Computationally Derived Points of Fragility of a Human Cascade Are Consistent with Current Therapeutic Strategies

Abstract

The role that mechanistic mathematical modeling and systems biology will play in molecular medicine and clinical development remains uncertain. In this study, mathematical modeling and sensitivity analysis were used to explore the working hypothesis that mechanistic models of human cascades, despite model uncertainty, can be computationally screened for points of fragility, and that these sensitive mechanisms could serve as therapeutic targets. We tested our working hypothesis by screening a model of the well-studied coagulation cascade, developed and validated from literature. The predicted sensitive mechanisms were then compared with the treatment literature. The model, composed of 92 proteins and 148 protein–protein interactions, was validated using 21 published datasets generated from two different quiescent in vitro coagulation models. Simulated platelet activation and thrombin generation profiles in the presence and absence of natural anticoagulants were consistent with measured values, with a mean correlation of 0.87 across all trials. Overall state sensitivity coefficients, which measure the robustness or fragility of a given mechanism, were calculated using a Monte Carlo strategy. In the absence of anticoagulants, fluid and surface phase factor X/activated factor X (fX/FXa) activity and thrombin-mediated platelet activation were found to be fragile, while fIX/FIXa and fVIII/FVIIIa activation and activity were robust. Both anti-fX/FXa and direct thrombin inhibitors are important classes of anticoagulants; for example, anti-fX/FXa inhibitors have FDA approval for the prevention of venous thromboembolism following surgical intervention and as an initial treatment for deep venous thrombosis and pulmonary embolism. Both in vitro and in vivo experimental evidence is reviewed supporting the prediction that fIX/FIXa activity is robust. When taken together, these results support our working hypothesis that computationally derived points of fragility of human relevant cascades could be used as a rational basis for target selection despite model uncertainty.

Author Summary

To date, mechanistic mathematical modeling, in general, has not played a significant role in the development of new therapies for cancer, cardiovascular diseases, or the treatment of acute events like thrombosis during surgery. One critical issue often cited for the lack of interest has been uncertainty; the conventional wisdom is that the data requirement to fully determine and validate large mechanistic models is just too high. We show, using tools from systems biology and sensitivity analysis, that it may be possible to extract qualitative information about the critical elements of human relevant cascades despite model uncertainty. Using a mechanistic model of the human coagulation cascade, we were able to identify the critical mechanisms controlling the formation of thrombin, a key protein active in the formation of blood clots. We were further able to support the hypothesis that the critical mechanisms identified by our analysis could serve as drug targets by comparing our findings with the thrombosis treatment literature and with current clinical trials. The results support the notion that mechanistic models could be used, despite model uncertainty, to pinpoint key mechanisms in complex networks, and that these mechanisms could potentially be therapeutically exploited.