Abstract 2543: Thrombolytic Efficacy of Encapsulated Plasminogen
Introduction: Incidence of hemorrhage linked to treatment of ischemic stroke with tissue plasminogen activator (tPA) has led to interest in combination therapies such as plasminogen (Plg), with the goal of decreasing the administered volume of tPA. In-vitro studies using Plg have shown enhancement of lysis. However, due to rapid deactivation of Plg-derived plasmin in-vivo, local delivery of Plg via encapsulation by liposomes and release by ultrasound (US) may be necessary. This study examined the enhancement of tPA-induced lysis using encapsulated Plg (EPlg), in an in-vitro clot model.
Methods: Blood was drawn from 26 subjects after local Institutional Review Board approval. Clots were made in 20-µL pipettes and placed in a water tank for microscopic visualization during treatment. Sample clots were exposed to tPA in human fresh-frozen plasma (hFFP) at a concentration of 3.15 µg/ml and EPlg at a concentration of 167 µg Plg/ml. Clots were exposed to no tPA (Control), tPA alone (+tPA), tPA and EPlg (+EPlg), tPA and 120-kHz US (+US), or tPA, EPlg, and 120-kHz US (+EPlg-US) for 30 minutes. The extent of thrombolysis was determined by assessing clot width as a function of time, using a time-lapse microscopic imaging technique; the fractional clot loss (FCL) at 30 minutes was used to determine thrombolytic efficacy.
Results: Each treatment group had a minimum of 6 clots (range: 6-158) from 2 different donors (range: 2-24). FCL for +tPA was 38% (95% Confidence Interval: 36-40%); FCL for +EPlg was 39% (30-46%) (p=0.48 vs. +tPA). FCL for +EPlg-US was 49% (43-54%) (p<0.01 vs. +tPA). However, it did not exceed FCL for +US at at 70% (64-76%) (p<0.01 vs. +EPlg-US).
Conclusions: Lysis with EPlg with tPA and US is more effective than tPA alone. This improvement of lytic efficacy using EPlg is dependent on concomitant use of US. Interaction between liposomes, Plg, and US is complex and merits further study.
- © 2012 by American Heart Association, Inc.