A hybrid-system model of the coagulation cascade: simulation, sensitivity, and validation

J Bioinform Comput Biol. 2013 Oct;11(5):1342004. doi: 10.1142/S0219720013420043. Epub 2013 Sep 5.

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.

Publication types

  • Validation Study

MeSH terms

  • Activated Protein C Resistance / blood
  • Algorithms
  • Blood Coagulation / physiology*
  • Blood Coagulation Factors / metabolism
  • Computational Biology
  • Computer Simulation
  • Fibrin / metabolism
  • Hemophilia A / blood
  • Humans
  • Kinetics
  • Models, Biological*
  • Models, Statistical
  • Protein Binding
  • Prothrombin Time
  • Systems Biology
  • Thrombin / metabolism

Substances

  • Blood Coagulation Factors
  • Fibrin
  • Thrombin

Supplementary concepts

  • Thrombophilia due to Activated Protein C Resistance