Using Stochastic Activity Network Simulations to Better Understand Disorders of Hemostasis

Stochastic Activity Networks (SAN) may have advantages over traditional modeling approaches for understanding the complex processes. We are using this tool to better understand the interacting biochemical events involved in the coagulation and fibrinolysis processes that cause Disseminated Intravascular Coagulation! (DIC). We use the UltraSAN2 software environment to simulate these processes. Within the SAN we can inactivate or alter certain proteins to mimic genetic defects and disease, and then compare the results to clinical observations for validation. We are developing this simulation project through 7 steps: 1) trypsinogen activation and trypsin inactivation, 2) normal blood coagulation, 3) disorders of blood coagulation, 4) normal fibrinolysis, 5) disorders of fibrinolysis, 6) normal hemostasis, and 7) DIC. Results of the successful simulations of steps 1?3 by Mounts and Liebman [1]3 provides a promising foundation. A combination of the SAN that separately represents of steps 2 and 4 is expected to adequately represent normal hemostasis. We will systematically inactivate sets of proteins in the final, linked SAN to generate results that are consistent with the clinical observations of DIC. The final, linked SAN will be used to assist in the identification of new therapeutic targets, suggest strategies for development of new diagnostics, and provide a network hypothesis for connecting to emerging genetic information.

Key personnel: Keith Erickson.

Collaborators: Michael Liebman and Adam P. Arkin.

Mounts, W.M. and Liebman, M.N. Qualitative Modeling of Normal Blood Coagulation and its Pathological States Using Stochastic Activity Networks. Intl J of Biological Macromolecules 20:265-281 (1997).

 
 

The premise of the agent paradigm, its related theory and methodologies together with advances in multilevel modeling of complex systems of interactions opened new frontiers for advancing the physical, natural, social, military, and information sciences and engineering...