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Smokers incur a sustained free radical load which may increase their vitamin E requirement. However, in the present study this was not apparent from plasma and red blood cells (RBC) vitamin E concentrations which were similar in both smokers and non-smokers. However, RBC from smokers were more susceptible to hydrogen peroxide-stimulated peroxidation than those from non-smokers (p<0.001). Furthermore, plasma concentrations of lipid peroxides, thiobarbituric acid reactive substances and conjugated dienes were also elevated in smokers compared with the non-smokers (p<0.05). These indices of oxidative stress were markedly decreased (p<0.001) in both the smokers, and non-smokers, following consumption of 280 mg dl- tocopherol acetate/day for ten weeks. Plasma and RBC vitamin E concentration increased substantially following supplementation, but the % increase in vitamin E required to improve resistance to in vitro RBC peroxidation was significantly greater in non-smokers (p<0.01). This may reflect an endogenous adaptive response to oxidant stress in RBC of smokers. Erythrocyte vitamin E concentrations increased in a dose dependent manner during 20 weeks of supplementation with either 70,140,560 or 1050mg d--tocopherol per day. In smokers each dose was associated with a significant decrease in susceptibility of erythrocytes to peroxidation (p<0.001). However, red cells of non-smokers on the 1050mg supplement demonstrated an increased susceptibility to peroxidation (p<0.001). Thus, vitamin E may demonstrate prooxidant activity in non-smokers at high and prolonged intakes. Moreover, prolonged supplementation with d--tocopherol in non-smokers induced a decline in plasma ascorbate concentration (p<0.02) in association with an increasing erythrocyte vitamin E uptake (p<0,001). Both smokers and non-smokers may benefit from increased vitamin E intakes, although their requirements may be very different. However pharmacological doses may not be required since it appears that doses as low as 70mg are equally effective.

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Microvascular transport is strongly influenced by the nonuniform partitioning of red blood cells at diverging microvessel bifurcations, where blood flows from one mother vessel into two daughter vessels. In such bifurcations, the volume fractions of red blood cells in the blood entering each daughter vessel typically differ significantly from the volume fraction in the mother vessel. This phenomenon is caused, to a first approximation, by nonuniform distribution of red blood cells in the cross-section of the mother vessel and the tendency of red blood cells to follow background fluid streamlines. In smaller vessels, however, red blood cell trajectories can deviate significantly from fluid streamlines. In this dissertation, the mechanical reasons for these deviations and their contributions to nonuniform partitioning are analyzed.A two-dimensional model is used to simulate the motion and deformation of flexible particles as they travel alone through a diverging microvessel bifurcation. Deviations of particle trajectories from background fluid streamlines result from migration towards the mother vessel centerline upstream of the bifurcation and flow perturbations caused by cell obstruction in the bifurcation region. Cell migration, which arises because of flexibility, causes more nonuniform partitioning while cell obstruction causes more uniform partitioning. Bifurcations with differently sized daughter vessels experience, on average, a higher red blood cell flux into the smaller branch. Partitioning is unaffected by daughter branching angles.The motion of two interacting cells is also considered. In diverging bifurcations several types of interactions were found, in which the presence of a nearby cell causes a cell to enter a different branch than it would have otherwise. The net effect of these interactions is to cause more uniform partitioning. In wall-bounded linear shear flow, a two-dimensional swapping interaction was identified, in which two cells on different background fluid streamlines approach each other, slowly move onto their partner's streamline, and then move away from each other.The simulations produced by this two-dimensional model provide insight into the effects of red blood cell deformability, bifurcation geometry and volume fraction of red blood cells on red blood cell partitioning and on the resultant distribution and transport of materials in the microvasculature.

Margination is the migration of particles in a channel towards the outer walls of the channel. In blood microcirculation, studying the margination of microparticles is important to understand platelet migration and the kinetics of drug delivery. Many new topics in drug delivery research examine the slow release of drugs through micro particles, such as micelles. The margination of such drug carriers is related to tissue absorption and, consequently, to the efficiency of drug delivery. We hypothesized that the intensity of red blood cell (RBC) aggregation will change the level of margination in a cylindrical channel. RBC aggregation is the reversible process of RBCs clumping together over time, under low fluid shear rate. A higher level of aggregation means that this clumping occurs more quickly. The goal of this thesis is to design an experiment that measures the level margination of microparticles and the effect that RBC aggregation has on margination, in a controlled in vitro environment. Fluorescent microparticles were added to human blood preparations. The aggregation properties of the blood preparation were modulated by the addition of a macromolecule (Dextran 500). The blood preparations were injected into PDMS microfluidic devices that were modified to have circular channels in order to better mimic the geometry of physiological microcirculation. We designed a circular microchannel that worked to capture the marginating microparticles and it was found that the level of margination of the microparticles increased with an increase in aggregation of the RBCs. This increase in margination was especially sensitive to aggregation levels in the range of physiological aggregation levels of whole blood, suggesting that aggregation plays an important role in margination in vivo.

An association between compatible but ABO non-identical red blood cell (RBC) transfusions and increased in-hospital mortality was identified in an observational study. A review of the literature was performed to explore plausible biological mechanisms and inflammation was chosen. This thesis describes a body of work that was performed to develop a PICOT research question and design a pilot feasibility randomized crossover trial in patients with myelodysplastic syndrome (MDS) to determine whether there is evidence of an inflammatory response resulting from transfusion of ABO non-identical RBCs compared with the transfusion of ABO identical RBCs. The work undertaken as part of this thesis included: identifying a theoretical framework to guide the selection of outcome measures that would detect inflammation; identifying an appropriate and feasible population to study; designing the feasibility pilot study to answer the research question that was developed; and a discussion of ethical issues that were considered as the design of the pilot study was developed. The work that was done to develop the elements of PICOT resulted in the following research question: Is it feasible to perform a randomized crossover trial in chronically transfused blood group A patients with myelodysplastic syndrome (MDS), that looks for laboratory evidence of inflammation (in vitro biomarkers measured at baseline and pre-specified times between 1 and 96 hours post transfusion), following the transfusion of group O RBCs (ABO non-identical) compared to transfusion of group A (ABO identical) RBCs? / Thesis / Master of Science (MSc)

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Human red blood cells (RBCs) must undergo severe deformation to pass through narrow capillaries and submicronic splenic slits for several hundred thousand times in their normal lifespan. Studies of RBC biomechanics have been mainly focused on cell deformability measured from a single application of stress using classical biomechanical techniques, such as optical tweezers and micropipette aspiration. Mechanical fatigue effect on RBCs under cyclic loadings of stress that contributes to the membrane failure in blood circulation is not fully understood. This research developed a new experimental method for mechanical fatigue testing of RBCs using amplitude-modulated electro-deformation technique. Biomechanical parameters of individually tracked RBCs show strong correlations with the number of the loading cycles. Effects of loading configurations on the cellular fatigue behavior of RBCs is further studied. The results uniquely establish the important role of mechanical fatigue in influencing physical properties of biological cells. They further provide insights into the accumulated membrane damage during blood circulation, paving the way for further investigations of the eventual failure of RBCs in various hemolytic pathologies. / Includes bibliography. / Dissertation (Ph.D.)--Florida Atlantic University, 2019. / FAU Electronic Theses and Dissertations Collection

The current practice of red blood cell banking for transfusion medicine relies primarily on a six-week liquid storage. A growing demand for red blood cell (RBC) products has prompted the search for alternative preservation methods including dry storage. Being desiccation sensitive, attempts to recover RBCs from the dry state have failed. This dissertation offers a new mechanistic understanding of desiccation-induced cellular injury that is correlated with the oxidative state of the hemoglobin. The general hypothesis states that RBC desiccation is accompanied with non-physiological oxidation of hemoglobin and, consequently, the release of toxic products capable of compromising cellular recovery through oxidative injury. Data acquired for this dissertation demonstrates that water loss induces a drastic increase in the rate of hemoglobin oxidation, formation of intracellular reactive oxygen species (ROS), and hemolysis. Pharmacological treatments of the hemoglobins oxygen binding site reveal that hemoglobin-induced cellular injury is more prominent in RBC samples that are partially dehydrated (about 3.5 to 5.5 g H2O/g dry weight) than in samples that are relatively dry ( 2 g H2O/g dry weight). Furthermore, partially dehydrated RBC samples contain higher levels of oxidized lipids than more fully dried samples. This dissertation also examined the role that glucose and glutathione play in enhancing desiccation tolerance of RBCs. Glucose treatment (5 mmol/L) significantly reduced ROS formation and hemolysis levels in partially dehydrated RBC samples (5.8 0.3 g H2O/g dry weight), but not in samples that are relatively dry (2.8 0.5 g H2O/g dry weight). Treating RBCs with DL-buthionine-(S,R)-sulfoximine, a glutathione depleting agent, was correlated with reduced levels of desiccation-induced hemolysis. This study suggests that desiccation-induced oxidative injury in RBCs is water dependent corresponding to earlier stages of water loss, in which cells can retain metabolic activity. Pharmacological treatments at this stage can significantly affect cell recovery as demonstrated with modifying the hemoglobins oxygen binding site, glutathione depletion, and glucose supplementation. On the other hand, increased cytoplasmatic viscosity compromises biochemical reactions at lower residual moisture contents, and cellular injury is likely the result of physical and mechanical stress. These differences should be taken into consideration in the design of innovative approaches to RBC preservation.