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

• 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
• 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

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）：

项目成果

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: 10.1111/jcmm.12875
• 发表时间: 2016-10
• 期刊: Journal of cellular and molecular medicine
• 影响因子: 5.3
• 作者: Gong L;Proulle V;Fang C;Hong Z;Lin Z;Liu M;Xue G;Yuan C;Lin L;Furie B;Flaumenhaft R;Andreasen P;Furie B;Huang M
• 通讯作者: Huang M