MECHANISMS BY WHICH THROMBOLYTIC THERAPY RESULTS IN NONUNIFORM LYSIS AND RESIDUAL THROMBUS AFTER REPERFUSION

A transport-reaction model describing penetration of plasmin by diffus ion and permeation into a dissolving fibrin gel was solved numerically to explore mechanisms that lead to the formation and growth of dissol ution fingers through blood clots during thrombolytic therapy. Under c onditions of fluid permeation driven by arterial pressures, small rand om spatial variations in the initial fibrin density within clots (+/-4 to 25% peak variations) were predicted by the simulation to result in dramatic dissolution fingers that grew in time. With in vitro experim ents, video microscopy revealed that the shape of the proximal face of a fibrin gel, when deformed by pressure-driven permeation, led to lyt ic breakthrough in the center of the clot, consistent with model predi ctions of increased velocities in this region leading to cannulation. Computer simulation of lysis of fibrin retracted by platelets (where m ore permeable regions are expected in the middle of the clot due to re traction) predicted cannulation of the clot during thrombolysis. This residual, annular thrombus was predicted to lyse more slowly, because radial pressure gradients to drive inner clot permeation were quite sm all. In conjunction with kinetic models of systemic pharmacodynamics a nd plasminogen activation biochemistry, a two-dimensional transport-re action model can facilitate the prediction of the time and causes of c lot cannulation, poor reperfusion, and embolism during thrombolysis.