Cancer, venous thromboembolic disease and tissue factor-bearing microparticles

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。在我们的初步研究中，以确定血栓形成与一个潜在的生物标志物，组织因子携带的微粒，这些微粒在癌症患者静脉血栓栓塞事件相比，没有静脉血栓栓塞事件的癌症患者的优势比为4.1。在具有可检测的携带组织因子的微粒的血栓形成阴性癌症患者中，他们发展血栓形成事件的一年率为35%，而在没有升高的携带组织因子的微粒的同一组中为0%。目标#1集中于体外研究，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来源和半衰期。目的#2描述了一项随机、安慰剂对照的干预性临床试验，涉及100多名胰腺癌患者，以确定携带肿瘤源性组织因子的微粒的患者是否会从普通肝素预防血栓形成中获益，以减少静脉血栓栓塞并发症。在目标#3中，具有人胰腺癌异种移植物的SCID小鼠将用作胰腺癌的小鼠模型。将通过活体显微镜对血栓形成期间人异种移植物衍生组织因子携带微粒的蓄积进行成像，以观察人组织因子在血栓形成中的蓄积以及异种移植物衍生组织因子对血栓形成的贡献。将确定血小板P-选择素在微粒积聚中的作用，并通过蛋白质印迹和质谱法鉴定肿瘤来源的微粒上的P-选择素配体。这些结果将推进这样的假设，即携带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，也是癌症相关血栓形成的发病机制的核心。考虑到优先确定可能发生血栓形成的癌症患者的更好标志物，通过建立仅关注血栓形成高风险的癌症患者的抗凝方案，证明肝素血栓预防对TF携带微粒阳性的胰腺癌患者的效用将在临床实践中产生重大影响。公共卫生相关性：携带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发病机制的核心。考虑到识别可能发展血栓形成的癌症患者的更好标记物的优先权，通过建立仅关注血栓形成高风险的癌症患者的抗凝剂方案，证明肝素血栓预防对携带TF的微粒阳性的胰腺癌患者的效用将在临床实践中具有显著影响。

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.