Novel Strategies to Improve Blood Transfusion Practice

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Project Summary Optimizing blood cell support for specific patient groups and clinical settings is an emerging priority in transfusion medicine. Patients undergoing hematopoietic cell transplantation (HCT) require significant transfusion support (including red blood cells, platelets, and granulocytes) because of the transplant-related bone marrow (BM) dysfunction state. However, challenges and shortcomings still exist for modern transfusion practices in the peri-transplant setting, limiting their clinical efficacy and cost effectiveness. Mechanisms underlying the effect and effectiveness of blood transfusion in the peri-transplant setting are important, understudied, and poorly understood, representing a critical gap in our biomedical knowledge. A coordinated, multi-disciplinary P01 program project on such mechanisms is warranted, considering the medical and public health significance of blood transfusion and cellular therapies, and will be innovative, constituting a distinct area of investigation in the current NIH portfolio. The long-term thematic objective of this research program is to provide more effective transfusion support for HCT recipients by better understanding the molecular and cellular mechanisms underlying the effect and effectiveness of blood transfusion in the peri-transplant setting. Drs. John Manis, Leslie Silberstein, and Shin-Young Park (Project 1) will elucidate the dynamic relationship between BM niche and HSPC in sickle cell disease (SCD) patients, specifically hypothesizing that insight into how BM vascular and perivascular niches are distorted in SCD and restored by RBC transfusion shall lead to opportunities for targeted intervention in HSC transplantation in SCD patients. Drs. Hongbo Luo and Li Chai (Project 2) will study cell death signaling in granulocyte transfusion (GTX), specifically hypothesizing that GTX can be improved by simultaneously targeting multiple death pathways. This study will assist us to design novel therapeutic strategies for improving the efficacy of GTX and combating neutropenia-related infections in the peri-transplant period. Drs Jose Cancelas and Yi Zheng (Project 3) will focus on platelet transfusion which is commonly used to prevent or treat bleeding in thrombocytopenic patients, including HCT recipients. The goal is to elucidate the role of RHOA/RAC1 signaling in cold storage-induced clearance of platelets and to design novel clinical procedures (e.g. pharmacological inhibition of RHOA) for the long-term storage and application of platelets in transfusion medicine. The 3 research projects will be bolstered by a unique Cytometry and Imaging Core, led by Dr. Shin-Young Park, to maximize efficiency, economy, and productivity. An Administrative Core will coordinate the activities of these projects and cores to form a cohesive whole. The overall scientific synergy of ideas, reagents and expertise afforded by the multiple collaborations shall enable this Program Project to advance our understanding of the biology of blood transfusion, and to apply findings made toward enhancing the effectiveness of modern-day blood transfusion therapy for specific patient groups in the peri-transplant setting.