Publications by authors named "Hara T Georgatzakou"

17 Publications

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Coagulation Abnormalities in Renal Pathology of Chronic Kidney Disease: The Interplay between Blood Cells and Soluble Factors.

Biomolecules 2021 Sep 4;11(9). Epub 2021 Sep 4.

Laboratory of Reliability and Quality Control in Laboratory Hematology (HemQcR), Department of Biomedical Sciences, School of Health & Caring Sciences, University of West Attica (UniWA), 12243 Egaleo, Greece.

Coagulation abnormalities in renal pathology are associated with a high thrombotic and hemorrhagic risk. This study aims to investigate the hemostatic abnormalities that are related to the interaction between soluble coagulation factors and blood cells, and the effects of hemodialysis (HD) on it, in end stage renal disease (ESRD) patients. Thirty-two ESRD patients under HD treatment and fifteen healthy controls were included in the study. Whole blood samples from the healthy and ESRD subjects were collected before and after the HD session. Evaluation of coagulation included primary and secondary hemostasis screening tests, proteins of coagulation, fibrinolytic and inhibitory system, and ADAMTS-13 activity. Phosphatidylserine (PS) exposure and intracellular reactive oxygen species (iROS) levels were also examined in red blood cells and platelets, in addition to the platelet activation marker CD62P. Platelet function analysis showed pathological values in ESRD patients despite the increased levels of activation markers (PS, CD62P, iROS). Activities of most coagulation, fibrinolytic, and inhibitory system proteins were within the normal range, but HD triggered an increase in half of them. Additionally, the increased baseline levels of ADAMTS-13 inhibitor were further augmented by the dialysis session. Finally, pathological levels of PS and iROS were measured in red blood cells in close correlation with variations in several coagulation factors and platelet characteristics. This study provides evidence for a complex coagulation phenotype in ESRD. Signs of increased bleeding risk coexisted with prothrombotic features of soluble factors and blood cells in a general hyperfibrinolytic state. Hemodialysis seems to augment the prothrombotic potential, while the persisted platelet dysfunction might counteract the increased predisposition to thrombotic events post-dialysis. The interaction of red blood cells with platelets, the thrombus, the endothelium, the soluble components of the coagulation pathways, and the contribution of extracellular vesicles on hemostasis as well as the identification of the unknown origin ADAMTS-13 inhibitor deserve further investigation in uremia.
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http://dx.doi.org/10.3390/biom11091309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8467225PMC
September 2021

Haemostatic profile of riboflavin-treated apheresis platelet concentrates.

Blood Transfus 2021 May 21. Epub 2021 May 21.

Laboratory of Haematology and Blood Bank Unit, Attikon University Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.

Background: The haemostatic activity of platelet concentrates (PCs) treated with pathogen reduction technology (PRT) remains a subject of debate. Our aim was to investigate the effect of Mirasol PRT on the haemostatic properties of PCs stored in plasma.

Material And Methods: Untreated and Mirasol-treated platelets stored in plasma and derived from ten split double-dose apheresis PCs were evaluated in vitro on days 1, 3 and 5 post collection for functionality, microparticle procoagulation activity (MPA), endogenous thrombin potential (ETP), and haemostatic profile using rotational thromboelastometry (ROTEM).

Results: P-selectin expression was significantly higher in Mirasol-treated platelets compared with untreated counterparts on days 3 and 5 (p=0.003 and p=0.002, respectively). Clot strength, as shown by EXTEM maximum clot firmness (MCF), was significantly lower in the Mirasol-treated platelets at all time points (days 1, 3, 5) than in untreated platelets (p=0.009, p<0.001, p<0.001, respectively). There was a considerable increase in MPA over time (p<0.001) and this was significantly higher in the Mirasol-treated platelets on day 5 (p=0.015). A notable acceleration of decrease in ETP values was observed for Mirasol-treated PCs over time (p<0.001), with significant differences between PRT-treated and untreated PCs on days 3 and 5 (p=0.038 and p=0.019, respectively). Clot strength attenuation was significantly associated with pH reduction (p<0.001, Spearman's rho: 0.84), increased microparticle procoagulant activity (p<0.001, Spearman's rho: -0.75), and with decreased ETP (p<0.032, Spearman's rho: 0.41).

Discussion: Increased platelet activation induced by PRT treatment leads to a decrease in in vitro haemostatic capacity as seen by reduced clot strength and thrombin generation capacity over time. The clinical relevance of this needs to be investigated.
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http://dx.doi.org/10.2450/2021.0089-21DOI Listing
May 2021

The Multi-Faced Extracellular Vesicles in the Plasma of Chronic Kidney Disease Patients.

Front Cell Dev Biol 2020 15;8:227. Epub 2020 Apr 15.

Department of Biology, School of Science, National and Kapodistrian University of Athens (NKUA), Athens, Greece.

Extracellular vesicles (EVs) are membrane-enclosed nanoparticles released by most cells in body fluids and extracellular matrix. They function as signal transducers in intercellular communication, contributing to the maintenance of cell and tissue integrity. EVs biogenesis is deregulated in various pathologies, in structural and functional connection to the pathophysiology of donor cells. Consequently, EVs are considered diagnostic and monitoring factors in many diseases. Despite consensus as to their activity in promoting coagulation and inflammation, there is evidence suggesting protective roles for EVs in stress states. Chronic kidney disease (CKD) patients are at high risk of developing cardiovascular defects. The pathophysiology, comorbidities, and treatment of CKD may individually and in synergy affect extracellular vesiculation in the kidney, endothelium, and blood cells. Oxidative and mechanical stresses, chronic inflammation, and deregulation of calcium and phosphate homeostasis are established stressors of EV release. EVs may affect the clinical severity of CKD by transferring biological response modifiers between renal, vascular, blood, and inflammatory cells. In this Review, we focus on EVs circulating in the plasma of CKD patients. We highlight some recent advances in the understanding of their biogenesis, the effects of dialysis, and pharmacological treatments on them and their potential impact on thrombosis and vascular defects. The strong interest of the scientific community to this exciting field of research may reveal hidden pieces in the pathophysiology of CKD and thus, innovative ways to treat it. Overcoming gaps in EV biology and technical difficulties related to their size and heterogeneity will define the success of the project.
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http://dx.doi.org/10.3389/fcell.2020.00227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7174738PMC
April 2020

"Valar morghulis": all red cells must die.

Blood Transfus 2020 03 17;18(2):83-85. Epub 2020 Mar 17.

Laboratory of Reliability and Quality Control in Laboratory Hematology (HemQcR), Department of Biomedical Sciences, School of Health & Caring Sciences, University of West Attica (UniWA), Egaleo, Greece.

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http://dx.doi.org/10.2450/2020.0028-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141935PMC
March 2020

Recipient's effects on stored red blood cell performance: the case of uremic plasma.

Transfusion 2019 06 19;59(6):1900-1906. Epub 2019 Mar 19.

Department of Biology, School of Science, National & Kapodistrian University of Athens (NKUA), Athens, Greece.

Background: Despite universal administration of erythropoiesis-stimulating agents, patients with end-stage renal disease (ESRD) are at high risk for presenting persistent anemia. Due to ambiguities in optimal hemoglobin targets and evidence of recombinant human erythropoietin (EPO)-related toxicity, an increase in blood transfusions has been observed in chronic renal disease over the past years. The probable effects of uremic plasma on the performance of stored red blood cells (RBCs) after transfusion have not been investigated.

Study Design And Methods: Leukoreduced RBCs after short or long storage in CPD-SAGM (n = 5) were assessed for hemolysis, surface removal signaling, reactive oxygen species (ROS) accumulation, and shape distortions before and after reconstitution with healthy (n = 10) or uremic plasma from ESRD patients (n = 20) for 24 hours at physiologic temperature, by using a previously reported in vitro model of transfusion.

Results: Temperature and cell environment shifts from blood bag to plasma independently and in synergy affected the RBC physiology. Outcome measures at transfusion-simulating conditions might not be analogous to timing of storage lesion. The uremic plasma ameliorated the susceptibility of stored RBCs to hemolysis, phosphatidylserine externalization, and ROS generation after stimulation by oxidants, but negatively affected shape homeostasis versus healthy plasma. Creatinine, uric acid, and EPO levels had correlations with the performance of stored RBCs in ESRD plasma.

Conclusion: Renal insufficiency and EPO supplementation likely affect the recovery of donor RBCs and the reactivity of RBCs after transfusion by exerting both toxic and cytoprotective influences on them. ESRD patients constitute a specific recipient group that deserves further examination.
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http://dx.doi.org/10.1111/trf.15257DOI Listing
June 2019

Redox Status, Procoagulant Activity, and Metabolome of Fresh Frozen Plasma in Glucose 6-Phosphate Dehydrogenase Deficiency.

Front Med (Lausanne) 2018 5;5:16. Epub 2018 Feb 5.

Department of Biology, School of Science, National and Kapodistrian University of Athens, Athens, Greece.

Objective: Transfusion of fresh frozen plasma (FFP) helps in maintaining the coagulation parameters in patients with acquired multiple coagulation factor deficiencies and severe bleeding. However, along with coagulation factors and procoagulant extracellular vesicles (EVs), numerous bioactive and probably donor-related factors (metabolites, oxidized components, etc.) are also carried to the recipient. The X-linked glucose 6-phosphate dehydrogenase deficiency (G6PD), the most common human enzyme genetic defect, mainly affects males. By undermining the redox metabolism, the G6PD cells are susceptible to the deleterious effects of oxidants. Considering the preferential transfusion of FFP from male donors, this study aimed at the assessment of FFP units derived from G6PD males compared with control, to show whether they are comparable at physiological, metabolic and redox homeostasis levels.

Methods: The quality of  = 12 G6PD and control FFP units was tested after 12 months of storage, by using hemolysis, redox, and procoagulant activity-targeted biochemical assays, flow cytometry for EV enumeration and phenotyping, untargeted metabolomics, in addition to statistical and bioinformatics tools.

Results: Higher procoagulant activity, phosphatidylserine positive EVs, RBC-vesiculation, and antioxidant capacity but lower oxidative modifications in lipids and proteins were detected in G6PD FFP compared with controls. The FFP EVs varied in number, cell origin, and lipid/protein composition. Pathway analysis highlighted the riboflavin, purine, and glycerolipid/glycerophospholipid metabolisms as the most altered pathways with high impact in G6PD. Multivariate and univariate analysis of FFP metabolomes showed excess of diacylglycerols, glycerophosphoinositol, aconitate, and ornithine but a deficiency in riboflavin, flavin mononucleotide, adenine, and arginine, among others, levels in G6PD FFPs compared with control.

Conclusion: Our results point toward a different redox, lipid metabolism, and EV profile in the G6PD FFP units. Certain FFP-needed patients may be at greatest benefit of receiving FFP intrinsically endowed by both procoagulant and antioxidant activities. However, the clinical outcome of G6PD FFP transfusion would likely be affected by various other factors, including the signaling potential of the differentially expressed metabolites and EVs, the degree of G6PD, the redox status in the recipient, the amount of FFP units transfused, and probably, the storage interval of the FFP, which deserve further investigation by future studies.
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http://dx.doi.org/10.3389/fmed.2018.00016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5807665PMC
February 2018

Donor-specific individuality of red blood cell performance during storage is partly a function of serum uric acid levels.

Transfusion 2018 01 23;58(1):34-40. Epub 2017 Oct 23.

Department of Biology, School of Science, National & Kapodistrian University of Athens (NKUA), Athens, Greece.

Background: Previous investigations in leukoreduced units of red blood cells (RBCs) in mannitol additive solution revealed the close association of uric acid (UA) levels in vivo with the susceptibility of RBCs to storage lesion markers. In this study, we examined whether UA has a similar correlation with the capability of RBCs to cope with the oxidative provocations of storage under different conditions, namely, in CPDA-1 and in the absence of leukoreduction.

Study Design And Methods: The UA-dependent antioxidant capacity of the supernatant was measured in nonleukoreduced units of RBCs in CPDA (n = 47). The possible effect of UA variability on the storage lesion profile was assessed by monitoring several physiologic properties of RBCs and supernatant, including cell shape, reactive oxygen species, and size distribution of extracellular vesicles, in units exhibiting the lowest or highest levels of UA activity (n = 16) among donors, throughout the storage period.

Results: In stored RBC units, the UA-dependent antioxidant activity of the supernatant declined as a function of storage duration but always in strong relation to the UA levels in fresh blood. Contrary to units of poor-UA activity, RBCs with the highest levels of UA activity exhibited better profile of calcium- and oxidative stress-driven modifications, including a significant decrease in the percentages of spherocytes and of 100- to 300-nm-sized vesicles, typically associated with the exovesiculation of stored RBCs.

Conclusion: The antioxidant activity of UA is associated with donor-specific differences in the performance of RBCs under storage in nonleukoreduced CPDA units.
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http://dx.doi.org/10.1111/trf.14379DOI Listing
January 2018

Short-term effects of hemodiafiltration versus conventional hemodialysis on erythrocyte performance.

Can J Physiol Pharmacol 2018 Mar 30;96(3):249-257. Epub 2017 Aug 30.

a Department of Biology, Section of Cell Biology & Biophysics, School of Science, National and Kapodistrian University of Athens (NKUA), Greece.

Hemodiafiltration (HDF) is a renal replacement therapy that is based on the principles of diffusion and convection for the elimination of uremic toxins. A significant and increasing number of end-stage renal disease (ESRD) patients are treated with HDF, even in the absence of definite and conclusive survival and anemia treatment data. However, its effects on red blood cell (RBC) physiological features have not been examined in depth. In this study, ESRD patients under regular HDF or conventional hemodialysis (cHD) treatment were examined for RBC-related parameters, including anemia, hemolysis, cell shape, redox status, removal signaling, membrane protein composition, and microvesiculation, in repeated paired measurements accomplished before and right after each dialysis session. The HDF group was characterized by better redox potential and suppressed exovesiculation of blood cells compared with the cHD group pre-dialysis. However, HDF was associated with a temporary but acute, oxidative-stress-driven increase in hemolysis, RBC removal signaling, and stomatocytosis, probably associated with the effective clearance of dialyzable natural antioxidant components, including uric acid, from the uremic plasma. The nature of these adverse short-term effects of HDF on post-dialysis plasma and RBCs strongly suggests the use of a parallel antioxidant therapy during the HDF session.
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http://dx.doi.org/10.1139/cjpp-2017-0285DOI Listing
March 2018

Temperature-dependent haemolytic propensity of CPDA-1 stored red blood cells vs whole blood - Red cell fragility as donor signature on blood units.

Blood Transfus 2017 Sep 10;15(5):447-455. Epub 2017 Apr 10.

Laboratory of Haematology and Transfusion Medicine, Department of Medical Laboratories, Technological and Educational Institute of Athens, Athens, Greece.

Background: To preserve cellular integrity and avoid bacterial growth, storage and transfer of blood and blood products follow strict guidelines in terms of temperature control. We evaluated the impact of ineligible warming of whole blood donations on the quality of blood components.

Materials And Methods: One-hundred and twenty units of whole blood (WB) from eligible blood donors were collected in CPDA-1 and stored at 4±2 °C. During shipment to the blood processing centre, a gradual warming up to 17 °C was recorded within a period of less than eight hours. The warmed units were processed to packed red blood cells (PRBCs) or stored as WB units at 4±2 °C. In-bag haemolysis, osmotic fragility (mean corpuscular fragility, MCF) and bacterial growth were assessed in blood and blood components throughout the storage period.

Results: Normal basal and early storage levels of haemolysis were recorded in both PRBC and WB units. Thereafter, PRBCs exhibited higher average in-bag haemolysis and MCF index compared to the WB units throughout the storage. Moreover, 14.3 and 52.4% of the PRBC units exceeded the upper permissible limit of 0.8% haemolysis at the middle (1.220±0.269%) or late (1.754±0.866%) storage period, respectively. MCF index was similar in all PRBCs at the middle of storage but significantly lower in the non-haemolysed compared to the haemolysed units of PRBCs on the last days. The fragility of stored RBCs was proportional to the donor-related values of day 2 samples (r=0.861, p<10). In the qualified PRBCs, MCF was correlated with haemolysis at every time point of the storage period (r=0.332, p<0.050). Bacterial growth was detected by blood culture in two units of PRBCs.

Discussion: Transient, gradient warming of whole blood from 4 to 17 °C led to increased incidence of in-bag haemolysis in PRBC but not in WB units. Haemolysis is a multi-parametric phenotype of stored blood, and MCF is a donor-related and highly dynamic measure that can, in part, predict the storage lesion.
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http://dx.doi.org/10.2450/2017.0332-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5589707PMC
September 2017

Pathophysiological aspects of red blood cells in end-stage renal disease patients resistant to recombinant human erythropoietin therapy.

Eur J Haematol 2017 Jun 12;98(6):590-600. Epub 2017 Apr 12.

Department of Biology, Section of Cell Biology & Biophysics, School of Science, National and Kapodistrian University of Athens (NKUA), Athens, Greece.

Objective: Modified, bioreactive red blood cells (RBCs) and RBC-derived microvesicles (MVs) likely contribute to the hematological and cardiovascular complications in end-stage renal disease (ESRD). This study assesses the physiological profile of RBCs in patients with ESRD receiving standard or high doses of recombinant human erythropoietin (rhEPO).

Method: Blood samples from twenty-eight patients under sustained hemodialysis, responsive, or not to standard rhEPO administration were examined for RBC morphology, fragility, hemolysis, redox status, removal signaling, membrane protein composition, and microvesiculation before and after dialysis. Acute effects of uremic plasma on RBC features were examined in vitro through reconstitution experiments.

Results: Overall, the ESRD RBCs were characterized by pathological levels of shape distortions, surface removal signaling, and membrane exovesiculation, but reduced fragility compared to healthy RBCs. Irreversible transformation of RBCs was found to be a function of baseline Hb concentration. The more toxic uremic context in non-responsive patients compared to rhEPO responders was blunted in part by the antioxidant, antihemolytic, and anti-apoptotic effects of high rhEPO doses, and probably, of serum uric acid. A selective lower expression of RBC membrane in complement regulators (CD59, clusterin) and of CD47 "marker-of-self" was detected in non-responders and responders, respectively. Evidence for different short-term dialysis effects and probably for a different erythrocyte vesiculation mechanism in rhEPO responsive compared to non-responsive patients was also revealed.

Conclusion: Deregulation of RBC homeostasis might involve diverse molecular pathways driving erythrocyte signaling and removal in rhEPO non-responders compared to responsive patients.
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http://dx.doi.org/10.1111/ejh.12875DOI Listing
June 2017

Data on how several physiological parameters of stored red blood cells are similar in glucose 6-phosphate dehydrogenase deficient and sufficient donors.

Data Brief 2016 Sep 23;8:618-27. Epub 2016 Jun 23.

Department of Biology, Section of Cell Biology and Biophysics, School of Science, NKUA, Athens 15784, Greece.

This article contains data on the variation in several physiological parameters of red blood cells (RBCs) donated by eligible glucose-6-phosphate dehydrogenase (G6PD) deficient donors during storage in standard blood bank conditions compared to control, G6PD sufficient (G6PD(+)) cells. Intracellular reactive oxygen species (ROS) generation, cell fragility and membrane exovesiculation were measured in RBCs throughout the storage period, with or without stimulation by oxidants, supplementation of N-acetylcysteine and energy depletion, following incubation of stored cells for 24 h at 37 °C. Apart from cell characteristics, the total or uric acid-dependent antioxidant capacity of the supernatant in addition to extracellular potassium concentration was determined in RBC units. Finally, procoagulant activity and protein carbonylation levels were measured in the microparticles population. Further information can be found in "Glucose 6-phosphate dehydrogenase deficient subjects may be better "storers" than donors of red blood cells" [1].
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http://dx.doi.org/10.1016/j.dib.2016.06.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4939423PMC
September 2016

Microparticles variability in fresh frozen plasma: preparation protocol and storage time effects.

Blood Transfus 2016 05 22;14(2):228-37. Epub 2016 Feb 22.

Department of Cell Biology and Biophysics, Faculty of Biology, University of Athens, Athens, Greece.

Background: Extracellular vesicles or microparticles exhibiting procoagulant and thrombogenic activity may contribute to the haemostatic potential of fresh frozen plasma.

Materials And Methods: Fresh frozen plasma was prepared from platelet-rich plasma at 20 °C (Group-1 donors) or directly from whole blood at 4 °C (Group-2 donors). Each unit was aseptically divided into three parts, stored frozen for specific periods of time, and analysed by flow cytometry for procoagulant activity immediately after thaw or following post-thaw storage for 24 h at 4 °C. Donors' haematologic, biochemical and life-style profiles as well as circulating microparticles were analysed in parallel.

Results: Circulating microparticles exhibited a considerable interdonor but not intergroup variation. Fresh frozen plasma units were enriched in microparticles compared to plasma in vivo. Duration of storage significantly affected platelet- and red cell-derived microparticles. Fresh frozen plasma prepared directly from whole blood contained more residual platelets and more platelet-derived microparticles compared to fresh frozen plasma prepared from platelet-rich plasma. Consequently, there was a statistically significant difference in total, platelet- and red cell-derived microparticles between the two preparation protocols over storage time in the freezer. Preservation of the thawed units for 24 h at 4 °C did not significantly alter microparticle accumulation. Microparticle accumulation and anti-oxidant capacity of fresh frozen plasma was positively or negatively correlated, respectively, with the level of circulating microparticles in individual donors.

Discussion: The preparation protocol and the duration of storage in the freezer, independently and in combination, influenced the accumulation of microparticles in fresh frozen plasma units. In contrast, storage of thawed units for 24 h at 4 °C had no significant effect on the concentration of microparticles.
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http://dx.doi.org/10.2450/2016.0179-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4918554PMC
May 2016

Glucose 6-phosphate dehydrogenase deficient subjects may be better "storers" than donors of red blood cells.

Free Radic Biol Med 2016 07 14;96:152-65. Epub 2016 Apr 14.

Department of Cell Biology and Biophysics, Faculty of Biology, NKUA, Athens 15784, Greece. Electronic address:

Storage of packed red blood cells (RBCs) is associated with progressive accumulation of lesions, mostly triggered by energy and oxidative stresses, which potentially compromise the effectiveness of the transfusion therapy. Concerns arise as to whether glucose 6-phosphate dehydrogenase deficient subjects (G6PD(-)), ~5% of the population in the Mediterranean area, should be accepted as routine donors in the light of the increased oxidative stress their RBCs suffer from. To address this question, we first performed morphology (scanning electron microscopy), physiology and omics (proteomics and metabolomics) analyses on stored RBCs from healthy or G6PD(-) donors. We then used an in vitro model of transfusion to simulate transfusion outcomes involving G6PD(-) donors or recipients, by reconstituting G6PD(-) stored or fresh blood with fresh or stored blood from healthy volunteers, respectively, at body temperature. We found that G6PD(-) cells store well in relation to energy, calcium and morphology related parameters, though at the expenses of a compromised anti-oxidant system. Additional stimuli, mimicking post-transfusion conditions (37°C, reconstitution with fresh healthy blood, incubation with oxidants) promoted hemolysis and oxidative lesions in stored G6PD(-) cells in comparison to controls. On the other hand, stored healthy RBC units showed better oxidative parameters and lower removal signaling when reconstituted with G6PD(-) fresh blood compared to control. Although the measured parameters of stored RBCs from the G6PD deficient donors appeared to be acceptable, the results from the in vitro model of transfusion suggest that G6PD(-) RBCs could be more susceptible to hemolysis and oxidative stresses post-transfusion. On the other hand, their chronic exposure to oxidative stress might make them good recipients, as they better tolerate exposure to oxidatively damaged long stored healthy RBCs.
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http://dx.doi.org/10.1016/j.freeradbiomed.2016.04.005DOI Listing
July 2016

Donor variation effect on red blood cell storage lesion: a multivariable, yet consistent, story.

Transfusion 2016 06 29;56(6):1274-86. Epub 2016 Mar 29.

Department of Cell Biology and Biophysics, Faculty of Biology, NKUA, Athens.

Background: Previous studies have shown that baseline hematologic characteristics concerning or influencing red blood cell (RBC) properties might affect storage lesion development in individual donors. This study was conducted to evaluate whether variation in hemolysis, microparticle accumulation, phosphatidylserine (PS) exposure, and other storage lesion-associated variables might be a function of the prestorage hematologic and biologic profiles of the donor.

Study Design And Methods: Ten eligible, regular blood donors were paired and studied before donation (fresh blood) and during storage of RBCs in standard blood banking conditions. Plasma and cellular characteristics and modifications were evaluated by standard laboratory and biochemical or biologic analyses as well as by statistical and network analysis tools.

Results: Nitrate/nitrite and other bioactive factors exhibited high interdonor variability, which further increased during storage in a donor-specific manner. Storage lesion evaluators, including RBC fragility and PS exposure, fluctuated throughout the storage period in proportion to their values in fresh blood. Donors' levels of phosphatidylserine exposure and hemoglobin F correlated with stored cells' mean cell (RBC) Hb concentration, oxidative stress markers, and cellular fragility.

Discussion: Storage lesion indicators change in an orderly fashion, namely, by following donor-related prestorage attributes. These correlations are illustrated for the first time in "prestorage versus storage" biologic networks, which might help determine the best candidates for in vivo biomarkers of storage quality and provide deeper insight into the apparently complex donor variation effect on the RBC storage lesion.
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http://dx.doi.org/10.1111/trf.13582DOI Listing
June 2016

Red blood cell abnormalities and the pathogenesis of anemia in end-stage renal disease.

Proteomics Clin Appl 2016 08 29;10(8):778-90. Epub 2016 Mar 29.

Department of Medical Laboratories, Faculty of Health and Caring Professions, Technological and Educational Institute of Athens, Greece.

Anemia is the most common hematologic complication in end-stage renal disease (ESRD). It is ascribed to decreased erythropoietin production, shortened red blood cell (RBC) lifespan, and inflammation. Uremic toxins severely affect RBC lifespan; however, the implicated molecular pathways are poorly understood. Moreover, current management of anemia in ESRD is controversial due to the "anemia paradox" phenomenon, which underlines the need for a more individualized approach to therapy. RBCs imprint the adverse effects of uremic, inflammatory, and oxidative stresses in a context of structural and functional deterioration that is associated with RBC removal signaling and morbidity risk. RBCs circulate in hostile plasma by raising elegant homeostatic defenses. Variability in primary defect, co-morbidity, and therapeutic approaches add complexity to the pathophysiological background of the anemic ESRD patient. Several blood components have been suggested as biomarkers of anemia-related morbidity and mortality risk in ESRD. However, a holistic view of blood cell and plasma modifications through integrated omics approaches and high-throughput studies might assist the development of new diagnostic tests and therapies that will target the underlying pathophysiologic processes of ESRD anemia.
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http://dx.doi.org/10.1002/prca.201500127DOI Listing
August 2016

Uric acid variation among regular blood donors is indicative of red blood cell susceptibility to storage lesion markers: A new hypothesis tested.

Transfusion 2015 Nov 14;55(11):2659-71. Epub 2015 Jul 14.

Department of Cell Biology and Biophysics, Faculty of Biology, NKUA.

Background: Oxidative stress orchestrates a significant part of the red blood cell (RBC) storage lesion. Considering the tremendous interdonor variability observed in the "storability," namely, the capacity of RBCs to sustain the storage lesion, this study aimed at the elucidation of donor-specific factors that affect the redox homeostasis during the storage of RBCs in standard systems.

Study Design And Methods: The hematologic profile of regular blood donors (n = 78) was evaluated by biochemical analysis of 48 different variables, including in vivo hemolysis and plasma oxidant and antioxidant factors and statistical analysis of the results. The possible effect of the uric acid (UA) variable on RBC storability was investigated in leukoreduced CPD/SAGM RBC units (n = 8) collected from donors exhibiting high or low prestorage levels of UA, throughout the storage period.

Results: Among the hematologic variables examined in vivo, cluster analysis grouped the donors according to their serum UA levels. Plasma antioxidant capacity, iron indexes, and protein carbonylation represented covariants of UA factor. RBCs prepared by low- or high-UA donors exhibited significant differences between them in spheroechinocytosis, supernatant antioxidant activity, and other RBC storage lesion-associated variables.

Conclusion: UA exhibits a storability biomarker potential. Intrinsic variability in plasma UA levels might be related to the interdonor variability observed in the storage capacity of RBCs. A model for the antioxidant effect of UA during the RBC storage is currently proposed.
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http://dx.doi.org/10.1111/trf.13211DOI Listing
November 2015

Blood modifications associated with end stage renal disease duration, progression and cardiovascular mortality: a 3-year follow-up pilot study.

J Proteomics 2014 Apr 15;101:88-101. Epub 2014 Feb 15.

Department of Cell Biology and Biophysics, Faculty of Biology, NKUA, Greece. Electronic address:

Unlabelled: Chronic kidney disease is a risk factor for cardiovascular mortality. This study uncovers pieces of hematological and erythrocyte protein variability observed in end stage renal disease (ESRD) in relation to disease progression/duration and mortality. Using a variety of experimental approaches, erythropoietin/dialysis-treated patients were compared to healthy individuals and had been followed for 36months. During that period, half of the patients died from cardiovascular diseases. The high levels of uremic toxins in those patients were associated with damaged erythrocytes, bad tolerance and poor response to hemodialysis therapy. The postmortem study revealed significant variation in alkaline phosphatase, duration of dialysis, erythrocyte transformation and intracellular hemoglobin concentration compared to the survived patients. The erythrocyte proteins showed substantial remodeling characteristic of pathologic regulation of cell hydration and susceptibility to the dialysis-induced oxidation defects. According to the follow-up study, duration of hemodialysis was associated with a trend towards increased intracellular hemoglobin concentration, membrane expression of glucose transporter-1 and stomatin as well as lower levels of circulating stomatocytes. The uremic index variation in long survived patients is accurately reflected in plasma and erythrocyte oxidative stress modifications. The ESRD patients exhibit impressive compensatory responses to the chronic challenges of the uremic milieu.

Biological Significance: This study demonstrates novel blood modifications probably associated with the duration of erythropoietin/hemodialysis treatment, disease progression and cardiovascular mortality in end stage renal disease. The observed variability adds new pieces to the erythrocyte pathophysiology puzzle in end stage renal disease and suggests novel hematologic and proteomic factors for consideration in future large scale studies on cardiovascular morbidity and mortality candidate biomarkers in uremic patients.
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http://dx.doi.org/10.1016/j.jprot.2014.02.009DOI Listing
April 2014
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