A Computational Analysis of the Synergistic Effect of Coagulation Inhibitors on the Generation of Thrombin

The coagulation system (CS) is a complex, inter-connected biological system with major physiological and pathological roles. The CS may be viewed as a complex adaptive system, in which individual components are linked through multiple feedback and feedforward loops. The non-linear relationships between the numerous coagulation factors and the interplay among the elements of the CS render the study of this biology at a molecular and cellular level nearly impossible. We present an Agent Based Modeling and Simulation (ABMS) approach for simulating these complex interactions. Our ABMS approach utilizes a subset of 52 rules to define the interactions among 33 enzymes and factors of the CS. These rules simulate the interaction of each “agent”, such as substrates, enzymes, and cofactors, on a two-dimensional grid of ~12,000 cells and ~300,000 agents. Our ABMS method successfully reproduces the initiation, propagation, and termination of thrombin formation due to the activation of the extrinsic pathway. Furthermore, the ABMS is able to demonstrate the emergence of a threshold effect for thrombin generation as a result of the synergistic effect of combining anticoagulant systems.