Preventing Post-Thrombotic Syndrome after Deep Vein Thrombosis with Perivascular Anti-Inflammatory Agent Delivery

项目总结 血栓后综合征(PTS)是一种以肢体肿胀和不适为特征的慢性衰弱疾病， 色素沉着、皮肤溃疡和生活质量受损。它发生在深静脉血栓形成的两年内。 (DVT)治疗50%-60%的髂股血栓患者和30%-50%的所有DVT患者 血栓形成部位(1)。即使使用药物导管定向溶栓(PCDT)或导管- 在最近的临床试验中使用的定向血栓切除术(CDT)(例如，Attact、CaVenT和CAVA)， PTS的发生率仍然保持在40%-50%。在NHLBI/NIH资助的随机试验中，例如，PCDT 与单纯抗凝相比，24个月后PTS的发生率并未降低。在子组中 分析，在髂股深静脉血栓(2，3)中，PCDT可减少中到重度的PTS，而PCDT没有好处 在症状出现后8天给药(4例)。总体而言，仍有一个明显未得到满足的需求，即扩大 在减轻PTS的临床和经济负担方面，超越选择性PCDT的各种治疗手段。 血栓形成后综合征由多种因素相互作用演变而来：纤维性静脉壁硬化导致 静脉瓣膜受损和随后的瓣膜返流，以及因以下原因而持续阻塞的静脉流出 血栓持续存在，导致静脉高压。这些结果中的每一种都可以由静脉注射引起 炎症，现在被认为是DVT治疗后PTS恶化过程中的关键(5，6)。 假设，具有抗炎特性的药物可能因此具有预防PTS的能力(7-10)。它 更有可能的是，如果在当地进行抗炎治疗可能会更有效， 同时配合导管引导的血栓清除(如PCDT/CDT)。 墨卡托医疗系统公司是局部血管周围药物输送的先驱，特别是在抗炎方面 地塞米松(一种强大、廉价的糖皮质激素)等药物。通过BullFrog®微量输液 导管平台(目前可用于治疗直径2-8 mm的血管)，墨卡托正在开发一种设备，以 治疗较大的髂股静脉，其直径将达到20毫米。局部抗炎药 递送被认为是一种新的治疗方法，可以减少DVT治疗后PTS的进展。 在这个第一阶段的STTR提案中，Aim 1将研究血管周围的抗炎能力 地塞米松在DVT小鼠模型中的释放，Aim 2将设计一种更大的BullFrog®设备来治疗 人类在直径达20毫米的静脉中使用。这项第一期工程完成后，中环 DVT治疗后局部给予静脉壁抗炎治疗的假设将是 在第二阶段的大型动物和人体试验中进行了调查。

PROJECT SUMMARY Post-thrombotic syndrome (PTS) is a chronic debilitating condition characterized by limb swelling and discomfort, hyperpigmentation, skin ulcers, and impaired quality of life. It occurs within 2 years of deep vein thrombosis (DVT) treatment in 50-60% of patients with iliofemoral thrombosis and in 30-50% of all DVT patients regardless of thrombosis location (1). Even with pharmacological catheter-directed thrombolysis (PCDT) or catheter- directed thrombectomy (CDT) as used in the most recent clinical trials (e.g. ATTRACT, CaVenT and CAVA), there remains a 40-50% rate of PTS. In the NHLBI/NIH-funded ATTRACT randomized trial, for example, PCDT did not reduce the incidence of PTS over 24 months, compared to control anticoagulation alone. In subgroup analysis, PCDT conferred reduced moderate-to-severe PTS in iliofemoral DVT (2,3), and no benefit when PCDT was administered after 8 days post-symptom onset (4). Overall, there remains a clear unmet need to expand the armamentarium of therapies beyond selective PCDT in reducing the clinical and economic burden of PTS. Post-thrombotic syndrome evolves from an interplay of multiple factors: fibrotic vein wall stiffening leading to damaged venous valves and subsequent valvular reflux, and continued obstruction of venous outflow due to thrombus persistence, leading to venous hypertension. Each of these outcomes can arise from venous inflammation, which is now considered a key in the process of deterioration to PTS after DVT treatment (5,6). Hypothetically, drugs with anti-inflammatory properties may therefore have the ability to prevent PTS (7-10). It is further plausible that anti-inflammatory therapy may be more efficacious if delivered locally, concomitantly with catheter-directed clearance of thrombosis (e.g. PCDT/CDT). Mercator MedSystems is the pioneer in local perivascular drug delivery, particularly with anti-inflammatory agents such as dexamethasone (a powerful, inexpensive glucocorticoid). Via the Bullfrog® Micro-Infusion Catheter platform (currently available to treat vessels of 2-8 mm diameter), Mercator is developing a device to treat the larger iliofemoral veins, which will have diameter up to 20 mm. Localized anti-inflammatory agent delivery is proposed as a novel therapy to reduce the progression to PTS after DVT treatment. In this Phase I STTR proposal, Aim 1 will investigate the anti-inflammatory capability of perivascular dexamethasone delivery in a mouse model of DVT, and Aim 2 will engineer a larger Bullfrog® device for human use in up to 20 mm-diameter veins. After completion of this Phase I project, the central hypothesis of locally delivered anti-inflammatory treatment of the vein wall post-DVT treatment will be investigated in large animals and human trials in Phase II research.