Enhanced Thrombolysis by Ultrasound-Assisted Catheter-Directed Thrombolysis and Microbubbles in an In Vitro Model of Iliofemoral Deep Vein Thrombosis

There is a need to improve the efficacy and safety of catheter-directed thrombolysis (CDT) for thrombo-occlusive diseases, and ultrasound-assisted CDT (USAT) is a promising approach. We tested if thrombolysis efficacy of USAT can be improved by adding gaseous microbubbles (MB). We developed an in vitro dynamic overflow model for iliofemoral deep vein thrombosis, and added MB to an USAT system with ultrasound energy and dose of tissue plasminogen activator according to clinical practice. A total of 64 clots (mean baseline weight of 8.231.12g, generated from citrated human whole blood from 7 healthy male volunteers) were randomly assigned to 1 of 4 study protocols of 30 minutes' duration: negative control, CDT, USAT, and USAT+MB. Thrombolysis efficacy was assessed by measuring the change in D-dimer levels in the overflow liquid and the percentage of clot weight reduction. Compared to negative control, change in D-dimer increased by 62% (p =0.017), 128% (p=0.002), and 177% (p<0.001) in the CDT, USAT, and USAT+MB groups, respectively. D-dimer increase was greater in the USAT than in the CDT group (p=0.014), and greater in the USAT+MB than in the USAT group (p=0.033). Compared to negative control, percentage of clot weight reduction increased by 123% (p=0.016), 154% (p=0.002), and 233% (p<0.001) in the CDT, USAT, and USAT+MB groups, respectively. Percentage of clot weight reduction was greatest in the USAT+MB group (p<0.05 compared with all other groups). In conclusion, our in vitro study suggests that the thrombolytic efficacy of USAT in human whole blood clots can be improved by local administration of MB.