A mathematical model of plasmin-mediated fibrinolysis of single fibrin fibers

by Roukayatou R. Ouedraogo, Hannah K. Sowers, Spencer R. Lynch, Nathan E. Hudson, Brittany E. Bannish

Fibrinolysis, the plasmin-mediated degradation of the fibrin mesh that stabilizes blood clots, is an important physiological process, and understanding mechanisms underlying lysis is critical for improved stroke treatment. Experimentalists are now able to study lysis on the scale of single fibrin fibers, but mathematical models of lysis continue to focus mostly on fibrin network degradation. Experiments have shown that while some degradation occurs along the length of a fiber, ultimately the fiber is cleaved at a single location. We built a 2-dimensional stochastic model of a fibrin fiber cross-section that uses the Gillespie algorithm to study single fiber lysis initiated by plasmin. We simulated the model over a range of parameter values to learn about patterns and rates of single fiber lysis in various physiological conditions. We also used epifluorescent microscopy to measure the cleavage times of fibrin fibers with different apparent diameters. By comparing our model results to the laboratory experiments, we were able to: 1) suggest value ranges for unknown rate constants(namely that the degradation rate of fibrin by plasmin should be ≤ 10 s⁻¹ and that if plasmin crawls, the rate of crawling should be between 10 s⁻¹ and 60 s⁻¹); 2) estimate the fraction of fibrin within a fiber cross-section that must be degraded for the fiber to cleave in two; and 3) propose that that fraction is higher in thinner fibers and lower in thicker fibers. Collectively, this information provides more details about how fibrin fibers degrade, which can be leveraged in the future for a better understanding of why fibrinolysis is impaired in certain disease states, and could inform intervention strategies.