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Simple Summary: SARS-CoV-2 alters the properties of oxygen-carrying red blood cells (RBCs) through a possible deterioration of hemorheological properties, such as aggregation and deformability. However, long-term changes in these properties and a possible association with morphological abnormalities remain unknown. Therefore, this study aims to investigate changes in the above-mentioned RBC properties in Long-COVID (LC). Venous blood was collected from n = 30 diagnosed LC and n = 30 non-Long-COVID controls (non-LC). Hematological parameters were measured, as well as the aggregation, deformability, and morphology of the RBCs and the mechanical sensitivity index (MS), which reflects the functional capacity of RBCs to deform. The results indicate that hematological parameters were not altered in LC. However, LC showed higher overall aggregation parameters. RBC deformability was higher in LC compared to non-LC; however, MS was limited in this group. LC showed a higher percentage of RBCs with abnormal shapes, which was related to MS and to fatigue, which is considered the leading symptom of LC. It is concluded that the symptoms of LC and changes in the blood flow determining the properties of RBCs are related to the morphological changes in RBCs. Future studies should investigate the underlying causes in order to develop appropriate therapies for this relatively new disease. Background: SARS-CoV-2 infection adversely affects rheological parameters, particularly red blood cell (RBC) aggregation and deformability, but whether these changes persist in patients suffering from Long-COVID (LC) and whether these changes are related to RBC morphology remain unknown. Methods: Venous blood was collected from n = 30 diagnosed LC patients and n = 30 non-LC controls and RBC deformability, RBC aggregation, and hematological parameters were measured. In addition, RBCs were examined microscopically for morphological abnormalities. The mechanical sensitivity index (MS) was assessed in n = 15 LC and n = 15 non-LC samples. Results: Hematological parameters did not differ between the groups. However, LC showed higher aggregation-related parameters. Although RBC deformability was higher in LC, MS, reflecting the functional capacity to deform, was limited in this group. RBCs from LC showed significantly more morphological abnormalities. The extent of morphological abnormalities correlated with MS and the FACIT-Fatigue score of the LC patients. Conclusion: RBCs from LC show a high degree of morphological abnormalities, which might limit the blood flow determining RBC properties and also be related to fatigue symptomatology in LC. Approaches are now needed to understand the underlying cause of these alterations and to ameliorate these permanent changes. [ABSTRACT FROM AUTHOR]

Introduction: The unique red blood cell (RBC) properties that characterize the rare neuroacanthocytosis syndromes (NAS) have prompted the exploration of osmotic gradient ektacytometry (Osmoscan) as a diagnostic tool for these disorders. In this exploratory study, we assessed if Osmoscans can discriminate NAS from other neurodegenerative diseases. Methods: A comprehensive assessment was conducted using Osmoscan on a diverse group of patients, including healthy controls (n = 9), neuroacanthocytosis syndrome patients (n = 6, 2 VPS13A and 4 XK disease), Parkinson's disease patients (n = 6), Huntington's disease patients (n= 5), and amyotrophic lateral sclerosis patients (n = 4). Concurrently, we collected and analyzed RBC indices and patients' characteristics. Results: Statistically significant changes were observed in NAS patients compared to healthy controls and other conditions, specifically in osmolality at minimal elongation index (Omin), maximal elongation index (EImax), the osmolality at half maximal elongation index in the hyperosmotic part of the curve (Ohyper), and the width of the curve close to the osmolality at maximal elongation index (Omax-width). Discussion: This study represents an initial exploration of RBC properties from NAS patients using osmotic gradient ektacytometry. While specific parameters exhibited differences, only Ohyper and Omax-width yielded 100% specificity for other neurodegenerative diseases. Moreover, unique correlations between Osmoscan parameters and RBC indices in NAS versus controls were identified, such as osmolality at maximal elongation index (Omax) vs. mean cellular hemoglobin content (MCH) and minimal elongation index (EImin) vs. red blood cell distribution width (RDW). Given the limited sample size, further studies are essential to establish diagnostic guidelines based on these findings. [ABSTRACT FROM AUTHOR]

Aging-related processes lead to significant metabolic and structural changes in red blood cells (RBCs) and, as a result, to heterogeneity in cell populations. Using the Percoll linear density gradient, separating the RBC population and obtaining fractions enriched with cells of different ages is possible. Previously, cells from the "light" fraction were characterized by increased deformability. However, the distribution of RBC deformability in subpopulations possessing a different density has not been studied. In this study, we measured the deformability of RBCs from cell fractions characterized by different densities. RBC deformability was determined using a computerized cell flow-properties analyzer, which provides the deformability distribution in a population of 10,000–15,000 cells. Our results demonstrate a strong correlation between the cytosol hemoglobin concentration and the cell deformation indexes. In addition, we show that the "lightest" fraction of RBCs contains the lowest number of deformable and the highest number of highly deformable cells. In contrast, the "dense" fraction is enriched with undeformable RBCs, with a minimal presence of highly deformable cells. In summary, we have shown that RBC fractions depleted or enriched with undeformable cells can be obtained by using a density gradient. However, these fractions are not homogeneous in their deformability properties. [ABSTRACT FROM AUTHOR]

The deformability of red blood cells (RBCs), expressing their ability to change their shape as a function of flow-induced shear stress, allows them to optimize oxygen delivery to the tissues and minimize their resistance to flow, especially in microcirculation. During physiological aging and blood storage, or under external stimulations, RBCs undergo metabolic and structural alterations, one of which is hemoglobin (Hb) redistribution between the cytosol and the membrane. Consequently, part of the Hb may attach to the cell membrane, and although this process is reversible, the increase in membrane-bound Hb (MBHb) can affect the cell's mechanical properties and deformability in particular. In the present study, we examined the correlation between the MBHb levels, determined by mass spectroscopy, and the cell deformability, determined by image analysis. Six hemoglobin subunits were found attached to the RBC membranes. The cell deformability was negatively correlated with the level of four subunits, with a highly significant inter-correlation between them. These data suggest that the decrease in RBC deformability results from Hb redistribution between the cytosol and the cell membrane and the respective Hb interaction with the cell membrane. [ABSTRACT FROM AUTHOR]

IntroductionThe unique red blood cell (RBC) properties that characterize the rare neuroacanthocytosis syndromes (NAS) have prompted the exploration of osmotic gradient ektacytometry (Osmoscan) as a diagnostic tool for these disorders. In this exploratory study, we assessed if Osmoscans can discriminate NAS from other neurodegenerative diseases.MethodsA comprehensive assessment was conducted using Osmoscan on a diverse group of patients, including healthy controls (n = 9), neuroacanthocytosis syndrome patients (n = 6, 2 VPS13A and 4 XK disease), Parkinson’s disease patients (n = 6), Huntington’s disease patients (n = 5), and amyotrophic lateral sclerosis patients (n = 4). Concurrently, we collected and analyzed RBC indices and patients’ characteristics.ResultsStatistically significant changes were observed in NAS patients compared to healthy controls and other conditions, specifically in osmolality at minimal elongation index (Omin), maximal elongation index (EImax), the osmolality at half maximal elongation index in the hyperosmotic part of the curve (Ohyper), and the width of the curve close to the osmolality at maximal elongation index (Omax-width).DiscussionThis study represents an initial exploration of RBC properties from NAS patients using osmotic gradient ektacytometry. While specific parameters exhibited differences, only Ohyper and Omax-width yielded 100% specificity for other neurodegenerative diseases. Moreover, unique correlations between Osmoscan parameters and RBC indices in NAS versus controls were identified, such as osmolality at maximal elongation index (Omax) vs. mean cellular hemoglobin content (MCH) and minimal elongation index (EImin) vs. red blood cell distribution width (RDW). Given the limited sample size, further studies are essential to establish diagnostic guidelines based on these findings.

Background: SARS-CoV-2 infection adversely affects rheological parameters, particularly red blood cell (RBC) aggregation and deformability, but whether these changes persist in patients suffering from Long-COVID (LC) and whether these changes are related to RBC morphology remain unknown. Methods: Venous blood was collected from n = 30 diagnosed LC patients and n = 30 non-LC controls and RBC deformability, RBC aggregation, and hematological parameters were measured. In addition, RBCs were examined microscopically for morphological abnormalities. The mechanical sensitivity index (MS) was assessed in n = 15 LC and n = 15 non-LC samples. Results: Hematological parameters did not differ between the groups. However, LC showed higher aggregation-related parameters. Although RBC deformability was higher in LC, MS, reflecting the functional capacity to deform, was limited in this group. RBCs from LC showed significantly more morphological abnormalities. The extent of morphological abnormalities correlated with MS and the FACIT-Fatigue score of the LC patients. Conclusion: RBCs from LC show a high degree of morphological abnormalities, which might limit the blood flow determining RBC properties and also be related to fatigue symptomatology in LC. Approaches are now needed to understand the underlying cause of these alterations and to ameliorate these permanent changes.

Aging-related processes lead to significant metabolic and structural changes in red blood cells (RBCs) and, as a result, to heterogeneity in cell populations. Using the Percoll linear density gradient, separating the RBC population and obtaining fractions enriched with cells of different ages is possible. Previously, cells from the “light” fraction were characterized by increased deformability. However, the distribution of RBC deformability in subpopulations possessing a different density has not been studied. In this study, we measured the deformability of RBCs from cell fractions characterized by different densities. RBC deformability was determined using a computerized cell flow-properties analyzer, which provides the deformability distribution in a population of 10,000–15,000 cells. Our results demonstrate a strong correlation between the cytosol hemoglobin concentration and the cell deformation indexes. In addition, we show that the “lightest” fraction of RBCs contains the lowest number of deformable and the highest number of highly deformable cells. In contrast, the “dense” fraction is enriched with undeformable RBCs, with a minimal presence of highly deformable cells. In summary, we have shown that RBC fractions depleted or enriched with undeformable cells can be obtained by using a density gradient. However, these fractions are not homogeneous in their deformability properties.

Background Reduced survival of red blood cells (RBCs) in patients with chronic kidney disease (CKD) is thought to contribute to renal anaemia. Although renal anaemia improved greatly because of the wide use of erythropoiesis-stimulating agents (ESAs) and the advancement of dialysis techniques, RBC longevity seems not to be obviously ameliorated. Methods In this single-centre, single-arm trial, patients who had been undergoing haemodialysis and ESA therapy with epoetin alfa for at least 12 weeks changed their anti-anaemia drugs from epoetin alfa to oral roxadustat three times per week for 24 weeks. The primary endpoint was the change in RBC lifespan from baseline at week 24. The change in the circulating percentage of eryptotic RBCs, RBC deformability and RBC oxygen transport ability were also assessed. Results A total of 27 patients were enrolled, with 26 completing the full course of intervention. At baseline, the average RBC lifespan was 60.1 days [standard deviation (SD) 14.4; n  = 27]. At the end of the study period, 26 patients had an RBC lifespan measurement (83.9 days on average; SD 21.9). The RBC lifespan increased by 22.8 days on average [95% confidence interval (CI) 15.5–30.0, P  < .001]. This equated to an average RBC lifespan increase of 39.2% (95% CI 27.8–50.6). The percentage of circulating eryptotic RBCs, erythrocyte filtration index and the pressure at which haemoglobin is 50% saturated decreased significantly from baseline to week 24 (1.39 ± 0.44% versus 0.89 ± 0.25%, P  < .0001; 0.29 ± 0.12 versus 0.16 ± 0.08, P  < .0001 and 32.54 ± 4.83 versus 28.40 ± 2.29, P  < .001, respectively). Conclusion Roxadustat prolonged RBC lifespan in patients with long-term haemodialysis. [ABSTRACT FROM AUTHOR]

Red blood cell (RBC) deformability, expressing their ability to change their shape, allows them to minimize their resistance to flow and optimize oxygen delivery to the tissues. RBC with reduced deformability may lead to increased vascular resistance, capillary occlusion, and impaired perfusion and oxygen delivery. A reduction in deformability, as occurs during RBC physiological aging and under blood storage, is implicated in the pathophysiology of diverse conditions with circulatory disorders and anemias. The change in RBC deformability is associated with metabolic and structural alterations, mostly uncharacterized. To bridge this gap, we analyzed the membrane protein levels, using mass spectroscopy, of RBC with varying deformability determined by image analysis. In total, 752 membrane proteins were identified. However, deformability was positively correlated with the level of only fourteen proteins, with a highly significant inter-correlation between them. These proteins are involved in membrane rafting and/or the membrane–cytoskeleton linkage. These findings suggest that the reduction of deformability is a programmed (not arbitrary) process of remodeling and shedding of membrane fragments, possibly mirroring the formation of extracellular vesicles. The highly significant inter-correlation between the deformability-expressing proteins infers that the cell deformability can be assessed by determining the level of a few, possibly one, of them. [ABSTRACT FROM AUTHOR]

Background: This study investigated the effects of 12-week resistance training on body composition, blood pressure, blood lipid levels, muscle cross-sectional area (CSA), isokinetic muscle function, and hemorheological properties in middle-aged obese women. Methods: Twenty-eight obese women with a mean age of 50.79 ± 5.80 years were randomly assigned to the control (CON, n = 13) or experimental (EXP, n = 15) group. The EXP group underwent a resistance training program composed of warm-up, main resistance exercise (deadlift, barbell squat, seated leg extension, and lying leg curl, bench press, preacher bench biceps curl, barbell rowing, and dumbbell shoulder press), and cool-down. The resistance exercise consisted of three sets of 8-10 repetitions (reps) performed with 70-80% of 1-rep maximum, and reps and sets were increased every 3 weeks. The training frequency was 80 min, 3 days per week for 12 weeks. The CON group maintained their daily lifestyle without training. All participants underwent measurements of body composition (weight, body mass index, lean body mass, fat mass, and % body fat), blood pressure (systolic blood pressure, diastolic blood pressure, mean arterial pressure, and pulse pressure), blood lipid levels (triglycerides, total cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol), CSA of the muscles (quadriceps, hamstring, and total thigh muscle), isokinetic muscle function (peak torque [PT], relative PT, mean power, and total work [TW]), and hemorheological properties (erythrocyte deformability and aggregation) before and after 12 weeks of training. Results: The EXP group showed a significant improved muscle function, including PT (p < 0.001), relative PT (p < 0.001) in extension 60°/s, TW (p < 0.001) in extension 180°/s, and TW (p = 0.018) in flexion 180°/s. Regarding hemorheological properties, the EXP group showed significant improvement in erythrocyte aggregation (p < 0.001) and deformability (p < 0.001). Conclusions: The present study verified that our resistance training program resulted in greater muscle function, decreased fat mass, and improved hemorheological properties. Clinical Trial Registration: This study was registered with cris.nih.go.kr (No. KCT0007412). [ABSTRACT FROM AUTHOR]

Hematological and hemorheological parameters are known to be altered in COVID-19; however, the value of combined monitoring in order to deduce disease severity is only scarcely examined. A total of 44 acute SARS-CoV-2-infected patients (aCOV) and 44 age-matched healthy controls (Con) were included. Blood of aCOV was sampled at admission (T0), and at day 2 (T2), day 5 (T5), day 10 (T10), and day 30 (T30) while blood of Con was only sampled once. Inter- and intra-group differences were calculated for hematological and hemorheological parameters. Except for mean cellular volume and mean cellular hemoglobin, all blood cell parameters were significantly different between aCOV and Con. During the acute disease state (T0–T5), hematological and hemorheological parameters were highly altered in aCOV; in particular, anemic conditions and increased immune cell response/inflammation, oxidative/nitrosative stress, decreased deformability, as well as increased aggregation, were observed. During treatment and convalescence until T30, almost all abnormal values of aCOV improved towards Con values. During the acute state of the COVID-19 disease, the hematological, as well as the hemorheological system, show fast and potentially pathological changes that might contribute to the progression of the disease, but changes appear to be largely reversible after four weeks. Measuring RBC deformability and aggregation, as well as oxidative stress induction, may be helpful in monitoring critically ill COVID-19 patients. [ABSTRACT FROM AUTHOR]

Patients with Fontan circulation are particularly dependent on low pulmonary vascular resistance because their lungs are passively perfused. Hypoxia drives pulmonary vasoconstriction; thus, red blood cell (RBC) deformability and stability of hematological parameters might be of particular importance, because alterations during hypoxia might further influence circulation. This study aimed to measure respective parameters in patients with Fontan circulation exposed to normobaric hypoxia. A total of 18 patients with Fontan circulation (16 to 38 years) were exposed to normobaric hypoxia (15.2% ambient oxygen). Blood samples were taken in normoxia, after 24 h in hypoxia, and 60 min after return to normoxia. Blood count, RBC age distribution, EPO, RBC deformability, marker of RBC nitric oxide, oxidative state, and RBC ATP were measured. Hypoxia increased oxidative stress in RBC, but without affecting RBC deformability. RBC age distribution remained unaffected, although EPO concentrations increased, followed by a rise in reticulocyte count at an already high hematocrit. NO metabolism was not affected by hypoxia. Modest normobaric hypoxia for 24 h did not impair RBC deformability in patients with Fontan circulation; however, the oxidative system seemed to be stressed. Given the high baseline Hct in these patients, hypoxia-induced erythropoiesis could adversely affect rheology with more prolonged hypoxia exposure. [ABSTRACT FROM AUTHOR]

Background: Despite increasing evidence that red blood cell (RBC) deformability is impaired in pathologic conditions, little research has been done on RBC deformability in hematologic diseases. The authors measured RBC deformability in patients with various hematologic diseases, including hematologic malignancies. Methods: A total of 568 patients who underwent bone marrow (BM) examination for initial diagnosis were enrolled. We collected the subjects' age, gender, diagnosis of BM examination, and complete blood count results. The RBC deformability, which was quantified by an elongation index, was measured by a microfluidic ektacytometer. Results: RBC deformability was lower in primary myelofibrosis, acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), chronic myeloid leukemia (CML), and acute lymphoblastic leukemia (ALL) from least to greatest. When the correlation between red blood cell distribution width (RDW) and RBC deformability was analyzed for 370 subjects in hematologic neoplasms, the correlation coefficient of RDW was -0.2974 (p < 0.01). When comparing MDS and aplastic anemia (AA), the deformability of MDS was significantly lower than that of AA. Conclusions: RBC deformability was decreased in leukemic diseases such as AML, MDS, CML, and ALL compared to control, and RDW showed a negative correlation with deformability. RBC deformability may be used as a complementary differential diagnostic test for MDS and AA. [ABSTRACT FROM AUTHOR]

About 50% of premature neonates (PN) are treated with transfusion of packed red blood cells (PRBC) collected from adult donors, which has been suggested to potentially provoke PN pathologies, characterized as blood circulation disorders. RBC have properties that are key determinants of blood circulation, primarily the cell deformability. In previous studies we have shown that transfusion of RBC with reduced deformability impaired the transfusion outcome. Although RBC of PN (PN-RBC) are larger, and their microvessels are narrower than those of adults, their blood circulation is very efficient, pointing to the possibility that the deformability of adults' PRBC is inferior to that of PN-RBC, and that treating PN with PRBC transfusion might, therefore, introduce a risk to the recipients. This would infer that PN should be given RBC with high deformability. However, since using PN-RBC is not feasible, the use of cord blood RBC (CB-RBC) is a sound alternative, assuming that the deformability of CB-RBC is comparable to that of PN-RBC.The present study is aimed at testing this hypothesis. We compared the deformability of (1) RBC of PN vs. the PRBC they received, and (2) PN-RBC vs. their autologous CB-RBC. 1. The deformability of the transfused PRBC is indeed inferior to that of PN-RBC. 2. The deformability of CB-RBC is equivalent to that of PN-RBC. This study supports the notion that treating PN with transfusion of adults' PRBC has the potential to introduce a circulatory risk to the recipients, while CB-RBC, with their superior deformability, provides a safer and more effective PN-specific transfusion therapy. [ABSTRACT FROM AUTHOR]

In acute malaria, the bulk of erythrocyte loss occurs after therapy, with a nadir of hemoglobin generally observed 3–7 days after treatment. The fine mechanisms leading to this early post-treatment anemia are still elusive. We explored pathological changes in RBC subpopulations by quantifying biochemical and mechanical alterations during severe malaria treated with artemisinin derivatives, a drug family that induce “pitting” in the spleen. In this study, the hemoglobin concentration dropped by 1.93 G/dl during therapy. During the same period, iRBC accounting for 6.12% of all RBC before therapy (BT) were replaced by pitted-RBC, accounting for 5.33% of RBC after therapy (AT). RBC loss was thus of 15.9%, of which only a minor part was due to the loss of iRBC or pitted-RBC. When comparing RBC BT and AT to normal controls, lipidomics revealed an increase in the cholesterol/phosphatidylethanolamine ratio (0.17 versus 0.24, p < 0.001) and cholesterol/ phosphatidylinositol ratio (0.36 versus 0.67, p = 0.001). Using ektacytometry, we observed a reduced deformability of circulating RBC, similar BT and AT, compared to health control donors. The mean Elongation Index at 1.69Pa was 0.24 BT and 0.23 AT vs. 0.28 in controls (p < 0.0001). At 30Pa EI was 0.56 BT and 0.56 AT vs. 0.60 in controls (p < 0.001). The retention rate (rr) of RBC subpopulations in spleen-mimetic microsphere layers was higher for iRBC (rr = 20% p = 0.0033) and pitted-RBC (rr = 19%, p = 0.0031) than for healthy RBC (0.12%). Somewhat surprisingly, the post-treatment anemia in malaria results from the elimination of RBC that were never infected. [ABSTRACT FROM AUTHOR]

In acute malaria, the bulk of erythrocyte loss occurs after therapy, with a nadir of hemoglobin generally observed 3–7 days after treatment. The fine mechanisms leading to this early post-treatment anemia are still elusive. We explored pathological changes in RBC subpopulations by quantifying biochemical and mechanical alterations during severe malaria treated with artemisinin derivatives, a drug family that induce “pitting” in the spleen. In this study, the hemoglobin concentration dropped by 1.93 G/dl during therapy. During the same period, iRBC accounting for 6.12% of all RBC before therapy (BT) were replaced by pitted-RBC, accounting for 5.33% of RBC after therapy (AT). RBC loss was thus of 15.9%, of which only a minor part was due to the loss of iRBC or pitted-RBC. When comparing RBC BT and AT to normal controls, lipidomics revealed an increase in the cholesterol/phosphatidylethanolamine ratio (0.17 versus 0.24, p < 0.001) and cholesterol/phosphatidylinositol ratio (0.36 versus 0.67, p = 0.001). Using ektacytometry, we observed a reduced deformability of circulating RBC, similar BT and AT, compared to health control donors. The mean Elongation Index at 1.69Pa was 0.24 BT and 0.23 AT vs. 0.28 in controls (p < 0.0001). At 30Pa EI was 0.56 BT and 0.56 AT vs. 0.60 in controls (p < 0.001). The retention rate (rr) of RBC subpopulations in spleen-mimetic microsphere layers was higher for iRBC (rr = 20% p = 0.0033) and pitted-RBC (rr = 19%, p = 0.0031) than for healthy RBC (0.12%). Somewhat surprisingly, the post-treatment anemia in malaria results from the elimination of RBC that were never infected.

The frequency-dependent contribution of spectrin, the main cytoskeletal protein of red blood cell (RBC) membrane, to the complex admittance and capacitance of suspended RBCs have revealed two dielectric relaxations, βsp (1.4 MHz) and γ1sp (7 MHz). The strength of these relaxations was related to the ability of RBC membrane to deform. In this study the two relaxations were inhibited by N-ethylmaleimide (up to 5 mM), known to impair the RBC deformability, and the degree of inhibition, i.e., the number of accessible SH-groups on spectrin, depended on the deformation of RBC membrane. Dithiothreitol (up to 5 mM), which does not affect RBC deformability, did not affect the above dielectric relaxations in line with the absence of S-S groups on spectrin. Phenylhydrazine (up to 3 mM) and hydrogen hydroperoxide (up to 450 μM) are known to denature the haemoglobin of RBCs producing nanoparticles (globins) that bind to spectrin turning the RBC membrane rigid. At the same concentrations they were shown to inhibit progressively the two relaxations on spectrin. The results are in line with the involvement of some globin-sized segments of spectrin in the dielectric activity of spectrin and in the ability of RBC plasma membrane to deform. [ABSTRACT FROM AUTHOR]

In this work, we compared the dynamics of motion in a linear shear flow of individual red blood cells (RBCs) from healthy and pathological donors (Sickle Cell Disease (SCD) or Sickle Cell-β-thalassemia) and of low and high densities, in a suspending medium of higher viscosity. In these conditions, at lower shear rates, biconcave discocyte-shaped RBCs present an unsteady flip-flopping motion, where the cell axis of symmetry rotates in the shear plane, rocking to and fro between an orbital angle ±ϕ observed when the cell is on its edge. We show that the evolution of ϕ depends solely on RBC density for healthy RBCs, with denser RBCs displaying lower ϕ values than the lighter ones. Typically, at a shear stress of 0.08 Pa, ϕ has values of 82 and 72° for RBCs with average densities of 1.097 and 1.115, respectively. Surprisingly, we show that SCD RBCs display the same ϕ-evolution as healthy RBCs of same density, showing that the flip-flopping behavior is unaffected by the SCD pathology. When the shear stress is increased further (above 0.1 Pa), healthy RBCs start going through a transition to a fluid-like motion, called tank-treading, where the RBC has a quasi-constant orientation relatively to the flow and the membrane rotates around the center of mass of the cell. This transition occurs at higher shear stresses (above 0.2 Pa) for denser cells. This shift toward higher stresses is even more remarkable in the case of SCD RBCs, showing that the transition to the tank-treading regime is highly dependent on the SCD pathology. Indeed, at a shear stress of 0.2 Pa, for RBCs with a density of 1.097, 100% of healthy RBCs have transited to the tank-treading regime vs. less than 50% SCD RBCs. We correlate the observed differences in dynamics to the alterations of RBC mechanical properties with regard to density and SCD pathology reported in the literature. Our results suggest that it might be possible to develop simple non-invasive assays for diagnosis purpose based on the RBC motion in shear flow and relying on this millifluidic approach. [ABSTRACT FROM AUTHOR]

In this work, we compared the dynamics of motion in a linear shear flow of individual red blood cells (RBCs) from healthy and pathological donors (Sickle Cell Disease (SCD) or Sickle Cell-β-thalassemia) and of low and high densities, in a suspending medium of higher viscosity. In these conditions, at lower shear rates, biconcave discocyte-shaped RBCs present an unsteady flip-flopping motion, where the cell axis of symmetry rotates in the shear plane, rocking to and fro between an orbital angle ±ϕ observed when the cell is on its edge. We show that the evolution of ϕ depends solely on RBC density for healthy RBCs, with denser RBCs displaying lower ϕ values than the lighter ones. Typically, at a shear stress of 0.08 Pa, ϕ has values of 82 and 72° for RBCs with average densities of 1.097 and 1.115, respectively. Surprisingly, we show that SCD RBCs display the same ϕ-evolution as healthy RBCs of same density, showing that the flip-flopping behavior is unaffected by the SCD pathology. When the shear stress is increased further (above 0.1 Pa), healthy RBCs start going through a transition to a fluid-like motion, called tank-treading, where the RBC has a quasi-constant orientation relatively to the flow and the membrane rotates around the center of mass of the cell. This transition occurs at higher shear stresses (above 0.2 Pa) for denser cells. This shift toward higher stresses is even more remarkable in the case of SCD RBCs, showing that the transition to the tank-treading regime is highly dependent on the SCD pathology. Indeed, at a shear stress of 0.2 Pa, for RBCs with a density of 1.097, 100% of healthy RBCs have transited to the tank-treading regime vs. less than 50% SCD RBCs. We correlate the observed differences in dynamics to the alterations of RBC mechanical properties with regard to density and SCD pathology reported in the literature. Our results suggest that it might be possible to develop simple non-invasive assays for diagnosis purpose based on the RBC motion in shear flow and relying on this millifluidic approach.

Patients with Fontan circulation are particularly dependent on low pulmonary vascular resistance because their lungs are passively perfused. Hypoxia drives pulmonary vasoconstriction; thus, red blood cell (RBC) deformability and stability of hematological parameters might be of particular importance, because alterations during hypoxia might further influence circulation. This study aimed to measure respective parameters in patients with Fontan circulation exposed to normobaric hypoxia. A total of 18 patients with Fontan circulation (16 to 38 years) were exposed to normobaric hypoxia (15.2% ambient oxygen). Blood samples were taken in normoxia, after 24 h in hypoxia, and 60 min after return to normoxia. Blood count, RBC age distribution, EPO, RBC deformability, marker of RBC nitric oxide, oxidative state, and RBC ATP were measured. Hypoxia increased oxidative stress in RBC, but without affecting RBC deformability. RBC age distribution remained unaffected, although EPO concentrations increased, followed by a rise in reticulocyte count at an already high hematocrit. NO metabolism was not affected by hypoxia. Modest normobaric hypoxia for 24 h did not impair RBC deformability in patients with Fontan circulation; however, the oxidative system seemed to be stressed. Given the high baseline Hct in these patients, hypoxia-induced erythropoiesis could adversely affect rheology with more prolonged hypoxia exposure.

Red blood cells (RBCs) deformability refers to the cells’ ability to adapt their shape to the dynamically changing flow conditions so as to minimize their resistance to flow. The high red cell deformability enables it to pass through small blood vessels and significantly determines erythrocyte survival. Under normal physiological states, the RBCs are attuned to allow for adequate blood flow. However, rigid erythrocytes can disrupt the perfusion of peripheral tissues and directly block microvessels. Therefore, RBC deformability has been recognized as a sensitive indicator of RBC functionality. The loss of deformability, which a change in the cell shape can cause, modification of cell membrane or a shift in cytosol composition, can occur due to various pathological conditions or as a part of normal RBC aging (in vitro or in vivo). However, despite extensive research, we still do not fully understand the processes leading to increased cell rigidity under cold storage conditions in a blood bank (in vitro aging), In the present review, we discuss publications that examined the effect of RBCs’ cold storage on their deformability and the biological mechanisms governing this change. We first discuss the change in the deformability of cells during their cold storage. After that, we consider storage-related alterations in RBCs features, which can lead to impaired cell deformation. Finally, we attempt to trace a causal relationship between the observed phenomena and offer recommendations for improving the functionality of stored cells.

A laser tweezer technique based on single and/or dual-laser beams is proposed as a biophotonic tool to trap single cells and investigate their biophysical and biomechanical characteristics. Optical deformability and changes in size and cellular morphology of living and nonliving cells can be measured using the proposed technique. Representative results of red blood cell (RBC) optical deformability of 20 homozygous patients with sickle cell disease, including follow-up patients after treating with hydroxyurea (HU) for at least 3 months and 20 healthy control groups, are presented and compared. Shape recovery of deformed RBCs and relaxation time are recorded for each RBC. Results showed that healthy blood and patients treated with HU demonstrate significantly higher optical deformability and degree of optical elongation with morphological change of RBCs than untreated patients. Moreover, the healthy control group and patients treated with HU exhibited faster relaxation time for RBCs than untreated patients. A trapping power that reaches 180 mW caused no observable photo-damage at a wavelength 1064 nm. [ABSTRACT FROM AUTHOR]

Background: Individuals with hereditary hemochromatosis (HH) receive frequent blood withdrawals (ie, venesections) as part of their primary treatment to assist in normalizing blood iron levels. It remains unclear whether this source of blood is suitable for use in blood product development, as current data indicate that red blood cell (RBC) deformability, both before and after shear stress exposure, is impaired in individuals with HH, relative to healthy controls. Given that venesection therapy is known to significantly reduce circulating iron levels in individuals with HH, the current study examined whether venesection therapy is effective at improving RBC mechanical properties, both before and after shear stress exposure, in individuals with HH. Study Design and Methods: Blood samples were initially collected from untreated HH patients (age, 61 ± 9 years; 14% female) undergoing their first venesection, and then again during their second (approx. 9 weeks later) and third (approx. 16 weeks later) venesections. RBC deformability was measured at each time point with a commercial ektacytometer. Moreover, to determine cell responses to mechanical stimuli, the mechanical sensitivity of blood samples was determined at each time point. Results: The salient findings indicate that venesection therapy used for managing plasma ferritin concentration significantly improves the cellular deformability of RBC in individuals with HH. Further, the sensitivity of RBC to supraphysiological mechanical stress is decreased (ie, improved) in a dose‐response fashion with routine venesection. Conclusion: While cellular mechanics of RBC from individuals with HH are impaired when untreated, venesection therapy significantly improves cellular properties of RBC, supporting the use of venesections in blood product development from individuals with well‐managed HH. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to examine the donor‐to‐donor variability in the deformability of red blood cells (RBCs) from freshly collected blood donations (F‐RBC) and packed RBCs. Background: Packed RBCs are supplied for transfusion by the first‐in‐first‐out (FIFO) criterion, assuming that their quality is the same for packed RBCs with equal storage duration. To challenge this notion, we determined the deformability of F‐RBC and packed RBCs stored for different durations. Methods: Three RBC groups were employed: A. 79 samples of F‐RBC; B. 76 samples of packed RBC units, randomly used for transfusion at different storage durations; and C. 65 samples of outdated packed RBCs stored for 35 to 37 days. All packed RBC units were non‐leukofiltrated and stored in Citrate‐phosphate‐dextrose solution with adenine (CPDA‐1). RBC deformability was determined using a computerised cell‐flow properties analyser, which monitors the shape change of cells directly visualised in a narrow‐gap flow chamber and provides the cells' deformability distribution in a large RBC population. Results: The F‐RBC deformability exhibited a wide‐range inter‐donor variability. The cold storage of packed RBCs exerted a mild reduction of deformability, which became significant, compared to the initial inter‐donor variability, only after 3 weeks of storage. Conclusion: Packed RBCs are generally supplied for transfusion by the FIFO criterion based on the assumption that the storage duration is a key factor of RBC quality. This study demonstrates that the deformability of red blood cells is significantly different in donors, and substantial variability persists throughout the entire process of their storage. Therefore, the FIFO criterion is not sufficient for assessing the RBC deformability, which should, therefore, be specifically characterised for each unit. [ABSTRACT FROM AUTHOR]

Blood exposure to supraphysiological shear stress within mechanical circulatory support is suspected of reducing red blood cell (RBC) deformability and being primal in the pathogenesis of several secondary complications. No prior works have explored RBC dynamics with the resolution required to determine shear elastic modulus, and/or cell capillary velocity, following exposure to mechanical stresses. Healthy RBCs were exposed to 0, 5, 50, and 100 Pa in a Couette shearing system. For comparison, blood was also exposed to heat treatment—a method that predictably increases RBC rigidity. Shear modulus assessment required aspiration of single RBCs through narrow micropipettes at known suction force. Cell transit velocities were measured within microchannels in regions of fully developed flow. Supraphysiological shear stress increased the elastic shear modulus by 39% and 69% following exposure to 50 and 100Pa, respectively. Cell transit velocity, however, did not change following shear, with concurrent decreases in cell volume likely nullifying increased shear modulus‐friction interactions. Differences observed were consistent with our internal control (heat treatment), supporting that cell mechanics are significantly impaired following supraphysiological‐sublethal shear exposure. Given mechanical circulatory support operates at shear stresses consistent with the present study, it is plausible that these devices induce fundamental impairment to the material properties of RBCs. [ABSTRACT FROM AUTHOR]

BACKGROUND: Previously, hemorheology studies using Rheoscan mainly focused on chronic kidney disease, cardiovascular disease, and endocrine disease in adults. The study using LORCA focused on erythrocyte disease. There were no studies using Rheoscan in children. OBJECTIVE: We aimed to investigate erythrocyte deformability among various hematologic diseases occurring in children, namely, iron deficiency anemia (IDA), hereditary spherocytosis (HS), immune thrombocytopenia (ITP), and aplastic anemia (AA). METHODS: Differences between those with HS, IDA, ITP, AA and healthy controls were compared among 43 patients, comprising 7 patients with HS, 8 patients with IDA, 6 patients with AA, 9 patients with ITP, and 13 healthy controls. Erythrocyte deformability was measured using a microfluidic ektacytometer (RheoScan-D, RheoMeditech, Seoul, Korea). The erythrocyte elongation index (EI) was defined as (L – W)/(L + W), where L and W are the major and minor axes of the ellipse, respectively. RESULTS: The EI values of IDA, HS and AA were significantly decreased compared with healthy controls, but those of ITP were similar to healthy controls. CONCLUSIONS: This study showed that erythrocyte deformability differed among various hematologic diseases. Further study concerning correlation in relation to the diagnostic and prognostic significance of erythrocyte deformability in hematologic disease is needed. [ABSTRACT FROM AUTHOR]

Red blood cells (RBC), the primary component of whole blood, play an essential role in maintaining blood fluidity and mass transport throughout the human body. RBC deformability is an important property that indicates RBC quality and diseases. Among the techniques for RBC deformability measurements, the hydrodynamic image-based approach represents the most advanced method. However, RBC have a complex shape and high deformability, they display a wide range of shapes during the transition in microvessels, making it a challenge for deformation measurement. Therefore, we propose an i mage-based R BC deformab i lity assessment via a s hape-classification approach (IRIS) to solve this issue, where six shapes are identified by deep learning technique. Then, the deformations of RBC stiffened by different glutaraldehyde (GA) concentrations are measured and compared. The results elucidate that IRIS is able to sensitively distinguish 0.001% GA treated RBC from the control. Moreover, it is superior to two-shape classification or zero-shape classification in terms of sensitivity for deformability quantification. IRIS demonstrates an improved sensitivity for deformability analysis, high automaticity and unprecedented large data volume by applying deep learning method, it has a vast potential to benefit the hemorheology field as a powerful tool for early detection and diagnosis of RBC related diseases. • Image-based deformability assessment of red blood cells (RBC) in microfluidics. • Identification of six RBC deformation shapes by deep learning. • Significant improvement of deformability quantification via shape-classification approach. • A scoring scheme proposed for the evaluation of RBC deformability in potential clinical applications. [ABSTRACT FROM AUTHOR]

Purpose: To investigate differences in red blood cell (RBC) deformability between birdshot chorioretinopathy (BCR) subjects and matched controls, and to postulate its relationship with lack of vascular occlusion in BCR. Methods: In a single center, prospective, non-randomized mechanistic study, blood samples were collected from eight healthy controls and nine BCR patients, and subjected to biochemical and hematological tests, as well as RBC indices assessment using dual-beam optical tweezers. Results: The mean age of the controls was 52.37 ± 10.70 years and BCR patients was 53.44 ± 12.39 years. Initial cell size (Io) for the controls was 8.48 ± 0.25 μm and 8.87 ± 0.31 μm for BCR RBCs (p = 0.014). The deformability index (DI) for the controls was 0.066 ± 0.02 and that for BCR RBCs was 0.063 ± 0.03 (p = 0.441). Conclusion: There was no statistically significant difference in DI between RBCs from BCR and healthy controls. This may explain the rare occurrence of retinal vascular occlusion despite the underlying vasculitic pathophysiology of BCR. [ABSTRACT FROM AUTHOR]

BACKGROUND AND OBJECTIVE: Hemorheologic alterations have been suggested to play a role in the pathogenesis of diabetic microvascular complications. We measured various hemorheologic parameters and assessed their possible role as a diagnostic tool for diabetic nephropathy (DN). METHODS: 248 subjects with type 2 diabetes and 222 subjects with prediabetes were included in this study. Hemorheologic parameters, including erythrocyte sedimentation rate (ESR), elongation index at 3 Pa (EI) were measured using microfluidic hemorheometer. Various metabolic parameters were measured from fasting blood samples. The subjects were stratified into three groups according to classification of DN by urinary albumin to creatinine ratio (ACR) and four groups by estimated glomerular filtration rate (GFR), than analyzed. RESULTS: Significant differences were observed in metabolic and hemorheologic parameters according to progression of DN. Among them, (Fibrinogen×ESR)/ EI differed in all three groups of urinary ACR. In multiple regression analysis, (Fibrinogen×ESR)/ EI was an independent predictor of urine ACR after adjusted with confounding factors (ß = 0.010, p < 0.001). (Fibrinogen×ESR)/ EI also showed significant difference no or minimal CKD stage, moderate CKD and severe CKD classified by GFR. This parameter showed area under curve (AUC) of the receiver operating characteristic (ROC) curve of 0.762, and moderate sensitivity and specificity to predict prevalence of microalbuminuria. CONCLUSIONS: (Fibrinogen×ESR)/ EI is a sensitive parameter for screening diabetic nephropathy. [ABSTRACT FROM AUTHOR]

BACKGROUND: The Nordic hamstring exercise (NHE) has been proven to be an effective preventive technique for hamstring injuries. Hemorheological parameters (erythrocyte deformability and aggregation) play a critical role in exercise influencing oxygenation. Although previous studies presented hemorheological alterations induced by different types of exercise, changes in red blood cell (RBC) deformability and aggregation following NHE remain unknown. Present study was designed to explore possible alterations in hemorheological and oxidative parameters after an acute bout of NHE. METHODS: 10 healthy, male, active students (mean age 19.9±0.23, BMI: 21.56±0.54) participated to the study. They performed a single session of seven-repetitions of NHE followed by a familiarisation period. Blood samples were obtained before and immediately after the exercise from the antecubital vein. Hemorheological parameters were measured by an ektacytometer. RESULTS: NHE did not change deformability, hematocrit and oxidative stress but, increased RBC aggregation index (AI, p = 0.011) and decreased RBC aggregation half time (t½, p = 0.009). CONCLUSIONS: Our results suggest that, increased RBC aggregation following an acute bout of NHE may result in increased plasma skimming and thus ease the flow of blood. [ABSTRACT FROM AUTHOR]

BACKGROUND: The Nordic hamstring exercise (NHE) has been proven to be an effective preventive technique for hamstring injuries. Hemorheological parameters (erythrocyte deformability and aggregation) play a critical role in exercise influencing oxygenation. Although previous studies presented hemorheological alterations induced by different types of exercise, changes in red blood cell (RBC) deformability and aggregation following NHE remain unknown. Present study was designed to explore possible alterations in hemorheological and oxidative parameters after an acute bout of NHE. METHODS: 10 healthy, male, active students (mean age 19.9±0.23, BMI: 21.56±0.54) participated to the study. They performed a single session of seven-repetitions of NHE followed by a familiarisation period. Blood samples were obtained before and immediately after the exercise from the antecubital vein. Hemorheological parameters were measured by an ektacytometer. RESULTS: NHE did not change deformability, hematocrit and oxidative stress but, increased RBC aggregation index (AI, p = 0.011) and decreased RBC aggregation half time (t½, p = 0.009). CONCLUSIONS: Our results suggest that, increased RBC aggregation following an acute bout of NHE may result in increased plasma skimming and thus ease the flow of blood. [ABSTRACT FROM AUTHOR]

BACKGROUND: Ozone is used intensively worldwide in treatment and research of various pathologies due to its healing effects. OBJECTIVE: The aim of this study is to investigate the effect of major ozone autohemotherapy on erythrocyte deformability and aggregation. METHODS: 10 and 50μg/ml doses of ozone was applied for 20 minute to venous blood samples obtained from 10 healthy male volunteers. Erythrocyte aggregation, deformability were measured by an ektacytometer. Total oxidant status, total antioxidant status were measured via a commercial kit. The oxidative stress index was calculated. RESULTS: Ozone at 10 and 50μg/ml doses did not alter erythrocyte aggregation. 50μg/ml ozone increased red blood cell (RBC) deformability measured at 0.53 Pa. Compared with the Control value, there was a significant increase in TOS, TAS for the doses of 10 and 50μg/ml. The increase in TAS was found to be more significant at 10μg/ml dose. The most obvious increase in OSI value was observed at 50μg/ml. CONCLUSION: Our results demonstrate that although 10μg/ml ozone has no effect on hemorheology, 50μg/ml ozone concentration has positive effects on RBC deformability, thus circulation at 0.53 Pa corresponding to the shear stress encountered during venous circulation. [ABSTRACT FROM AUTHOR]

The main function of red blood cells (RBCs) is the transport of respiratory gases along the vascular tree. To fulfill their task, RBCs are able to elastically deform in response to mechanical forces and, pass through the narrow vessels of the microcirculation. Decreased RBC deformability was observed in pathological conditions linked to increased oxidative stress or decreased nitric oxide (NO) bioavailability, like hypertension. Treatments with oxidants and with NO were shown to affect RBC deformability ex vivo, but the mechanisms underpinning these effects are unknown. In this study we investigate whether changes in intracellular redox status/oxidative stress or nitrosation reactions induced by reactive oxygen species (ROS) or NO may affect RBC deformability. In a case-control study comparing RBCs from healthy and hypertensive participants, we found that RBC deformability was decreased, and levels of ROS were increased in RBCs from hypertensive patients as compared to RBCs from aged-matched healthy controls, while NO levels in RBCs were not significantly different. To study the effects of oxidants on RBC redox state and deformability, RBCs from healthy volunteers were treated with increasing concentrations of tert-butylhydroperoxide (t-BuOOH). We found that high concentrations of t-BuOOH (≥ 1 mM) significantly decreased the GSH/GSSG ratio in RBCs, decreased RBC deformability and increased blood bulk viscosity. Moreover, RBCs from Nrf2 knockout (KO) mice, a strain genetically deficient in a number of antioxidant/reducing enzymes, were more susceptible to t-BuOOH-induced impairment in RBC deformability as compared to wild type (WT) mice. To study the role of NO in RBC deformability we treated RBC suspensions from human volunteers with NO donors and nitrosothiols and analyzed deformability of RBCs from mice lacking the endothelial NO synthase (eNOS). We found that NO donors induced S-nitrosation of the cytoskeletal protein spectrin, but did not affect human RBC deformability or blood bulk viscosity; moreover, under unstressed conditions RBCs from eNOS KO mice showed fully preserved RBC deformability as compared to WT mice. Pre-treatment of human RBCs with nitrosothiols rescued t-BuOOH-mediated loss of RBC deformability. Taken together, these findings suggest that NO does not affect RBC deformability per se, but preserves RBC deformability in conditions of oxidative stress.

The primary goal of red blood cell (RBC) transfusion is to supply oxygen to tissues and organs. However, due to a growing number of studies that have reported negative transfusion outcomes, including reduced blood perfusion, there is rising concern about the risks in blood transfusion. RBC are characterized by unique flow-affecting properties, specifically adherence to blood vessel wall endothelium, cell deformability, and self-aggregability, which define their hemodynamic functionality (HF), namely their potential to affect blood circulation. The role of the HF of RBC in blood circulation, particularly the microcirculation, has been documented in numerous studies with animal models. These studies indicate that the HF of transfused RBC (TRBC) plays an important role in the transfusion outcome. However, studies with animal models must be interpreted with reservations, as animal physiology may not reflect human physiology. To test this concept in humans, we have directly examined the effect of the HF of TRBC, as expressed by their deformability and adherence to vascular endothelium, on the transfusion-induced effect on the skin blood flow and hemoglobin increment in β-thalassemia major patients. The results demonstrated, for the first time in humans, that the TRBC HF is a potent effector of the transfusion outcome, expressed by the transfusion-induced increase in the recipients' hemoglobin level, and the change in the skin blood flow, indicating a link between the microcirculation and the survival of TRBC in the recipients' vascular system. The implication of these findings for blood transfusion practice and to vascular function in blood recipients is discussed.

The main function of red blood cells (RBCs) is the transport of respiratory gases along the vascular tree. To fulfill their task, RBCs are able to elastically deform in response to mechanical forces and, pass through the narrow vessels of the microcirculation. Decreased RBC deformability was observed in pathological conditions linked to increased oxidative stress or decreased nitric oxide (NO) bioavailability, like hypertension. Treatments with oxidants and with NO were shown to affect RBC deformability ex vivo, but themechanisms underpinning these effects are unknown. In this study we investigate whether changes in intracellular redox status/oxidative stress or nitrosation reactions induced by reactive oxygen species (ROS) or NO may affect RBC deformability. In a case-control study comparing RBCs from healthy and hypertensive participants, we found that RBC deformability was decreased, and levels of ROS were increased in RBCs from hypertensive patients as compared to RBCs from aged-matched healthy controls, while NO levels in RBCs were not significantly different. To study the effects of oxidants on RBC redox state and deformability, RBCs from healthy volunteers were treated with increasing concentrations of tert-butylhydroperoxide (t-BuOOH). We found that high concentrations of t-BuOOH (= 1mM) significantly decreased the GSH/GSSG ratio in RBCs, decreased RBC deformability and increased blood bulk viscosity. Moreover, RBCs from Nrf2 knockout (KO) mice, a strain genetically deficient in a number of antioxidant/reducing enzymes, were more susceptible to t-BuOOH-induced impairment in RBC deformability as compared to wild type (WT) mice. To study the role of NO in RBC deformability we treated RBC suspensions from human volunteers with NO donors and nitrosothiols and analyzed deformability of RBCs from mice lacking the endothelial NO synthase (eNOS). We found that NO donors induced S-nitrosation of the cytoskeletal protein spectrin, but did not affect human RBC deformability or blood bulk viscosity; moreover, under unstressed conditions RBCs from eNOS KO mice showed fully preserved RBC deformability as compared to WT mice. Pre-treatment of human RBCs with nitrosothiols rescued t-BuOOH-mediated loss of RBC deformability. Taken together, these findings suggest that NO does not affect RBC deformability per se, but preserves RBC deformability in conditions of oxidative stress. [ABSTRACT FROM AUTHOR]

The primary goal of red blood cell (RBC) transfusion is to supply oxygen to tissues and organs. However, due to a growing number of studies that have reported negative transfusion outcomes, including reduced blood perfusion, there is rising concern about the risks in blood transfusion. RBC are characterized by unique flow-affecting properties, specifically adherence to blood vessel wall endothelium, cell deformability, and self-aggregability, which define their hemodynamic functionality (HF), namely their potential to affect blood circulation. The role of the HF of RBC in blood circulation, particularly the microcirculation, has been documented in numerous studies with animal models. These studies indicate that the HF of transfused RBC (TRBC) plays an important role in the transfusion outcome. However, studies with animal models must be interpreted with reservations, as animal physiology may not reflect human physiology. To test this concept in humans, we have directly examined the effect of the HF of TRBC, as expressed by their deformability and adherence to vascular endothelium, on the transfusion-induced effect on the skin blood flow and hemoglobin increment in b-thalassemia major patients. The results demonstrated, for the first time in humans, that the TRBC HF is a potent effector of the transfusion outcome, expressed by the transfusion-induced increase in the recipients' hemoglobin level, and the change in the skin blood flow, indicating a link between the microcirculation and the survival of TRBC in the recipients' vascular system. The implication of these findings for blood transfusion practice and to vascular function in blood recipients is discussed. [ABSTRACT FROM AUTHOR]

Red blood cell (RBC) deformability has a significant impact on microcirculation by affecting cell dynamics. Despite previous studies that have demonstrated the margination of rigid cells and particles in vitro, little information is available on the in vivo margination of deformability-impaired RBCs under physiological flow and hematocrit conditions. Thus, in this study, we examined how the deformability-dependent, RBC migration alters the cell distribution under physiological conditions, particularly in arteriolar network flows. The hardened RBCs (hRBCs) were found to preferentially flow near the vessel walls of small arterioles (diameter = 47.1–93.3 μm). The majority of the hRBCs (63%) were marginated within the range of 0.7R-0.9R (R: radial position normalized by vessel radius), indicating that the hRBCs preferentially accumulated near the vessel walls. The laterally marginated hRBCs maintained their lateral positions near the walls while traversing downstream with attenuated radial dispersion. In addition, the immediate displacement of RBCs while traversing a bifurcation also contributes to the near-wall accumulation of hRBCs. The notable difference in the inward migration between the marginated nRBCs and hRBCs after bifurcations further supports the potential role of bifurcations in the accumulation of hRBCs near the walls.

The hemorheologic disorders, which are potentially deleterious in a wide range of pathologies, were studied in patients with type-1 and type-2 diabetes mellitus. The significant determinants of blood viscosity, red blood cells (RBC) deformability and RBC reversible aggregation were assessed by ektacytometry and by laser backscattering technique, respectively. For both types of the disease, we observed acceleration of the first phase of RBC aggregation that contrasted with its deceleration at the second phase. The hydrodynamic stability of the aggregates, especially the smallest ones, exceeded the normal values in both cases. The influence of GP IIb/IIIa receptor inhibitor, monafram on RBC aggregation and disaggregation was the same in the cases of patients and normal subjects. The maximal shear induced RBC stretching exceeded the normal one in patients of both groups. The data reveal not only pathological but also compensatory character of hemorheological alterations in patients with type-1 and type-2 diabetes mellitus.

Red blood cell (RBC) deformability has a significant impact on microcirculation by affecting cell dynamics. Despite previous studies that have demonstrated themargination of rigid cells and particles in vitro, little information is available on the in vivo margination of deformability-impaired RBCs under physiological flow and hematocrit conditions. Thus, in this study, we examined how the deformability-dependent, RBC migration alters the cell distribution under physiological conditions, particularly in arteriolar network flows. The hardened RBCs (hRBCs) were found to preferentially flow near the vessel walls of small arterioles (diameter = 47.1-93.3μm). The majority of the hRBCs (63%) were marginated within the range of 0.7R-0.9R (R: radial position normalized by vessel radius), indicating that the hRBCs preferentially accumulated near the vessel walls. The laterally marginated hRBCs maintained their lateral positions near the walls while traversing downstream with attenuated radial dispersion. In addition, the immediate displacement of RBCs while traversing a bifurcation also contributes to the near-wall accumulation of hRBCs. The notable difference in the inward migration between the marginated nRBCs and hRBCs after bifurcations further supports the potential role of bifurcations in the accumulation of hRBCs near the walls. [ABSTRACT FROM AUTHOR]

The rheological properties of blood play a significant role in the onset and progression of arterial hypertension. The aim of our work was to evaluate the effect of the angiotensin-converting enzyme inhibitor captopril (20 mg/kg/d), pentoxifylline (PTX; 100 mg/kg/d), and the combination of captopril + PTX (20 + 100 mg/kg/d) on the hemodynamic and hemorheological parameters in spontaneously hypertensive rats (SHRs) during the development of arterial hypertension. In the group of animals that received captopril, the mean arterial pressure (MAP) was significantly lower by 30% due to a decrease in cardiac output of 23% and in total peripheral resistance (TPR) of 26% compared with the control group, whereas blood viscosity did not change significantly. PTX-treated SHRs had significantly lower MAP and TPR (by 19% and 31%, respectively) and blood viscosity (by 4%–6%) and a higher erythrocyte deformability index (by 1.5%–2%) than the control group. In the group of animals that received captopril + PTX, MAP and TPR were significantly lower, by 41% and 46%, than those in the control group, and by 16% and 27% than those in the captopril group. The combination of the angiotensin-converting enzyme inhibitor captopril and the hemorheological agent PTX, affecting various systems that are involved in blood pressure regulation, exhibits synergism and prevents an increase in arterial blood pressure during the development of arterial hypertension in SHRs (ie, from 5 to 11 weeks of life). [ABSTRACT FROM AUTHOR]

Significance: Recent clinical evidence identified anemia to be correlated with severe complications of cardiovascular disease (CVD) such as bleeding, thromboembolic events, stroke, hypertension, arrhythmias, and inflammation, particularly in elderly patients. The underlying mechanisms of these complications are largely unidentified. Recent Advances: Previously, red blood cells (RBCs) were considered exclusively as transporters of oxygen and nutrients to the tissues. More recent experimental evidence indicates that RBCs are important interorgan communication systems with additional functions, including participation in control of systemic nitric oxide metabolism, redox regulation, blood rheology, and viscosity. In this article, we aim to revise and discuss the potential impact of these noncanonical functions of RBCs and their dysfunction in the cardiovascular system and in anemia. Critical Issues: The mechanistic links between changes of RBC functional properties and cardiovascular complications related to anemia have not been untangled so far. Future Directions: To allow a better understanding of the complications associated with anemia in CVD, basic and translational science studies should be focused on identifying the role of noncanonical functions of RBCs in the cardiovascular system and on defining intrinsic and/or systemic dysfunction of RBCs in anemia and its relationship to CVD both in animal models and clinical settings. Antioxid. Redox Signal. 26, 718-742. [ABSTRACT FROM AUTHOR]

Background: This study investigated the effects of 12-week resistance training on body composition, blood pressure, blood lipid levels, muscle cross-sectional area (CSA), isokinetic muscle function, and hemorheological properties in middle-aged obese women., Methods: Twenty-eight obese women with a mean age of 50.79 ± 5.80 years were randomly assigned to the control (CON, n = 13) or experimental (EXP, n = 15) group. The EXP group underwent a resistance training program composed of warm-up, main resistance exercise (deadlift, barbell squat, seated leg extension, and lying leg curl, bench press, preacher bench biceps curl, barbell rowing, and dumbbell shoulder press), and cool-down. The resistance exercise consisted of three sets of 8-10 repetitions (reps) performed with 70-80% of 1-rep maximum, and reps and sets were increased every 3 weeks. The training frequency was 80 min, 3 days per week for 12 weeks. The CON group maintained their daily lifestyle without training. All participants underwent measurements of body composition (weight, body mass index, lean body mass, fat mass, and % body fat), blood pressure (systolic blood pressure, diastolic blood pressure, mean arterial pressure, and pulse pressure), blood lipid levels (triglycerides, total cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol), CSA of the muscles (quadriceps, hamstring, and total thigh muscle), isokinetic muscle function (peak torque [PT], relative PT, mean power, and total work [TW]), and hemorheological properties (erythrocyte deformability and aggregation) before and after 12 weeks of training., Results: The EXP group showed a significant improved muscle function, including PT ( p < 0.001), relative PT ( p < 0.001) in extension 60°/s, TW ( p < 0.001) in extension 180°/s, and TW ( p = 0.018) in flexion 180°/s. Regarding hemorheological properties, the EXP group showed significant improvement in erythrocyte aggregation ( p < 0.001) and deformability ( p < 0.001)., Conclusions: The present study verified that our resistance training program resulted in greater muscle function, decreased fat mass, and improved hemorheological properties., Clinical Trial Registration: This study was registered with cris.nih.go.kr (No. KCT0007412)., Competing Interests: The authors declare no conflict of interest., (Copyright: © 2023 The Author(s). Published by IMR Press.)

Biophysical properties are widely used to detect pathophysiological processes of vascular diseases or clinical states. For early detection of cardiovascular diseases, it is necessary to simultaneously measure multiple biophysical properties in a microfluidic environment. However, a microfluidic-based technique for measuring multiple biophysical properties has not been demonstrated. In this study, a simple measurement method was suggested to quantify three biophysical properties of blood, including red blood cell (RBC) deformability, RBC aggregation, and hematocrit. To demonstrate the suggested method, a microfluidic device was constructed, being composed of a big-sized channel (BC), a parallel micropillar (MP), a main channel, a branch channel, inlet, and outlets. By operating a single syringe pump, blood was supplied into the inlet of the microfluidic device, at a periodic on-off profile (i.e., period = 240 s). The RBC deformability index (DI) was obtained by analyzing the averaged blood velocity in the branch channel. Additionally, the RBC aggregation index (AIN) and the hematocrit index (HiBC) were measured by analyzing the image intensity of blood flows in the MP and the BC, respectively. The corresponding contributions of three influencing factors, including the turn-on time (Ton), the amplitude of blood flow rate (Q0), and the hematocrit (Hct) on the biophysical indices (DI, AIN, and HiBC) were evaluated quantitatively. As the three biophysical indices varied significantly with respect to the three factors, the following conditions (i.e., Ton = 210 s, Q0 = 1 mL/h, and Hct = 50%) were maintained for consistent measurement of biophysical properties. The proposed method was employed to detect variations of biophysical properties depending on the concentrations of autologous plasma, homogeneous hardened RBCs, and heterogeneous hardened RBCs. Based on the observations, the proposed method exhibited significant differences in biophysical properties depending on base solutions, homogeneous hardened RBCs (i.e., all RBCs fixed with the same concentration of glutaraldehyde solution), and heterogeneous hardened RBCs (i.e., partially mixed with normal RBCs and homogeneous hardened RBCs). Additionally, the suggested indices (i.e., DI, AIN, and HiBC) were effectively employed to quantify three biophysical properties, including RBC deformability, RBC aggregation, and hematocrit.

Aim Red blood cell (RBC) deformability, the ability of RBCs to change shape under stress, is known to be decreased in type 2 diabetes (T2D). However, as yet little is known of the association between RBC deformability and diabetic complications in T2D. For this reason, this study has investigated the association between RBC deformability and diabetic complications. Methods In this cross-sectional study, 452 T2D patients were initially enrolled. RBC deformability was measured using a microfluidic ektacytometer and expressed as an elongation index at 3 Pa (EI@3Pa, %). Results A final total of 373 patients (mean age: 60.04 ± 11.93 years; males: 201) were included in the study. When categorized into quartiles of RBC deformability, the lower EI@3Pa groups had higher glycated haemoglobin (HbA 1c ), triglycerides and prevalence of diabetic retinopathy compared with the higher quartiles ( P < 0.05 for trend). In particular, the EI@3Pa was significantly lower in patients with retinopathy than in those without retinopathy (30.53 ± 1.95 vs 31.20 ± 1.53, P = 0.001). Between the lowest EI@3Pa quartile (Q1) to the highest (Q4, reference), the odds ratio (OR) for Q1 was 2.81 (95% CI: 1.21–6.49, P = 0.004 for trend), after adjusting for age, gender, presence of hypertension and smoking, duration of diabetes, HbA 1c , glomerular filtration rate and triglycerides. Conclusion In terms of diabetic complications, the lowest EI@3Pa group was closely associated with only the risk of diabetic retinopathy in our study. These results suggest that RBC deformability might be contributory to the development of the microvascular complication. [ABSTRACT FROM AUTHOR]

In a number of human diseases such as diabetes mellitus and sickle cell anemia, variations in mechanical properties of red blood cells (RBCs) occur and cause reduced deformability. Investigating the behavior of such abnormal, hardened RBCs in microcapillary flow is of prime importance because of their effects on oxygen transport process. In the present paper, dynamic response of a RBC to a microcapillary flow is numerically studied at steady and transient conditions, considering the effect of essential parameters including RBC deformability, its initial orientation, velocity, and flow pressure gradient. Simulations are performed using a three-dimensional hybrid method, combining lattice Boltzmann method for plasma flow, finite element method for RBC membrane analysis, and immersed boundary method for their interaction. Quantitative and qualitative validations with the experimental data for different RBC velocities verify the accuracy of applied numerical method. Apart from the initial orientation, RBC experiences a complex shape deformation in which the biconcave discoid shape changes to a parachute-like shape. While deformation index of RBC does not change considerably with RBC deformability at steady state condition, it plays an important role in its shape evolution under transient condition. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Even though exercise hemorheology at hypoxic condition has been considered as a good tool to understand clinical hemorheology, there have been limited studies reported. Previous researches showed that hemorheological variables are closely correlated with oxygen delivery capacity during exercise. The present study investigated hypoxic responses including RBC deformability and aggregation, metabolic parameters and complete blood cell counts at various hypoxic conditions during cycling exercise and recovery. Eleven Korean healthy male subjects performed submaximal bike exercise at sea level (20.9% O2) and under various hypoxic conditions (16.5% O2, 14.5% O2, 12.8% O2, and 11.2% O2) in a random order. The submaximal bike exercise intensity of the subjects was 70% maximum heart rate at sea level. All variables were measured at rest, during exercise and recovery 30-minute, respectively. As oxygen partial pressure decreased, arterial blood oxygen saturation decreased but oxygen uptake did not change much. Heart rate and lactate concentration during exercise increased when oxygen partial pressure is less than or equal to 14.5% O2 condition. Red blood cell (RBC) counts, hemoglobin counts, and hematocrit level were not apparently altered with hypoxic conditions. RBC deformability showed significant alterations at 11.2% O2 conditions compared with other hypoxic conditions during exercise or recovery, except at 10 minutes recovery. However, decreases in oxygen partial pressure did not affect red blood cell aggregation. Therefore, we conclude that alterations in RBC deformability may reduce aerobic capabilities at hypoxic condition. [ABSTRACT FROM AUTHOR]