Abstract
BACKGROUND: Many diseased conditions alter the fibrinogen and clotting activator concentrations, resulting in a unique network structure that may be resistant or susceptible to lysis. While much is known about the relationship between structure and lysis, previous studies overlooked confounding factors in the fibrin network structure that must be considered to develop targeted therapeutics. OBJECTIVES: We aimed to determine how fiber diameter, network pore size, and protofibril packing density work together and individually to impact lysis. METHODS: We used turbidimetry to kinetically monitor clot formation, protofibril packing, and lysis of clots formed with the 2 activators. We characterized the unique clot structures during lysis using confocal and scanning electron microscopy. With our stochastic multiscale mathematical model of fibrinolysis, we varied the fibrin content per fiber to probe the role of protofibril packing density on a clot's susceptibility to degradation. RESULTS: Plasma clots activated with tissue factor had denser fibrin networks with looser protofibril packing that were initially degraded faster than clots activated with thrombin, which had loose fibrin networks and dense protofibril packing. Modeling revealed that the fibrin content per fiber dictates individual fiber lysis time and the time it takes tissue-type plasminogen activator to travel between fibers. CONCLUSION: The present work highlights the crucial role that protofibril packing density plays in fibrinolysis. Our results suggest a need to consider the effect a disease has on protofibril packing density to inform about clot resistance and the development for more personalized lytic agents.