A number of adverse effects of blood transfusion persist. One is the recent recognition that adverse effects increase with time of storage of packed red cells (PC). This has led surgeons to demand only recent PC, an added strain on limited supply. The explanation for the adverse effects has been conjectural, but it is known that red blood cells (RBC) release microparticles (RMP) during storage, which accumulate with time. There is new evidence that RMP, like MP from other cell types, can be injurious, especially at high levels. Accordingly, the hypothesis underlying the proposal is that RMP contribute substantially to adverse effects of PC transfusion;and that removal of RMP prior to transfusion will reduce indicators of adverse effects. The study has two major aims.
Aim 1 is to assess the potentially pathologic properties of RMP as they emerge in PC with time. Although MP from other cells have been studied extensively and linked to many disorders, RMP have been little studied and have not been considered to be hazardous. However, recent evidence indicates that they do have significant potential to cause harm, such as microvascular ischemias. The assays to be performed include MP- mediated thrombin generation, MP-bound complement components, and other prothrombotic and inflammatory markers. We will perform this time study on a total of 60 PC units, since significant donor variability has been observed. When sufficient data is accumulated (after year 2) from in vitro and patient study, selected groups of samples will undergo proteomic profiling in effort to identify the most hazardous components of RMP. Anticipated results. It is expected from prior work that time of storage will be the dominant factor of adverse properties of RMP. However, donor-specific adverse MP are also likely and will be investigated by proteomic study.
Aim 2 is a clinical study to directly test the hypothesis by administering to randomized patients scheduled for coronary artery bypass surgery either conventional PC (Group 1) or PC washed prior to transfusion to deplete MP (Group 2). Patients who do not require transfusion will serve as patient controls (Group 3). The 4-year period will recruit n=500 patients, half of whom are randomized to Groups 1 and 2;and half of all subjects will not require transfusion (Group 3). The study is not designed to evaluate major transfusion reactions, which are rare. Differential effects between the groups will be assessed primarily by a panel of sensitive biomarkers capable of detecting subclinical but adverse responses such as endothelial injury, platelet activation, and other markers of inflammation, oxidation, and coagulation. Clinical responses, surgical outcomes, etc. will also be monitored and recorded. Anticipated results: It is expected that patients who received PC-MP will exhibit fewer or less severe complications and adverse biomarkers. The significance of the work is self-explanatory. The long-term objective is to improve transfusion safety.

Public Health Relevance

A number of adverse effects of packed red cell (PC) transfusion present serious heath hazard and their mechanisms of untoward reactions remain to be elucidated. In the proposed project, we plan to study the effects of microparticles shedding from packed red cells on the transfusion complication bu using washed packed red cells for transfusion as compared to regular packed red cells. The long- term objective is to improve transfusion practice and their safety.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL098031-04
Application #
8309254
Study Section
Special Emphasis Panel (ZHL1-CSR-S (S1))
Program Officer
Welniak, Lisbeth A
Project Start
2009-09-18
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2014-07-31
Support Year
4
Fiscal Year
2012
Total Cost
$581,897
Indirect Cost
$201,572
Name
University of Miami School of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
Wagner, Stephen J; Glynn, Simone A; Welniak, Lisbeth A et al. (2014) Research opportunities in optimizing storage of red blood cell products. Transfusion 54:483-94
Jy, Wenche; Johansen, Max E; Bidot Jr, Carlos et al. (2013) Red cell-derived microparticles (RMP) as haemostatic agent. Thromb Haemost 110:751-60
Jy, Wenche; Ricci, Marco; Shariatmadar, Sherry et al. (2011) Microparticles in stored red blood cells as potential mediators of transfusion complications. Transfusion 51:886-93
Jy, Wenche; Horstman, Lawrence L; Ahn, Yeon S (2010) Microparticle size and its relation to composition, functional activity, and clinical significance. Semin Thromb Hemost 36:876-80