title: A hybrid-system model of the coagulation cascade: simulation, sensitivity, and validation.
abstract: The process of human blood clotting involves a complex interaction of continuous-time/continuous-state processes and discrete-event/discrete-state phenomena, where the former comprise the various chemical rate equations and the latter comprise both threshold-limited behaviors and binary states (presence/absence of a chemical). Whereas previous blood-clotting models used only continuous dynamics and perforce addressed only portions of the coagulation cascade, we capture both continuous and discrete aspects by modeling it as a hybrid dynamical system. The model was implemented as a hybrid Petri net, a graphical modeling language that extends ordinary Petri nets to cover continuous quantities and continuous-time flows. The primary focus is simulation: (1) fidelity to the clinical data in terms of clotting-factor concentrations and elapsed time; (2) reproduction of known clotting pathologies; and (3) fine-grained predictions which may be used to refine clinical understanding of blood clotting. Next we examine sensitivity to rate-constant perturbation. Finally, we propose a method for titrating between reliance on the model and on prior clinical knowledge. For simplicity, we confine these last two analyses to a critical purely-continuous subsystem of the model.
authors.affiliation: Department of Electrical Engineering and Computer Science, University of California, Berkeley, USA , International Computer Science Institute, Berkeley, CA 94720, USA.
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Makin
authors.forename: Srini
authors.initials: S
authors.lastname: Narayanan
mesh_terms: D020016:Activated Protein C Resistance / Q000097:blood; D000465:Algorithms; D001777:Blood Coagulation / Q000502:physiology*; D001779:Blood Coagulation Factors / Q000378:metabolism; D019295:Computational Biology; D003198:Computer Simulation; D005337:Fibrin / Q000378:metabolism; D006467:Hemophilia A / Q000097:blood; D006801:Humans; D007700:Kinetics; D008954:Models, Biological; D015233:Models, Statistical; D011485:Protein Binding; D011517:Prothrombin Time; D049490:Systems Biology; D013917:Thrombin / Q000378:metabolism
chemical_list: D001779:Blood Coagulation Factors; D005337:Fibrin; D013917:Thrombin