Improving safety and efficacy of platelet transfusion through systems biology

点击翻译按钮获取中文摘要

Project Summary Platelet transfusion is critical for severely bleeding patients and nearly 6 million units are transfused in the United States and Europe annually. In the United States, platelets are typically stored for 5 days resulting in a waste of 20% of their supply. Short storage duration is a consequence of bacterial contamination and platelet quality considerations. Though many methods have been developed for bacterial testing and pathogen inactivation, fewer have been developed for improving quality of stored platelets. Platelet additive solutions have the possibility to increase storage quality and duration, reduce plasma-related allergic reactions, impact the efficacy of pathogen reduction techniques, and save plasma which can then be used as an additional transfusion product. While the benefits are well known, there has been little progress in developing new platelet additive solutions for increasing quality and safety of platelet transfusion because there is a lack of broad understanding of biochemical and signaling changes during storage. There has been interest to utilize high-throughput metabolite profiling for global understanding of platelet metabolic decline but data analysis of complex datasets has been a daunting challenge. In Phase I of this program, we developed the first, robust computational platform involving statistical analysis and systems biology of metabolic and signaling networks to interpret and analyze PLT metabolomic and proteomic profiles in a complete network context. Using time- course global, quantitative metabolite profiling, we determined that PLTs undergo a non-linear decay process and computationally identified key metabolic enzymes and cellular process that drive this decay. Based on the computational results, we have devised two novel additive solution strategies to mitigate the decay process and improve the length of PLT units. In this Phase II proposal, we will validate the computationally determined additive solutions for efficacy in alleviating the non-linear decay process through 1) metabolomics experiments, and 2) non-metabolic PLT physiology experiments including cell activation and hemostatic effectiveness. A successful additive solution will be progressed to media refinement and preclinical testing.