Abstract 12431: Continuous Localized Monitoring of Plasmin Activity Identifies Differential and Regional Effects of the Serine Protease Inhibitor Aprotinin: Relevance to Antifibrinolytic Therapy
Background: Antifibrinolytic therapy, such as the use of the serine protease inhibitor aprotinin, was a mainstay for hemostasis following cardiac surgery. However, aprotinin was empirically dosed, and while the pharmacological target was the inhibition of plasmin activity (PLact) this was never monitored, off-target effects occurred, and led to withdrawn from clinical use. The present study developed a validated fluorogenic-microdialysis method to continuously measure PLact and tested the hypothesis that standardized clinical emperical aprotinin dosing would impart differential and regional effects on PLact.
Methods/Results: Pigs (30 kg) were instrumented with microdialysis probes to continuously measure PLact in myocardial, kidney and skeletal muscle compartments (deltoid) and then randomized to High Dose aprotinin administration (2 mKIU load/ 0.5 mKIU/hr infusion; n=7), Low Dose aprotinin administration (1 mKIU load/ 0.250 mKIU/hr infusion; n=6). PLact was compared to time matched vehicle (n=4), and PLact was also measured in plasma by an in-vitro fluorogenic method. Aprotinin suppressed PLact in the myocardium and kidney at both High and Low Doses- indicative that both doses exceeded a minimal concentration necessary for PLact inhibition. However, differential effects of aprotinin on PLact were observed in the skeletal muscle indicative of different compartmentalization of aprotinin.
Conclusions: Using a large animal model and a continuous method to monitor regional plasmin activity, these unique results demonstrated that an emperical aprotinin dosing protocol causes maximal and rapid suppression in the myocardium and kidney and in turn would likely increase the probability of off-target effects and adverse events. Further, this proof of principle study demonstrated that continuous monitoring of determinants of fibrinolysis may provide a novel approach for managing fibrinolytic therapy.
- © 2010 by American Heart Association, Inc.