Cancer, venous thromboembolic disease and tissue factor-bearing microparticles

癌症、静脉血栓栓塞性疾病和携带组织因子的微粒

基本信息

批准号：
8321526
负责人：
Bruce Furie
金额：
$ 42.08万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-26 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8321526
关键词：
Advanced Malignant Neoplasm Antibodies Anticoagulants Antigens Biological Markers Blood Blood Platelets Cancer Model Cancer Patient Cause of Death Clinical Investigator Clinical Trials Collaborations Dana-Farber Cancer Institute Development Discrimination Disease Doctor of Philosophy Event Excision Fibrin Flow Cytometry Generations Half-Life Health Hemostatic function Heparin Human Image In Vitro Laboratories Ligands Malignant - descriptor Malignant Neoplasms Malignant neoplasm of pancreas Mass Spectrum Analysis Measures Mediating Metabolic Clearance Rate Morbidity - disease rate Mus Nude Mice Odds Ratio P-Selectin P-selectin ligand protein Pancreatic carcinoma Pathogenesis Patients Pilot Projects Placebo Control Play Prevalence Prophylactic treatment Randomized Regimen Research Research Personnel Risk Risk Factors Role SCID Mice Surveys Testing Thromboplastin Thrombosis Thrombus Tissues Tumor Markers Tumor-Derived Venous Western Blotting Xenograft procedure base clinical practice design electric impedance functional status high risk human tissue intravital microscopy mortality mouse model neoplastic cell pancreatic neoplasm prospective randomized placebo controlled trial

项目摘要

DESCRIPTION (provided by applicant): Thrombosis associated with malignant disease is a leading cause of morbidity and mortality in cancer patients, yet its pathophysiologic basis remains unknown. In our pilot study to ascertain the association of thrombosis with a potential biomarker, tissue factor-bearing microparticles, the odds ratio for these microparticles in cancer patients with venous thromboembolic events compared with cancer patients without venous thromboembolic events was 4.1. In thrombosis- negative cancer patients with detectable tissue factor-bearing microparticles, the one-year rate of their developing a thrombotic event was 35% versus 0% in the same group without elevated tissue factor-bearing microparticles. Aim #1 focuses on in vitro studies to determine the functional status of tissue factor expressed on cancer microparticles, and the tissue origin and half-life of these microparticles. Aim #2 describes a randomized, placebo-controlled interventional clinical trial involving over 100 patients with pancreatic carcinoma to determine whether patients with tumor-derived tissue factor-bearing microparticles will benefit from thromboprophylaxis with unfractionated heparin to reduce venous thromboembolic complications. In Aim #3, SCID mice with human pancreatic carcinoma xenografts will be used as a mouse model of pancreatic carcinoma. The accumulation of human xenograft-derived tissue factor-bearing microparticles during thrombus formation will be imaged by intravital microscopy to observe the accumulation of human tissue factor in the developing thrombus and the contribution of xenograft-derived tissue factor to thrombus formation. The role of platelet P- selectin in microparticle accumulation will be determined, and the P-selectin ligand on tumor- derived microparticles identified by Western blotting and mass spectroscopy. The results will advance the hypothesis that tissue factor-bearing microparticles are both a biomarker for thrombosis risk in pancreatic carcinoma and that they are central to the pathogenesis of cancer- associated thrombosis. Given the priority of identifying better markers of cancer patients likely to develop thrombosis, the demonstration of the utility of heparin thromboprophylaxis of patients with pancreatic carcinoma who are positive for TF-bearing microparticles will have significant impact in clinical practice by establishing an anticoagulant regimen focused on only cancer patients at high risk of thrombosis. PUBLIC HEALTH RELEVANCE: Tissue factor-bearing microparticles are both a biomarker for thrombosis risk in cancer and likely central to the pathogenesis of cancer-associated thrombosis. Given the priority that identifying better markers of cancer patients likely to develop thrombosis, the demonstration of the utility of heparin thromboprophylaxis of patients with pancreatic carcinoma who are positive for TF-bearing microparticles will have significant impact in clinical practice by establishing an anticoagulant regimen focused on only cancer patients a high risk of thrombosis.

描述（由申请人提供）：与恶性疾病相关的血栓形成是癌症患者发病和死亡的主要原因，但其病理生理学基础仍不清楚。在我们的初步研究中，以确定血栓形成与潜在生物标志物——携带组织因子的微粒之间的关系，与没有静脉血栓栓塞事件的癌症患者相比，这些微粒在发生静脉血栓栓塞事件的癌症患者中的优势比为 4.1。在具有可检测到的携带组织因子的微粒的血栓形成阴性癌症患者中，他们一年内发生血栓事件的比率为35%，而在没有升高的携带组织因子的微粒的同一组中，该患者的一年发生血栓事件的率为0%。目标#1侧重于体外研究，以确定癌症微粒上表达的组织因子的功能状态，以及这些微粒的组织起源和半衰期。目标 #2 描述了一项随机、安慰剂对照的介入临床试验，涉及 100 多名胰腺癌患者，以确定携带肿瘤源性组织因子微粒的患者是否会受益于普通肝素的血栓预防，以减少静脉血栓栓塞并发症。在目标#3中，具有人类胰腺癌异种移植物的SCID小鼠将被用作胰腺癌的小鼠模型。通过活体显微镜对血栓形成过程中人移植组织因子负载微粒的积累进行成像，以观察人组织因子在血栓形成过程中的积累以及异种移植组织因子对血栓形成的贡献。将确定血小板P-选择素在微粒积累中的作用，并通过蛋白质印迹和质谱鉴定肿瘤来源的微粒上的P-选择素配体。这些结果将推进以下假设：携带组织因子的微粒既是胰腺癌血栓形成风险的生物标志物，又是癌症相关血栓形成发病机制的核心。鉴于优先确定可能发生血栓形成的癌症患者的更好标志物，通过建立专注于以下方面的抗凝治疗方案，证明肝素对携带 TF 的微粒呈阳性的胰腺癌患者进行血栓预防的效用将对临床实践产生重大影响。只有血栓形成高风险的癌症患者。公共健康相关性：携带组织因子的微粒既是癌症血栓形成风险的生物标志物，也可能是癌症相关血栓形成发病机制的核心。鉴于优先确定可能发生血栓形成的癌症患者的更好标志物，证明肝素对携带 TF 的微粒呈阳性的胰腺癌患者进行血栓预防的效用将通过建立专注于以下方面的抗凝方案对临床实践产生重大影响：只有癌症患者发生血栓的风险较高。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Measurement of platelet microparticles.

血小板微粒的测量。

DOI：
10.1007/978-1-61779-307-3_10
发表时间：
2024-09-14
期刊：
Methods in molecular biology
影响因子：
0
作者：
J. Zwicker;R. Lacroix;F. Dignat;B. Furie;B. Furie
通讯作者：
B. Furie

A specific plasminogen activator inhibitor-1 antagonist derived from inactivated urokinase.

一种源自失活尿激酶的特异性纤溶酶原激活剂抑制剂 1 拮抗剂。

DOI：
发表时间：
2016-10
期刊：
影响因子：
5.3
作者：
Gong, Lihu;Proulle, Valerie;Fang, Chao;Hong, Zebin;Lin, Zhonghui;Liu, Min;Xue, Guangpu;Yuan, Cai;Lin, Lin;Furie, Barbara;Flaumenhaft, Robert;Andreasen, Peter;Furie, Bruce;Huang, Mingdong
通讯作者：
Huang, Mingdong

Platelets are required for enhanced activation of the endothelium and fibrinogen in a mouse thrombosis model of APS.

在 APS 小鼠血栓形成模型中，血小板对于增强内皮和纤维蛋白原的激活是必需的。