An in silico model of clot degradation under the action of histotripsy and thrombolytic drugs

For venous thrombosis patients, catheter-directed thrombolytic drugs remain the standard-of-care to restore vascular flow. Improved outcomes are observed when thrombolytic drugs are combined with histotripsy, a focused ultrasound therapy that breaks down tissue via bubble activity. To gain insight into the mechanisms of this combination approach, an in silico model of bubble/thrombolytic/clot interaction was developed. A Monte Carlo-like simulation was used to gauge the extent of histotripsy ablation. The local tissue properties that dictate bubble nucleation were adjusted based on annotated histological sections of venous thrombi. The distribution of thrombolytic drug within the clot was computed using a finite-difference time domain solution of the perfusion-diffusion equation. Fibrin degradation was computed using the known reaction rate of thrombolytic drug. Predictions of ablation were dependent on the clot subgroup, with a reduction in the extend of ablation as the concentration of fibrin increased. Thrombolytic drug was more uniformly distributed throughout the clot when the effects of histotripsy ablation were consistent, consistent with recent in vitro measurements. Overall, the findings here indicate histotripsy primarily enhances the activity of thrombolytic drugs is via debulking red blood cells within a clot.