Transport Phenomena and Clot Dissolving Therapy: An Experimental Investigation of Diffusion-Controlled and Permeation-Enhanced Fibrinolysis

Abstract

We have investigated the effects of diffusive and convective transport on fibrinolysis. Using a constant pressure drop (ΔP/L) from 0 to 3.7 mmHg/cm-clot to drive fluid permeation, various regimes of lytic agents were delivered into fine and coarse fibrin gels (3 mg/ml) and whole blood clots. Using plasmin (1 μM) delivered into pure fibrin or urokinase (1 μM) delivered into glu-plasminogen (2.2 μM)-laden fibrin, the velocity at which a lysis front moved across fibrin was greatly enhanced by increasing ΔP/L. Lysis of fine and coarse fibrin clots by 1 μM plasmin at ΔP/L of 3.67 and 1.835 mmHg/cm-clot, respectively, led to a 12-fold and 16-fold enhancement of the lysis front velocity compared to lysis without pressure-driven permeation. For uPA-me-diated lysis of coarse fibrin at ΔP/L = 3.67 mmHg/cm-clot, the velocity of the lysis front was 25-fold faster than the lysis front velocity measured in the absence of permeation. Similar permeation-enhanced phenomenon was seen for the lysis of whole blood clots. Without permeation, the placement of a lytic agent adjacent to a clot boundary led to a reaction front that moved at a velocity dependent on the concentration of plasmin or uPA used. Overall, these studies suggest that transport phenomena within the clot can play a major role in determining the time needed for reperfusion during fibrinolysis.