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A Mathematical Model of the Bivalent Binding of Thrombin to Fibrin

Thursday, May 31, 2018 - 10:00am - 10:50am
Lind 305
Karin Leiderman (Colorado School of Mines)
Thrombin is an enzyme that plays many roles in the clotting process; it is associated with multiple positive and negative feedback loops and cleaves the soluble protein fibrinogen into fibrin, which polymerizes to form a stabilizing gel matrix in and around a growing blood clot. Another important role is binding to the fibrin matrix, but it is not yet understood whether this role has beneficial and/or pathological consequences; both have been hypothesized. Thrombin is sequestered by fibrin through two independent binding events, typically described as high- and low-affinity. It has recently been shown experimentally that thrombin incorporated into a preformed fibrin matrix stays bound for long periods of time and is resistant to removal by flow and chemical inhibitors and kinetic rates for two independent binding events do not support these data. In this work, we develop a mathematical model of bivalent binding interactions and simulate an experiment where dissociation of radiolabeled thrombin from an intact fibrin clot is monitored in time. We model the clot as a spherical fibrin mass and track the concentration of a mobile species of thrombin (unbound, and subject to transport by diffusion) and a bound species of thrombin, using partial differential equations. Our results show that the model with bivalent binding, but not without, is able to produce time courses that match well with experimental data. Our preliminary results suggest that bivalent binding of thrombin to fibrin aids in long-term residency of thrombin within an intact, fibrin clot. These studies as well as future studies that consider the allosteric nature of thrombin, could aid in developing strategies for removal of thrombin from a clot and regulation of its function.