Treatment of chronic venous thrombosis with histotripsy and thrombolytics

Summary: Deep vein thrombosis (DVT) is a major public health problem that affects 640,000 Americans each year, and accrues $10B in healthcare costs. For critical thromboses, the American Heart Association and Society for Interventional Radiology recommend thrombolytic drugs be administered to break down the thrombus and restore flow in the vessel. Thrombolytic drugs are not effective for the 43% of DVT cases with chronic thrombus, resulting in poor clinical outcomes for these patients. Adjuvant strategies are therefore needed to ensure effective treatments for the entire thrombus. The scientific premise of this renewal project is combining thrombolytic drugs with histotripsy, an ultrasound therapy that ablates tissue with the mechanical action of bubble clouds, will improve outcomes for DVT patients. In the prior period of this project, we established this combination treatment (histotripsy+) addresses all thrombus components, and resulted in better outcomes than either approach individually in vitro and in vivo. In contrast, only a subset of thrombus components could be treated with histotripsy or thrombolytic alone, which increases the likelihood for vascular re-occlusion. These lessons have informed our revised approach in this Renewal Project, with an objective to address current gaps that limit clinical deployment of histotripsy+. In Aim 1, we will upgrade our histotripsy+ instrumentation. A phased source will be produced that generates bubble activity along a 1 cm length of thrombus for single transmitted pulses, and enables treatment for up to a 5 cm segment with electronic steering. Bubble activity will be monitored volumetrically with a coaxial matrix imaging probe using our passive and active imaging algorithms. We will adjust transmitted pulses in real time to account for defocusing from tissue heterogeneity using the send/receive capabilities of the phased, cylindrical transducer. Finally, treatment protocols and imaging markers will be established that ensure effective outcomes based on time-resolved measurements of in vitro clot degradation, and confirmed with ex vivo chronic human specimen. Studies in Aim 2 will assess the safety of histotripsy+ for DVT. Mechanisms of platelet activation during histotripsy+ will be assess in vitro, and effective antithrombotic strategies to counter will be determined in vivo. For chronically thrombosed veins that have a reduced compliance to strain, we will identify exposure conditions that effectively treat chronic DVT but avoid vascular rupture in vivo. Additionally, we will assess treatment-related changes to cellular composition of treated veins with our microfluidics-based scRNA-Seq technique. Finally, studies in Aim 3 will gauge the influence of thrombus age (0 to 30 days) on treatment outcomes of histotripsy+ to develop personalized treatment strategies based on stage of disease. Following successful completion of the proposed studies, we will have produced a validated system for rapid treatment of DVT, with sufficient data to confirm the safety and efficacy needed for clinical testing. Further, new information will be gathered to address currently intractable venous thrombi.