An overview of the role of microparticles/microvesicles in blood components: Are they clinically beneficial or harmful?

Transfusion and Apheresis Science

Volumn 53, Issue 2, 2015, Pages 137-145

  Burnouf, Thierry ^a   Chou, Ming Li ^b   Goubran, Hadi ^c   Cognasse, Fabrice ^d,e   Garraud, Olivier ^e,f   Seghatchian, Jerard ^g  

^a TAIPEI MEDICAL UNIVERSITY   (Taiwan)

^b TAIPEI MEDICAL UNIVERSITY   (Taiwan)

^c UNIVERSITY OF SASKATCHEWAN   (Canada)

^d ETABLISSEMENT FRANÇAIS DU SANG   (France)

^e UNIVERSITÉ DE LYON   (France)

^f INSTITUT NATIONAL DE LA TRANSFUSION SANGUINE   (France)

^g International Consultancy in Blood Components Quality Safety Improvement   (United Kingdom)

Author keywords

Blood; Inflammation; Microparticles; Microvesicles; Plasma; Platelets; Red blood cells; Thrombosis; Transfusion medicine

Indexed keywords

ANTICOAGULANT AGENT; GROWTH FACTOR; LIPID; MEMBRANE RECEPTOR; MICRORNA; PHOSPHATIDYLSERINE; LIPID BILAYER; SIGNAL PEPTIDE;

APHERESIS; BLOOD CLOTTING; BLOOD COMPONENT; BLOOD SAFETY; BLOOD SAMPLING; BLOOD STORAGE; BLOOD TRANSFUSION; BLOOD TRANSFUSION REACTION; CELL VIABILITY; CENTRIFUGATION; COMPLEMENT SYSTEM; ENDOTHELIUM CELL; ERYTHROCYTE; EX VIVO STUDY; HUMAN; INFLAMMATION; LEUKOCYTE; MEGAKARYOCYTE; MEMBRANE MICROPARTICLE; MITOCHONDRION; PARTICLE SIZE; PHOSPHOLIPID BILAYER; PLATELET MICROPARTICLE; REVIEW; SHEAR STRESS; ACTIVE TRANSPORT; ANIMAL; BLOOD; BLOOD CELL; BLOOD COMPONENT THERAPY; DISINFECTION; LIPID BILAYER; METABOLISM; PATHOLOGY;

ANIMALS; BIOLOGICAL TRANSPORT, ACTIVE; BLOOD CELLS; BLOOD COMPONENT TRANSFUSION; BLOOD PRESERVATION; CELL-DERIVED MICROPARTICLES; DISINFECTION; HUMANS; INTERCELLULAR SIGNALING PEPTIDES AND PROTEINS; LIPID BILAYERS; MICRORNAS; MITOCHONDRIA;

EID: 84951838953     PISSN: 14730502     EISSN: 18781683     Source Type: Journal    
DOI: 10.1016/j.transci.2015.10.010     Document Type: Review

References (115)

1. Simak J., Gelderman M.P. Cell membrane microparticles in blood and blood products: potentially pathogenic agents and diagnostic markers. Transfus Med Rev 2006, 20:1-26.
2. Burnouf T., Goubran H.A., Chou M.L., et al. Platelet microparticles: detection and assessment of their paradoxical functional roles in disease and regenerative medicine. Blood Rev 2014, 28:155-166.
3. Goubran H.A., Burnouf T., Stakiw J., et al. Platelet microparticle: a sensitive physiological "fine tuning" balancing factor in health and disease. Transfus Apher Sci 2015, 52:12-18.
4. Mooberry M.J., Key N.S. Microparticle analysis in disorders of hemostasis and thrombosis. Cytometry A 2015, 10.1002/cyto.a.22647.
5. Rank A., Nieuwland R., Crispin A., et al. Clearance of platelet microparticles in vivo. Platelets 2011, 22:111-116.
6. Mause S.F., Weber C. Microparticles: protagonists of a novel communication network for intercellular information exchange. Circ Res 2010, 107:1047-1057.
7. Kriebardis A., Antonelou M., Stamoulis K., et al. Cell-derived microparticles in stored blood products: innocent-bystanders or effective mediators of post-transfusion reactions?. Blood Transfus 2012, 10(Suppl. 2):s25-38.
8. Ronnlund D., Yang Y., Blom H., et al. Fluorescence nanoscopy of platelets resolves platelet-state specific storage, release and uptake of proteins, opening up future diagnostic applications. Adv Healthc Mater 2012, 1:707-713.
9. Shai E., Rosa I., Parguina A.F., et al. Comparative analysis of platelet-derived microparticles reveals differences in their amount and proteome depending on the platelet stimulus. J Proteomics 2012, 76. Spec No.: 287-96.
10. Horstman L.L., Ahn Y.S. Platelet microparticles: a wide-angle perspective. Crit Rev Oncol Hematol 1999, 30:111-142.
11. Garraud O., Cognasse F., Hamzeh-Cognasse H., et al. [Blood transfusion and inflammation]. Transfus Clin Biol 2013, 20:231-238.
12. Herring J.M., McMichael M.A., Smith S.A. Microparticles in health and disease. J Vet Intern Med 2013, 27:1020-1033.
13. Jy W., Ricci M., Shariatmadar S., et al. Microparticles in stored red blood cells as potential mediators of transfusion complications. Transfusion 2011, 51:886-893.
14. Krailadsiri P., Seghatchian J. Microvesicles in platelet concentrates 2000, Elsevier, Chapter 12.
15. Tissot J.D., Rubin O., Canellini G. Analysis and clinical relevance of microparticles from red blood cells. Curr Opin Hematol 2010, 17:571-577.
16. Vamvakas E.C., Blajchman M.A. Transfusion -related immunomodulation (TRIM): an update. Blood Rev 2007, 21:327-348.
17. Krailadsiri P., Seghatchian J., Bode A.P. Microvesicles in blood components: laboratory and clinical aspects. Clin Appl Thromb-Hem 1997, 3:86-95.
18. Cognasse F., Hamzeh-Cognasse H., Laradi S., et al. The role of microparticles in inflammation and transfusion: a concise review. Transfus Apher Sci 2015, 53(2):159-167.
19. Gilbert G.E., Sims P., Wiedmer T., et al. Platelet-derived microparticles express high affinity receptors for factor VIII. J Biol Chem 1991, 266:17261-17268.
20. Hoyer F.F., Nickenig G., Werner N. Microparticles - messengers of biological information. J Cell Mol Med 2010, 14:2250-2256.
21. Morel O., Jesel L., Freyssinet J.M., et al. Cellular mechanisms underlying the formation of circulating microparticles. Arterioscler Thromb Vasc Biol 2011, 31:15-26.
22. Gyorgy B., Szabo T.G., Pasztoi M., et al. Membrane vesicles, current state-of-the-art: emerging role of extracellular vesicles. Cell Mol Life Sci 2011, 68:2667-2688.
23. Gyulkhandanyan A.V., Mutlu A., Freedman J., et al. Markers of platelet apoptosis: methodology and applications. J Thromb Thrombolysis 2012, 33:397-411.
24. Flaumenhaft R., Dilks J.R., Richardson J., et al. Megakaryocyte-derived microparticles: direct visualization and distinction from platelet-derived microparticles. Blood 2009, 113:1112-1121.
25. Sims P., Wiedmer T., Esmon C.T., et al. Assembly of the platelet prothrombinase complex is linked to vesiculation of the platelet plasma membrane. Studies in Scott syndrome: an isolated defect in platelet procoagulant activity. J Biol Chem 1989, 264:17049-17057.
26. Wiedmer T., Shattil S.J., Cunningham M., et al. Role of calcium and calpain in complement-induced vesiculation of the platelet plasma membrane and in the exposure of the platelet factor Va receptor. Biochemistry 1990, 29:623-632.
27. Italiano J.E., Mairuhu A.T., Flaumenhaft R. Clinical relevance of microparticles from platelets and megakaryocytes. Curr Opin Hematol 2010, 17:578.
28. Zwaal R.F., Comfurius P., Bevers E.M. Platelet procoagulant activity and microvesicle formation. Its putative role in hemostasis and thrombosis. Biochim Biophys Acta 1992, 1180:1-8.
29. Delabranche X., Berger A., Boisrame-Helms J., et al. Microparticles and infectious diseases. Med Mal Infect 2012, 42:335-343.
30. Briede J.J., Heemskerk J.W., Hemker H.C., et al. Heterogeneity in microparticle formation and exposure of anionic phospholipids at the plasma membrane of single adherent platelets. Biochim Biophys Acta 1999, 1451:163-172.
31. Sims P.J., Wiedmer T. Repolarization of the membrane potential of blood platelets after complement damage: evidence for a Ca++-dependent exocytotic elimination of C5b-9 pores. Blood 1986, 68:556-561.
32. Hugel B., Socié G., Vu T., et al. Elevated levels of circulating procoagulant microparticles in patients with paroxysmal nocturnal hemoglobinuria and aplastic anemia. Blood 1999, 93:3451-3456.
33. Schneider S., Nuschele S., Wixforth A., et al. Shear-induced unfolding triggers adhesion of von Willebrand factor fibers. PNAS 2007, 104:7899-7903.
34. Miyazaki Y., Nomura S., Miyake T., et al. High shear stress can initiate both platelet aggregation and shedding of procoagulant containing microparticles. Blood 1996, 88:3456-3464.
35. Holme P.A., Ørvim U., Hamers M.J., et al. Shear-induced platelet activation and platelet microparticle formation at blood flow conditions as in arteries with a severe stenosis. Arterioscler Thromb Vasc Biol 1997, 17:646-653.
36. Chow T.W., Hellums J.D., Thiagarajan P. Thrombin receptor activating peptide (SFLLRN) potentiates shear-induced platelet microvesiculation. J Lab Clin Med 2000, 135:66-72.
37. Owens A.P., Mackman N. Microparticles in hemostasis and thrombosis. Circ Res 2011, 108:1284-1297.
38. Ayers L., Kohler M., Harrison P., et al. Measurement of circulating cell-derived microparticles by flow cytometry: sources of variability within the assay. Thromb Res 2011, 127:370-377.
39. Lacroix R., Judicone C., Poncelet P., et al. Impact of pre-analytical parameters on the measurement of circulating microparticles: towards standardization of protocol. Int J Lab Hematol 2012, 34:159-160.
40. Lacroix R., Robert S., Poncelet P., et al. Standardization of platelet-derived microparticle enumeration by flow cytometry with calibrated beads: results of the International Society on Thrombosis and Haemostasis SSC Collaborative Workshop. J Thromb Haemost 2010, 8:2571-2574.
41. Artoni A., Merati G., Padovan L., et al. Residual platelets are the main determinants of microparticles count in frozen-thawed plasma. Thromb Res 2012, 130:561-562.
42. Gyorgy B., Szabo T.G., Turiak L., et al. Improved flow cytometric assessment reveals distinct microvesicle (cell-derived microparticle) signatures in joint diseases. PLoS ONE 2012, 7. e49726.
43. Lawrie A.S., Cardigan R.A., Williamson L.M., et al. The dynamics of clot formation in fresh-frozen plasma. Vox Sang 2008, 94:306-314.
44. Sugawara A., Nollet K.E., Yajima K., et al. Preventing platelet-derived microparticle formation - and possible side effects - with prestorage leukofiltration of whole blood. Arch Pathol Lab Med 2010, 134:771-775.
45. Seghatchian J., Krailadsiri P. The platelet storage lesion. Transfus Med Rev 1997, 11:130-144.
46. Tinmouth A., Chin-Yee I. The clinical consequences of the red cell storage lesion. Transfus Med Rev 2001, 15:91-107.
47. Hagberg I.A., Akkok C.A., Lyberg T., et al. Apheresis-induced platelet activation: comparison of three types of cell separators. Transfusion 2000, 40:182-192.
48. Rank A., Nieuwland R., Liebhardt S., et al. Apheresis platelet concentrates contain platelet-derived and endothelial cell-derived microparticles. Vox Sang 2011, 100:179-186.
49. Bode A.P., Orton S.M., Frye M.J., et al. Vesiculation of platelets during in vitro aging. Blood 1991, 77:887-895.
50. Krailadsiri P., Seghatchian J. Are all leucodepleted platelet concentrates equivalent? Comparison of Cobe LRS Turbo, haemonetics MCS plus LD, and filtered pooled buffy-coat-derived platelets. Vox Sang 2000, 78:171-175.
51. Nollet K.E., Saito S., Ono T., et al. Microparticle formation in apheresis platelets is not affected by three leukoreduction filters. Transfusion 2013, 53:2293-2298.
52. Rubin O., Crettaz D., Canellini G., et al. Microparticles in stored red blood cells: an approach using flow cytometry and proteomic tools. Vox Sang 2008, 95:288-297.
53. Diquattro M., De Francisci G., Bonaccorso R., et al. Evaluation of amotosalem treated platelets over 7 days of storage with an automated cytometry assay panel. Int J Lab Hematol 2013, 35:637-643.
54. Solheim B.G. Pathogen reduction of blood components. Transfus Apher Sci 2008, 39:75-82.
55. Mundt J.M., Rouse L., Van den Bossche J., et al. Chemical and biological mechanisms of pathogen reduction technologies. Photochem Photobiol 2014, 90:957-964.
56. Bost V., Odent-Malaure H., Chavarin P., et al. A regional haemovigilance retrospective study of four types of therapeutic plasma in a ten-year survey period in France. Vox Sang 2013, 104:337-341.
57. Hamzeh-Cognasse H., Laradi S., Osselaer J., et al. Amotosalen-HCl-UVA pathogen reduction does not alter poststorage metabolism of soluble CD40 ligand, Ox40 ligand and interkeukin-27, the cytokines that generally associate with serious adverse events. Vox Sang 2015, 108:205-207.
58. Chavarin P., Cognasse F., Argaud C., et al. In vitro assessment of apheresis and pooled buffy coat platelet components suspended in plasma and SSP+ photochemically treated with amotosalen and UVA for pathogen inactivation (INTERCEPT Blood System™). Vox Sang 2011, 100:247-249.
59. Li J., de Korte D., Woolum M.D., et al. Pathogen reduction of buffy coat platelet concentrates using riboflavin and light: comparisons with pathogen-reduction technology-treated apheresis platelet products. Vox Sang 2004, 87:82-90.
60. Lawrie A.S., Green L., Canciani M.T., et al. The effect of prion reduction in solvent/detergent-treated plasma on haemostatic variables. Vox Sang 2010, 99:232-238.
61. Salunkhe V., van der Meer P.F., de Korte D., et al. Development of blood transfusion product pathogen reduction treatments: a review of methods, current applications and demands. Transfus Apher Sci 2014, 52:19-34.
62. van der Pol E., Coumans F., Varga Z., et al. Innovation in detection of microparticles and exosomes. J Thromb Haemost 2013, 11(Suppl. 1):36-45.
63. Gardiner C., Shaw M., Hole P., et al. Measurement of refractive index by nanoparticle tracking analysis reveals heterogeneity in extracellular vesicles. J Extracell Vesicles 2014, 3:25361.
64. van der Pol E., Hoekstra A.G., Sturk A., et al. Optical and non-optical methods for detection and characterization of microparticles and exosomes. J Thromb Haemost 2010, 8:2596-2607.
65. Gyorgy B., Modos K., Pallinger E., et al. Detection and isolation of cell-derived microparticles are compromised by protein complexes resulting from shared biophysical parameters. Blood 2011, 117:e39-48.
66. Colhoun H.M., Otvos J.D., Rubens M.B., et al. Lipoprotein subclasses and particle sizes and their relationship with coronary artery calcification in men and women with and without type 1 diabetes. Diabetes 2002, 51:1949-1956.
67. Poncelet P., Robert S., Bailly N., et al. Tips and tricks for flow cytometry-based analysis and counting of microparticles. Transfus Apher Sci 2015, 53(2):110-126.
68. Amiral J., Seghatchian J. The diagnostic usefulness of capture assays for measuring global/specific extracellular microparticles in plasma. Transfus Apher Sci 2015, 53(2):127-136.
69. Filipe V., Hawe A., Jiskoot W. Critical evaluation of Nanoparticle Tracking Analysis (NTA) by NanoSight for the measurement of nanoparticles and protein aggregates. Pharm Res 2010, 27:796-810.
70. Aatonen M.T., Ohman T., Nyman T.A., et al. Isolation and characterization of platelet-derived extracellular vesicles. J Extracell Vesicles 2014, 3. 10.3402/jev.v3.24692.
71. Yuana Y., Bertina R.M., Osanto S. Pre-analytical and analytical issues in the analysis of blood microparticles. Thromb Haemost 2011, 105:396-408.
72. Rubin O., Crettaz D., Tissot J.D., et al. Microparticles in stored red blood cells: submicron clotting bombs?. Blood Transfus 2010, 8(Suppl. 3):s31-8.
73. Magee G., Inaba K., Chouliaras K., et al. Volume of red blood cells and plasma is associated with increased risk of venous thromboembolism in trauma patients. J Am Coll Surg 2014, 219:e190.
74. Puetz J., Witmer C., Huang Y.S., et al. Widespread use of fresh frozen plasma in US children's hospitals despite limited evidence demonstrating a beneficial effect. J Pediatr 2012, 160:210-215.e1.
75. Puetz J., Darling G., Brabec P., et al. Thrombotic events in neonates receiving recombinant factor VIIa or fresh frozen plasma. Pediatr Blood Cancer 2009, 53:1074-1078.
76. Chou M.L., Lin L.T., Devos D., et al. Nanofiltration to remove microparticles and decrease the thrombogenicity of plasma: in vitro feasibility assessment. Transfusion 2015, 10.1111/trf.13162.
77. Sabatier F., Lacroix R., Camoin-Jau L., et al. [Circulating endothelial cells, microparticles and progenitors: towards the definition of vascular competence]. Rev Med Interne 2011, 32:54-63.
78. Kent M.W., Kelher M.R., West F.B., et al. The pro-inflammatory potential of microparticles in red blood cell units. Transfus Med 2014, 24:176-181.
79. Koch C.G., Li L., Sessler D.I., et al. Duration of red-cell storage and complications after cardiac surgery. N Engl J Med 2008, 358:1229-1239.
80. Weinberg J.A., McGwin G., Griffin R.L., et al. Age of transfused blood: an independent predictor of mortality despite universal leukoreduction. J Trauma 2008, 65:279-282. discussion 82-4.
81. Eder A.F., Chambers L.A. Noninfectious complications of blood transfusion. Arch Pathol Lab Med 2007, 131:708-718.
82. Bosman G.J., Lasonder E., Luten M., et al. The proteome of red cell membranes and vesicles during storage in blood bank conditions. Transfusion 2008, 48:827-835.
83. Maslanka K., Uhrynowska M., Lopacz P., et al. Analysis of leucocyte antibodies, cytokines, lysophospholipids and cell microparticles in blood components implicated in post-transfusion reactions with dyspnoea. Vox Sang 2015, 108:27-36.
84. Nakao M., Nakao T., Yamazoe S. Adenosine triphosphate and maintenance of shape of the human red cells. Nature 1960, 187:945-946.
85. Kriebardis A.G., Antonelou M.H., Stamoulis K.E., et al. RBC-derived vesicles during storage: ultrastructure, protein composition, oxidation, and signaling components. Transfusion 2008, 48:1943-1953.
86. Xiong Z.Y., Cavaretta J., Qu L.R., et al. Red blood cell microparticles show altered inflammatory chemokine binding and release ligand upon interaction with platelets. Transfusion 2011, 51:610-621.
87. Jy W., Mao W.W., Horstman L., et al. Platelet microparticles bind, activate and aggregate neutrophils in vitro. Blood Cells Mol Dis 1995, 21:217-231. discussion 31a.
88. Belizaire R.M., Prakash P.S., Richter J.R., et al. Microparticles from stored red blood cells activate neutrophils and cause lung injury after hemorrhage and resuscitation. J Am Coll Surg 2012, 214:648-655. discussion 56-7.
89. Tung J.P., Fung Y.L., Nataatmadja M., et al. A novel in vivo ovine model of transfusion-related acute lung injury (TRALI). Vox Sang 2011, 100:219-230.
90. Khan S.Y., Kelher M.R., Heal J.M., et al. Soluble CD40 ligand accumulates in stored blood components, primes neutrophils through CD40, and is a potential cofactor in the development of transfusion-related acute lung injury. Blood 2006, 108:2455-2462.
91. Kitazawa J., Nollet K., Morioka H., et al. Non-D Rh antibodies appearing after apheresis platelet transfusion: stimulation by red cells or microparticles?. Vox Sang 2011, 100:395-400.
92. Morel O., Morel N., Freyssinet J.M., et al. Platelet microparticles and vascular cells interactions: a checkpoint between the haemostatic and thrombotic responses. Platelets 2008, 19:9-23.
93. Matijevic N., Wang Y.W., Kostousov V., et al. Decline in platelet microparticles contributes to reduced hemostatic potential of stored plasma. Thromb Res 2011, 128:35-41.
94. George J.N., Pickett E.B., Heinz R. Platelet membrane microparticles in blood bank fresh frozen plasma and cryoprecipitate. Blood 1986, 68:307-309.
95. Krailadsiri P., Seghatchian J., Macgregor I., et al. The effects of leukodepletion on the generation and removal of microvesicles and prion protein in blood components. Transfusion 2006, 46:407-417.
96. Lawrie A.S., Harrison P., Cardigan R.A., et al. The characterization and impact of microparticles on haemostasis within fresh-frozen plasma. Vox Sang 2008, 95:197-204.
97. Chan K.S.K., Sparrow R.L. Microparticle profile and procoagulant activity of fresh-frozen plasma is affected by whole blood leukoreduction rather than 24-hour room temperature hold. Transfusion 2014, 54:1935-1944.
98. Gerritsen S.W., Akkerman J.W., Sixma J.J. Correction of the bleeding time in patients with storage pool deficiency by infusion of cryoprecipitate. Br J Haematol 1978, 40:153-160.
99. Callum J.L., Karkouti K., Lin Y. Cryoprecipitate: the current state of knowledge. Transfus Med Rev 2009, 23:177-188.
100. El-Ekiaby M., Goubran H.A., Radosevich M., et al. Pharmacokinetic study of minipooled solvent/detergent-filtered cryoprecipitate factor VIII. Haemophilia 2011, 17:e884-8.
101. Cauwenberghs S., van Pampus E., Curvers J., et al. Hemostatic and signaling functions of transfused platelets. Transfus Med Rev 2007, 21:287-294.
102. Radwanski K., Garraud O., Cognasse F., et al. The effects of red blood cell preparation method on in vitro markers of red blood cell aging and inflammatory response. Transfusion 2013, 53:3128-3138.
103. Etulain J., Negrotto S., Carestia A., et al. Acidosis downregulates platelet haemostatic functions and promotes neutrophil proinflammatory responses mediated by platelets. Thromb Haemost 2012, 107:99-110.
104. Comfurius P., Senden J.M., Tilly R.H., et al. Loss of membrane phospholipid asymmetry in platelets and red cells may be associated with calcium-induced shedding of plasma membrane and inhibition of aminophospholipid translocase. Biochim Biophys Acta 1990, 1026:153-160.
105. Hoffman M., Monroe D., Roberts H. Coagulation factor IXa binding to activated platelets and platelet-derived microparticles: a flow cytometric study. Thromb Haemost 1992, 68:74-78.
106. Sinauridze E.I., Kireev D.A., Popenko N.Y., et al. Platelet microparticle membranes have 50-to 100-fold higher specific procoagulant activity than activated platelets. Thromb Haemost 2007, 97:425-434.
107. Jagoditsch M., Pozgainer P., Klingler A., et al. Impact of blood transfusions on recurrence and survival after rectal cancer surgery. Dis Colon Rectum 2006, 49:1116-1130.
108. Cata J., Wang H., Gottumukkala V., et al. Inflammatory response, immunosuppression, and cancer recurrence after perioperative blood transfusions. Br J Anaesth 2013, 110:690-701.
109. Goubran H.A., Sabry W., Kotb R., et al. Platelet microparticles and cancer: an intimate cross-talk. Transfus Apher Sci 2015, 53(2):168-172.
110. Wolf P. The nature and significance of platelet products in human plasma. Br J Haematol 1967, 13:269-288.
111. Harrison P., Cramer E.M. Platelet alpha-granules. Blood Rev 1993, 7:52-62.
112. Diehl P., Fricke A., Sander L., et al. Microparticles: major transport vehicles for distinct microRNAs in circulation. Cardiovasc Res 2012, 93:633-644.
113. Hunter M.P., Ismail N., Zhang X., et al. Detection of microRNA expression in human peripheral blood microvesicles. PLoS ONE 2008, 3:e3694.
114. Boudreau L.H., Duchez A.C., Cloutier N., et al. Platelets release mitochondria serving as substrate for bactericidal group IIA-secreted phospholipase A2 to promote inflammation. Blood 2014, 124:2173-2183.
115. Lacroix J., Hébert P.C., Fergusson D.A., et al. Age of transfused blood in critically ill adults. NEJM 2015, 372(15):1410-1418.