COMPUTER-SIMULATION OF SYSTEMIC CIRCULATION AND CLOT LYSIS DYNAMICS DURING THROMBOLYTIC THERAPY THAT ACCOUNTS FOR INNER CLOT TRANSPORT AND REACTION

Background We developed a computer model to predict lysis rates of thr ombi for intravenous thrombolytic regimens based on the convective/dif fusive penetration of reacting and adsorbing fibrinolytic species from the circulation into the proximal face of a dissolving clot. Methods and Results Solution of a one-compartment plasma model provided the dy namic concentrations of fibrinolytic species that served as inlet cond itions for simulation of the one-dimensional spatiodynamics within a d issolving fibrin clot of defined composition. The model predicted the circulating levels of tissue plasminogen activator (TPA) and plasminog en levels found in clinical trials for various intravenous therapies. To test the model predictions under in vitro conditions, plasma clots were perfused with TPA (0.1 mu mol/L) and plasminogen (1.0 mu mol/L) d elivered at constant permeation velocity of 0.1 or 0.2 mm/min. The mod el provided an accurate prediction of the measured lysis front movemen t. For TPA administration regimens used clinically, simulations predic ted clot dissolution rates that were consistent with observed reperfus ion times. For unidirectional permeation, the continual accumulation o f adsorbing species at the moving lysis front due to prior rounds of s olubilization and rebinding was predicted to provide for a marked conc entration of TPA and plasmin and the eventual depletion of antiplasmin and macroglobulin in an advancing (approximate to 0.25 mm thick) lysi s zone. Conclusions Pressure-driven permeation greatly enhances and is a primary determinant of the overall rate of dot lysis and creates a complex local reaction environment at the plasma/clot interface. With simulation of reaction and transport, it becomes possible to quantitat ively link the administration regimen, plasminogena activator properti es, and thrombolytic outcome.