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

通过血管周围抗炎剂输送预防深静脉血栓形成后的血栓后综合征

• 批准号: 10325584
• 负责人: Farouc Amin Jaffer
• 金额: $ 29.97万
• 依托单位: MERCATOR MEDSYSTEMS, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-20 至 2023-06-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10325584
• 关键词: Address; Affect; American; Animals; Anti-Inflammatory Agents; Anticoagulation; Area; Blood Vessels; Blood flow; COVID-19; Caliber; Catheters; Chronic; Cicatrix; Clinical; Clinical Trials; Combined Modality Therapy; Deep Vein Thrombosis; Deterioration; Devices; Dexamethasone; Drug Delivery Systems; Economic Burden; Engineering; Excision; Fibrosis; Funding; Future; General Hospitals; Glucocorticoids; Health; Human; Hyperpigmentation; Hypertension; Impairment; Incidence; Individual; Inferior vena cava structure; Inflammation; Inflammatory; Infusion procedures; Injury; Intervention; Lead; Ligation; Limb structure; Location; Long-Term Effects; Massachusetts; Measurement; Mechanics; Mediating; Medical; Methods; Modeling; Modification; Mus; National Heart, Lung, and Blood Institute; Notification; Obstruction; Outcome; Pathology; Patients; Pharmaceutical Preparations; Pharmacology; Phase; Phosphate Buffer; Postphlebitic Syndrome; Process; Property; Publishing; Quality of life; Rana catesbeiana; Reflux; Reporting; Research; Resolution; Risk; Saline; Severities; Signal Pathway; Small Business Technology Transfer Research; Stents; Subgroup; Swelling; Symptoms; Testing; Therapeutic; Thrombectomy; Thrombophilia; Thrombosis; Thrombus; Translating; United States National Institutes of Health; Veins; Venous; base; case-based; cytokine; design; experience; improved; innovation; mouse model; non-compliance; novel; novel therapeutics; prevent; randomized trial; research study; response to injury; restoration; skin ulcer; stent thrombosis; success; technological innovation; thrombolysis; thrombotic complications

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.

项目总结