A local and global sensitivity analysis of a mathematical model of coagulation and platelet deposition under flow

Abstract

The hemostatic response involves blood coagulation and platelet aggregation to stop blood loss from an injured blood vessel. The complexity of these processes make it difficult to intuit the overall hemostatic response without quantitative methods. Mathematical models aim to address this challenge but are often accompanied by numerous parameters choices and thus need to be analyzed for sensitivity to such choices. Here we use local and global sensitivity analyses to study a model of coagulation and platelet deposition under flow. To relate with clinical assays, we measured the sensitivity of three specific thrombin metrics: lag time, maximum relative rate of generation, and final concentration after 20 minutes. In addition, we varied parameters of three different classes: plasma protein levels, kinetic rate constants, and platelet characteristics. In terms of an overall ranking of the model’s sensitivities, we found that the local and global methods provided similar information. Our local analysis, in agreement with previous findings, shows that varying parameters within 50-150% of baseline values, in a one-at-a-time (OAT) fashion, always leads to significant thrombin generation in 20 minutes. Our global analysis gave a different and novel result highlighting groups of parameters, still varying within the normal 50-150%, that produced little or no thrombin in 20 minutes. Variations in either plasma levels or platelet characteristics, using either OAT or simultaneous variations, always led to strong thrombin production and overall, relatively low output variance. Simultaneous variation in kinetics rate constants or in a subset of all three parameter classes led to the highest overall output variance, incorporating instances with little to no thrombin production. The global analysis revealed multiple parameter interactions in the lag time and final concentration leading to relatively high variance; high variance was also observed in the thrombin generation rate, but parameters attributed to that variance acted independently and additively.