PET fibrin imaging of DVT and PE

摘要 静脉血栓栓塞（VTE）仍然是一个重大的医疗保健问题，每年有超过10万人死亡 在美国，仍然是一个诊断挑战。即使在今天，在靶向治疗的时代， 癌症和自身免疫性疾病的免疫疗法，不存在直接的成像方法， 血管内血栓目前可用的诊断VTE的成像方法依赖于间接评估， 检测血栓，如CT血管造影术上的充盈缺陷或超声检查缺乏静脉可压缩性， 遭受导致高假阳性和假阴性率的诊断错误， 肺栓塞导致的死亡风险，或不必要的抗凝治疗导致的大出血。我们的长期 本转化研究的研究目标是使用 一种新的纤维蛋白特异性探针用于正电子发射断层扫描（PET）成像，以克服限制 间接VTE诊断，并与一个单一的测试，提供了一个整体的评估新鲜 血管内凝血。 该提案旨在使用血栓体扫描或TBS为VTE诊断提供有力证据 从最初的小规模转化研究（将证明更大规模的临床研究是合理的）到获得临床批准， 汤匙我们假设TBS使用我们的新PET纤维蛋白探针，特异性结合新鲜的 聚合纤维蛋白凝块（< 1周龄），可直接检测体内任何部位的血栓，类似于18F- FDG PET扫描对癌结节的诊断，将对深静脉血栓形成有更好的诊断准确性 和肺栓塞（DVT-PE）相比，目前的成像模式，可以量化全身 新鲜血凝块负荷，可在肾功能不全患者中进行。在我们完全测试这个之前 假设在一个适当的动力临床研究，我们提出了一个概念验证研究在一个较小的队列 测试患者的以下具体目标： SA-1：比较PET纤维蛋白探头诊断的PE与常规成像（CT或PA血管造影）。 SA-2：比较PET纤维蛋白探头诊断的DVT与常规成像（静脉双功超声）。 SA-3：评估除PE-DVT外的上肢和盆腔血栓的患病率，并比较 用PET纤维蛋白探针对血浆D-二聚体水平进行成像。 这项研究的成功执行将为临床试验奠定基础，以比较凝块的疗效- 特定的成像模式（血栓体扫描或TBS），有可能更准确地 VTE的诊断，能够更好地建立在体内的总血块负荷与一个单一的测试和更广泛 适用于肾功能衰竭和肺部疾病患者。

ABSTRACT Venous thromboembolism (VTE) remains a significant healthcare problem with over a 100,000 deaths per year in the United States and still remains a diagnostic challenge. Even today, in the era of targeted therapeutics for cancer and immunologic therapies for autoimmune diseases, there exists no direct method to image intravascular thrombi. Currently available imaging methods to diagnose VTE rely on indirect assessments to detect thrombi, such as filling defects on CT angiography or lack of venous compressibility with ultrasound and suffer from diagnostic errors leading to high false positive and false negative rates that subject patients to the risk of death from pulmonary embolus, or major bleeding from unnecessary anticoagulation. Our long-term research objective of this translational study is to establish a novel thrombus body scan (TBS) using a new fibrin-specific probe for positron emission tomography (PET) imaging to overcome the limitations of indirect VTE diagnosis, and, with one single test, provide a total-body assessment of fresh intravascular clot. This proposal aims to generate strong evidence for VTE diagnosis using the thrombus body scan or TBS from an initial small translational study that will justify larger clinical study to obtain clinical approval for the TBS. We hypothesize that TBS using our new PET fibrin probe that specifically binds to fresh polymerized fibrin clot (< 1 week old), can directly detect thrombus anywhere in the body similar to 18F- FDG PET scans for cancer nodules, will have better diagnostic accuracy for deep venous thrombosis and pulmonary embolus (DVT-PE) compared to current imaging modalities, can quantify the total body burden of fresh clot and can be performed in patients with renal dysfunction. Before we can fully test this hypothesis in an appropriately-powered clinical study, we propose a proof-of-concept study in a smaller cohort of patients to test the following specific aims: SA-1: Compare PE diagnosed by the PET fibrin probe with conventional imaging (CT- or PA-angiogram). SA-2: Compare DVT diagnosed by the PET fibrin probe with conventional imaging (venous duplex ultrasound). SA-3: Assess the prevalence of upper extremity and pelvic clot in addition to PE-DVT and compare the extent of total body clot burden imaged with the PET fibrin probe to the plasma D-dimer level. Successful execution of this study will lay the groundwork for a clinical trial to compare the efficacy of a clot- specific imaging modality (thrombus body scan or TBS) that has the potential to be more accurate for the diagnosis of VTE, better able to establish the total clot burden in the body with a single test and more widely applicable to patients with renal failure and lung disease.