urn:nbn:de:hebis:04-z2015-05981 whole blood German Verformbarkeit Vollblut Bluttransfusion Blutströmung ths Prof. Dr. med., M. Sc. Karger Ralf Karger, Ralf (Prof. Dr. med., M. Sc.) 2015-12-16 Einfluss einer kontrollierten Stabilisatorzuführung während der Spende auf die Lagerungseigenschaften leukozytendepletierten Vollblutes Blutsammlungsschaden https://archiv.ub.uni-marburg.de/diss/z2015/0598/cover.png Medizin Rheologie lesion of storage 2015-11-16 Aggregation opus:6453 Philipps-Universität Marburg The influence of maintaining the correct whole blood-to-anticoagulant ratio during donation on the quality of leukoreduced whole blood Gerinnung Erythrozyten Hintergrund: Die Transfusion von Blutkomponenten und Vollblut ist ein essentieller Bestandteil lebensrettender und lebenserhaltender Maßnahmen. In den entwickelten Industrienationen erfolgte in den 1970er und 1980er Jahren der Übergang von der Vollblutspende zur Blutkomponentenspende. Die Vollblutspende hat jedoch weiterhin einen Stellenwert bei der autologen Eigenblutspende und in Ländern der dritten Welt, in welchen die logistischen Gegebenheiten für die aufwendige Blutkomponentenspende nicht vorliegen. Zudem gewinnt in heutiger Zeit die Verwendung von – insbesondere frischem – Vollblut im klinischen Zustand einer massiven Hämorrhagie, im schweren hämorrhagischen Schock als auch bei einer Koagulopathie wieder vermehrt an Interesse. In der transfusionsmedizinischen Forschung bestehen fortwährend Bemühungen, die Qualität von Blutprodukten stetig weiter zu verbessern und somit auch die Dauer ihrer Lagerungsfähigkeit auszuweiten. Gibson et al. beschrieben 1956 den so genannten Sammlungsschaden („lesion of collection“). Bei der Blutsammlung in dem Antikoagulanz- und Konservierungsmedium ACD zeigten die Erythrozyten in den ersten 100 ml ein deutlich geringeres Posttransfusionsüberleben als der Durchschnitt aller Erythrozyten der gesamten Transfusionseinheit. Gibson et al. führten diese Beobachtung auf die schädigende Wirkung der hohen Citrat-Konzentration der in den Blutbeuteln vorgelegten ACD-Lösung zurück (1). Später registrierten Matthes et al. bei Blutsammlung mit dem Zellseparator MCS 3P® (Haemonetics Corp., USA), einem Apherese-system, eine bessere Bewahrung der erythrozytären ATP- und 2,3-DPG-Konzentrationen im Vergleich zur Blutsammlung mittels konventioneller Blutsammelwaagen (2). Bei der Apheresetechnik wird das gesammelte Blut kontinuierlich mit der Antikoagulanzlösung in einem konstanten Konzentrationsverhältnis vermischt und stellt somit eine schonendere Blutsammlung dar. Ausgehend von diesen Beobachtungen bestand die Fragestellung der vorliegenden ABC-Studie darin, ob durch die kontinuierliche Zuführung des Antikoagulanz- und Konservierungsmediums CPDA-1 zum gesammelten Vollblut die Qualität des anschließend gelagerten Vollblutes besser bewahrt werden könnte als bei Vollblut, das in einen Blutbeutel mit einer vorgelegten CPDA-1-Antikoagulanzlösung gesammelt wird. Da sich in jüngerer Zeit Studien mehren, in welchen negative Auswirkungen von Bluttransfusionen auf den Empfängerorganismus, eine erhöhte Morbidität und Mortalität publiziert wurden, welche möglicherweise auf die intrinsischen Eigenschaften der gelagerten Erythrozyten mit Beeinträchtigung der Mikrozirkulation zurückzuführen sind, wurden in der vorliegenden Studie rheologische Untersuchungen der Erythrozyten-verformbarkeit und Erythrozytenaggregation eingeschlossen. Material und Methoden: Die als randomisierte Kontrollstudie konzipierte Untersuchung umfasste in beiden Gruppen jeweils 20 Untersuchungseinheiten. In der ABC-Gruppe wurde Vollblut mit der ABC®-Waage (MacoPharma, Frankreich) gewonnen. Bei der ABC®-Waage wurde mittels eines Rollerpumpensystems die CPDA-1-Lösung kontinuierlich in gleichbleibender Konzentration dem gewonnen Vollblut beigemengt. Die Blutsammlung in der konventionellen Gruppe erfolgte mit der Blutentnahmewaage Compomixer M2® (Fresenius HemoCare, Deutschland), bei der mithilfe der Schwerkraft Spendeblut in einen mit CPDA-1-Antikoagulanzlösung vorgelegten Beutel floss. Anschließend erfolgte nach zwei Stunden bei allen Untersuchungseinheiten eine Leukozytendepletion. Der Untersuchungszeitraum erstreckte sich über 49 Lagerungstage. An den Lagerungstagen 1, 7, 21, 35, 42 und 49 wurden die Werte folgender Parameter im Vollblut bestimmt: pH-Wert, Glukose, ATP, 2,3-DPG (bis zum Tag 42), Hb, freies Hb, K+ sowie die Gerinnungszeiten TT, PT und aPTT, Faktor-V-Aktivität, Faktor-VIII-Aktivität, Fibrinogen, AT, D-Dimere und TAT-Komplexe. Die rheologischen Untersuchungen erfolgten mit dem LORCA™ (R + R Mechatronics, Niederlande). Die Verformbarkeit der Erythrozyten wurde mit dem Elongationsindex, die Aggregation mit dem Aggregationsindex beschrieben. Am ersten Untersuchungstag wurde einmalig der Restleukozytengehalt der leukozytendepletierten Vollblutkonserven bestimmt. Zudem wurden die beiden Gruppen hinsichtlich der Präzision des durch die Blutwaagen erzielten Spendevolumens, der Dauer der Blutspende und der Dauer der Leukozytendepletion verglichen. Ergebnisse: Mit beiden Blutwaagesystemen wurden annähernd gleiche Sammelvolumina erzielt, 525 (SD 5,3) ml in der ABC-Gruppe und 524 (SD 10,2) ml in der konventionellen Gruppe. Die Hb-Konzentrationen der Blutkonserven zeigten sich in beiden Untersuchungsgruppen mit 65,9 (SD 5,1) g pro Konserve in der ABC-Gruppe bzw. 67,5 (SD 7,8) g pro Konserve in der konventionellen Gruppe nahezu gleich. In der konventionellen Gruppe fanden sich jedoch eine signifikant höhere Variation der Konservenvolumina (p = 0,006), eine signifikant höhere Variation bei dem durch den Filtrationsprozess verursachten Blutverlust (p = 0,0002) und zudem eine Tendenz zu einer höheren Variation des Hb-Gehaltes pro Blutkonserve (p = 0,07). Die untersuchten Qualitätsparameter unterschieden sich in beiden Untersuchungsgruppen nicht signifikant voneinander. Die Konzentrationen von freiem Hb und K+ wiesen in der konventionellen Gruppe eine signifikant höhere Variation auf (p = 0,04), die Konzentration von Glukose zeigte eine Tendenz zu einer höheren Variation in der konventionellen Gruppe (p = 0,07). Die mittlere ATP-Konzentration betrug am 42. Lagerungstag in der ABC-Gruppe 2,33 (SD 0,41) µmol/g Hb versus 2,24 (SD 0,39) µmol/g Hb in den konventionellen Gruppe. In beiden Untersuchungsgruppen fanden sich eine Abnahme der Verformbarkeit und eine Verminderung der Aggregationsneigung der Erythrozyten. Der Aggregationsindex war in der konventionellen Gruppe höher als in der ABC-Gruppe (p = 0,056). Bis zum 21. Lagerungstag war diese Differenz signifikant (p = 0,03), verminderte sich aber gegen Ende des Untersuchungszeitraumes. Schlussfolgerung: Die klinische Einordnung der beobachteten rheologischen Veränderungen ist vor dem Hintergrund des heutigen Standes der Wissenschaft schwierig. Sowohl die Aggregationsfähigkeit als auch die Verformbarkeit der Erythrozyten bestimmen maßgeblich die Strömungseigenschaften des Blutes. Eine Abnahme der Verformbarkeit könnte zu einer vermehrten Sequestrierung der weniger flexiblen Erythrozyten in der Milz, aber auch in der Leber, der Lunge und dem Sternum führen. Bei Eintritt weniger verformbarer Erythrozyten in kleinste Blutgefäße wird ein größerer Perfusionsdruck benötigt und der Strömungswiderstand steigt an. Möglicherweise könnte es auch zu einer kompletten Verlegung kleinster Gefäße kommen, die FCD (functional capillary density, funktionelle kapillare Dichte) könnte sich vermindern und die O2-Versorgung der Gewebe eingeschränkt werden. Zudem wird bei Abnahme der Verformbarkeit durch Einschränkung des „tank-treadings“ und der Fähigkeit, sich zu Ellipsen auszudehnen, das Strömungsprofil des Blutes gestört. Eine erhöhte Aggregationsneigung steht in Zusammenhang mit einer ungünstigen Beeinflussung des Strömungswiderstandes, des Strömungsprofils und der Blutviskosität. Bei einer verstärkten Aggregationsneigung bedarf es eines höheren Energieaufwandes, um Aggregate aufzulösen. Die FCD könnte sich vermindern und durch größere Aggregate könnten Gefäße ganz verlegt werden. Insofern könnte sich eine verminderte Aggregation durchaus günstig auf das Strömungsverhalten des Blutes und die O2-Versorgung in der Mikrozirkulation auswirken. Auf der anderen Seite scheint aber eine bestimmte Aggregationsstärke zur Aufrechterhaltung der mikrozirkulatorischen Perfusion notwendig zu sein. Neben rheologischen Veränderungen bestehen zahlreiche weitere, v. a. immunologische Veränderungen, welche für die negativen Auswirkungen von Bluttransfusionen verantwortlich sein könnten. Zusammenfassend lässt sich aus den Ergebnissen der vorliegenden ABC-Studie schließen, dass die ABC®-MacoPharma-Waage ein besser standardisiertes Blutprodukt liefert. Ein Überschuss der Antikoagulanzlösung CPDA-1 am Beginn der Blutsammlung scheint die Qualität der Lagerungsparameter nicht signifikant zu beeinflussen. Quellen 1. Gibson JG, 2nd, Murphy WP, Jr., Rees SB, and Scheitlin WA. The influence of extracelluar factors involved in the collection of blood in ACD on maintenance of red cell viability during refrigerated storage. Am J Clin Pathol 26: 855-873, 1956. 2. Matthes G, Tofote U, Krause KP, Pawlow I, Kucera W, and Lerche D. Improved red cell quality after erythroplasmapheresis with MCS-3P. J Clin Apher 9: 183-188, 1994. 2015 doctoralThesis application/pdf Publikationsserver der Universitätsbibliothek Marburg Universitätsbibliothek Marburg Lukow, Christian Lukow Christian Medizin erythrocyte deformability Blutspende, Koagulation https://doi.org/10.17192/z2015.0598 erythrocyte aggregation Blutlagerungsschaden Background: It is unclear whether maintaining the correct whole blood-to-anticoagulant (WB : AC) ratio during collection can improve the quality of red blood cell (RB.C)-containing blood products to a clinically relevant degree. Study design and methods: A total of 2 x 20 CPDA-1 leukoreduced whole blood units suspended in CPDA-1 were investigated. In one group, the anticoagulation was continuously added to the donated blood, maintaining the correct WB : AC ratio during collection, using a new drawing device (MacoPharma ABC®). In the other group, WB units were produced conventionally. ATP, 2,3-DPG, free Hb, K+, glucose, lactate, pH and variables of coagulation were determined on Days 1, 7, 21, 35, 42, and 49 of storage. Variables of RBC deformability and aggregability were determined using a laser-assisted optical rotational cell analyzer (LORCA™). Results: The ABC and the conventional group showed comparable unit volumes of 525 (SD 5,3) ml versus 524 (SD 10,2) ml and Hb content of 65,9 (SD 5,1) g/unit versus 67,5 (SD 7,8) g/unit, but higher variation after conventional blood drawing (p = 0,006 and p = 0,07, respectively) was observed. During storage, none of the measured quality variables were significantly different between the groups, but in the conventional group there was a higher variation for fHb and K+ (p = 0,04), as well a tendency for a higher variation in the glucose-concentration (p = 0.07). Mean (SD) ATP was 2,33 (0,41) µmol/g Hb versus 2,24 (0,39) µmol/g Hb after 42-day storage. Deformability was not different (p = 0,44), whereas the extent of the aggregation was higher in the conventional group. Conclusion: The ABC device provided a better standardized blood product but did not improve RBC storage variables or plasma quality. Excess anticoagulant CPDA-1 at the beginning of a donation appears not to significantly affect RBC storage in conventional blood drawing. It is unclear whether the lower degree of aggregation in the ABC-Group means to be of any advance for the recipients or may even has adverse effects. monograph Medical sciences Medicine Medizin lesion of collection Simchon S, Jan KM, and Chien S. Influence of reduced red cell deformability on regional blood flow. The American journal of physiology 253: H898-903, 1987. Soutani M, Suzuki Y, Tateishi N, and Maeda N. Quantitative evaluation of flow dynamics of erythrocytes in microvessels: influence of erythrocyte aggregation. The American journal of physiology 268: H1959-1965, 1995. Pearson MJ, and Lipowsky HH. Influence of erythrocyte aggregation on leukocyte margination in postcapillary venules of rat mesentery. American journal of physiology Heart and circulatory physiology 279: H1460-1471, 2000. Yalcin O, Uyuklu M, Armstrong JK, Meiselman HJ, and Baskurt OK. Graded alterations of RBC aggregation influence in vivo blood flow resistance. American journal of physiology Heart and circulatory physiology 287: H2644-2650, 2004. Kim S, Popel AS, Intaglietta M, and Johnson PC. Aggregate formation of erythrocytes in postcapillary venules. Am J Physiol Heart Circ Physiol 288: H584-590, 2005. Tsai AG, Acero C, Nance PR, Cabrales P, Frangos JA, Buerk DG, and Intaglietta M. Elevated plasma viscosity in extreme hemodilution increases perivascular nitric oxide concentration and microvascular perfusion. Am J Physiol Heart Circ Physiol 288: H1730-1739, 2005. Kim S, Popel AS, Intaglietta M, and Johnson PC. Effect of erythrocyte aggregation at normal human levels on functional capillary density in rat spinotrapezius muscle. Am J Physiol Heart Circ Physiol 290: H941-947, 2006. Reglin B, Secomb TW, and Pries AR. Structural adaptation of microvessel diameters in response to metabolic stimuli: where are the oxygen sensors? American journal of physiology Heart and circulatory physiology 297: H2206-2219, 2009. Hemoglobin encapsulation in vesicles retards NO and CO binding and O2 release when perfused through narrow gas-permeable tubes. American journal of physiology Heart and circulatory physiology 298: H956-965, 2010. Spinella PC, Sparrow RL, Hess JR, and Norris PJ. Properties of stored red blood cells: understanding immune and vascular reactivity. Transfusion 51: 894-900, 2011. Lipowsky HH. Blood Rheology Aspects of the Microcirculation. In: Handbook of Hemorheology, edited by Baskurt OK, Hardeman MR, Rampling MW, and Meiselman HJ. Hardeman MR, Goedhart PT, and Shin S. Methods in Hemorheology. In: Handbook of Hemorheology and Hemodynamics, edited by Baskurt OK, and Meiselman HJ. Rainer C, Kawanishi DT, Chandraratna PA, Bauersachs RM, Reid CL, Rahimtoola SH, and Meiselman HJ. Changes in blood rheology in patients with stable angina pectoris as a result of coronary artery disease. Circulation 76: 15-20, 1987. Tuvia S, Levin S, Bitler A, and Korenstein R. Mechanical fluctuations of the membrane-skeleton are dependent on F-actin ATPase in human erythrocytes. The Journal of cell biology 141: 1551-1561, 1998. Sheetz MP, and Singer SJ. On the mechanism of ATP-induced shape changes in human erythrocyte membranes. I. The role of the spectrin complex. The Journal of cell biology 73: 638-646, 1977. Suresh S. Viscoelasticity of the human red blood cell. American journal of physiology Cell physiology 293: C597-605, 2007. Ziegler T, Silacci P, Harrison VJ, and Hayoz D. Nitric oxide synthase expression in endothelial cells exposed to mechanical forces. Hypertension 32: 351-355, 1998. Meiselman HJ. Red blood cell aggregation: 45 years being curious. Biorheology 46: 1-19, 2009. Yedgar S, Hovav T, and Barshtein G. Red blood cell intercellular interactions in oxidative stress states. Clinical hemorheology and microcirculation 21: 189-193, 1999. Lacroix J, Hebert P, Fergusson D, Tinmouth A, Blajchman MA, Callum J, Cook D, Marshall JC, McIntyre L, and Turgeon AF. The Age of Blood Evaluation (ABLE) randomized controlled trial: study design. Transfusion medicine reviews 25: 197-205, 2011. Spitalnik SL. Stored red blood cell transfusions: iron, inflammation, immunity, and infection. Transfusion 54: 2365-2371, 2014. Pantaleo A, Ferru E, Giribaldi G, Mannu F, Carta F, Matte A, de Franceschi L, and Turrini F. Oxidized and poorly glycosylated band 3 is selectively phosphorylated Quellen 228 by Syk kinase to form large membrane clusters in normal and G6PD-deficient red blood cells. The Biochemical journal 418: 359-367, 2009. MacLennan S, and Murphy MF. Survey of the use of whole blood in current blood transfusion practice. Clinical and laboratory haematology 23: 391-396, 2001. O'Donnell J, and Laffan MA. The relationship between ABO histo-blood group, factor VIII and von Willebrand factor. Transfus Med 11: 343-351, 2001. Luk CS, Gray-Statchuk LA, Cepinkas G, and Chin-Yee IH. WBC reduction reduces storage-associated RBC adhesion to human vascular endothelial cells under conditions of continuous flow in vitro. Transfusion 43: 151-156, 2003. Gov N. Less is more: removing membrane attachements stiffens the RBC cytoskeleton. New Journal of Physics 9: 2007. Lohman AW, Billaud M, and Isakson BE. Mechanisms of ATP release and signalling in the blood vessel wall. Cardiovascular research 95: 269-280, 2012. Walsh TS. Is stored blood good enough for critically ill patients? Crit Care Med 33: 238 -239, 2005. Vlaar AP, de Korte D, and Juffermans NP. The aged erythrocyte: key player in cancer progression, but also in infectious and respiratory complications of blood transfusion? Anesthesiology 111: 444, 2009. Spinella PC, and Doctor A. Role of transfused red blood cells for shock and coagulopathy within remote damage control resuscitation. Shock 41 Suppl 1: 30-34, 2014. Tsai AG, Cabrales P, and Intaglietta M. Microvascular perfusion upon exchange transfusion with stored red blood cells in normovolemic anemic conditions. Transfusion 44: 1626-1634, 2004. Jeanne M, Piquet Y, Ivanovic Z, Vezon G, and Salmi LR. Variations of factor VIII:C plasma levels with respect to the blood group ABO. Transfusion medicine 14: 187-188, 2004. Turner S, Williams AR, and Rees JM. The role of mean corpuscular haemoglobin concentration in limiting the storage life of human blood. Vox sanguinis 52: 177-181, 1987. Picker SM, Sturner SS, Oustianskaja L, and Gathof BS. Leucodepletion leads to component-like storage stability of whole blood--suggesting its homologous use? Vox sanguinis 87: 173-181, 2004. Verhoeven AJ, Hilarius PM, Dekkers DW, Lagerberg JW, and de Korte D. Prolonged storage of red blood cells affects aminophospholipid translocase activity. Vox sanguinis 91: 244-251, 2006. Raat NJ, and Ince C. Oxygenating the microcirculation: the perspective from blood transfusion and blood storage. Vox sanguinis 93: 12-18, 2007. Wood L, and Beutler E. The viability of human blood stored in phosphate adenine media. Transfusion 7: 401-408, 1967. Sparrow RL, and Patton KA. Supernatant from stored red blood cell primes inflammatory cells: influence of prestorage white cell reduction. Transfusion 44: 722-730, 2004. Hogman CF, and Meryman HT. Red blood cells intended for transfusion: quality criteria revisited. Transfusion 46: 137-142, 2006. Kriebardis AG, Antonelou MH, Stamoulis KE, Economou-Petersen E, Margaritis LH, and Papassideri IS. Storage-dependent remodeling of the red blood cell Quellen 223 membrane is associated with increased immunoglobulin G binding, lipid raft rearrangement, and caspase activation. Transfusion 47: 1212-1220, 2007. Kuruvilla DJ, Nalbant D, Widness JA, and Veng-Pedersen P. Mean remaining life span: a new clinically relevant parameter to assess the quality of transfused red blood cells. Transfusion 54: 2724-2729, 2014. Jiwaji Z, Nunn KP, Conway-Morris A, Simpson AJ, Wyncoll D, Rossi AG, and Walsh TS. Leukoreduced blood transfusion does not increase circulating soluble markers of inflammation: a randomized controlled trial. Transfusion 54: 2404-2411, 2014. Mohandas N, and Evans E. Mechanical properties of the red cell membrane in relation to molecular structure and genetic defects. Annu Rev Biophys Biomol Struct 23: 787- 818, 1994. Yalcin O, Ulker P, Yavuzer U, Meiselman HJ, and Baskurt OK. Nitric oxide generation by endothelial cells exposed to shear stress in glass tubes perfused with red blood cell suspensions: role of aggregation. American journal of physiology Heart and circulatory physiology 294: H2098-2105, 2008. Yedgar S, Koshkaryev A, and Barshtein G. The red blood cell in vascular occlusion. Pathophysiol Haemost Thromb 32: 263-268, 2002. Wiebecke D, Fischer K, Keil G, Leibling R, Reissigl H, and Stangel W. Zur Geschichte der Transfusionsmedizin in der ersten Hälfte des 20. Jahrhunderts (unter der besonderen Berücksichtigung ihrer Entwicklung in Deutschland). Transfus Med Hemother 31: 12-31, 2004. Pirrelli A. Arterial hypertension and hemorheology. What is the relationship? Clinical hemorheology and microcirculation 21: 157-160, 1999. Hardeman MR, and Ince C. Clinical potential of in vitro measured red cell deformability, a myth? Clinical hemorheology and microcirculation 21: 277-284, 1999. Izzo P, Manicone A, Spagnuolo A, Lauta VM, Di Pasquale A, and Di Monte D. Erythrocytes stored in CPD SAG-mannitol: evaluation of their deformability. Clinical hemorheology and microcirculation 21: 335-339, 1999. Neu B, Armstrong JK, Fisher TC, and Meiselman HJ. Aggregation of human RBC in binary dextran-PEG polymer mixtures. Biorheology 38: 53-68, 2001. Werre JM, Willekens FL, Bosch FH, de Haans LD, van der Vegt SG, van den Bos AG, and Bosman GJ. The red cell revisited--matters of life and death. Cellular and molecular biology 50: 139-145, 2004. Vaya A, Camara R, Hernadez-Mijares A, Romagnoli M, Sola E, Corella D, and Laiz B. Erythrocyte deformability in morbid obesity before bariatric surgery. Steiner ME, Ness PM, Assmann SF, Triulzi DJ, Sloan SR, Delaney M, Granger S, Bennett-Guerrero E, Blajchman MA, Scavo V, Carson JL, Levy JH, Whitman G, D'Andrea P, Pulkrabek S, Ortel TL, Bornikova L, Raife T, Puca KE, Kaufman RM, Nuttall GA, Young PP, Youssef S, Engelman R, Greilich PE, Miles R, Josephson CD, Bracey A, Cooke R, McCullough J, Hunsaker R, Uhl L, McFarland JG, Park Y, Cushing MM, Klodell CT, Karanam R, Roberts PR, Dyke C, Hod EA, and Stowell CP. Effects of red-cell storage duration on patients undergoing cardiac surgery. The New England Journal of Medicine 372: 1419-1429, 2015. Johnson RM. pH effects on red cell deformability. Blood Cells 11: 317-321, 323-314, 1985. Haradin AR, Weed RI, and Reed CF. Changes in physical properties of stored erythrocytes relationship to survival in vivo. Transfusion 9: 229-237, 1969. Neumeister B, Grauer M, Koch M, Hornlein R, Dinkelmann S, Bernhard R, Haap M, and Northoff H. [Effects of leukocyte depletion on the storage quality of whole blood]. Anaesthesist 46: 979-982, 1997. Sakr Y, Chierego M, Piagnerelli M, Verdant C, Dubois MJ, Koch M, Creteur J, Gullo A, Vincent JL, and De Backer D. Microvascular response to red blood cell transfusion in patients with severe sepsis. Crit Care Med 35: 1639-1644, 2007. Willekens FL, Werre JM, Kruijt JK, Roerdinkholder-Stoelwinder B, Groenen- Dopp YA, van den Bos AG, Bosman GJ, and van Berkel TJ. Liver Kupffer cells rapidly remove red blood cell-derived vesicles from the circulation by scavenger receptors. Blood 105: 2141-2145, 2005. Neumann FJ, Katus HA, Hoberg E, Roebruck P, Braun M, Haupt HM, Tillmanns H, and Kubler W. Increased plasma viscosity and erythrocyte aggregation: indicators of an unfavourable clinical outcome in patients with unstable angina pectoris. Br Heart J 66: 425-430, 1991. Somer T, and Meiselman HJ. Disorders of blood viscosity. Ann Med 25: 31-39, 1993. Ju M, Ye SS, Low HT, Zhang J, Cabrales P, Leo HL, and Kim S. Effect of deformability difference between two erythrocytes on their aggregation. Phys Biol 10: 036001, 2013. Reid HL, Barnes AJ, Lock PJ, Dormandy JA, and Dormandy TL. A simple method for measuring erythrocyte deformability. Journal of clinical pathology 29: 855-858, 1976. Jensen FB. The dual roles of red blood cells in tissue oxygen delivery: oxygen carriers and regulators of local blood flow. J Exp Biol 212: 3387-3393, 2009. Salaria ON, Barodka VM, Hogue CW, Berkowitz DE, Ness PM, Wasey JO, and Frank SM. Impaired red blood cell deformability after transfusion of stored allogeneic blood but not autologous salvaged blood in cardiac surgery patients. Anesthesia and analgesia 118: 1179-1187, 2014. Walsh TS, McArdle F, McLellan SA, Maciver C, Maginnis M, Prescott RJ, and McClelland DB. Does the storage time of transfused red blood cells influence regional or global indexes of tissue oxygenation in anemic critically ill patients? Critical care medicine 32: 364-371, 2004. Keller ME, Jean R, LaMorte WW, Millham F, and Hirsch E. Effects of age of transfused blood on length of stay in trauma patients: a preliminary report. The Journal of trauma 53: 1023-1025, 2002. Weinberg JA, McGwin G, Jr., Griffin RL, Huynh VQ, Cherry SA, 3rd, Marques MB, Reiff DA, Kerby JD, and Rue LW, 3rd. Age of transfused blood: an independent predictor of mortality despite universal leukoreduction. The Journal of trauma 65: 279-282; discussion 282-274, 2008. Kiraly LN, Underwood S, Differding JA, and Schreiber MA. Transfusion of aged packed red blood cells results in decreased tissue oxygenation in critically injured trauma patients. The Journal of trauma 67: 29-32, 2009. Villela NR, Cabrales P, Tsai AG, and Intaglietta M. Microcirculatory effects of changing blood hemoglobin oxygen affinity during hemorrhagic shock resuscitation in an experimental model. Shock 31: 645-652, 2009. Strandenes G, De Pasquale M, Cap AP, Hervig TA, Kristoffersen EK, Hickey M, Cordova C, Berseus O, Eliassen HS, Fisher L, Williams S, and Spinella PC. Emergency whole-blood use in the field: a simplified protocol for collection and transfusion. Shock 41 Suppl 1: 76-83, 2014. Meyerstein N, Mazor D, and Dvilansky A. Erythrocyte agglomeration and survival studies in citrate-phosphate-dextrose (CPD) units. Blut 39: 211-216, 1979. Namgung B, Ong PK, Johnson PC, and Kim S. Effect of cell-free layer variation on arteriolar wall shear stress. Ann Biomed Eng 39: 359-366, 2011. Pries AR, and Secomb TW. Microcirculatory network structures and models. Annals of Biomedical Engineering 28: 916-921, 2000. Greenwalt TJ, Steane EA, Lau FO, and Sweeney-Hammond K. Aging of the human erythrocyte. Progress in clinical and biological research 43: 195-212, 1980. Secomb TW, and Pries AR. Basic Principles of Hemodynamics. In: Handbook of Hemorheology and Hemodynamics, edited by Baskurt OK, Hardeman MR, Rampling MW, and Meiselman HJ. Amstersam: IOS Press, 2007, p. 289 -306. Lamprecht W, and Trautschold I. ATP, Bestimmung mit Hexokinase und Glukose-g-phosphat-Dehydrogenase. In: Methoden der Enzymatischen Analyse edited by Bergmeyer HU. Weinheim: Verlag Chemie, 1974, p. 2151–2160. Klinikum der Philipps-Universität Marburg IfTuH. Bestimmung von freiem Hämoglobin (Verfahrensanweisung). Klinikum der Philipps-Universität Marburg, 2005. Heim MU. [Blood, blood components and plasma derivatives. Guideline-based implementation]. Med Klin Intensivmed Notfmed 106: 183-188, 2011. Hess B, and Brand K. Cell and Tissue Disintegration -General. In: Methods of Enzymatic Analysis, edited by Bergmeyer HU, Bergmeyer J, and Graßl M. Weinheim, Deutschland: VCH Verlagsgesellschaft, 1988, p. 26 -30. Isbister JP. Hyperviscosity: Clinical Disorders. In: Handbook of Hemorheology and Hemodynamics, edited by Baskurt OK, Hardeman MR, Rampling MW, and Meiselman HJ. Influence of abdominal obesity. Clin Hemorheol Microcirc 46: 313-320, 2010. Rampling MW. Compositional Properties of Blood. In: Handbook of Hemorheology, edited by Baskurt OK, Hardeman MR, Rampling MW, and Meiselman HJ. Amsterdam, NL: IOS Press, 2007, p. 34-44. Hoffbrand AV, Lewis SM, and Tuddenham EGD. Inherited haemolytic anaemias. In: Postgraduate Haematology. Oxford: Butterworth-Heinemann, 1999, p. 120-143. Rolf-Greiner-BioChemica. ATP Hexokinase. In: Reagenz für die quantitative in vitro- Bestimmung von ATP in Blut und Erythrozytenkonzentraten mit der Hexokinase-Methode an photometrischen SystemenRolf Greiner BioiChemica, 2004. von Bormann B. Klinische Aspekte der Therapie mit Erythrozyten, "Leasons learnes" von den Zeugen Jehovahs? Der Anaesthesist 56: 380-384, 2007. Hardeman MR, Goedhart PT, Dobbe JGG, and Lettinga KP. Laser-assisted optical rotational cell analyser (L.O.R.C.A.); I. A new instrument for measurement of various structural hemorheological parameters. Clinical Hemorheology 14: 605 -618, 1994. Neu B, and Meiselman HJ. Macromolecular depletion as a determinant of RBC adhesive interactions: why blood is thicker than water. Biorheology 51: 91-97, 2014. Wang X, Zhao H, Zhuang FY, and Stoltz JF. Measurement of erythrocyte deformability by two laser diffraction methods. Clinical hemorheology and microcirculation 21: 291-295, 1999. Huruta RR, Barjas-Castro ML, Saad ST, Costa FF, Fontes A, Barbosa LC, and Cesar CL. Mechanical properties of stored red blood cells using optical tweezers. Blood 92: 2975-2977, 1998. Lang KS, Lang PA, Bauer C, Duranton C, Wieder T, Huber SM, and Lang F. Mechanisms of suicidal erythrocyte death. Cell Physiol Biochem 15: 195-202, 2005. In: Bergmeyer, Methods of Enzymatic AnalysisVCH Verlagsgesellschaft mbH, 1989, p. 346-357. Ling E, Danilov YN, and Cohen CM. Modulation of red cell band 4.1 function by cAMP-dependent kinase and protein kinase C phosphorylation. J Biol Chem 263: 2209- 2216, 1988. Klein HG. Mollison's Blood Transfusion in Clinical Medicine. Blackwell Publishing, 2005. Simmonds MJ, Detterich JA, and Connes P. Nitric oxide, vasodilation and the red blood cell. Biorheology 51: 121-134, 2014. Tateishi N, Suzuki Y, Cicha I, and Maeda N. O(2) release from erythrocytes flowing in a narrow O(2)-permeable tube: effects of erythrocyte aggregation. American journal of physiology Heart and circulatory physiology 281: H448-456, 2001. Vicaut E. Opposite effects of red blood cell aggregation on resistance to blood flow. J Cardiovasc Surg (Torino) 36: 361-368, 1995. Rapoport S, and Wing M. Dimensional, Osmotic, and Chemical Changes of Erythrocytes in Stored Blood. I. Blood Preserved in Sodium Citrate, Neutral, and Acid Citrate-Glucose (Acd) Mixtures. J Clin Invest 26: 591-615, 1947. Stefanovic M, Puchulu-Campanella E, Kodippili G, and Low PS. Oxygen regulates the band 3-ankyrin bridge in the human erythrocyte membrane. The Biochemical journal 449: 143-150, 2013. Tsai AG, Hofmann A, Cabrales P, and Intaglietta M. Perfusion vs. oxygen delivery in transfusion with "fresh" and "old" red blood cells: the experimental evidence. Transfus Apher Sci 43: 69-78, 2010. Moroff G, Sohmer PR, and Button LN. Proposed standardization of methods for determining the 24-hour survival of stored red cells. Transfusion 24: 109-114, 1984. von Bormann B, Wirtz S, Weiler J, von Bormann C, and Trobisch H. [Quality of whole blood as a result of storage and preparation (inline-leukocyte depletion). Evidence for autologous predeposit]. Anasthesiol Intensivmed Notfallmed Schmerzther 35: 326-332, 2000. Neu B, and Meiselman HJ. Red blood cell aggregation. In: Handbook of hemorheology and hemodynamics, edited by Baskurt OK, Hardeman MR, Rampling MW, and Meiselman HJ. Amsterdam, Berlin, Oxford, Tokyo, Washingthon DC: IOS Press, 2007, p. 114 -136. Rubin O, Canellini G, Delobel J, Lion N, and Tissot JD. Red blood cell microparticles: clinical relevance. Transfusion medicine and hemotherapy : offizielles Organ der Deutschen Gesellschaft fur Transfusionsmedizin und Immunhamatologie 39: 342-347, 2012. Hess JR. Red cell storage: when is better not good enough? Blood transfusion = Trasfusione del sangue 7: 172-173, 2009. Pries AR, Secomb TW, Gessner T, Sperandio MB, Gross JF, and Gaehtgens P. Resistance to blood flow in microvessels in vivo. Circulation research 75: 904-915, 1994. Hsia CC. Respiratory function of hemoglobin. The New England Journal of Medicine 338: 239-247, 1998. Kirby BS, Hanna G, Hendargo HC, and McMahon TJ. Restoration of intracellular ATP production in banked red blood cells improves inducible ATP export and suppresses RBC-endothelial adhesion. American journal of physiology Heart and circulatory physiology 307: H1737-1744, 2014. Meiselman HJ. Rheology of shape-transformed human red cells. Biorheology 15: 225-237, 1978. Siemens-Healthcare-Diagnostics-Products-GmbH. Wagner GM, Chiu DT, Qju JH, Heath RH, and Lubin BH. Spectrin oxidation correlates with membrane vesiculation in stored RBCs. Blood 69: 1777-1781, 1987. Ranney HM, and Sharma V. Structure and function of hemoglobin In: Williams Hematology, edited by Beutler E, Lichtman MA, Coller BS, Kipps TJ, and Seligsohn UMcGraw-Hill Professional, 2000. Hogman CF, de Verdier CH, and Borgstrom L. Studies on the mechanism of human red cell loss of viability during storage at +4 degrees C. II. Relation between cellular morphology and viability. Vox Sang 52: 20-23, 1987. Zijlstra WG. Syllectometry, a new method for studying rouleaux formation of red blood cells. Netherlands society for physiology and pharmacology 8: 153-154, 1957. Hardeman MR, Dobbe JG, and Ince C. The Laser-assisted Optical Rotational Cell Analyzer (LORCA) as red blood cell aggregometer. Clinical hemorheology and microcirculation 25: 1-11, 2001. Roy TK, Pries AR, and Secomb TW. Theoretical comparison of wall-derived and erythrocyte-derived mechanisms for metabolic flow regulation in heterogeneous microvascular networks. American journal of physiology Heart and circulatory physiology 302: H1945-1952, 2012. Weinberg JA, McGwin G, Jr., Marques MB, Cherry SA, 3rd, Reiff DA, Kerby JD, and Rue LW, 3rd. Transfusions in the less severely injured: does age of transfused blood affect outcomes? The Journal of trauma 65: 794-798, 2008. Thurston GB, and Henderson NM. Viscoelasticity of Human Blood. In: Handbook of Hemorheology and Hemodynamics, edited by Baskurt OK, Hardeman MR, Rampling MW, and Meiselman HJ. Amsterdam: IOS Press, 2007, p. 72 -90. Murdock AD, Berseus O, Hervig T, Strandenes G, and Lunde TH. Whole blood: the future of traumatic hemorrhagic shock resuscitation. Shock 41 Suppl 1: 62-69, 2014. Regan F, Teesdale P, Garner S, Callaghan T, Brennan M, and Contreras M. Comparison of in vivo red cell survival of donations collected by Haemonetics MCS versus conventional collection. Transfusion medicine 7: 25-28, 1997. Meyerstein N, Mazor D, and Dvilansky A. Changes in agglomeration of human red blood cells in liquid storage in CPD media. Transfusion 17: 115-122, 1977. Nilsson L, Hedner U, Nilsson IM, and Robertson B. Shelf-life of bank blood and stored plasma with special reference to coagulation factors. Transfusion 23: 377-381, 1983. Wolfe LC. The membrane and the lesions of storage in preserved red cells. Transfusion 25: 185-203, 1985. Hughes C, Thomas KB, Schiff P, Herrington RW, Polacsek EE, and McGrath KM. Effect of delayed blood processing on the yield of factor VIII in cryoprecipitate and factor VIII concentrate. Transfusion 28: 566-570, 1988. Heddle NM, Klama LN, Griffith L, Roberts R, Shukla G, and Kelton JG. A prospective study to identify the risk factors associated with acute reactions to platelet and red cell transfusions. Transfusion 33: 794-797, 1993. Hovav T, Yedgar S, Manny N, and Barshtein G. Alteration of red cell aggregability and shape during blood storage. Transfusion 39: 277-281, 1999. Laine E, Steadman R, Calhoun L, Blackall D, Levin P, Braunfeld M, Nourmand H, Neelakanta G, Ting L, Gornbein J, Busuttil R, and Petz L. Comparison of RBCs and FFP with whole blood during liver transplant surgery. Transfusion 43: 322-327, 2003. Heiden M, Salge U, Henschler R, Pfeiffer HU, Volkers P, Hesse J, Sireis W, and Seitz R. Plasma quality after whole-blood filtration depends on storage temperature and filter type. Transfus Med 14: 297-304, 2004. Heaton A, Keegan T, and Holme S. In vivo regeneration of red cell 2,3- diphosphoglycerate following transfusion of DPG-depleted AS-1, AS-3 and CPDA-1 red cells. Br J Haematol 71: 131-136, 1989. Heaton WA, Holme S, Smith K, Brecher ME, Pineda A, AuBuchon JP, and Nelson E. Effects of 3-5 log10 pre-storage leucocyte depletion on red cell storage and metabolism. British journal of haematology 87: 363-368, 1994. Willekens FL, Werre JM, Groenen-Dopp YA, Roerdinkholder-Stoelwinder B, de Pauw B, and Bosman GJ. Erythrocyte vesiculation: a self-protective mechanism? British journal of haematology 141: 549-556, 2008. Natukunda B, Schonewille H, and Smit Sibinga CT. Assessment of the clinical transfusion practice at a regional referral hospital in Uganda. Transfusion medicine 20: 134- 139, 2010. Linko K, and Saxelin I. Electrolyte and acid-base disturbances caused by blood transfusions. Acta anaesthesiologica Scandinavica 30: 139-144, 1986. Greenwalt TJ, Zehner Sostok C, and Dumaswala UJ. Studies in red blood cell preservation. 2. Comparison of vesicle formation, morphology, and membrane lipids during storage in AS-1 and CPDA-1. Vox Sang 58: 90-93, 1990. Zimrin AB, and Hess JR. Current issues relating to the transfusion of stored red blood cells. Vox sanguinis 96: 93-103, 2009. Verzeichnis akademischer Lehrer 237 Rapoport I, Berger H, Elsner R, and Rapoport S. PH-dependent changes of 2,3-bisphosphoglycerate in human red cells during transitional and steady states in vitro. European journal of biochemistry / FEBS 73: 421-427, 1977. Sugiura T, Kouwaki M, Goto K, Endo T, Ito K, Koyama N, and Togari H. Effects of exchange transfusion on cytokine profiles in necrotizing enterocolitis. Pediatr Int 54: 931-933, 2012. La Celle PL. Alteration of deformability of the erythrocyte membrane in stored blood. Transfusion 9: 238-245, 1969. Greenwalt TJ. The how and why of exocytic vesicles. Transfusion 46: 143-152, 2006. Tinmouth A, Fergusson D, Yee IC, and Hebert PC. Clinical consequences of red cell storage in the critically ill. Transfusion 46: 2014-2027, 2006. Relevy H, Koshkaryev A, Manny N, Yedgar S, and Barshtein G. Blood banking-induced alteration of red blood cell flow properties. Transfusion 48: 136-146, 2008. Luten M, Roerdinkholder-Stoelwinder B, Schaap NP, de Grip WJ, Bos HJ, and Bosman GJ. Survival of red blood cells after transfusion: a comparison between red cells concentrates of different storage periods. Transfusion 48: 1478-1485, 2008. Karon BS, Hoyer JD, Stubbs JR, and Thomas DD. Changes in Band 3 oligomeric state precede cell membrane phospholipid loss during blood bank storage of red blood cells. Transfusion 49: 1435-1442, 2009. Lelubre C, Piagnerelli M, and Vincent JL. Association between duration of storage of transfused red blood cells and morbidity and mortality in adult patients: myth or reality? Transfusion 49: 1384-1394, 2009. Hess JR, Sparrow RL, van der Meer PF, Acker JP, Cardigan RA, and Devine DV. Red blood cell hemolysis during blood bank storage: using national quality management data to answer basic scientific questions. Transfusion 49: 2599-2603, 2009. Henkelman S, Dijkstra-Tiekstra MJ, de Wildt-Eggen J, Graaff R, Rakhorst G, and van Oeveren W. Is red blood cell rheology preserved during routine blood bank storage? Transfusion 50: 941-948, 2010. Wang D, Sun J, Solomon SB, Klein HG, and Natanson C. Transfusion of older stored blood and risk of death: a meta-analysis. Transfusion 52: 1184-1195, 2012. Nordt FJ. Hemorheology in cerebrovascular diseases: approaches to drug development. Annals of the New York Academy of Sciences 416: 651-661, 1983. Osei EN, Odoi AT, Owusu-Ofori S, and Allain JP. Appropriateness of blood product transfusion in the Obstetrics and Gynaecology (O+G) department of a tertiary hospital in West Africa. Transfusion medicine 23: 160-166, 2013. Sparrow RL, Sran A, Healey G, Veale MF, and Norris PJ. In vitro measures of membrane changes reveal differences between red blood cells stored in saline-adenine- glucose-mannitol and AS-1 additive solutions: a paired study. Transfusion 54: 560-568, 2014. Yalcin O, Ortiz D, Tsai AG, Johnson PC, and Cabrales P. Microhemodynamic aberrations created by transfusion of stored blood. Transfusion 54: 1015-1027, 2014. Kay M. Immunoregulation of cellular life span. Annals of the New York Academy of Sciences 1057: 85-111, 2005. Raat NJ, Verhoeven AJ, Mik EG, Gouwerok CW, Verhaar R, Goedhart PT, de Korte D, and Ince C. The effect of storage time of human red cells on intestinal microcirculatory oxygenation in a rat isovolemic exchange model. Critical care medicine 33: 39-45; discussion 238-239, 2005. Shevkoplyas SS, Yoshida T, Gifford SC, and Bitensky MW. Direct measurement of the impact of impaired erythrocyte deformability on microvascular network perfusion in a microfluidic device. Lab on a chip 6: 914-920, 2006. Hou HW, Bhagat AA, Chong AG, Mao P, Tan KS, Han J, and Lim CT. Deformability based cell margination--a simple microfluidic design for malaria-infected erythrocyte separation. Lab Chip 10: 2605-2613, 2010. Lip GY. Fibrinogen and cardiovascular disorders. QJM : monthly journal of the Association of Physicians 88: 155-165, 1995. Sims PJ, and Wiedmer T. Unraveling the mysteries of phospholipid scrambling. Trautschold I, Lamprecht W, and Schweitzer G. Adenosine 5'-Triphosphate. Ranucci M, Carlucci C, Isgro G, Boncilli A, De Benedetti D, De la Torre T, Brozzi S, and Frigiola A. Duration of red blood cell storage and outcomes in pediatric cardiac surgery: an association found for pump prime blood. Crit Care 13: R207, 2009. Willekens FL, Roerdinkholder-Stoelwinder B, Groenen-Dopp YA, Bos HJ, Bosman GJ, van den Bos AG, Verkleij AJ, and Werre JM. Hemoglobin loss from erythrocytes in vivo results from spleen-facilitated vesiculation. Blood 101: 747-751, 2003. Tsai AG, Cabrales P, Manjula BN, Acharya SA, Winslow RM, and Intaglietta M. Dissociation of local nitric oxide concentration and vasoconstriction in the presence of cell-free hemoglobin oxygen carriers. Blood 108: 3603-3610, 2006. Pasini EM, Kirkegaard M, Mortensen P, Lutz HU, Thomas AW, and Mann M. In-depth analysis of the membrane and cytosolic proteome of red blood cells. Blood 108: 791-801, 2006. Lew VL, Daw N, Etzion Z, Tiffert T, Muoma A, Vanagas L, and Bookchin RM. Effects of age-dependent membrane transport changes on the homeostasis of senescent human red blood cells. Blood 110: 1334-1342, 2007. Sutera SP, Gardner RA, Boylan CW, Carroll GL, Chang KC, Marvel JS, Kilo C, Gonen B, and Williamson JR. Age-related changes in deformability of human erythrocytes. Blood 65: 275-282, 1985. Terpstra V, and van Berkel TJ. Scavenger receptors on liver Kupffer cells mediate the in vivo uptake of oxidatively damaged red blood cells in mice. Blood 95: 2157- 2163, 2000. Salzer U, and Prohaska R. Stomatin, flotillin-1, and flotillin-2 are major integral proteins of erythrocyte lipid rafts. Blood 97: 1141-1143, 2001. Salzer U, Hinterdorfer P, Hunger U, Borken C, and Prohaska R. Ca(++)- dependent vesicle release from erythrocytes involves stomatin-specific lipid rafts, synexin (annexin VII), and sorcin. Blood 99: 2569-2577, 2002. Li Q, Jungmann V, Kiyatkin A, and Low PS. Prostaglandin E2 stimulates a Ca2+-dependent K+ channel in human erythrocytes and alters cell volume and filterability. Tsai AG, Friesenecker B, and Intaglietta M. Capillary flow impairment and functional capillary density. Int J Microcirc Clin Exp 15: 238-243, 1995. Karger R, Lukow C, and Kretschmer V. Deformability of Red Blood Cells and Correlation with ATP Content during Storage as Leukocyte-Depleted Whole Blood. Transfusion medicine and hemotherapy : offizielles Organ der Deutschen Gesellschaft fur Transfusionsmedizin und Immunhamatologie 39: 277-282, 2012. Lee JS, and Gladwin MT. Bad blood: the risks of red cell storage. Nat Med 16: 381-382, 2010. Nakao M, Nakao T, and Yamazoe S. Adenosine triphosphate and maintenance of shape of the human red cells. Nature 187: 945-946, 1960. Liu C, Zhao W, Christ GJ, Gladwin MT, and Kim-Shapiro DB. Nitric oxide scavenging by red cell microparticles. Free radical biology + medicine 65: 1164-1173, 2013. Levin S, and Korenstein R. Membrane fluctuations in erythrocytes are linked to MgATP-dependent dynamic assembly of the membrane skeleton. Biophysical journal 60: 733- 737, 1991. Lim HWG, Wortis M, and Mukhopadhyay R. Stomatocyte-discocyte-echinocyte sequence of the human red blood cell: evidence for the bilayer-couple hypothesis from membrane mechanics. Proceedings of the National Academy of Sciences of the United States of America 99: 16766-16769, 2002. Whittaker SR, and Winton FR. The apparent viscosity of blood flowing in the isolated hindlimb of the dog, and its variation with corpuscular concentration. The Journal of physiology 78: 339-369, 1933. Jan KM, and Chien S. Role of surface electric charge in red blood cell interactions. J Gen Physiol 61: 638-654, 1973. Loutit JF, and Mollison PL. Disodium-Citrate-Glucose Mixture as a Blood Preservative. Br Med J (Clin Res Ed) 2: 744-745, 1943. Salomao M, Zhang X, Yang Y, Lee S, Hartwig JH, Chasis JA, Mohandas N, and An X. Protein 4.1R-dependent multiprotein complex: new insights into the structural organization of the red blood cell membrane. Proc Natl Acad Sci U S A 105: 8026-8031, 2008. Mohandas N, and Gallagher PG. Red cell membrane: past, present, and future. Blood 112: 3939-3948, 2008. Secomb TW. Theoretical models for regulation of blood flow. Microcirculation 15: 765-775, 2008. Zhang ZW, and Neu B. Role of macromolecular depletion in red blood cell adhesion. Biophysical journal 97: 1031-1037, 2009. Hess JR. Conventional blood banking and blood component storage regulation: opportunities for improvement. Blood Transfus 8 Suppl 3: s9-15, 2010. Weed RI, LaCelle PL, and Merrill EW. Metabolic dependence of red cell deformability. The Journal of clinical investigation 48: 795-809, 1969. Karon BS, van Buskirk CM, Jaben EA, Hoyer JD, and Thomas DD. Temporal sequence of major biochemical events during blood bank storage of packed red blood cells. Blood transfusion = Trasfusione del sangue 10: 453-461, 2012. Solomon SB, Wang D, Sun J, Kanias T, Feng J, Helms CC, Solomon MA, Alimchandani M, Quezado M, Gladwin MT, Kim-Shapiro DB, Klein HG, and Natanson C. Mortality increases after massive exchange transfusion with older stored blood in canines with experimental pneumonia. Blood 121: 1663-1672, 2013. Mohandas N, Clark MR, Jacobs MS, and Shohet SB. Analysis of factors regulating erythrocyte deformability. The Journal of clinical investigation 66: 563-573, 1980. Peng Z, Li X, Pivkin IV, Dao M, Karniadakis GE, and Suresh S. Lipid bilayer and cytoskeletal interactions in a red blood cell. Proceedings of the National Academy of Sciences of the United States of America 110: 13356-13361, 2013. Wolfe LC, Byrne AM, and Lux SE. Molecular defect in the membrane skeleton of blood bank-stored red cells. Abnormal spectrin-protein 4.1-actin complex formation. J Clin Invest 78: 1681-1686, 1986. Nash TW, Libby DM, and Horwitz MA. Interaction between the legionnaires' disease bacterium (Legionella pneumophila) and human alveolar macrophages. Influence of antibody, lymphokines, and hydrocortisone. The Journal of clinical investigation 74: 771-782, 1984. Strumia MM, Blake AD, Jr., and Wicks WA. The preservation of whole blood. J Clin Invest 26: 667-671, 1947. Silliman CC, Clay KL, Thurman GW, Johnson CA, and Ambruso DR. Partial characterization of lipids that develop during the routine storage of blood and prime the neutrophil NADPH oxidase. The Journal of laboratory and clinical medicine 124: 684-694, 1994. Silliman CC, Voelkel NF, Allard JD, Elzi DJ, Tuder RM, Johnson JL, and Ambruso DR. Plasma and lipids from stored packed red blood cells cause acute lung injury in an animal model. The Journal of clinical investigation 101: 1458-1467, 1998. Johnson PC, Bishop JJ, Popel S, and Intaglietta M. Effects of red cell aggregation on the venous microcirculation. Biorheology 36: 457-460, 1999. Riggert J. [Improvement of the coagulation potential in whole blood through leukocyte depletion]. Anasthesiol Intensivmed Notfallmed Schmerzther 35: 645-648, 2000. Hebert PC, Wells G, Blajchman MA, Marshall J, Martin C, Pagliarello G, Tweeddale M, Schweitzer I, and Yetisir E. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group. The New England Journal of Medicine 340: 409-417, 1999. Koch CG, Li L, Sessler DI, Figueroa P, Hoeltge GA, Mihaljevic T, and Blackstone EH. Duration of red-cell storage and complications after cardiac surgery. The New England Journal of Medicine 358: 1229-1239, 2008. Nakashima K, and Beutler E. Effect of anti-spectrin antibody and ATP on deformability of resealed erythrocyte membranes. Proceedings of the National Academy of Sciences of the United States of America 75: 3823-3825, 1978. Lancaster JR, Jr. Simulation of the diffusion and reaction of endogenously produced nitric oxide. Proc Natl Acad Sci U S A 91: 8137-8141, 1994. Yalcin O, Meiselman HJ, Armstrong JK, and Baskurt OK. Effect of enhanced red blood cell aggregation on blood flow resistance in an isolated-perfused guinea pig heart preparation. Biorheology 42: 511-520, 2005. Rampling MW, Meiselman HJ, Neu B, and Baskurt OK. Influence of cell- specific factors on red blood cell aggregation. Biorheology 41: 91-112, 2004. Tuvia S, Levin S, and Korenstein R. Correlation between local cell membrane displacements and filterability of human red blood cells. FEBS letters 304: 32-36, 1992. Secomb TW, and Skalak R. A two-dimensional model for capillary flow of an asymmetric cell. Microvasc Res 24: 194-203, 1982. Pries AR, Ley K, Claassen M, and Gaehtgens P. Red cell distribution at microvascular bifurcations. Microvasc Res 38: 81-101, 1989. Politsmakher A, Doddapaneni V, Seeratan R, and Dosik H. Effective reduction of blood product use in a community teaching hospital: when less is more. The American journal of medicine 126: 894-902, 2013. Neu B, and Meiselman HJ. Depletion-mediated red blood cell aggregation in polymer solutions. Biophysical journal 83: 2482-2490, 2002. Neu B, Sowemimo-Coker SO, and Meiselman HJ. Cell-cell affinity of senescent human erythrocytes. Biophysical journal 85: 75-84, 2003. Neu B, Wenby R, and Meiselman HJ. Effects of dextran molecular weight on red blood cell aggregation. Biophysical journal 95: 3059-3065, 2008. Zielinski MD, Jenkins DH, Hughes JD, Badjie KS, and Stubbs JR. Back to the future: the renaissance of whole-blood transfusions for massively hemorrhaging patients. Surgery 155: 883-886, 2014. Uzoigwe C. The human erythrocyte has developed the biconcave disc shape to optimise the flow properties of the blood in the large vessels. Med Hypotheses 67: 1159-1163, 2006. Hess JR, and Greenwalt TG. Storage of red blood cells: new approaches. Transfus Med Rev 16: 283-295, 2002. Hogman CF, and Meryman HT. Storage parameters affecting red blood cell survival and function after transfusion. Transfusion medicine reviews 13: 275-296, 1999. Solheim BG, Flesland O, Brosstad F, Mollnes TE, and Seghatchian J. Improved preservation of coagulation factors after pre-storage leukocyte depletion of whole blood. Transfusion and apheresis science : official journal of the World Apheresis Association : official journal of the European Society for Haemapheresis 29: 133-139, 2003. Steiner ME, Assmann SF, Levy JH, Marshall J, Pulkrabek S, Sloan SR, Triulzi D, and Stowell CP. Addressing the question of the effect of RBC storage on clinical outcomes: the Red Cell Storage Duration Study (RECESS) (Section 7). Transfusion and apheresis science : official journal of the World Apheresis Association : official journal of the European Society for Haemapheresis 43: 107-116, 2010. Vandromme MJ, McGwin G, Jr., and Weinberg JA. Blood transfusion in the critically ill: does storage age matter? Scand J Trauma Resusc Emerg Med 17: 35, 2009. Rubin O, Crettaz D, Tissot JD, and Lion N. Microparticles in stored red blood cells: submicron clotting bombs? Blood transfusion = Trasfusione del sangue 8 Suppl 3: s31-38, 2010.