This proposal describes a 5-year training program that will ultimately develop Dr. Alexander Benson into an independent academic clinical and translational investigator. He will investigate clinical transfusion strategies and identify patien-specific biomarkers to identify and reduce the incidence of transfusion-related acute lung injury (TRALI) in patients with chronic liver disease. This integrated program consists of coursework in the clinical sciences, intensive mentoring by three internationally renowned local experts, basic scientific study of the mechanisms of TRALI, and practical experience in clinical and translational research design, conduct and interpretation. This award will pave the way for Alexander Benson to become an independently funded clinical investigator with skills in the design and conduct of clinical and translational studies, advanced statistical analysis, and planned biologic sampling strategies necessary for biomarker discovery. In addition, he will gain an ability to translate basic scientific knowledge into clinical study design, and conversely, will develop skills to translate observed clinical associations into new basic scientific studies. These skills will lead to a successful independent research career focused on understanding the clinical and biologic relationship between plasma transfusion and acute lung injury in critically il patients. Dr. Benson's overall research goal is to 1) determine whether clinical strategies that alter the clinical use of plasma transfusions will decrease the risk of TRALI and 2) to determine whether a mechanistic biomarker can predict pre-transfusion TRALI risk. To achieve this first goal, Dr. Benson will perform a randomized clinical trial of two different transfusion strategies o pulmonary and bleeding complications in bleeding patients with chronic liver disease. To achieve the second goal, Dr. Benson will perform a translational observational study to determine whether the accumulation of systemic heparinoids in the peripheral blood is a predictive biomarker for the development of TRALI. These studies will be the first to evaluate the difference in efficacy of two different plasma transfusion triggers in the critically ill and t examine the performance characteristics of a potential biomarker for the development of TRALI.
Transfusion-related acute lung injury (TRALI) is the most common cause of transfusion-related morbidity and mortality in the United States. It is very common and often unrecognized in the critically ill with the greatest incidence occurring in bleeding patients with liver disease. Plasma is the most common blood component associated with this deadly complication and therefore patients with liver disease who frequently receive transfused plasma are at increased risk. The optimal plasma transfusion strategy for bleeding patients with liver disease is unknown and we will evaluate this clinical question in a small randomized controlled trial. In addition, we will determine whether a novel biomarker, the detection of endogenous heparinoids in peripheral blood, will predict which patients will subsequently develop TRALI.