SBIR/STTR Award attributes
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.RELEVANCE Prior to COVID-19, Americans had experienced between 200,000 and 700,000 new cases of deep vein thrombosis (DVT) each year, with estimates varying widely due to the likelihood of under-reporting. Thirty to fifty percent of all DVT patients develop the morbid post-thrombotic syndrome (PTS), which is a national health crisis. It is further recognized there is an increased risk for DVT with concomitant COVID-19. While it is not yet known what long-term effects COVID-19 may have on individuals, there is a distinct potential for thrombotic complications such as PTS. Research in this area is therefore more relevant than it has ever been, with the need to address a growing health crisis and potentially avert an even larger crisis in the future.
