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。的发病率。 这些患者的VTE通过抗肿瘤药物的使用而进一步增加，如 化疗药物吉西他滨和顺铂，以及联合疗法。然而，这些机制 癌症患者的静脉血栓栓塞率在很大程度上是未知的。这项提案的总体目标是确定是否有 循环微粒中组织因子活性与静脉血栓形成的关系 在胰腺癌或结肠癌患者以及荷瘤小鼠身上。MPS是一种小(1微米)膜 从激活或凋亡的细胞中释放出来的小泡。我们的普遍假设是化疗 药物增加了肿瘤细胞和宿主细胞中TF阳性MPS的释放，并使其进入循环 这些MPS水平的升高与无症状和 胰腺癌和结肠癌患者的症状性静脉血栓栓塞，以及荷瘤患者血栓大小的增加 老鼠。该提案分为两个目标。在具体目标1中，我们将确定治疗的效果 化疗药物对荷瘤小鼠外周血中肿瘤细胞来源的Tf阳性MPS的影响 不同的宿主细胞以及它们在静脉血栓模型中的作用。我们将测量Tf的水平 吉西他滨或吉西他滨联合顺铂治疗荷瘤小鼠的分离MPS的活性。我们 将使用一系列新的小鼠品系来区分来自I/Tumor和宿主的Tf阳性MPS 细胞和II/不同宿主细胞(单核细胞、内皮细胞和血小板)。其中包括丙型肝炎病毒小鼠，它 在没有小鼠Tf的情况下表达人Tf，以及具有各种细胞类型特异性Tf缺失的小鼠 使用Cre-loxP技术产生的基因。最后，我们将有选择地分析任一种肿瘤细胞的作用- 静脉血栓形成模型中来源或宿主细胞来源的Tf阳性MPS。在具体目标2中，我们将 确定晚期高血压患者循环MPS中TF活性与VTE之间是否存在关联 抗肿瘤药物治疗胰腺癌和结肠癌的多中心前瞻性观察 学习。患者将在接受抗肿瘤药物治疗前和治疗后采集血液样本。 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。 使用抗肿瘤药物。我们将测量分离的MPS中的TF活性水平，并确定这是否 与无症状和/或有症状的静脉血栓形成有关。我们还将测量全血转铁蛋白活性，细胞 Tf阳性的MPS和凝血激活标志物(凝血酶、抗凝血酶复合体和D- 二聚体)。这项研究的结果将确定Tf阳性的MPS在静脉血栓形成中的作用 癌症和化疗。分离的MPS中的Tf活性可能是一个有用的生物标志物，可以用于 在癌症患者血栓风险的临床预测模型中单独或作为辅助生物标志物 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.