On April 5-6, 2016, the NHLBI, DHHS/OASH, and FDA sponsored a meeting on Scientific Priorities in Pediatric Transfusion Medicine at NHLBI in Bethesda, MD. The goal of this meeting was to identify important research questions that could be answered in the next 5-10 years, and which would have the potential to transform the clinical practice of pediatric transfusion medicine. These questions could be addressed by basic, translational, and/or clinical research studies and focused on six areas: Neonatology and Perinatology, Oncology and Transplant, Chronic Transfusion, Devices and Surgery, Intensive Care and Trauma and Teenage Blood Donation. Prior to the meeting, six groups, one for each topic, convened by phone to discuss key research priorities in their area and identified five major research questions for further discussion and prioritization at the in-person meeting. Additional questions were also generated from the discussion at the meeting. The meeting was attended by 80 participants representing multiple stakeholders, including academic medicine, researchers, clinicians and government. The participants had expertise in multiple relevant disciplines and included transfusion medicine, pediatrics, neonatology, hematology, surgery, critical care, trauma, internal medicine and basic and translational science. The speakers and participants identified research priorities based on unmet needs in the pediatric transfusion medicine space and proposed strategies to overcome existing obstacles and address unanswered questions.
Presentations and Discussions
The opening address by Dr. Gary Gibbons, Dr. Keith Hoots, and Dr. Simone Glynn of the NHLBI and Dr. Naomi Luban, of Children’s National provided the context for the two-day meeting. After the introductory presentations, three lectures set the stage for the discussion: 1) “Blood Elements” presented by Dr. Steven Spitalnik of Columbia University; 2) “NICHD Resources and Networks” presented by Dr. Rosemary Higgins; and 3) “Regulatory Pathways in Neonatology and Pediatric Transfusion Medicine” by Pamela Clark of the FDA. After these presentations, there were sessions which addressed the six key areas: Neonatology and Perinatology, Oncology and Transplant, Chronic Transfusion, Devices and Surgery, Intensive Care and Trauma and Teenage Blood Donation. Each area’s leader and co-leader presented to all the participants their initial proposed priority research questions with background and supporting information. This was followed by an open discussion of the proposed questions, modification of and addition to the proposed research priorities, and at the end, a summary presentation of the final 5 priorities identified by consensus at the meeting. During each presentation, participants were able to bring up points addressed in their pre-meeting calls for open discussion by all attendees. Each priority was discussed extensively and valuable feedback was provided by other groups. Ample opportunity was provided to ask questions, state opinions, and propose alternatives. These open discussions were particularly valuable in ensuring that all voices were heard and all alternatives were thoughtfully considered. The in-person meeting involving all of the attendees was valuable for ensuring that everyone had the opportunity to participate in each area; it also provided the opportunity to identify general cross-cutting concepts relevant to a full discussion of all topics.
Consensus and Recommendations: Overarching Areas of Need in Pediatric Transfusion Medicine Research
Several cross-cutting areas of need relevant to each of the six groups were identified, including:
1. Lack of baseline data and databases for retrospective and longitudinal studies in neonates to young adults receiving blood products:
All participants stressed the lack of databases as a critical need in pediatric transfusion medicine research. Each of the groups stressed that such data would inform the ability to successfully plan, implement and complete future clinical studies in pediatric transfusion medicine. Many of the participants recommended the need to have a REDS (Recipient Epidemiology and Donor Study Evaluation)- like program with a focus on pediatric research. Overall, all participants agreed that this was a major area of need in order to move the field forward and to develop future studies to tailor the utilization of blood products in pediatric populations according to age and disease state. In addition, participants agreed that coordinating the addition of transfusion data acquisition with existing sub-specialty societies and organization databases would possibly be a high yield approach.
2. Need for novel in vitro and in vivo models to study impact of transfusion in specific diseases/conditions
Meeting participants noted that in-vitro and in-vivo models need to be developed to answer basic research questions in pediatric transfusion medicine. This may require modification of existing models or creation of new models.
3. Randomized Clinical Trials to Evaluate Outcomes in Pediatric Patients receiving Blood Products
Well designed, well controlled clinical trials are needed to improve clinical guidelines and therapies in pediatric transfusion medicine. A few areas were identified where clinical trials could be done in a relatively short period of time, but most would require baseline epidemiological data and more translational research before a clinical trial could be developed and successfully implemented. All participants agreed that mechanistic questions and translational science components should be included as part of the clinical trial when possible to maximize the efficiency and impact of the trial.
Consensus and Recommendations: Major Unanswered Questions
The 5 most compelling questions in pediatric transfusion medicine necessitating additional basic, translational or clinical research follows for each of the six areas:
NEONATOLOGY AND PERINATOLOGY
1. What are the best strategies to identify neonates who will benefit from transfusion (RBCs, platelets, or Fresh Frozen Plasma), and what are the systemic effects of transfusions of each and a combination of products in this population?
2. What is the best mechanism to gather national epidemiological data on neonatal transfusions?
3. What are the best blood management strategies for neonates?
4. How can primary RBC or platelet glycoprotein alloimmunization be prevented in the setting of pregnancy setting?
5. How can the dangers of pre-existing maternal RBC alloantibodies or platelet glycoprotein alloantibodies be minimized, using targeted therapies that go beyond intrauterine transfusions, therapeutic plasma exchange, or IVIg?
ONCOLOGY AND TRANSPLANT
1. What are the mechanisms, biomarkers, and treatment adjuncts to prevent and manage hemorrhage in this patient population?
2. What is the impact of pre-transplant platelet and red cell transfusions on transplant and oncology patients’ outcomes?
3. What are the physiologic responses, clinical consequences and optimal use of red cell transfusions in transplant and oncology patients?
4. What are the best strategies to optimize the appropriate use of platelets in the setting of oncology treatment, transplant support and platelets refractoriness?
5. What are the effects of irradiation and pathogen reduction technology on the safety and efficacy of blood products and what studies are required in children to ensure there are no short or long term effects?
CHRONICALLY TRANSFUSED POPULATIONS
1. In children with Sickle Cell Disease (SCD) thalassemia and other transfusion-dependent anemias, what are the host immunologic and donor red blood cell (RBC) factors that determine alloimmunization risk?
2. Is chronic erythrocytapheresis a more effective RBC transfusion modality compared to chronic simple transfusion, assessed by adequate hemoglobin S suppression and ability to avoid or mitigate iron overload in patients with SCD?
3. What donor RBC characteristics in stored blood impact RBC survival, function, and clearance (immunologic or non-immunologic) in vivo in patients requiring chronic transfusion?
DEVICES AND SURGERY
1. What are optimal transfusion strategies to prevent and treat severe bleeding for children who require surgery and/or extracorporeal device support?
2. What are optimal red blood cell (RBC) transfusion strategies for anemia, not related to acute hemorrhage, in children who undergo surgery?
3. What are optimal RBC transfusion strategies for anemia not related to acute hemorrhage, in children supported by extracorporeal devices (e.g., ECMO, ventricular assist devices [VAD], cardiopulmonary by-pass [CPB])?
4. What are the mechanisms of hemostatic dysfunction for children with severe intra-operative bleeding or who are supported by extracorporeal devices, both short term and long term?
5. What are optimal blood conservation/management methods to reduce unnecessary blood and blood derivative exposure for intra/post-operative patients and patients supported by extracorporeal devices (ECMO, VAD, CPB)?
INTENSIVE CARE AND TRAUMA
1. What are the optimum means to monitor and manage hemostatic dysfunction in trauma and critical illness?
2. What are the optimal means for RBC transfusion decision making in critical illness and trauma?
3. What are the consequences of transfusion and how can we optimize approaches to identify and mitigate non-infectious serious hazards of transfusion (NISHOT), including transfusion-related acute lung injury (TRALI), transfusion-associated circulatory overload (TACO), acute respiratory distress syndrome (ARDS) and transfusion-related immunomodulation (TRIM)?
4. What are the strategies to optimize blood product stewardship, including the best ways to identify, evaluate, and disseminate safe and effective blood management strategies?
TEENAGE BLOOD DONATION
1. Does the age at first blood donation correlate with behaviours likely to result in future donation and long-term donation behavior in adulthood?
2. What are the long- term effects of blood donation-induced iron deficiency including neurocognition in teenagers?
3. Can blood centers reduce the risk of syncope and injuries after blood donation on high school blood drives?
4. What are the short term effects of blood donation-induced iron deficiency in teenagers?
Research collaborations with other institutes and pre-existing research collaboratives are encouraged, when possible, and can be facilitated through NHLBI DBDR program staff.
Simone Glynn, MD, MSc, MPH
Chief, Blood Epidemiology and Clinical Therapeutics Branch
Division of Blood Diseases and Resources, National Heart, Lung, and Blood Institute
Naomi L.C. Luban, MD Children’s National Health System
Neonatology and Perinatology
Martha Sola-Visner, MD Boston Children’s Hospital
Jeanne Hendrickson, MD Yale University
Oncology and Transplant
Simon Stanworth, MD NHS Blood and Transplant
William Savage, MD Brigham and Women’s Hospital
Cassandra Josephson, MD Emory University School of Medicine
Stella Chou, MD Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine
Devices and Surgery
Philip Spinella, MD Washington University in St. Louis School of Medicine
Melania Bembea, MD John Hopkins University School of Medicine
Intensive Care and Trauma
Allan Doctor, MD Washington University School of Medicine
Marie Steiner, MD University of Minnesota
Teenage Blood Donation
Anne Eder, MD Department of Transfusion Medicine, NIH Clinical Center
Alan Mast, MD Blood Center of Wisconsin