Platelet-driven routes to chaos in a model of hepatitis

Hepatitis is a general term used to describe inflammation in the liver, the regulation of which involves a complex array of interactions between liver cells, inflammatory mediators and cells of the immune system (macrophages and neutrophils, in particular). There is increasing evidence that platelets (small blood cells that are primarily responsible for clotting) affect numerous mechanisms that underlie hepatitis, including the rates of cell migration, liver damage and mediator production, giving rise to a complex and diverse range of inflammatory outcomes. In particular, platelet activation has the scope to promote both healthy and chronic outcomes in a highly unpredictable and potentially state-dependent manner that is not currently well-understood. In this paper, we take an existing model of the inflammatory dynamics associated with hepatitis, and introduce platelets and their effects. We interrogate this new model via numerical simulations in Matlab and bifurcation analysis in XPPAUT, and find that amplification of certain key interactions by platelets can stimulate chaotic dynamics that correspond to complex chronic outcomes. We initially introduce a single parameter to represent the scale of the platelet stimulus and, through bifurcation analysis, illustrate that as this parameter is gradually increased we see the emergence of a period-doubling cascade that results in chaotic dynamics. We then explore individual mechanisms in more detail and illustrate that, while neutrophils can promote chaos in some settings, routes to chaos are primarily driven by macrophage-related platelet stimuli. Finally, we briefly comment upon the implications of our observations in terms of the ongoing hunt for new therapeutic interventions in hepatitis, as well as other inflammation-related medical conditions.