Accelerated Low Dose Thrombolytic Catheter Directed Sonothrombolysis

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Abstract Venous thromboembolism (VTE), comprising Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE), is a major health care challenge resulting in significant mortality, morbidity, and societal cost. Annually, there are approximately 900,000 recurrent, fatal and nonfatal VTE events resulting in 300,000 deaths. In total, annual direct healthcare expenditures attributable to VTE are $7 – 10 B/yr with an additional $10 – 15B attributable to premature death and lost productivity caused by both short and long-term disability. Currently, VTE is usually treated via outpatient management using conventional anticoagulants prevent thrombus extension, pulmonary embolism and recurrence, but do not dissolve or remove the clot. Approximately half of all patients undergoing therapy with conventional anticoagulants develop venous dysfunction resulting in post-thrombotic syndrome. PTS frequently involves: pain, swelling, sensation of heaviness, edema, pigmentation, and deterioration of the skin, including venous ulcers in severe cases. The key technological advancement proposed involves a new endovascular approach that accelerates thrombolysis while simultaneously requiring a significantly reduced dose of thrombolytic drug. The proposed catheter combines local administration of low-dose thrombolytic, in the immediate vicinity of the blood clot, with adjuvant ultrasound energy and large diameter (~20 m), low sta- bility microbubbles (MB) that, when exposed to ultrasound, accelerate thrombus dissolution. Using this ap- proach, we have demonstrated a 4.5x increase in the rate of volumetric clot loss relative to conventional tPA administration in an in vitro model and enabled a 3.33x tPA dose reduction in a model of ischemic stroke. After clinical translation (beyond the scope of the current proposal), following large animal trials, “first in hu- man” and a phased clinical trial, our vision is that a catheter, derivative from that proposed, be used as a direct substitute for current catheter directed therapy, which frequently requires several days of continuous catheteri- zation to resolve the thrombus. The proposed program of research is organized around the following specific aims: Specific Aim 1: Develop sonothrombolysis catheter with on-board micro-Coulter microbubble monitoring sys- tem, high power ultrasound “delivery” transducer and high-resolution transducer for real-time characterization of thrombolysis progress Specific Aim 2: Perform an Investigation of ultrasound, thrombolytic drug and microbubbble interactions in a well-controlled laboratory benchtop in vitro thrombolysis model Specific Aim 3: Test efficacy of approach in vivo using a murine DVT model