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 regardlessof 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, PCDTdid not reduce the incidence of PTS over 24 months, compared to control anticoagulation alone. In subgroupanalysis, PCDT conferred reduced moderate-to-severe PTS in iliofemoral DVT (2,3), and no benefit when PCDTwas administered after 8 days post-symptom onset (4). Overall, there remains a clear unmet need to expand thearmamentarium 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 todamaged venous valves and subsequent valvular reflux, and continued obstruction of venous outflow due tothrombus persistence, leading to venous hypertension. Each of these outcomes can arise from venousinflammation, 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). Itis 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-inflammatoryagents such as dexamethasone (a powerful, inexpensive glucocorticoid). Via the Bullfrog® Micro-InfusionCatheter platform (currently available to treat vessels of 2-8 mm diameter), Mercator is developing a device totreat the larger iliofemoral veins, which will have diameter up to 20 mm. Localized anti-inflammatory agentdelivery 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 perivasculardexamethasone delivery in a mouse model of DVT, and Aim 2 will engineer a larger Bullfrog® device forhuman use in up to 20 mm-diameter veins. After completion of this Phase I project, the centralhypothesis of locally delivered anti-inflammatory treatment of the vein wall post-DVT treatment will beinvestigated 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. Affect ; Animals ; Anti-Inflammatory Agents ; Anti-Inflammatories ; Anti-inflammatory ; Antiinflammatories ; Antiinflammatory Agents ; antiinflammatory ; Anticoagulation ; Blood Vessels ; vascular ; Cicatrix ; Scars ; Clinical Trials ; Combined Modality Therapy ; Multimodal Therapy ; Multimodal Treatment ; combination therapy ; combined modality treatment ; combined treatment ; multi-modal therapy ; multi-modal treatment ; Dexamethasone ; Pharmaceutical Preparations ; Drugs ; Medication ; Pharmaceutic Preparations ; drug/agent ; Engineering ; Limb structure ; Extremities ; Limbs ; Non-Trunk ; Fibrosis ; Future ; Glucocorticoids ; Health ; General Hospitals ; Human ; Modern Man ; Hypertension ; Vascular Hypertensive Disease ; Vascular Hypertensive Disorder ; high blood pressure ; hyperpiesia ; hyperpiesis ; hypertensive disease ; Incidence ; Inflammation ; Lead ; Pb element ; heavy metal Pb ; heavy metal lead ; Ligation ; Closure by Ligation ; Long-Term Effects ; Longterm Effects ; Massachusetts ; Methods ; Mus ; Mice ; Mice Mammals ; Murine ; United States National Institutes of Health ; NIH ; National Institutes of Health ; Obstruction ; Pathology ; Patients ; Pharmacology ; Postphlebitic Syndrome ; Post thrombotic syndrome ; Post-phlebitic Disease ; Postphlebitic Disease ; Postthrombotic syndrome ; Venous ulcer-leg syndrome ; post-phlebitic syndrome ; Publishing ; Quality of life ; QOL ; Rana catesbeiana ; Bullfrog ; Research ; Risk ; Saline ; Saline Solution ; Signal Pathway ; skin ulcer ; ulcerative wounds ; Stents ; Swelling ; Testing ; Thrombosis ; thrombotic disease ; thrombotic disorder ; Translating ; Veins ; Inferior vena cava structure ; Inferior Vena Cava ; cytokine ; Drug Delivery Systems ; Drug Delivery ; Catheters ; Mediating ; Thrombus ; Deep Vein Thrombosis ; Deep-Venous Thrombosis ; Thrombectomy ; Hyperpigmentation ; Hypermelanoses ; Hypermelanosis ; Injury ; injuries ; base ; improved ; Area ; Chronic ; Clinical ; Phase ; Medical ; Blood flow ; Reflux ; Individual ; Measurement ; Funding ; Therapeutic ; Inflammatory ; Venous ; mechanical ; Mechanics ; Hypercoagulability ; Thrombophilia ; Notification ; Severities ; restoration ; Location ; non-compliant ; noncompliance ; noncompliant ; non-compliance ; thrombolysis ; Infusion ; Infusion procedures ; American ; experience ; success ; novel ; research study ; technological innovation ; Devices ; Reporting ; Abscission ; Extirpation ; Removal ; Surgical Removal ; resection ; Excision ; Deterioration ; Modeling ; Property ; Intervention Strategies ; interventional strategy ; Intervention ; Phosphate Buffer ; preventing ; prevent ; Diameter ; Caliber ; Address ; Symptoms ; Economic Burden ; Resolution ; Subgroup ; Small Business Technology Transfer Research ; STTR ; Process ; Modification ; National Heart, Lung, and Blood Institute ; NHLBI ; design ; designing ; response to injury ; injury response ; Outcome ; innovation ; innovate ; innovative ; Impairment ; case-based ; novel therapeutics ; new drug treatments ; new drugs ; new therapeutics ; new therapy ; next generation therapeutics ; novel drug treatments ; novel drugs ; novel therapy ; mouse model ; murine model ; randomized trial ; Randomization trial ; stent thrombosis ; stent induced thrombosis ; COVID-19 ; COVID19 ; CV-19 ; CV19 ; corona virus disease 2019 ; coronavirus disease 2019 ; thrombotic complications ; thromboembolic complications ; thrombosis complications ;
