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U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

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Studies on Safety and Efficacy of Platelets and Other Transfused Blood Products

Principal Investigator: J.G. Vostal, MD, PhD
Office / Division / Lab: OBRR / DH / LCH


General Overview

Our laboratory studies ways to improve the safety and effectiveness of platelet and red cell transfusion products. We are trying to understand how the cells that will be transfused are affected by collection, processing, storage conditions and new materials used to make equipment for these activities. Our staff is developing new ways to measure the quality of current and future transfusion products to,understand how changes in the quality of the products could impact the health of patients.

One safety issue relevant to current transfusion products is contamination by pathogens, such as bacteria, during the collection process. The current approach to transfusion of contaminated products is to test them for the presence of pathogens. However, pathogen testing has drawbacks. Post-marketing clinical trials of a culture-based bacterial detection system found that these methods lack sensitivity and often falsely reported that there was no bacterial contaminated of platelets. European countries faced with the same problem use pathogen reduction (PR)--treatments that reduce the number of infectious microorganisms--as an alternative to testing blood products for the presence of pathogens. In the US, a Phase 3 clinical trial that investigated the safety and efficacy of platelets treated with a pathogen reduction process found an unexpectedly high rate of lung related adverse events associated with this technique. These and other clinically significant problems found by this study have raised serious questions about the safety and efficacy of platelets treated by PR.

Another safety issue concerns the age of stored red cells. Recent reports on retrospective clinical studies have noted that there may be a difference in clinical outcomes of patients transfused either with fresh or stored red cells. Prospective studies will be needed to resolve this issue, but such studies did raise concerns about the safety of stored red cells.

Our laboratory is working to find solutions to the problems associated with stored and processed platelets and red blood cells. Specifically, we are developing an animal model of acute lung injury in response to platelet products exposed to pathogen reduction methods. This project involves characterizing changes to platelets exposed to PR methods (ultraviolet light) and monitoring physiological changes associated with infusion of PR platelets into the animal model. We are also trying to identify the differences between stored and fresh red cells that could account for the unexpected clinical outcomes following transfusion. This research could lead to safer and more effective transfusion products. The training and experience it provides to our staff will make them more effective regulators of blood products.


Scientific Overview

Our laboratory studies ways to improve on the safety and efficacy of platelet and red cell transfusion products. We work to understand how these cellular transfusion products are affected by collection and processing methods, storage conditions, and new materials used to make equipment for these activities. We are working to develop new ways to evaluate current and future transfusion products that maintain and improve their safety and efficacy and to understand how their transfusion impacts the welfare of patients.

As part of this work we exposed human platelets to UV A or UV B light at doses similar to those used in current pathogen reduction methods. We characterized the exposed platelets with in vitro tests and infused them into immunodeficient animals to monitor intravascular recovery and survival. To measure in vivo distribution, we infused fluorescently labeled platelets into anaesthetized animals and monitored the platelet distribution into organs in real time and post mortem. Using cell staining and microscopy we also studied alterations in lung physiology and used confocal microscopy to localize human platelets in lung tissue. Our studies found that infused, UV-exposed platelets accumulated in the lungs but only in animals that were sensitized by an infusion of bacterial extract (LPS) to simulate sepsis. This also led to increased numbers of leukocytes and platelets in bronchoalveolar lavage fluid, which reflects acute lung injury. Platelets that were not processed with UV light did not accumulate in the lungs. These results suggest that the clinical lung-related adverse events could have been the result of UV exposed platelets accumulating in lung of patients who may have had a simultaneous bacterial infection. We are currently investigating the molecular mechanisms in platelets induced by UV light that mediate platelet accumulation in the lungs and acute lung injury.

Our work with red cells focuses on the changes that take place during their storage. As red cells age in storage they become more fragile, less flexible, and more likely to lyse. These changes could potentially pose health risks to transfused patients as has been suggested by some recent clinical studies. Hemoglobin released during red cell lysis is highly toxic to vascular cells and organs, such as the kidney. Release of hemoglobin in clinical situations could lead to acute organ damage or could increase the morbidity of the patient in the long term.

One characteristic of stored red cells is a decrease in resistance to osmotic stress, which has been correlated with loss of both cell membrane and intrinsic membrane flexibility. We found that incubating stored red cells with medium containing extra nutrients to replenish their internal energy stores improved the resilience of stored red cells to physical and osmotic stress. We compared the resistance of fresh and red cells to osmotic stress or physical stress induced by repeated passage through a pump that squeezes the cells. Cells that were rejuvenated in the high nutrient solution had significant improvement in resistance to osmotic and physical stress. Rejuvenation of stored red cells may be useful in improving clinical performance of red cell transfusions.


Publications

Transfusion 2014 Jan;54(1):74-85
Human platelets pathogen reduced with riboflavin and ultraviolet light do not cause acute lung injury in a two-event SCID mouse model.
Chi X, Zhi L, Vostal JG

PLoS One 2013 Nov 1;8(11):e79869
In vitro and in vivo characterization of ultraviolet light C-irradiated human platelets in a 2 event mouse model of transfusion.
Zhi L, Chi X, Vostal JG

Transfusion 2013 Jun;53(6):1178-86
Temperature cycling improves in vivo recovery of cold-stored human platelets in a mouse model of transfusion.
Xu F, Gelderman MP, Farrell J, Vostal JG

Transfusion 2013 Apr;53(4):722-31
Activation of platelet protein kinase C by ultraviolet light B mediates platelet transfusion-related acute lung injury in a two-event animal model.
Zhi L, Chi X, Gelderman MP, Vostal JG

Transfusion 2013 Jan;53(1):232-3
FDA contributions to reduction of bacterial contamination in platelet products within the United States.
Epstein JS, Vostal JG

Transfusion 2012 Nov;52(11):2492-3
In reply.
Gelderman MP, Vostal JG

Transfusion 2012 Nov;52(11):2492-3
In Reply to: "Is the SCID mouse model applicable to human acute lung injury?" - In reply
Gelderman MP, Vostal JG

J Trauma Acute Care Surg 2012 Oct;73(4):809-17
Hypothermia and hemostasis in severe trauma: A new crossroads workshop report.
Alam HB, Pusateri AE, Kindzelski A, Egan D, Hoots K, Andrews MT, Rhee P, Tisherman S, Mann K, Vostal J, Kochanek PM, Scalea T, Deal V, Sheppard F, Sopko G

PLoS One 2012;7(9):e44829
Host platelets and, in part, neutrophils mediate lung accumulation of transfused UVB-irradiated human platelets in a mouse model of acute lung injury.
Chi X, Zhi L, Gelderman MP, Vostal JG

Transfusion 2012 Apr;52(4):919-20
Is the SCID mouse model applicable to human acute lung injury? In reply.
Gelderman MP, Vostal JG

Gastroenterology 2012 Apr;142(4):957-966
Integrative genomic identification of genes on 8p associated with hepatocellular carcinoma progression and patient survival.
Roessler S, Long EL, Budhu A, Chen Y, Zhao X, Ji J, Walker R, Jia HL, Ye QH, Qin LX, Tang ZY, He P, Hunter KW, Thorgeirsson SS, Meltzer PS, Wang XW

Transfusion 2011 Nov;51(11):2343-57
Ultraviolet B light-exposed human platelets mediate acute lung injury in a two-event mouse model of transfusion.
Gelderman MP, Chi X, Zhi L, Vostal JG

Transfusion 2011 May;51(5):1012-21
Underestimation of the expression of cellular prion protein on human red blood cells.
Panigaj M, Brouckova A, Glierova H, Dvorakova E, Simak J, Vostal JG, Holada K

Transfusion 2011 May;51(5):1096-104
Rejuvenation improves roller pump-induced physical stress resistance of fresh and stored red blood cells.
Gelderman MP, Vostal JG

Transfusion 2010 Oct;20(5):341-5
Serial oxygen equilibrium and kinetic measurements during RBC storage.
Gelderman MP, Yazer MH, Jia Y, Wood F, Alayash AI, Vostal JG

Clin Lab Med 2010 Jun;30(2):443-52
Current and future cellular transfusion products.
Gelderman MP, Vostal JG

Mol Cancer Ther 2009 May;8(5):1292-304
Two types of human malignant melanoma cell lines revealed by expression patterns of mitochondrial and survival-apoptosis genes: implications for malignant melanoma therapy.
Su DM, Zhang Q, Wang X, He P, Zhu YJ, Zhao J, Rennert OM, Su YA

Biochim Biophys Acta 2008 Nov;1782(11):615-20
Human cellular prion protein interacts directly with clusterin protein.
Xu F, Karnaukhova E, Vostal JG

Apoptosis 2008 Aug;13(8):993-1004
Molecular mechanism underlying differential apoptosis between human melanoma cell lines UACC903 and UACC903(+6) revealed by mitochondria-focused cDNA microarrays.
Zhang Q, Wu J, Nguyen A, Wang BD, He P, Laurent GS, Rennert OM, Su YA

Blood Cells Mol Dis 2008 May-Jun;40(3):302-7
Reduced erythroid cell and erythropoietin production in response to acute anemia in prion protein-deficient (Prnp-/-) mice.
Zivny JH, Gelderman MP, Xu F, Piper J, Holada K, Simak J, Vostal JG

Transfusion 2007 Dec;47(12):2223-32
Divergent expression of cellular prion protein on blood cells of human and nonhuman primates.
Holada K, Simak J, Brown P, Vostal JG

Transfusion 2007 Aug;47(8):1540-9
In vivo recovery of human platelets in severe combined immunodeficient mice as a measure of platelet damage.
Piper JT, Gelderman MP, Vostal JG

Haematologica 2006 Aug;91(8):1126-9
Expression of cellular prion protein on platelets from patients with gray platelet or Hermansky-Pudlak syndrome and the protein's association with alpha-granules.
Holada K, Glierova H, Simak J, Vostal JG

J Trauma 2006 Jun;60(6 Suppl):S78-82
Efficacy evaluation of current and future platelet transfusion products.
Vostal JG

Transfus Med 2006 Feb;16(1):41-8
A multistate cluster of red blood cell transfusion reactions associated with use of a leucocyte reduction filter.
Alvarado-Ramy F, Kuehnert MJ, Alonso-Echanove J, Sledge L, Haley NR, Epstein J, Vostal J, Pearson M

Cancer Res 2005 Aug 15;65(16):7370-7
Endogenous osteonectin/SPARC/BM-40 expression inhibits MDA-MB-231 breast cancer cell metastasis.
Koblinski JE, Kaplan-Singer BR, VanOsdol SJ, Wu M, Engbring JA, Wang S, Goldsmith CM, Piper JT, Vostal JG, Harms JF, Welch DR, Kleinman HK

Br J Haematol 2004 Jun;125(6):804-13
Elevated circulating endothelial membrane microparticles in paroxysmal nocturnal haemoglobinuria.
Simak J, Holada K, Risitano AM, Zivny JH, Young NS, Vostal JG

     
 

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