Abstract 612: Biochemical And Structural Regulation Of The Enzymatic Degradation Of Blood Clots

Blood clots perform a critical biological function in cessation of bleeding following injury. However, their function is transient and after performing their physiological function they must be resolved via fibrinolysis. Fibrinolysis is the enzymatic cleavage of the blood clot component fibrin(ogen). Excessive, early fibrinolysis can lead to bleeding whereas impaired fibrinolysis can result in heart attacks and strokes (thrombosis). The balance of resolution is a critical step in preventing life threatening complications, but the influence of changes in the fibrin structure on the biochemical regulation of fibrinolysis is poorly understood. We used turbidimetric experiments to assess the biochemical regulation of fibrinolysis and microscopy studies to characterize the microstructure of human blood plasma with varying network structure and its effect on fibrinolysis. Experiments are combined with a 3D stochastic multiscale computational model to probe the individual influence of changes in network density, pore size, and fiber diameter. Experimental studies show that increasing fibrinogen concentration leads to changes in fibrin density, pore size, and fiber diameter and ultimately results in impaired fibrinolysis. Analysis of simulations and experiments indicate that the pore size of the fibrin network makes the most significant contribution to the rate of fibrinolysis. We show that this effect is strongly influenced by the ratio of protein:enzyme when compared to absolute enzyme concentration. Our findings suggest that fibrin structure, which is altered in pathological conditions, is an important factor for the development of enzymatic treatments with increased efficacy in treating bleeding and/or thrombosis.