The disease of human thrombocytosis is a type of myeloproliferative disorder (MPD) characterized by a complex alteration of genetic and epigenetic factors. Consequently, the pathological cellular environment is permeated by transcriptomic deregulation, interferomic aberrations, protein level irregularity and disrupted cellular pathways. In this dissertation, we present a novel study of the human thrombocytosis disease through a multi-layered genetic, microRNA and proteomic platelet modeling and analysis in a systems biology scheme. This includes (1) the extraction of distinctive messenger RNA and microRNA expression profiles in human platelets for two subtypes of thrombocytosis patients versus the normal control group, (2) the derivation of a classification model that differentiates between subtypes of thrombocytosis as well as between general diseased and normal subjects using classical and modern discriminant analysis methods, (3) the profiling of platelet microRNAs in thrombocytosis and controls, (4) a microRNA-mRNA correlational analysis to identify a joint genetic and microRNA biological regulatory network in thrombocytotic platelets, and (5) The final validation of identified joint genetic and microRNA platelet regulatory pathways using preliminary proteomics data. This system biological study of the thrombocytosis sets stage for further exploration of the disease mechanism and a more comprehensive recognition of the underlying etiologies. In summary, this dissertation features the discoveries of cellular regulatory networks underlying human thrombocytosis based on the analysis of the joint platelet genetic, microRNA and proteomic data under the system biology scheme. Further expansion is expected to advance our understanding of the platelet maturation pathway under the pathological environment of human thrombocytosis.