Mechanisms of Venous Thromboembolism in Cancer

静脉血栓形成（VTE）是癌症患者死亡和残疾的主要原因。的发生率 这些患者中的VTE通过施用抗肿瘤药物进一步增加，例如 化疗药物吉西他滨和顺铂，以及联合治疗。然而，机制 癌症患者的VTE在很大程度上是未知的。本提案的总体目标是确定 在循环微粒（MP）中的组织因子（TF）活性与静脉血栓形成之间存在关联 在胰腺癌或结肠癌患者以及荷瘤小鼠中。MP是小（<1微米）膜 从活化或凋亡细胞释放的囊泡。我们的假设是化疗 药物增加TF阳性MP从肿瘤细胞和宿主细胞释放到循环中， 这些MP水平的增加与无症状性和 胰腺癌和结肠癌患者中的症状性VTE，以及肿瘤患者中血栓尺寸的增加 小鼠该提案分为两个目标。在具体目标1中，我们将确定以下治疗的效果 用化疗药物对来自肿瘤细胞的循环TF-阳性MP的荷瘤小鼠， 不同的宿主细胞以及它们在静脉血栓形成模型中的作用。我们将测量TF的水平 在用吉西他滨或吉西他滨和顺铂治疗的荷瘤小鼠中分离的MP的活性。我们 将使用一系列新的小鼠系来区分来源于i/肿瘤与宿主的TF阳性MP 细胞，和ii/不同的宿主细胞（单核细胞、内皮细胞和血小板）。其中包括HCV小鼠， 在缺乏小鼠TF的情况下表达人TF，以及具有TF的各种细胞类型特异性缺失的小鼠 使用Cre-loxP技术产生的基因。最后，我们将选择性地分析肿瘤细胞的作用- 衍生的或宿主细胞衍生的TF阳性MP在静脉血栓形成模型中的作用。具体目标2 确定晚期肺栓塞患者循环MP中的TF活性与VTE之间是否存在相关性。 胰腺癌和结肠癌用抗肿瘤药物治疗的多中心前瞻性观察 study.将在抗肿瘤药物治疗前后采集患者的血液样本。 无症状的深静脉血栓形成将在治疗前后使用压缩超声进行评估 抗肿瘤药物我们将测量孤立MP的TF活性水平，并确定这是否是 与无症状和/或症状性VTE相关。我们还将测量全血TF活性、细胞TF活性、 TF阳性MP和凝血活化标志物（凝血酶抗凝血酶复合物和D- 二聚体）。本研究的结果将确定TF阳性MP在静脉血栓形成相关的 癌症和化疗。分离的MP中的TF活性可能是一种有用的生物标志物，可以用于 单独或作为癌症患者血栓形成风险临床预测模型中的连续生物标志物 正在接受化疗

Venous thrombombolism (VTE) is a leading cause of death and disability in cancer patients. The incidence of VTE in these patients in further increased by the administration of anti-neoplastic drugs, such as the chemotherapy drugs gemcitabine and cisplatin, as well as combination therapies. However, the mechanisms of VTE in cancer patients are largely unknown. The overall goal of this proposal is to determine whether an association exists between tissue factor (TF) activity in circulating microparticles (MPs) and venous thrombosis in patients with pancreatic or colon cancer, and in tumor-bearing mice. MPs are small (<1 micron) membrane vesicles that are released from activated or apoptotic cells. Our general hypothesis is that chemotherapy drugs increase the release of TF-positive MPs from both tumor cells and host cells into the circulation, and that an increase in the level of these MPs is associated with an increase in the incidence of asymptomatic and symptomatic VTE in pancreatic and colon cancer patients, and an increase in thrombus size in tumor-bearing mice. The proposal is divided into two aims. In Specific Aim 1 we will determine the effect of treatment of tumor-bearing mice with chemotherapeutic drugs on circulating TF-positive MPs derived from tumor cells and different host cells as well as their role in a model of venous thrombosis. We will measure the levels of TF activity in isolated MPs in tumor-bearing mice treated with either gemcitabine or gemcitabine and cisplatin. We will use a series of novel mouse lines to distinguish between TF-positive MPs derived from i/ tumor versus host cells, and ii/ different host cells (monocytes, endothelial cells and platelets). These include HCV mice, which express human TF in the absence of mouse TF, and mice with various cell type-specific deletions of the TF gene generated using the Cre-loxP technology. Finally, we will selectively analyze the role of either tumor cell- derived or host cell-derived TF-positive MPs in a model of venous thrombosis. In Specific Aim 2 we will determine if there is an association between TF activity in circulating MPs and VTE in patients with advanced pancreatic and colon cancer treated with anti-neoplastic drugs in a multi-center prospective observational study. Blood samples will be obtained from patients before and after treatment with anti-neoplastic drugs. Asymptomatic deep vein thrombosis will be assessed using compression ultrasound before and after treatment with anti-neoplastic drugs. We will measure levels of TF activity in isolated MPs and determine if this is associated with asymptomatic and/or symptomatic VTE. We will also measure whole blood TF activity, cellular origin of the TF-positive MPs and coagulation activation markers (thrombin anti thrombin complexes and D- dimer). The results of this study will determine the role of TF-positive MPs in venous thrombosis associated with cancer and chemotherapy. TF activity in isolated MPs may be a useful biomarker that can be used either alone or as an adjunctive biomarker in clinical predictive models of thrombotic risk in cancer patients undergoing chemotherapy.