Assessment of clot degradation under the action of histotripsy and a thrombolytic drug

Abstract

Deep vein thrombosis is a major source of morbidity worldwide, affecting 5% of the population. For critical obstructions, catheter-directed thrombolytics are the frontline therapy for vessel recanalization. Adjuvant therapies to lytics are under development to improve treatment efficacy and reduce procedure-related complications. One such adjuvant is histotripsy, a focused ultrasound therapy that relies on the nucleation of bubble cloud to modulate tissue. This combination approach has been successful in vitro, and is hypothesized to promote clot dissolution via two mechanisms: mechanical hemolysis and enhanced fibrinolysis. In this study, the contributions of hemolysis and fibrinolysis to clot degradation under histotripsy and a thrombolytic were quantified with measurements of hemoglobin and D-dimer, respectively. Linear regression analysis was used to determine the relationship between hemoglobin, D-dimer, and the overall treatment efficacy (clot mass loss). A similar analysis was conducted to gauge the contribution of bubble activity assessed with passive cavitation imaging on hemolysis and fibrinolysis. Tabulation of these data demonstrated hemolysis and fibrinolysis contributed equally to clot mass loss. Furthermore, bubble cloud activity promoted the generation of hemoglobin and D-dimer in equal proportion. These studies indicate a multifactorial process for clot degradation under the action of histotripsy and a lytic therapy.