A biomathematical model of human erythropoiesis and iron metabolism

Sibylle Schirm,Markus Scholz

doi:10.1038/s41598-020-65313-5

Abstract

Anaemia therapy or perisurgical support of erythropoiesis often require both, EPO and iron medication. However, excessive iron medication can result in iron overload and it is challenging to control haemoglobin levels in a desired range. To support this task, we develop a biomathematical model to simulate EPO- and iron medication in humans. We combine our previously established model of human erythropoiesis including comprehensive pharmacokinetic models of EPO applications with a newly developed model of iron metabolism including iron supplementation. Equations were derived by translating known biological mechanisms into ordinary differential equations. Qualitative model behaviour is studied in detail considering a variety of interventions such as bleeding, iron malnutrition and medication. The model can explain time courses of erythrocytes, reticulocytes, haemoglobin, haematocrit, red blood cells, EPO, serum iron, ferritin, transferrin saturation, and transferrin under a variety of scenarios including EPO and iron application into healthy volunteers or chemotherapy patients. Unknown model parameters were determined by fitting the predictions of the model to time series data from literature. We demonstrate how the model can be used to make predictions of untested therapy options such as cytotoxic chemotherapy supported by iron and EPO. Following our ultimate goal of establishing a model of anaemia treatment in chronic kidney disease, we aim at translating our model to this pathological condition in the near future.

Highlights

Anaemia therapy or perisurgical support of erythropoiesis often require both, EPO and iron medication
To optimize treatment schedules of anaemia, we developed a biomathematical model of human erythropoiesis[1,2] in the past
Our iron model consists on ordinary differential equations of the following biological quantities: storage iron, plasma transferrin, non-transferrin bound iron, iron stored in cells of the red blood cell lineage and iron in enterocytes

Summary

Introduction

Anaemia therapy or perisurgical support of erythropoiesis often require both, EPO and iron medication. Excessive iron medication can result in iron overload and it is challenging to control haemoglobin levels in a desired range To support this task, we develop a biomathematical model to simulate EPO- and iron medication in humans. Anaemia treatment options result in a complex dynamic behaviour of iron metabolism, bone marrow erythropoiesis, cells in circulation, haemoglobinization of red blood cells and cytokine levels that is difficult to predict. We here aim at developing a biomathematical model of iron metabolism and combine it with our erythropoiesis model For this purpose, we consider key biological features of iron homoeostasis and translate them into ordinary differential equations. The model is studied under different conditions such as single and combined EPO and iron applications, iron malnutrition, blood donation and cytotoxic chemotherapy. Model predictions are quantitatively compared to available time series data of laboratory parameters measured under these conditions including red blood cell parameters, plasma iron parameters and erythropoietin levels

Methods

Results

Conclusion