An Analysis of the Robustness and Fragility of the Coagulation System

The coagulation system (CS) is a complex, inter-connected biological system with major physiological and pathological roles. Adaptive mechanisms such as ubiquitous feedback and feedforward loops create non-linear relationships among its individual components and render the study of this biology at a molecular and cellular level nearly impossible. Computational modeling aims to overcome limitations of current analytical methods through in silico simulation of these complex interplays. We present herein an Agent Based Modeling and Simulation (ABMS) approach for simulating these complex interactions. Our ABMS approach utilizes a subset of 48 rules to define the interactions among 24 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 ~3,000 cells and ~500,000 agents. Our ABMS method demonstrates the robustness of the physiologic CS system over large ranges of tissue factor (TF) concentrations. The system also demonstrates fragility as complete coagulation occurs at sufficiently high concentrations of TF. Removal of individual coagulation inhibitors from the physiologic system results in system fragility at relatively lower TF concentrations. The complete removal of coagulation inhibitors leads to a system that is incapable of controlling coagulation at all TF concentrations. The synergistic effects of the inhibitory pathways create an intricate regulatory mechanism that allows sufficient clot formation while preventing system wide activation of the CS; a robust system emerges. Introduction