(416e) Factor XI Is a Potential Therapeutic Target for Thrombosis That Maintains Hemostasis

The systems biology approach, together with computational, experimental and observational inquiry, is highly relevant to drug discovery and the optimization of medical treatments. In this study, we test our working hypothesis that fXI related mechanisms are fragile in the process of blood coagulation and could be a potential therapeutic target for thrombosis treatment. A mathematical model of the blood coagulation cascade including fXI activities was built and validated against 12 published data sets generated from two cell-based models. The simulation results show that the addition of intrinsic pathway protease fXI to the TF initiated coagulation resulted in the formation of extra amount of thrombin and thrombin was reciprocally generated in a fXI-dependent way. To gauge the robustness and fragility of each interaction in the cascade, overall state sensitivity coefficients were calculated for each of the 215 model parameters over a family of random parameter sets. Analysis of the sensitivity results for the combined case disclose that fXI auto-activations are additional fragile mechanisms to fX/FXa and thrombin related interactions. Theoretical considerations and experimental data suggest that fXI/FXIa could be excellent candidates as clinical targets in treatment of thrombotic diseases. Inhibition of fXI/FXIa could potentially reduce the risk of occlusive thrombi formation without sacrificing hemostasis as deficiency of fXI results in bleeding manifestations only after trauma or surgery. When taken together, these preliminary results support our hypothesis that fXI related mechanisms are fragile in the process of blood coagulation and could be a potential therapeutic target for thrombosis treatment.