Fibrin Density and Tension Regulates Fibrinolytic Susceptibility

Abstract

Fibrin fibers provide structural and mechanical integrity to blood clots until their dissolution during fibrinolysis. This work seeks to deconvolve the respective fibrinolytic influences of enzyme kinetics and enzyme perfusion rates into clots from clot structure and fiber properties. Here we consider the lysis of fibers within small, 2-D networks, which have polymerized between ridges. We tracked changes in fiber morphology within a 24-hour period during lysis. We find that fibers follow several possible degradation pathways during the lytic process including transverse cleavage, fiber bundling, structural elongation due to network rearrangements, tension loss, and network collapse. Transverse cleavage of individual fibers results in network rearrangements due to the redistribution of the tension in the yet-to-be-cleaved fibers. Network rearrangements and remnants of cleaved fibers often lead to fibers bundling into thicker fibers which are more resistant to fibrinolysis. When the final strand holding the network in place is transversely cleaved, the remaining fibers recoil and collapse onto the ridge. These effects highlight the inherent tension in fibrin networks and its role in governing fibrinolytic degradation. This is further emphasized by the observation that lysis kinetics depend strongly on fiber density. Fibers in high-density areas, and presumably under more tension, lyse at earlier time points and more rapidly than fibers in low-density areas. Fibrinolysis initiated with low (0.1 U/mL) concentrations of plasmin occurs more slowly than with high (1.0 U/mL) concentrations of plasmin, and structural rearrangement due to tension redistribution is more prominent. These results identify the different pathways whereby a fibrin network is cleared out of an area by the lytic enzyme plasmin. Inherent fiber tension plays an important role in regulating this process.