Mechanisms by which thrombolytic therapy results in nonuniform lysis and residual thrombus after reperfusion

Abstract

A transport-reaction model describing penetration of plasmin by diffusion and permeation into a dissolving fibrin gel was solved numerically to explore mechanisms that lead to the formation and growth of dissolution fingers through blood clots during thrombolytic therapy. Under conditions of fluid permeation driven by arterial pressures, small random 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 experiments, video microscopy revealed that the shape of the proximal face of a fibrin gel, when deformed by pressure-driven permeation, led to lytic breakthrough in the center of the clot, consistent with model predictions of increased velocities in this region leading to cannulation. Computer simulation of lysis of fibrin retracted by platelets (where more permeable regions are expected in the middle of the clot due to retraction) 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 small. In conjunction with kinetic models of systemic pharmacodynamics and plasminogen activation biochemistry, a two-dimensional transport-reaction model can facilitate the prediction of the time and causes of clot cannulation, poor reperfusion, and embolism during thrombolysis.

Accelerating thrombolysis with chitosan-coated plasminogen activators encapsulated in poly-(lactide-co-glycolide) (PLGA) nanoparticles

“…Several studies have demonstrated that the clot front comprises fibrin polymers and other plasma proteins to which plasminogen and free PA readily absorb, confining the lysis of the leading edge of blood-thrombus boundary, resulting in frontal-edge clot lysis or channeling [12][13][14]26]. PA-encapsulated liposomes or microparticles significantly reduce the adsorption of particles in the front of clots that associated with pressure-driven permeation, promoting the penetration of the particles into clots, resulting in intra-clot thrombolysis, and therefore accelerating thrombolysis [12,13].…”

The t‐PA‐encapsulated PLGA nanoparticles shelled with CS or CS‐GRGD alter both permeation through and dissolving patterns of blood clots compared with t‐PA solution: An in vitro thrombolysis study

“…Because the pressure drop is negligible in this tube model, the diffusion‐like pattern of plasma permeation through the clots lysed with t‐PA solution (e.g., Fig. 5) would be likely to due to channeling lysis 10, 11, 19. Notably, because the zeta potential of fibrinogen solution is −38.5 mV at pH of 7.4, the zeta potentials for fibrins in blood clots would assumedly remain negative.…”

“…5), suggest that clot lysis phenomena and mechanisms differ. Without mediators such as pressure or convective transport, earlier investigators have demonstrated that the clot front comprises fibrin polymers and other plasma proteins to which plasminogen and free PA readily absorb, confining the lysis of the leading edge of blood‐thrombus boundary and resulting in frontal‐edge or channeling clot lysis 10–12, 19. Because the pressure drop is negligible in this tube model, the diffusion‐like pattern of plasma permeation through the clots lysed with t‐PA solution (e.g., Fig.…”

An experimental and theoretical study on the dissolution of mural fibrin clots by tissue‐type plasminogen activator

“…Diamond et al (Anand et al, 1995;Diamond and Anand, 1993) used a porous transport with heterogeneous chemistry modeling framework to describe tPAmediated lysis. The same framework, which included drug kinetics and transport via both diusion and permeation, was applied to plasmin-mediated lysis of twodimensional clots and the eect of nonuniform permeability on the genesis of residual thrombus was explored (Anand et al, 1997). In the current study the goal was to develop an experimental model to quantify the tPAmediated lysis pattern of mural ®brin clots under low arterial, arterial, and higher¯ow conditions and a mathematical model to account for the processes that regulate mural thrombolysis.…”