| Description |
Fibrinolysis, the proteolytic degradation of the fibrin fibers th a t stabilize blood clots, is initiated when tissue-type plasminogen activator (tPA) activates plasminogen to plasmin, the main fibrinolytic enzyme. Many experiments have shown that coarse clots made of thick fibers lyse more quickly than fine clots made of thin fibers, despite the fact that individual thick fibers lyse more slowly than individual thin fibers. Other experiments show the opposite result. Reaction-diffusion models have been the standard tool for investigating fibrinolysis, and have been successful in capturing the wave-like behavior of lysis seen in experiments. These previous models treat the distribution of fibrin within a clot as homogeneous, and therefore cannot be used directly to study lysis of fine and coarse clots. We create a model that includes a spatially heterogeneous fibrin concentration, as well as a more accurate description of the role of fibrin as a cofactor in the activation of plasmin. Our model predicts spatiotemporal protein distributions in reasonable quantitative agreement with experimental data. The model also predicts observed behavior such as a front of lysis moving through the clot with an accumulation of lytic proteins at the front. In spite of the model improvements, however, we find that one-dimensional (1-D) continuum models are unable to accurately describe the observed differences in lysis behavior between fine and coarse clots. Hence, we develop a three-dimensional (3-D) stochastic multiscale model of fibrinolysis. A microscale model representing a fiber cross section and containing detailed biochemical reactions provides information about single fiber lysis times and the length of time tPA stays bound to a given fiber cross section. Data from the microscale model is used in a macroscale model of the full fibrin clot, from which we obtain lysis front velocities and tPA distributions. We find that the number of fibers in a clot impacts lysis rate, but so does the number of tPA molecules relative to the surface area of the clot exposed to those molecules. Depending on the values of these two quantities (tPA number and surface area), for given kinetic parameters, the model predicts coarse clots lyse faster or slower than fine clots, thus providing a possible explanation for the divergent experimental observations. We also use the model to predict values of unmeasured reaction rates and to suggest desirable characteristics of fibinolytic drugs. We find that a tPA variant that binds less strongly to fibrin causes faster degradation rates than normal tPA. We conclude by studying the effect of the inhibitors a 2-antiplasmin ( a 2-AP), plasminogen activator inhibitor-1 (PAI-1), and thrombin activatable fibrinolysis inhibitor (TAFI) on lysis. We find that a 2-AP is the stongest inhibitor, but lysis is most delayed when a 2-AP and TAFI work together. |
