Normal and pathological dynamics of platelets in humans

Abstract: We develop a comprehensive mathematical model of platelet, megakaryocyte, and thrombopoietin dynamics in humans. We show that there is a single stationary solution that can undergo a Hopf bifurcation, and use this information to investigate both normal and pathological platelet production, specifically cyclic thrombocytopenia. Carefully estimating model parameters from laboratory and clinical data, we then argue that a subset of parameters are involved in the genesis of cyclic thrombocytopenia based on clinical information. We provide excellent model fits to the existing data for both platelet counts and thrombopoietin levels by changing six parameters that have physiological correlates. Our results indicate that the primary change in cyclic thrombocytopenia is a major interference with or destruction of the thrombopoietin receptor with secondary changes in other processes, including immune-mediated destruction of platelets and megakaryocyte deficiency and failure in platelet production. This study makes a major contribution to the understanding of the origin of cyclic thrombopoietin as well as significantly extending the modeling of thrombopoiesis.

Review text

Recent laboratory and clinical data suggest to develop a more physiologically realistic model for the regulation of mammalian platelet production concentrating on humans, which takes into account both megararyocytes and platelets and the effects on trombopoietin (TPO). The presented mathematical model describes the dynamics of the megararyocytes as an age-structured model, which is divided in two stages: mitosis, and endomitosis. Platelet and trombopoietin dynamics deal with endomitosis. The model of mitosis simply gives an effective proliferation rate that includes both cellular birth and death. The choice of the Hill function in the model reflects the fact that TPO has a stimulatory, yet saturating, effect on the process. The platelet population dynamics are governed by the balance between platelet production and destruction. The authors model the TPO dynamics as the balance between production and destruction of platelets. Here the same Hill function is used, because it is assumed that the endogenous removal rate is proportional to the saturable Hill function. Thus, the model of thrombopoiesis consists of two integro-differential equations with constant delays and an integral equation. The two differential equations model the dynamics of platelets and TPO, while the integral equation models the volume of megakaryocytes in the bone marrow. In contrast to previous models the given model incorporates the regulation mechanisms and the dynamics of megararyocytes and trombopoietin. The authors extend linear techniques to this model and develop numerical methods to perform a stability analysis. The mathematical analysis of the nonlinear model indicates that there remain details to be understood, which could be explored further and possibly give insight into the transitions from the stable normal state to the diseased state, specifically in patients with cyclic thrombocytopenia.

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