Room: Track 4
Purpose: Deep vein thrombosis is a major burden worldwide. Catheter-directed thrombolytic drugs are the frontline therapy for vessel recanalization, but have limited efficacy for chronic, well-organized thrombus. Histotripsy is an image-guided focused ultrasound therapy that generates in situ mechanical activity via bubble cloud activation. When combined with a lytic therapy, histotripsy bubble cloud activity causes robust degradation of non-responsive clots. The purpose of this study is to investigate the relative contributions of two proposed mechanisms to histotripsy-induced clot degradation: mechanical ablation of cellular components, and enhanced thrombolytic delivery.
Methods: Whole blood clots were exposed to plasma, the thrombolytic recombinant tissue plasminogen activator, rt-PA (0 or 2.68 µg/mL), and histotripsy pulses over a range of pulse durations (1–20 cycles) and peak negative pressures (0-35 MPa). Following histotripsy exposure, samples of the perfusate were assayed to quantify ablation via the presence of hemoglobin, and thrombolysis via the fibrin degradation product D-dimer. For each treatment arm, clot mass loss was assessed to gauge overall treatment efficacy. Acoustic emissions generated by the bubble cloud were mapped with passive cavitation imaging, a diagnostic ultrasound imaging modality.
Results: For the application of 1-cycle pulses, histotripsy bubble activity and rt-PA produced limited enhancement in D-dimer and hemoglobin relative to the application of rt-PA alone. In contrast, multi-cycle bubble activity generated strong increases in D-dimer and hemoglobin relative to baseline measurements. Mass loss correlated strongly with both hemoglobin and D-dimer (r > 0.85). Strong cavitation emissions were observed with passive cavitation imaging for all histotripsy pulsing schemes, providing an imaging metric to gauge treatment efficacy.
Conclusion: Mechanical ablation and enhanced thrombolytic delivery are both important mechanisms for histotripsy-aided clot degradation, particularly for multi-cycle pulses. These results demonstrate histotripsy will be an effective adjuvant to catheter-directed lytics in the treatment of deep vein thrombi non-responsive to standard interventions.