INNER CLOT DIFFUSION AND PERMEATION DURING FIBRINOLYSIS

A model of fibrinolysis was developed using multicomponent convection- diffusion equations with homogeneous reaction and heterogeneous adsorp tion and reaction. Fibrin is the dissolving stationary phase and plasm inogen, tissue plasminogen activator (tPA), urokinase (uPA), and plasm in are the soluble mobile species. The model is based on an accurate m olecular description of the fibrin fiber and protofibril structure and contains no adjustable parameters and one phenomenological parameter estimated from experiment. The model can predict lysis fronts moving a cross fibrin clots (fine or coarse fibers) of various densities under different administration regimes using uPA and tPA. We predict that pr essure-driven permeation is the major mode of transport that allows fo r kinetically significant thrombolysis during clinical situations. Wit hout permeation, clot lysis would be severely diffusion limited and wo uld require hundreds of minutes. Adsorption of tPA to fibrin under con ditions of permeation was a nonequilibrium process that tended to fron t load clots with tPA. Protein engineering efforts to design optimal t hrombolytics will likely be affected by the permeation processes that occur during thrombolysis.