The National Heart, Lung, and Blood Institute (NHLBI) convened a Working Group (WG) of invited external experts including transfusion medicine, hematology, and immunology research scientists, blood service executives and blood bank directors, as well as end users of transfusion including intensivists and trauma experts. The meeting was held in conjunction with the annual NHLBI RFA 08-005 "Immunomodulatory, inflammatory and vasoregulatory properties of transfused red blood cell units as a function of preparation and storage" grantee's meeting at the Bethesda offices of the NHLBI on August 30 and 31, 2011. The purpose of this Working Group was to provide recommendations to the NHLBI that guide informed decisions on research objectives and priorities in the field of Transfusion Medicine with particular emphasis on the emerging questions related to the optimal storage of red blood cell products. The Working Group was responsive to NHLBI Strategic Plan Goals 2 and 3.
In 2010, NHLBI funded eight teams of investigators to conduct basic and translational research including animal models and/or basic human physiologic studies aimed at further characterizing the storage lesion and understanding the interaction between the storage lesion components and recipient/host cells such as endothelial and hematopoietic cells. In day 1 of the meeting, these investigators reported on the progress of these studies.
Four of the teams have proposed that transfusion damage from stored blood is a result of suboptimal tissue oxygenation engendered by a loss of proper control of blood flow. Drs. Gladwin and Kim-Shapiro provided evidence that the red cell storage lesion is driven by increased nitric oxide (NO) catabolism and loss of NO generating functionality mediated by cell free hemoglobin and red blood cell microparticles which increase over time during storage. The team of Drs. Patel, Barnum and Weinberg have proposed that stored RBC may fail to improve tissue oxygen availability due to alterations that impact microcirculatory perfusion following blood transfusion. They presented evidence that two mechanisms contribute to these age-related changes to stored blood: higher rates of NO-dioxygenation and nitrite oxidation by older RBC; as well as complement activation during RBC storage. Dr. Roback also presented evidence that stored RBCs can inhibit NO signaling. In agreement with Dr. Patel's research these effects were not removed by washing the cells prior to study. Drs. Stamler and Reynolds reported on their studies investigating the loss of S-nitrosylated hemoglobin during RBC storage with a subsequent impaired ability of banked RBCs to induce vasodilation and deliver oxygen to tissues.
Dr. Jy presented his work examining the development of RBC, leukocyte and platelet microparticles and the influence of product processes such as leukoreduction on their accumulation in the blood unit. Drs. Blumberg and Phipps described their studies examining the development of cell free hemoglobin and lipid mediators in the supernatant. Drs. Norris and Sparrow presented the status of their studies investigating the inflammatory and immunomodulatory effects of stored blood. Dr. Spitanik presented on studies performed with Dr. Hod that examine the changes in circulatory iron load following transfusion of stored RBCs with evidence that RBCs, and not free hemoglobin or microparticles in the unit, are responsible for these results.
The day concluded with status reports on several ongoing and proposed large randomized trials that test the hypothesis that transfusion of blood that has been stored for shorter periods may be more beneficial clinically than transfusions of RBCs that have been stored for longer periods.
Dr. Simone Glynn, Chief of the Transfusion Medicine and Cellular Therapeutics Branch, NHLBI, began the working group on day 2 of the meeting by summarizing the current state of translational and clinical research aimed at understanding the RBC storage lesion that was described in the presentations and discussion on the previous day. She charged the group to identify the major areas of research needed to optimize preparation and storage of RBC products considering the nature of the storage lesion elements identified so far and the potential detrimental impact on blood availability that would currently result with a sudden shift to use of fresher blood.
Working group presentations were organized to highlight the recent progress and to identify barriers to future advances in the implementation of three general strategies currently in pre-clinical and clinical testing (renitrosylation, washing prior to transfusion, and novel storage solutions and conditions). Each of the various strategies target different aspects of the stored RBC product that are thought to contribute to the RBC storage lesion. In addition, an assessment of shortened RBC shelf life on a large community blood program was presented to the group.
The working group agreed that the so-called "storage lesion" is most likely a result of changes in multiple parameters leading to the development of numerous intermediates in the blood bag over time. Based on the studies presented in the first day of the meeting, targeting any single parameter would likely have only a fractional improvement on the quality of the blood product. Thus, multiple strategies will be needed to improve the safety and efficacy of transfused red blood cell components.
The working group discussions also drew attention to the multiple gaps in knowledge in areas that will be fundamental for the successful development and assessment of these anticipated changes to red blood cell storage and transfusion practices. These gaps could be divided into the need to gain a better understanding of red blood cells and the effects of storage on these properties; gaining better insight into the benefits and adverse outcomes associated with the age of the transfused red blood cell units; and determining where the scientific and blood management communities can impact the field.
Consensus and Recommendations
The Working Group made a series of recommendations to NHLBI, which can be broadly categorized into:1) a need for methodologies, biomarkers, and animal models to measure the clinical benefits of RBC transfusions; 2) a need for research to optimize RBC products and develop new and improved preparations and solutions for RBC products, and 3) a need for a multidisciplinary approach to transfusion medicine research.
- The working group emphasized the limits of the current measures of the efficacy of RBC transfusion. The lack of robust methods to measure oxygen delivery and utilization as well as other surrogate markers to measure the clinical benefit of RBC transfusions has hampered clinical research. The working group recommended that NHLBI support development of new methods, animal models, and biomarkers to evaluate the benefits and adverse outcomes of RBC transfusion. Areas of need include:
- Develop new, robust methods for the measurement of oxygen delivery by transfused RBCs and its utilization by tissues.
- Develop better methods and surrogate markers for the efficacy of the transfusion including better measures of 24 hour post-transfusion RBC survival.
- Develop new and more clinically relevant animal models to interrogate the effects of stored RBC transfusions.
- Develop and validate new measurements of the clinical effectiveness of RBC transfusions in different settings.
- Encourage the conduct of metabolomic and proteomic studies on fresh and stored blood cells to provide baseline characteristics.
- Create a database linking collection, storage and other pre-transfusion processes with adverse transfusion events.
- The panel identified the need to support research to develop new and improved processes and solutions for RBC components. These research areas will need to be addressed through basic research, development of new technologies and clinical research to guide the practice of transfusion medicine and blood bank management. The transfusion medicine field currently relies on basic research studies that were performed 30-50 years ago and have not been adequately reassessed in light of current knowledge and technologies. Recommended research topics include:
- The impact of donor variability on the development of RBC 'storage lesion' associated changes.
- Study RBC energetics during 1-6 oC storage.
- Evaluate the contributions of current and novel blood bank processes and blood bag materials to the development and/or correction of the intermediates that constitute the RBC storage lesion.
- Develop and test strategies to identify and deliver the best blood product for each patient indication.
- Transfusion medicine is unique in that the field does not have direct access to the patient population that receives the intervention. The working group recognized the need to continue to improve communication and develop collaborative efforts with the clinical fields that constitute the major users of blood products including cardiac surgeons, and trauma specialists. Increased education of the medical community on the practice of RBC component transfusion is also needed.
Simone Glynn, MD, MPH
Chief, Transfusion Medicine and Cellular Therapies Branch
Division of Blood Diseases and Resources
Lisbeth Welniak, PhD
Transfusion Medicine and Cellular Therapies Branch
Division of Blood Diseases and Resources
Workshop Group Participants
- Stephen Wagner, PhD, American Red Cross, Chair
- James P. AuBuchon, MD, Puget Sound Blood Center
- Scott Barnum, PhD, University of Alabama at Birmingham
- Richard J Benjamin, MD, PhD, American Red Cross
- Elliot Bennett-Guerrero, MD, Duke University
- Neil Blumberg, MD, University of Rochester
- Michael Busch, MD, PhD, Blood Systems Research Institute
- Mitchell Jay Cohen MD, University of California San Francisco
- Dana Devine, PhD, Canadian Blood Services
- Allan Doctor, MD, Washington University School of Medicine
- Roger Dodd, PhD, American Red Cross
- Bill Flegel, MD, National Institutes of Health
- Mark Gladwin, MD, University of Pittsburgh
- Jerome L. Gottschall, MD, Medical College Wisconsin
- John R. Hess, MD, MPH, University of Maryland Medical Center
- Wenche Jy, PhD, University of Miami School of Medicine
- Daniel Kim-Shapiro, PhD, Wake Forest University
- Harvey Klein, MD, National Institutes of Health
- Steven H. Kleinman, MD, University of British Columbia
- Jacques Lacroix, MD, CHU Sainte-Justine Centre de recherché
- Alan Mast, MD, PhD, Blood Center of Wisconsin
- Augustin Min, PhD, Fenwal Inc.
- Gary Moroff, PhD, American Red Cross
- Mohandas Narla, DSc, New York Blood Center, Inc.
- Robert Neuman, PhD, Emory Clinical Cardiovascular Res. Institute
- Philip J. Norris, MD, Blood Systems Research Institute
- Shibani Pati, MD, PhD, UTHSC-Houston
- Rakesh Pravinchandra Patel, PhD, University of Alabama at Birmingham
- Richard Phipps, PhD, University of Rochester
- James Reynolds, MD, Case Western Reserve University
- John D. Roback, MD, PhD, Emory University, School of Medicine
- William Savage, MD, Johns Hopkins University School of Medicine
- Merlyn H. Sayers, MBBCh, PhD, University of Texas Southwestern
- Christopher C Silliman, MD, PhD, University of Colorado Denver
- David Singel, PhD, Montana State University
- Edward L. Snyder, MD, Yale University Medical School
- Rosemary Sparrow, PhD, Australian Red Cross Blood Service
- Bryan R. Spencer, MPH, American Red Cross
- Philip Spinella, MD, Washington University School of Medicine
- Sherry Spinelli, PhD, University of Rochester
- Steven Spitalnik, MD, Columbia University
- Jonathan S. Stamler, MD, Case Western Reserve University
- Marie E. Steiner, MD, University of Minnesota
- Roy L. Sutliff, PhD, Emory University/Atlanta VA Medical Center
- Peter Tomasulo, MD, Blood Systems Laboratories, Inc.
- Marisa Tucci, MD, CHU Sainte-Justine Centre de recherche
- Jordan Weinberg, MD, University of Tennessee Health Science Center
- Tatsuro Yoshida, PhD, New Health Sciences, Inc.
- Majid Zia, PhD, Hemerus Medical, LLC
Last Updated November 2011