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: 8114132
• 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/8114132
• 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）： 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，但其病理生理基础仍然未知。在我们的试点研究中，以确定血栓形成与潜在的生物标志物，组织因子的微粒的关联，与没有静脉血栓栓塞事件的癌症患者相比，这些微粒的这些微粒的比值比为4.1。在血栓形成 - 阴性癌症患者患有含有组织因子因子的微粒的患者中，同一组中的一年率为35％，而没有较高的组织因子的微粒。 AIM＃1专注于体外研究，以确定在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。 AIM＃2描述了一项随机的，安慰剂对照的介入临床试验，涉及100多名胰腺癌患者，以确定肿瘤来源的含有组织因子因子的微粒粒子是否会受益于与未分配的肝素的血栓预防症，以减少静脉血栓栓塞性。在AIM＃3中，具有人类胰腺癌异种移植物的SCID小鼠将用作胰腺癌的小鼠模型。在血栓形成过程中，人类异种移植物因子因子因子的积累将通过插入性显微镜成像，以观察人体组织因子在发育中的血栓中的积累以及异种移植的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，并确定P-选择素配体在通过蛋白质印迹和质谱鉴定的肿瘤衍生的微粒中的作用。结果将推动以下假设：含有组织因子的微粒既是胰腺癌中血栓形成风险的生物标志物，又是它们对癌症相关血栓形成的发病机理的核心。鉴于确定可能发展血栓形成的癌症患者更好的标志物的优先级，胰腺癌患者的肝素血栓预防效果的证明是对TF持有TF的微粒呈阳性的阳性，这将通过建立抗癌药物以高风险为癌症患者来对临床实践产生重大影响。公共卫生相关性：含有组织因子的微粒既是癌症中血栓形成风险的生物标志物，也可能是癌症相关血栓形成的发病机理的中心。考虑到确定可能发展血栓形成的癌症患者更好的标志物的优先级，胰岛素血栓预防的效用表明胰腺癌患者的肝素血栓预防症的实用性，这些患者对TF持有TF的微粒呈阳性，将通过建立抗癌治疗方案对仅具有抗癌药物的癌症患者的临床实践产生重大影响。