Improving safety and efficacy of platelet transfusion through systems biology

Project Summary Platelet transfusion is critical for severely bleeding patients and nearlymillion units are transfused in the United States and Europe annuallyIn the United Statesplatelets are typically stored fordays resulting in a waste ofof their supplyShort storage duration is a consequence of bacterial contamination and platelet quality considerationsThough many methods have been developed for bacterial testing and pathogen inactivationfewer have been developed for improving quality of stored plateletsPlatelet additive solutions have the possibility to increase storage quality and durationreduce plasma related allergic reactionsimpact the efficacy of pathogen reduction techniquesand save plasma which can then be used as an additional transfusion productWhile the benefits are well knownthere 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 storageThere 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 challengeIn Phase I of this programwe developed the firstrobust 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 contextUsing timecourse globalquantitative metabolite profilingwe determined that PLTs undergo a non linear decay process and computationally identified key metabolic enzymes and cellular process that drive this decayBased on the computational resultswe have devised two novel additive solution strategies to mitigate the decay process and improve the length of PLT unitsIn this Phase II proposalwe will validate the computationally determined additive solutions for efficacy in alleviating the non linear decay process throughmetabolomics experimentsandnon metabolic PLT physiology experiments including cell activation and hemostatic effectivenessA successful additive solution will be progressed to media refinement and preclinical testing