Transfusion of red blood cells (RBCs), the most common therapeutic procedure performed in US hospitals, is usually effective at preventing morbidity and mortality in anemic patients. However, recent studies indicate that some RBC units have functional defects that impair their efficacy and may actually cause harm to transfused patients. These defects, which appear to increase the longer RBC units are stored prior to transfusion, have been called RBC storage lesions. Transfusion of RBC units with storage lesions may adversely affect thousands of patients annually, but at present we have no accurate methods to identify such units. During the previous funding period for this R01 grant, we observed unexpected donor-to-donor variability in RBC metabolism during blood bank storage. Based on these data, we propose to identify specific metabolic (human RBCs) and genetic (murine RBCs) biomarkers that not only reflect the underlying differences in RBC function due to storage time and/or donor factors, but also can be used clinically to predict which RBC units may cause adverse post-transfusion events, allowing them to be removed from the blood supply before transfusion. To provide the most powerful approach to achieve this goal, we propose an integrated research effort that combines (1) the relevancy of donor/recipient-based human RBC transfusion investigations, with (2) the mechanistic power of mouse models. The human studies will utilize methodologies we have developed to identify metabolic biomarkers that predict RBC function, post-transfusion RBC survival, and vascular effects. The advantages of mouse studies include finely characterized genetics, rapid breeding times, ease of generating complex pedigrees, and the power of phenotype-genotype analysis. These advantages will be exploited by performing GWAS to identify genetic markers for mouse RBC storage phenotypes, and then selectively backcrossing to establish causality between selected genetic elements and phenotypes of interest. The proposed coordinated investigations allow each model to be used for its unique strengths, while compensating for intrinsic weaknesses, and thus provides efficient cross- validation of selected biomarkers. These studies will extend work started during the previous funding period, and will lead to the validation of RBC biomarkers that we believe will identify RBC units most likely to cause adverse recipient effects, allowing them to be sequestered prior to transfusion.

Public Health Relevance

Blood transfusion is the most common therapeutic procedure performed for hospitalized patients in the US. Evidence suggests that some transfusions of older blood units collected from certain donors may cause harm to patients. The development of tests to detect these units will significantly improve clinical outcomes for transfused patients.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL095479-08
Application #
9318524
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Mondoro, Traci
Project Start
2009-09-17
Project End
2019-07-31
Budget Start
2017-08-01
Budget End
2019-07-31
Support Year
8
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Emory University
Department
Pathology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Schultz, William M; Kelli, Heval M; Lisko, John C et al. (2018) Socioeconomic Status and Cardiovascular Outcomes: Challenges and Interventions. Circulation 137:2166-2178
Samman Tahhan, Ayman; Hammadah, Muhammad; Raad, Mohamad et al. (2018) Progenitor Cells and Clinical Outcomes in Patients With Acute Coronary Syndromes. Circ Res 122:1565-1575
Uppal, Karan; Ma, Chunyu; Go, Young-Mi et al. (2018) xMWAS: a data-driven integration and differential network analysis tool. Bioinformatics 34:701-702
Hajjar, Ihab; Hayek, Salim S; Goldstein, Felicia C et al. (2018) Oxidative stress predicts cognitive decline with aging in healthy adults: an observational study. J Neuroinflammation 15:17
Ghasemzedah, Nima; Hayek, Salim S; Ko, Yi-An et al. (2017) Pathway-Specific Aggregate Biomarker Risk Score Is Associated With Burden of Coronary Artery Disease and Predicts Near-Term Risk of Myocardial Infarction and Death. Circ Cardiovasc Qual Outcomes 10:
Hayek, Salim S; Ko, Yi-An; Awad, Mosaab et al. (2017) Cardiovascular Disease Biomarkers and suPAR in Predicting Decline in Renal Function: A Prospective Cohort Study. Kidney Int Rep 2:425-432
Qi, Zhen; Roback, John D; Voit, Eberhard O (2017) Effects of Storage Time on Glycolysis in Donated Human Blood Units. Metabolites 7:
Samman Tahhan, Ayman; Hayek, Salim S; Sandesara, Pratik et al. (2017) Circulating soluble urokinase plasminogen activator receptor levels and peripheral arterial disease outcomes. Atherosclerosis 264:108-114
Hammadah, Muhammad; Al Mheid, Ibhar; Wilmot, Kobina et al. (2017) Telomere Shortening, Regenerative Capacity, and Cardiovascular Outcomes. Circ Res 120:1130-1138
Samman Tahhan, Ayman; Sandesara, Pratik B; Hayek, Salim S et al. (2017) Association between oxidative stress and atrial fibrillation. Heart Rhythm 14:1849-1855

Showing the most recent 10 out of 30 publications