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: 7690929
• 负责人: Bruce Furie
• 金额: $ 42.5万
• 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 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7690929
• 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; 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; Research; Research Personnel; Risk; Risk Factors; Role; SCID Mice; Surveys; Testing; Thromboplastin; Thrombosis; Thrombus; Tissues; Treatment Protocols; 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; public health relevance; 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)： 与恶性疾病相关的血栓形成是癌症患者发病率和死亡率的主要原因，但其病理生理学基础尚不清楚。在我们的初步研究中，为了确定血栓形成与一种潜在的生物标记物--携带组织因子的微粒之间的关联，有静脉血栓事件的癌症患者与没有静脉血栓栓塞事件的癌症患者相比，这些微粒的优势比为4.1。在血栓形成阴性的癌症患者中，带有可检测到的组织因子微粒的患者发生血栓事件的一年比率为35%，而在没有组织因子微粒升高的同一组中，他们发生血栓事件的一年比率为0%。目的1主要研究肿瘤微粒上表达的组织因子的功能状态，以及这些微粒的组织来源和半衰期。目的#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，以确定携带肿瘤衍生组织因子微粒的患者是否将从普通肝素预防血栓中受益，以减少静脉血栓栓塞并发症。在目标3中，人胰腺癌移植瘤的SCID小鼠将被用作胰腺癌的小鼠模型。血栓形成过程中人类异种来源的组织因子微粒的积聚将通过活体显微镜成像，以观察人类组织因子在血栓形成过程中的积聚以及异种来源的组织因子在血栓形成中的作用。将确定血小板P-选择素在微粒聚集中的作用，并通过Western blotting和质谱学鉴定肿瘤来源微粒上的P-选择素配体。这一结果将推进这样一种假设，即携带组织因子的微粒既是胰腺癌血栓形成风险的生物标记物，也是癌症相关血栓形成的核心发病机制。考虑到优先寻找可能发生血栓形成的癌症患者的更好的标志物，证明肝素对携带Tf微粒阳性的胰腺癌患者的血栓预防作用将在临床实践中产生重大影响，因为它只针对血栓形成的高危癌症患者建立抗凝方案。公共卫生相关性：携带组织因子的微粒既是癌症血栓形成风险的生物标记物，也可能是癌症相关血栓形成发病机制的核心。考虑到优先寻找更好的肿瘤患者血栓形成的标志物，证明携带Tf的微粒阳性的胰腺癌患者肝素预防血栓的有效性将在临床实践中产生重大影响，因为它只针对血栓形成的高危癌症患者。