title: Multistability in an age-structured model of hematopoiesis: Cyclical neutropenia.
abstract: Cyclical neutropenia (CN) is a rare hematopoietic disorder in which the patient's neutrophil level drops to extremely low levels for a few days approximately every three weeks. CN is effectively treated with granulocyte colony stimulating factor (G-CSF), which is known to interfere with apoptosis in neutrophil precursors and to consequently increase the circulating neutrophil level. However, G-CSF treatment usually fails to eliminate the oscillation. In this study, we establish an age-structured model of hematopoiesis, which reduces to a set of four delay differential equations with specific forms of initial functions. We numerically investigate the possible stable solutions of the model equations with respect to changes in the parameters as well as the initial conditions. The results show that the hematopoietic system possesses multistability for parameters typical of the normal healthy state. From our numerical results, decreasing the proliferation rate of neutrophil precursors or increasing the stem cell death rate are two possible mechanisms to induce cyclical neutropenia, and the periods of the resulting oscillations are independent of the changing parameters. We also discuss the dependence of the model solution on the initial condition at normal parameter values corresponding to a healthy state. Using insight from our results we design a hybrid treatment method that is able to abolish the oscillations in CN.
authors.affiliation: Zhou Pei-Yuan Center for Applied Mathematics, Tsinghua University, Beijing, China. jzlei@mail.tsinghua.edu.cn
authors.forename: Jinzhi
authors.initials: J
authors.lastname: Lei
authors.forename: Michael C
authors.initials: MC
authors.lastname: Mackey
mesh_terms: D000465:Algorithms; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001772:Blood Cell Count; D001792:Blood Platelets / Q000473:pathology; D001803:Blood Transfusion; D002452:Cell Count; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D003198:Computer Simulation; D004912:Erythrocytes / Q000473:pathology; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology / Q000627:therapeutic use; D006410:Hematopoiesis / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007700:Kinetics; D007962:Leukocytes / Q000473:pathology; D008954:Models, Biological; D009503:Neutropenia / Q000097:blood / Q000188:drug therapy / Q000209:etiology / Q000628:therapy; D009504:Neutrophils / Q000473:pathology; D013234:Stem Cells / Q000187:drug effects / Q000473:pathology; D013997:Time Factors
chemical_list: D016179:Granulocyte Colony-Stimulating Factor