Extracellular membrane vesicles in blood products-biology and clinical relevance

  • Emilija Krstova Krajnc Zavod RS za transfuzijsko medicino
  • Mojca Jež Zavod RS za transfuzijsko medicino
  • Primož Rožman Zavod RS za transfuzijsko medicino
Keywords: extracellular membrane vesicles, blood products, transfusion, detection, biology


Extracellular membrane vesicles are fragments shed from plasma membranes off all cell types that are undergoing apoptosis or are being subjected to various types of stimulation or stress.  Even in the process of programmed cell death (apoptosis), cell fall apart of varying size vesicles. They expose phosphatidylserine (PS) on the outer leaflet of their membrane, and bear surface membrane antigens reflecting their cellular origin. Extracellular membrane vesicles have been isolated from many types of biological fluids, including serum, cerebrospinal fluid, urine, saliva, tears and conditioned culture medium. Flow cytometry is one of the many different methodological approaches that have been used to analyze EMVs. The method attempts to characterize the EMVs cellular origin, size, population, number, and structure. EMVs are present and accumulate in blood products (erythrocytes, platelets) as well as in fresh frozen plasma during storage. The aim of this review is to highlight the importance of extracellular vesicles as a cell-to-cell communication system and the role in the pathogenesis of different diseases. Special emphasis will be given to the implication of extracellular membrane vesicles in blood products and their clinical relevance. Although our understanding of the role of  EMVs in disease is far from comprehensive, they display promise as biomarkers for different diseases in the future and also as a marker of quality and safety in the quality control of blood products.


Download data is not yet available.


Chargaff E, West R. The biological significance of the thromboplastic protein of blood. J Biol Chem. 1946;166:189-97.

Wolf P. The nature and significance of platelet products in human plasma. Haematol, Br J. 1967;13:269-88.

Mause Sebastian F, Weber C. Microparticles:protagonists of a novel communication network for intercellular information exchange. Circ Res. 2010;107:1047-57.

Biancone L, Bruno S, Deregibus MC, Tetta C, Camussi G. Therapeutic potential of mesenchymal stem cell-derived microvesicles. Nephrol Dial Transpl. 2012;27:3037-42.

Van der Pol E, Boing AN, Harrison P, Sturk A, Nieuwland R. Classification functions, and clinical relevance of extracellular vesicles. Pharmacol Rev. 2012;64:676-705.

Vanwijk MJ, Svedas E, Boer K, Nieuwland R, VanBavel E Kublickiene KR. Isolated microparticles, but not whole plasma from women with preeclampsia impair endothelium-dependent relaxation isolated myometrial arteries from healthy pregnant women. Am J Obs Gynecol. 2002;187:1686-93.

Morel O, Jesel L, Freyssinet JM, Toti F. Cellular mechanisms underlying the formation of circulating microparticles. Aterioscler Thromb Vasc Biol. 2011;31:15-26.

Hoyer FF, Nickenig G, Werner N. Microparticles-messengers of biological information. J Cell Mol Med. 2010;14:2250-56.

Diehl P, Fricke A, Sander L, Stamm J, Bassler N, Htun N, et al. Microparticles: major transport vehicles for distinct microRNAs in circulation. Cardiovasc Res. 2012;93:633-44.

Zwaal RF, Comfurius P, Bevers E. Surface exposure of phosphatidylserine in pathological cells. Cell Mol Life Sci. 2005;62:971-88.

Hugel B, Martinez MC, Kunzelmann C, Freyssinet JM. Membrane microparticles:two sides of the coin. Physiology. 2005;20:22-7.

Rubin O, Crettaz D, Canellini G, Tissot JD, Lion N. Microparticles in stored red blood cells:an approach using flow cytometry and prot

eomic tools. Vox Sang. 2008;95(4):288-97.

Lacroix R, Judicone C, Poncelet P, Robert S, Arnaud L, Sampol J et al. Impact of pre-analytical parameters on the measurement of circulating microparticles: towards standardization of protocol. J Thromb Haemost. 2012;10:437-46.

Ayers L, Kohler M, Harrison P, Sargent I, Dragovic R, Schaap M et al. Measurement of circulating cell-derived microparticles by flow cytometry:sources of variability within the assay. Thromb Res. 2011;127:370-77.

Zwicker JI, Lacroix R, Dignat-George F, Furie BC, Furie B. Measurement of platelet microparticles. Methods Mol Biol. 2012;788:127-39.

Lawrie AS, Albanyan A, Cardigan RA, Mackie IJ HP. Microparticles sizing by dynamic light scattering in fresh-frozen plasma. Vox Sang. 2009;96:206-12.

Xu Y, Nakane N, Maurer-Spurej E. Novel test for microparticles in platelet-rich plasma and platelet concentrates using dynamic light scattering. Transfusion. 2011;51:363-70.

Gyorgy B, Szabo TG, Turiac L, Wright M, Herczeg P, Ledeczi Z et al. Improved flow cytometric assessment reveals distinct microvesicle( cell-derived microparticle) signatures in joint diseases. PLoS One. 2012;7.

Combes V, Simon AC, Grau GE, Arnoux D, Camoin L, Sabatier F et al. In vitro generation of endothelial microparticles and possible prothrombotic activity in patients with lupus anticoagulant. J Clin Invest. 1999;104:93-102.

Rumsby MG, Trotter J, Allan D, Michell R. Recovery of membrane micro-vesicles from human erythrocytes stored for transfusion:a mechanism for the erythrocyte discocyte-to-spherocyte shape transformation. Biochem Soc Trans. 1977;5:126-28.

Card RT. Red cell membrane changes during storage. Transfus Med Rev. 1988;2:40-7.

Lang KS, Duranton C, Poehlmann H, Myssina S, Bauer C, Lang F et al. Cation channels trigger apoptotic death of erythrocytes. Cell Death Differ. 2003;10:249-56.

Barvitenko NN, Adragna NC, Weber RE. Erythrocyte signal transduction pathways,their oxygenation dependence and functional significance. Cell Physiol Biochem. 2005;15(1-4):1-18

Allan D, Michell RH. Calcium iondependent diacylglycerol accumulation in erythrocytes is associated with microvesiculation but not with efflux of potassium ions. Biochem J. 1977;166:495-99.

Niemoeller OM, Akel A, Lang PA, Attanasio P, Kempe DS, Hermle T et al. Induction of eryptosis by cyclosporine. Naunyn Schmiederbergs Arch Pharmacol. 2006;374:41-9.

Lang F, Gulbins E, Lerche H, Huber SM, Kempe DS, Foller M. Eryptosis, a window to systemic disease. Cell Physiol Biochem. 2008;22:373-80.

Tissot JD, Rubin O, Canellini G. Analysis and clinical relevance of microparticles from red blood cells. Curr Opin Hematol. 2010;17(6):571-7.

Shukla SD, Coleman R, Finean JB, Michell RH. The use of phospholipase c to detect structural changes in the membranes oh human erythrocytes aged by storage. Biochim Biophys Acta. 1978;512:341-9.

Antonelou MH, Kriebardis AG, Stamoulis KE, Economou-Petersen E, Margaritis LH, Papassideri IS. Red blood cell aging markers during storage in citrate-phosphate-dextrose-saline-adenine-glucose-mannitol. Transfusion. 2010;50:376-89.

Rubin O, Crettaz D, Tissot JD, Lion N. Microparticles in stored red blood cells:submicron clotting bombs? Blood Transfus. 2010;8(Suppl 3):s31-s38.

Bosman GJ, Lasonder E, Luten M, Roerdinkholder-Stoelwinder B, Novotny VM, Bos H, et al. The proteom of red cell membranes and vesicles during storage in blood bank conditions. Transfusion. 2008;48:827-35.

Kozuma Y, Sawahata Y, Takei Y, Chiba S, Ninomiya H. Procoagulant properties of microparticles released from red blood cells in paroxysmal nocturnal haemoglobinuria. Br J Haematol. 2011;152:631-9.

Bosman GJ. Erythrocyte aging in sickle cell disease. Cell Mol Biol. 2004;50:81-6.

van Beers EJ, Schaap MC, Berckmans RJ, Nieuwland R, Sturk A, van Doormaal FF, et al. Circulating erythrocyte-derived microparticles are associated with coagulation activation in sickle cell disease. Haematologica. 2009;94:1513-9.

Tung JP, Fung YL, Nataatmadja M, Colebourne KI, Esmaeel HM, Wilson K, et al. A novel in vivo ovine model of transfusion-related acute lung injury(TRALI). Vox Sang. 2011;100:219-30.

Tung JP, Fraser JF, Nataamadja M, Barnett, Adrian G, Colebourne, et al. Dissimilar respiratory and hemodynamic response in TRALI induced by stored cells and whole blood platelets. Blood. 2010;116:484-5.

Greenwalt TJ. The how and why of exocytic vesicles. Transfusion. 2006;46:143-52.

Oreskovic RT, Dumaswala UJ, Greenwalt TJ. Expression of blood group antigens on red cell microvesicles. Transfusion. 1992;32:848-9.

Liu R, Klich I, Ratajczak J, Ratajczak MZ, Zuba-Surma EK. Erythrocyte-derived microvesicles may transfer phosphatidylserine to the surface of nucleated cells and falsely“mark” them as apoptotic. Eur J Haematol. 2009;83:220-9.

Shrivastava M. The platelet storage lesion. Transfus Apher Sci. 2009;41:105-13.

George JN, Pickett EB, Heinz R. Platelet membrane glycoprotein changes during the preparation and storage of platelet concentrates. Transfusion. 1988;28:123-6.

Lynch SF, Ludlam CA. Plasma microparticles and vascular disorders. Br J Haematol. 2007;137:36-48.

Simak J, Gelderman MP. Cell membrane microparticles in blood products:potentially pathogenic agents and diagnostic markers. Transfus Med Rev. 2006;20:1-26.

Saas P, Angelot F, Bardiaux L, Seilles E, Garnache-Ottou F, Perruche S. Phosphatidylserine expressing cell by products in transfusion: A pro-inflammatory or an anti-inflammatory effect? Transfus Clin Biol. 2012;19:90-7.

Garcia BA, Smalley DM, Cho H, Shabanowitz J, Ley K, Hunt DF. The platelet microparticle proteome. J Proteome Res. 2005;4:1516-21.

Boulanger CM, Amabile N, Tedqui A. Circulating microparticles: a potential prognostic marker for atherosclerotic vascular disease. Hypertension. 2006;48:180-6.

Michelsen AE, Brodin E, Brosstad F, Hansen JB. Increased level of platelet microparticles in survivors of myocardial infarction. Sc Clin Lab Invest. 2008;68:386-92.

Giesen PL, Rauch U, Bohrmann B, Kling D, Roque M, Fallon JT, et al. Blood-borne tissue factor: another view of thrombosis. Proc Natl Acad Sci U S A. 1999;96:2311-5.

Zwaal RF, Comfurius P, Bevers EM. Scott syndrome, a bleeding disorder caused by defective scrambling of membrane phospholipids. Biochim Biophys Acta. 2004;1636:119-28.

Zwaal RF, Schroit AJ. Pathophysiologic implications of membrane phospholipid asymmetry in blood cell. Blood. 1997;89:1121-32.

Kim HK, Song KS, Chung JH, Lee KR, Lee SN. Platelet microparticles induce angiogenesis in vitro. Br J Haematol. 2004;124:376-84.

Falanga A, Tartari CJ, Marchetti M. Microparticles in tumor progression. Thromb Res. 2012;129 Suppl 1 :s132-6.

Toth B, Liebhardt S, Steinig K, Ditsch N, Rank A, Bauerfeind I, et al. Platelet-derived microparticles and coagulation activation in breast cancer patients. Thromb Haemost. 2008;100:663-9.

Boilard E, Nigrovic PA, Larabee K, Watts GF, Coblyn JS, Weinblatt ME et al. Platelets amplify inflammation in arthritis via collagen-dependent microparticle production. Science. 2010;327:580-3.

Lawrie AS, Harrison P, Cardigan RA, Mackie IJ. The characterization and impact of microparticles on haemostasis within fresh-frozen plasma. Vox Sang. 2008;95:197-204.

Krailadsiri P, Seghatchian J, Macgregor I, Drummond O, Perrin R, Spring F, et all. The effects of leukodepletion on the generation and removal of microvesicles and prion protein in blood components. Transfusion. 2006;46:407-17.

Lawrie AS, Cardigan RA, Williamson LM, Machin SJ, Mackie IJ. The dynamics of clot formation in fresh-frozen plasma. Vox Sang. 2008;94:306-14.

Quesenberry PJ, Aliotta JM. The paradoxical dynamism of marrow stem cells:considerations of stem cells, niches and microvesicles. Stem Cell Rev. 2008;4:137-47.

Ratajczak J, Miekus K, Kucia M, Zhang J, Reca R, Dvorak P, et al. Embryonic stem cell-derived microvesicles reprogram hematopoietic progenitors:evidence for horizontal transfer of mRNA and protein delivery. Leukemia. 2006;20:847-56.

Rožman P, Jež M. Matične celice in napredno zdravljenje (zdravljenje s celicami, gensko zdravljenje in tkivno inženirstvo. Pojmovnik:Celjska Mohorjeva družba; 2011:289.

Bruno S, Grange C, Deregibus MC, Calogero RA, Saviozzi S,Collino F, et al. Mesenchymal stem cell-derived microvesicles protect against acute tubular injury. J Am Soc Nephrol. 2009;20:1053-67.

Timmers L, Lim SK, Arslan F, Armstrong JS, Hoefer IE, Doevendans PA et al. Reduction of myocardial infarct size by human mesenchymal stem cell conditioned medium. Stem Cell Res. 2007;1:129-37.

Lai RC, Chen TS, Lim SK. Mesenchymal stem cell exosome: a novel stem cell-based therapy for cardiovascular disease. Regen Med. 2011;6:481-92.

Herrera MB, Fonsato V, Gatti S, Deregibus MC, Sordi A, Cantarella D, et al. Human liver stem cell-derived microvesicles accelerate hepatic regeneration in hepatectomized rats. J Cell Mol Med. 2010;14:1605-18.

How to Cite
Krstova Krajnc E, Jež M, Rožman P. Extracellular membrane vesicles in blood products-biology and clinical relevance. ZdravVestn [Internet]. 14Jan.2016 [cited 23Aug.2019];84(12). Available from: https://vestnik.szd.si/index.php/ZdravVest/article/view/1345