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

项目摘要 血栓形成后综合征（PTS）是一种慢性衰弱性疾病，其特征是肢体肿胀和不适， 色素沉着过度、皮肤溃疡和生活质量受损。它发生在深静脉血栓形成的2年内 (DVT)50-60%的髂股血栓形成患者和30-50%的所有DVT患者接受治疗， 血栓位置（1）。即使使用药物导管溶栓（PCDT）或导管- 最近的临床试验中使用的定向血栓切除术（CDT）（例如，ATTRACT、CaVenT和CAVA）， PTS的发生率仍为40-50%。例如，在NHLBI/NIH资助的ATTRACT随机试验中， 与单纯抗凝治疗相比，24个月内未降低PTS的发生率。亚组 分析，PCDT降低了髂股DVT的中度至重度PTS（2，3），当PCDT 在症状发作后8天给药（4）。总的来说，在扩大 在减少PTS的临床和经济负担方面，除了选择性PCDT之外，还有其他治疗方法。 血栓形成后综合征是由多种因素相互作用引起的：纤维化静脉壁硬化， 静脉瓣膜受损和随后的瓣膜返流，以及由于 血栓持续存在，导致静脉高压。这些结果中的每一个都可能来自静脉 炎症，现在认为这是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 进一步合理的是，如果局部递送，抗炎治疗可能更有效， 伴随导管定向清除血栓形成（例如PCDT/CDT）。 Mercator MedSystems是局部血管周围药物输送的先驱，特别是抗炎药物 药物如地塞米松（一种强效、廉价的糖皮质激素）。通过牛蛙®微输液 导管平台（目前可用于治疗2-8 mm直径的血管），Mercator正在开发一种器械， 治疗较大的髂股静脉，其直径可达20 mm。局部抗炎剂 递送被提出作为一种新的疗法，以减少DVT治疗后向PTS的进展。 在这个I期STTR提案中，目标1将研究血管周围的抗炎能力， 地塞米松递送在DVT小鼠模型中，Aim 2将设计一个更大的牛蛙®装置， 用于直径达20 mm的静脉。一期工程完成后， DVT治疗后静脉壁局部递送抗炎治疗的假设将是 在大型动物和人体试验中进行了II期研究。

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.