots from Jak2<sup>V617F</sup> mice compared with Jak2<sup>WT</sup> mice. Among MPN patients, impaired tPA-related fibrinolysis with prolonged clot lysis time was observed in <em>JAK2</em>V617F and <em>CALR</em> patients. Plasminogen activator inhibitor-1 and α2-antiplasmin were significantly increased in plasma from <em>JAK2</em>V617F patients compared with controls.</div></div><div><h3>Conclusion</h3><div>Our results suggest that impaired tPA-mediated fibrinolysis represents an important prothrombotic mechanism in MPN patients that requires confirmation in larger studies.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":null,"pages":null},"PeriodicalIF":5.5000,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Impaired fibrinolysis in JAK2V617F-related myeloproliferative neoplasms\",\"authors\":\"Marie-Charlotte Bourrienne ,&nbsp;Stéphane Loyau ,&nbsp;Dorothée Faille ,&nbsp;Juliette Gay ,&nbsp;Séléna Akhenak ,&nbsp;Carine Farkh ,&nbsp;Véronique Ollivier ,&nbsp;Mialitiana Solonomenjanahary ,&nbsp;Sébastien Dupont ,&nbsp;Christine Choqueux ,&nbsp;Jean-Luc Villeval ,&nbsp;Isabelle Plo ,&nbsp;Valérie Edmond ,&nbsp;Benoît Ho-Tin-Noé ,&nbsp;Nadine Ajzenberg ,&nbsp;Mikaël Mazighi\",\"doi\":\"10.1016/j.jtha.2024.07.031\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Background</h3><div>Myeloproliferative neoplasms (MPNs) are characterized by a high rate of thrombotic complications that contribute to morbidity and mortality. MPN-related thrombogenesis is assumed to be multifactorial, involving both procoagulant and proinflammatory processes. Whether impaired fibrinolysis also participates in the prothrombotic phenotype of MPN has been poorly investigated.</div></div><div><h3>Objectives</h3><div>We determined whether MPN, particularly <em>JAK2</em>V617F-positive MPN, is associated with fibrinolytic changes.</div></div><div><h3>Methods</h3><div>Tissue-type plasminogen activator (tPA)–mediated fibrinolysis was evaluated both in whole blood and plasma from mice with a hematopoietic-restricted Jak2<sup>V617F</sup> expression compared with wild-type (WT) mice (Jak2<sup>WT</sup>) using (1) halo clot lysis, (2) front lysis, and (3) plasmin generation assays. tPA clot lysis assay was performed in the plasma from 65 MPN patients (<em>JAK2</em>V617F mutation, <em>n</em> = 50; <em>CALR</em> mutations, <em>n</em> = 9) compared with 28 healthy controls.</div></div><div><h3>Results</h3><div>In whole blood from Jak2<sup>V617F</sup> mice, we observed a decreased fibrinolysis characterized by a significantly lower halo clot lysis rate compared with Jak2<sup>WT</sup> (95 ± 22 vs 147 ± 39 AU/min; <em>P</em> &lt; .05). Similar results were observed in plasma (halo clot lysis rate, 130 ± 27 vs 186 ± 29 AU/min; front lysis rate, 2.8 ± 1.6 vs 6.1 ± 1.2 μm.min<sup>−1</sup>; <em>P</em> &lt; .05). Plasmin generation was significantly decreased both in plasma clots and standardized fibrin clots from Jak2<sup>V617F</sup> mice compared with Jak2<sup>WT</sup> mice. Among MPN patients, impaired tPA-related fibrinolysis with prolonged clot lysis time was observed in <em>JAK2</em>V617F and <em>CALR</em> patients. Plasminogen activator inhibitor-1 and α2-antiplasmin were significantly increased in plasma from <em>JAK2</em>V617F patients compared with controls.</div></div><div><h3>Conclusion</h3><div>Our results suggest that impaired tPA-mediated fibrinolysis represents an important prothrombotic mechanism in MPN patients that requires confirmation in larger studies.</div></div>\",\"PeriodicalId\":17326,\"journal\":{\"name\":\"Journal of Thrombosis and Haemostasis\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":5.5000,\"publicationDate\":\"2024-09-12\",\"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://www.sciencedirect.com/science/article/pii/S1538783624004872\",\"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://www.sciencedirect.com/science/article/pii/S1538783624004872","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"HEMATOLOGY","Score":null,"Total":0}
引用次数: 0

摘要

背景骨髓增殖性肿瘤(MPN)的特点是血栓并发症发生率高,导致死亡率增加。与 MPN 相关的血栓形成被认为是多因素的,涉及促凝血和促炎症过程。纤溶功能受损是否也参与了 MPN 促血栓形成表型的形成,这一问题尚未得到深入研究。患者与野生型小鼠(Jak2WT)相比,我们使用(1)光环凝块裂解法、(2)前端裂解法和(3)血浆蛋白酶生成测定法,对造血受限的 Jak2V617F 表达小鼠的全血(WB)和血浆中组织纤溶酶原激活剂(tPA)介导的纤溶进行了评估。结果在Jak2V617F小鼠的WB中,我们观察到纤维蛋白溶解减少,其特征是与Jak2WT相比,晕凝块溶解率显著降低(95±22 vs 147±39 UA/min,p<0.05)。在血浆中也观察到类似的结果(晕凝块溶解率:130±27 vs 186±29 UA/min):130±27 vs 186±29 UA/min;正面裂解率:2.8±1.6 vs 6.1±1.2 μm.min-1,p<0.05)。与 Jak2WT 小鼠相比,Jak2V617F 小鼠血浆凝块和标准化纤维蛋白凝块中产生的凝血酶明显减少。在骨髓增生性疾病患者中,JAK2V617F 和 CALR 患者的 tPA 相关纤溶功能受损,血块溶解时间延长。与对照组相比,JAK2V617F 患者血浆中的纤溶酶原激活物抑制剂-1 和α-2-抗蛋白酶显著增加。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
Impaired fibrinolysis in JAK2V617F-related myeloproliferative neoplasms

Background

Myeloproliferative neoplasms (MPNs) are characterized by a high rate of thrombotic complications that contribute to morbidity and mortality. MPN-related thrombogenesis is assumed to be multifactorial, involving both procoagulant and proinflammatory processes. Whether impaired fibrinolysis also participates in the prothrombotic phenotype of MPN has been poorly investigated.

Objectives

We determined whether MPN, particularly JAK2V617F-positive MPN, is associated with fibrinolytic changes.

Methods

Tissue-type plasminogen activator (tPA)–mediated fibrinolysis was evaluated both in whole blood and plasma from mice with a hematopoietic-restricted Jak2V617F expression compared with wild-type (WT) mice (Jak2WT) using (1) halo clot lysis, (2) front lysis, and (3) plasmin generation assays. tPA clot lysis assay was performed in the plasma from 65 MPN patients (JAK2V617F mutation, n = 50; CALR mutations, n = 9) compared with 28 healthy controls.

Results

In whole blood from Jak2V617F mice, we observed a decreased fibrinolysis characterized by a significantly lower halo clot lysis rate compared with Jak2WT (95 ± 22 vs 147 ± 39 AU/min; P < .05). Similar results were observed in plasma (halo clot lysis rate, 130 ± 27 vs 186 ± 29 AU/min; front lysis rate, 2.8 ± 1.6 vs 6.1 ± 1.2 μm.min−1; P < .05). Plasmin generation was significantly decreased both in plasma clots and standardized fibrin clots from Jak2V617F mice compared with Jak2WT mice. Among MPN patients, impaired tPA-related fibrinolysis with prolonged clot lysis time was observed in JAK2V617F and CALR patients. Plasminogen activator inhibitor-1 and α2-antiplasmin were significantly increased in plasma from JAK2V617F patients compared with controls.

Conclusion

Our results suggest that impaired tPA-mediated fibrinolysis represents an important prothrombotic mechanism in MPN patients that requires confirmation in larger studies.
求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
Journal of Thrombosis and Haemostasis
Journal of Thrombosis and Haemostasis 医学-外周血管病
CiteScore
24.30
自引率
3.80%
发文量
321
审稿时长
1 months
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.
期刊最新文献
Validating International Classification of Diseases Code 10th Revision algorithms for accurate identification of pulmonary embolism. High risk of long-term recurrence after a first episode of venous thromboembolism during pregnancy or postpartum: the REcurrence after a PrEgnAncy related Thrombosis (REPEAT) Study. Validation of clinical risk assessment scores for venous thromboembolism in patients with cancer: a population-based cohort study. Déjà vu all over again: a recurrent flaw in anticoagulant study design. Intensive FVIII replacement in haemophilia patients with hypertrophic synovium: a randomized study.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1