Decreased erythrocyte aggregation in Glenn and Fontan: univentricular circulation as a rheologic disease model.

BACKGROUND: In the Fontan palliation for single ventricle heart disease (SVHD), pulmonary blood flow is non-pulsatile/passive, low velocity, and low shear, making viscous power loss a critical determinant of cardiac output. The rheologic properties of blood in SVHD patients are essential for understanding and modulating their limited cardiac output and they have not been systematically studied. We hypothesize that viscosity is decreased in single ventricle circulation. METHODS: We evaluated whole blood viscosity, red blood cell (RBC) aggregation, and RBC deformability to evaluate changes in healthy children and SVHD patients. We altered suspending media to understand cellular and plasma differences contributing to rheologic differences. RESULTS: Whole blood viscosity was similar between SVHD and healthy at their native hematocrits, while viscosity was lower at equivalent hematocrits for SVHD patients. RBC deformability is increased, and RBC aggregation is decreased in SVHD patients. Suspending SVHD RBCs in healthy plasma resulted in increased RBC aggregation and suspending healthy RBCs in SVHD plasma resulted in lower RBC aggregation. CONCLUSIONS: Hematocrit corrected blood viscosity is lower in SVHD vs. healthy due to decreased RBC aggregation and higher RBC deformability, a viscous adaptation of blood in patients whose cardiac output is dependent on minimizing viscous power loss. IMPACT: Patients with single ventricle circulation have decreased red blood cell aggregation and increased red blood cell deformability, both of which result in a decrease in blood viscosity across a large shear rate range. Since the unique Fontan circulation has very low-shear and low velocity flow in the pulmonary arteries, blood viscosity plays an increased role in vascular resistance, therefore this work is the first to describe a novel mechanism to target pulmonary vascular resistance as a modifiable risk factor. This is a novel, modifiable risk factor in this patient population.

Blood Rheology and Hemodynamics.

Seminars in Thrombosis and Hemostasis (STH) celebrates 50 years of publishing in 2024. To celebrate this landmark event, STH is republishing some archival material. This manuscript represents the most highly cited paper ever published in STH. The original abstract follows.Blood is a two-phase suspension of formed elements (i.e., red blood cells [RBCs], white blood cells [WBCs], platelets) suspended in an aqueous solution of organic molecules, proteins, and salts called plasma. The apparent viscosity of blood depends on the existing shear forces (i.e., blood behaves as a non-Newtonian fluid) and is determined by hematocrit, plasma viscosity, RBC aggregation, and the mechanical properties of RBCs. RBCs are highly deformable, and this physical property significantly contributes to aiding blood flow both under bulk flow conditions and in the microcirculation. The tendency of RBCs to undergo reversible aggregation is an important determinant of apparent viscosity because the size of RBC aggregates is inversely proportional to the magnitude of shear forces; the aggregates are dispersed with increasing shear forces, then reform under low-flow or static conditions. RBC aggregation also affects the in vivo fluidity of blood, especially in the low-shear regions of the circulatory system. Blood rheology has been reported to be altered in various physiopathological processes: (1) Alterations of hematocrit significantly contribute to hemorheological variations in diseases and in certain extreme physiological conditions; (2) RBC deformability is sensitive to local and general homeostasis, with RBC deformability affected by alterations of the properties and associations of membrane skeletal proteins, the ratio of RBC membrane surface area to cell volume, cell morphology, and cytoplasmic viscosity. Such alterations may result from genetic disorders or may be induced by such factors as abnormal local tissue metabolism, oxidant stress, and activated leukocytes; and (3) RBC aggregation is mainly determined by plasma protein composition and surface properties of RBCs, with increased plasma concentrations of acute phase reactants in inflammatory disorders a common cause of increased RBC aggregation. In addition, RBC aggregation tendency can be modified by alterations of RBC surface properties because of RBC in vivo aging, oxygen-free radicals, or proteolytic enzymes. Impairment of blood fluidity may significantly affect tissue perfusion and result in functional deteriorations, especially if disease processes also disturb vascular properties.

Individual red blood cell nitric oxide production in sickle cell anemia: Nitric oxide production is increased and sickle shaped cells have unique morphologic change compared to discoid cells.

Sickle cell anemia (SCA) is characterized by decreased red blood cell (RBC) deformability due to polymerization of deoxygenated hemoglobin, leading to abnormal mechanical properties of RBC, increased cellular adhesion, and microcirculatory obstruction. Prior work has demonstrated that NO• influences RBC hydration and deformability and is produced at a basal rate that increases under shear stress in normal RBC. Nevertheless, the origin and physiological relevance of nitric oxide (NO•) production and scavenging in RBC remains unclear. We aimed to assess the basal and shear-mediated production of NO• in RBC from SCA patients and control (CTRL) subjects. RBCs loaded with a fluorescent NO• detector, DAF-FM (4-Amino-5-methylamino- 2',7'-difluorofluorescein diacetate), were imaged in microflow channels over 30-min without shear stress, followed by a 30-min period under 0.5Pa shear stress. We utilized non-specific nitric oxide synthase (NOS) blockade and carbon monoxide (CO) saturation of hemoglobin to assess the contribution of NOS and hemoglobin, respectively, to NO• production. Quantification of DAF-FM fluorescence intensity in individual RBC showed an increase in NO• in SCA RBC at the start of the basal period; however, both SCA and CTRL RBC increased NO• by a similar quantity under shear. A subpopulation of sickle-shaped RBC exhibited lower basal NO• production compared to discoid RBC from SCA group, and under shear became more circular in the direction of shear when compared to discoid RBC from SCA and CTRL, which elongated. Both CO and NOS inhibition caused a decrease in basal NO• production. Shear-mediated NO• production was decreased by CO in all RBC, but was decreased by NOS blockade only in SCA. In conclusion, total NO• production is increased and shear-mediated NO• production is preserved in SCA RBC in a NOS-dependent manner. Sickle shaped RBC with inclusions have higher NO• production and they become more circular rather than elongated with shear.

Nattokinase atherothrombotic prevention study: A randomized controlled trial.

BACKGROUND: Described to be antithrombotic and antihypertensive, nattokinase is consumed for putative cardiovascular benefit. However, no large-scale, long-term cardiovascular study has been conducted with nattokinase supplementation. OBJECTIVE: To determine the effect of nattokinase on subclinical atherosclerosis progression and atherothrombotic biomarkers. METHODS: In this double-blinded trial, 265 individuals of median age 65.3 years, without clinical evidence of cardiovascular disease (CVD) were randomized to oral nattokinase 2,000 fibrinolytic units or matching placebo. Primary outcome was rate of change in subclinical atherosclerosis measured by serial carotid ultrasound every 6 months as carotid artery intima-media thickness (CIMT) and carotid arterial stiffness (CAS). Additional outcomes determined at least every 6 months were clinical parameters including blood pressure and laboratory measures including metabolic factors, blood rheology parameters, blood coagulation and fibrinolysis factors, inflammatory markers and monocyte/macrophage cellular activation markers. RESULTS: After median 3 years of randomized treatment, annualized rate of change in CIMT and CAS did not significantly differ between nattokinase supplementation and placebo. Additionally, there was no significant effect of nattokinase supplementation on blood pressure or any laboratory determination. CONCLUSIONS: Results of this trial show that nattokinase supplementation has a null effect on subclinical atherosclerosis progression in healthy individuals at low risk for CVD.

Phenazine methosulphate-treated red blood cells activate NF-κB and upregulate endothelial ICAM-1 expression.

Although enhanced Red Blood Cell (RBC) - Endothelial Cell (EC) interaction, as well as RBC induced EC activation, have been extensively studied in several RBC-linked pathologies, the specific individual effects of oxidatively modified RBC on EC activation has not yet been documented. However, increasing evidence in both experimental and clinical studies suggests that oxidatively modified RBC could be considered potential pathogenic determinants in several acute and chronic diseases displaying systemic oxidative stress. Therefore, the present study aimed to explore the specific effects of oxidized RBC interaction with endothelial cells on intracellular signaling pathways that promote EC activation. RBC were exposed to oxidative stress induced by phenazine methosulphate (PMS). It is shown that the interaction of oxidatively modified RBC with cultured human umbilical vein endothelial cells (HUVEC) results in: a) EC activation as indicated by the increased surface expression of intercellular adhesion molecule -1 (ICAM-1); b) the activation of transcription factor NF-κB, an indicator of cellular oxidant stress. These results emphasize the specific contribution of oxidatively modified RBC interaction to EC activation and their possible pathological role in vascular diseases and oxidative stress.

Depletion interaction forces contribute to erythrocyte-endothelial adhesion in diabetes.

Abnormal adhesion of red blood cells (RBC) to the endothelium has been linked to the pathophysiology of several diseases associated with vascular disorders. Various biochemical changes on the outer membrane of RBC, as well as plasma protein levels, have been identified as possibly playing key roles, but the detailed interplay between plasma factors and cellular factors often remains unclear. In this work, we identified an alternative pathway by demonstrating that non-adsorbing macromolecules can also have a marked impact on the adhesion efficiency of RBC from patients with type 2 Diabetes (T2DM) to endothelial cells (EC). RBC isolated from blood samples of T2DM patients were suspended in isotonic solutions of dextran in order to mimic the impact of non-adsorbing macromolecules. Static and continuous flow adhesion assays were used to determine the adhesion behavior of T2DM RBC with EC and the results compared with those of normal controls. We found that the presence of non-adsorbing molecules promotes an increase in T2DM RBC - EC adhesion and that these RBC exhibit much greater adhesion than normal red cells. Our results thus suggest that the depletion mechanism might be an alternative phenomenon through which plasma proteins could cause enhanced RBC-EC adhesion in diabetes mellitus. These findings contribute towards the comprehensive understanding of pathophysiological mechanisms of vascular complications in diabetes and other diseases with similar vascular sequelae.

Sickle cell microvascular paradox-oxygen supply-demand mismatch.

We have previously demonstrated that sickle cell disease (SCD) patients maintain normal global systemic and cerebral oxygen delivery by increasing cardiac output. However, ischemic end-organ injury remains common suggesting that tissue oxygen delivery may be impaired by microvascular dysregulation or damage. To test this hypothesis, we performed fingertip laser Doppler flowmetry measurements at the base of the nailbed and regional oxygen saturation (rSO2 ) on the dorsal surface of the same hand. This was done during flow mediated dilation (FMD) studies in 26 chronically transfused SCD, 75 non-transfused SCD, and 18 control subjects. Chronically transfused SCD patients were studied prior to and following a single transfusion and there was no acute change in rSO2 or perfusion. Laser Doppler estimates of resting perfusion were 76% higher in non-transfused and 110% higher in transfused SCD patients, compared to control subjects. In contrast, rSO2 was 12 saturation points lower in non-transfused SCD patients, but normal in the transfused SCD patients. During cuff occlusion, rSO2 declined at the same rate in all subjects suggesting similar intrinsic oxygen consumption rates. Upon cuff release, laser doppler post occlusive hyperemia was blunted in SCD patients in proportion to their resting perfusion values. Transfusion therapy did not improve the hyperemia response. FMD was impaired in SCD subjects but partially ameliorated in transfused SCD subjects. Taken together, non-transfused SCD subjects demonstrate impaired conduit artery FMD, impaired microcirculatory post-occlusive hyperemia, and resting hypoxia in the hand despite compensated oxygen delivery, suggesting impaired oxygen supply-demand matching. Transfusion improves FMD and oxygen supply-demand matching but not microcirculation hyperemic response.

Red blood cell adhesion can be reduced by non-reactive macromolecules.

To date, the mechanisms behind red blood cell (RBC) adhesion remain unclear. However, polymer depletion at the red cell surface has been shown to play a significant role. Interestingly, most previous studies have focused on the adhesion-promoting effects of one type of large polymer or plasma protein. However, the situation in vivo is more complex in that one needs to consider a mixture of various bio-macromolecules. To explore this complexity, Interference Reflection Microscopy was used to investigate how mixtures of various polymers affect RBC adhesion. RBC adhesion to albumin-coated glass coverslips was studied in the presence of two pro-adhesion polymers [dextran70 kDa and 35 kDa poly(ethylene glycol) (PEG 35)] with and without three types of smaller polymers: dextran 10 kDa, PEG 10 kDa and Poloxamer 188. Our findings show that the presence of small polymers can inhibit the adhesion-promoting effects of dextran 70 and PEG 35, with a more pronounced reduction for heterogeneous mixtures. Interpretation of our results in terms of the depletion model appears appropriate, in that our findings are consistent with the assumption that this reduction occurs because of an increase of small molecules in the depletion region. This study thus suggests that depletion interaction can control cell-cell interactions in complex environments (e.g., in vivo), and indicates that considering the interplay of all plasma constituents is important in order to understand the pathophysiology of diseases associated with cell adhesion and vascular complications.

Therapeutic plasma exchange for the treatment of systemic sclerosis: A comprehensive review and analysis.

Background: Therapeutic plasma exchange has been tried as a treatment approach for systemic sclerosis since 1978 based on the rationale that some circulating factor is involved in disease pathogenesis, for example, autoantibodies or immune complexes, and that removing the potential pathogenic factors could lead to symptom improvement. Based on our impression that clinicians and researchers are largely unaware that a large volume of research has been published about the use of therapeutic plasma exchange as a treatment for systemic sclerosis, we conducted a comprehensive review and analysis of all published research on this topic. Results: We identified 46 relevant articles that met our search criteria, involving a total of 572 patients. Of these, 19 were case studies; the rest ranged from small observational studies to prospective randomized clinical trials. In all but two studies, most patients receiving therapeutic plasma exchange showed improvements in both clinical symptoms and laboratory markers, including significant improvement in Raynaud's symptoms and healing of digital ulceration after three to four weekly treatments. The beneficial effects from even a short course of therapeutic plasma exchange treatments were long-lasting, typically 6 months or longer. Therapeutic plasma exchange was very well tolerated. Adverse events were rare and, in almost all cases, mild and transitory. Conclusion: These results suggest that long-term therapeutic plasma exchange may offer a low-risk way to control and in some cases reverse systemic sclerosis symptoms. The mechanism for the clinical improvements seen from therapeutic plasma exchange in systemic sclerosis patients is unclear. Therefore, additional studies of therapeutic plasma exchange effects in systemic sclerosis appear to be highly desirable.

Biophysical markers of the peripheral vasoconstriction response to pain in sickle cell disease.

Painful vaso-occlusive crisis (VOC), a complication of sickle cell disease (SCD), occurs when sickled red blood cells obstruct flow in the microvasculature. We postulated that exaggerated sympathetically mediated vasoconstriction, endothelial dysfunction and the synergistic interaction between these two factors act together to reduce microvascular flow, promoting regional vaso-occlusions, setting the stage for VOC. We previously found that SCD subjects had stronger vasoconstriction response to pulses of heat-induced pain compared to controls but the relative degrees to which autonomic dysregulation, peripheral vascular dysfunction and their interaction are present in SCD remain unknown. In the present study, we employed a mathematical model to decompose the total vasoconstriction response to pain into: 1) the neurogenic component, 2) the vascular response to blood pressure, 3) respiratory coupling and 4) neurogenic-vascular interaction. The model allowed us to quantify the contribution of each component to the total vasoconstriction response. The most salient features of the components were extracted to represent biophysical markers of autonomic and vascular impairment in SCD and controls. These markers provide a means of phenotyping severity of disease in sickle-cell anemia that is based more on underlying physiology than on genotype. The marker of the vascular component (BMv) showed stronger contribution to vasoconstriction in SCD than controls (p = 0.0409), suggesting a dominant myogenic response in the SCD subjects as a consequence of endothelial dysfunction. The marker of neurogenic-vascular interaction (BMn-v) revealed that the interaction reinforced vasoconstriction in SCD but produced vasodilatory response in controls (p = 0.0167). This marked difference in BMn-v suggests that it is the most sensitive marker for quantifying combined alterations in autonomic and vascular function in SCD in response to heat-induced pain.

Empirical model of human blood transverse relaxation at 3 T improves MRI T2 oximetry.

PURPOSE: We sought a human blood T2 -oximetery calibration curve over the wide range of hematocrits commonly found in anemic patients applicable with T2 relaxation under spin tagging (TRUST). METHODS: Blood was drawn from five healthy control subjects. Ninety-three in vitro blood transverse relaxation (T2b ) measurements were performed at 37°C over a broad range of hematocrits (10-55%) and oxygen saturations (14-100%) at 3 Tesla (T). In vivo TRUST was performed on 35 healthy African American control subjects and 11 patients with chronic anemia syndromes. RESULTS: 1/T2 rose linearly with hematocrit (r2 = 0.96), for fully saturated blood. Upon desaturation, 1/T2 rose linearly with the square of the oxygen extraction, (1-Y)2 , and the slope was linearly proportional to hematocrit (r2 = 0.88). The resulting bilinear model between 1/T2 , (1-Y)2 , and hematocrit had a combined r2 of 0.96 and a coefficient of variation of 6.1%. Using the in vivo data, the bilinear model had significantly lower bias and variability than existing calibrations, particularly for low hematocrits. In vivo Bland Altman analysis demonstrated clinically relevant bias that was -6% (absolute saturation) for hematocrits near 30% and rose to + 6% for hematocrits near 45%. CONCLUSION: This work introduces a robust bilinear calibration model that should be used for MRI oximetry. Magn Reson Med 77:2364-2371, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Successful long-term (22 year) treatment of limited scleroderma using therapeutic plasma exchange: Is blood rheology the key?

While a number of studies have shown short-term beneficial effects of therapeutic plasma exchange (TPE) for treating systemic scleroderma (SSc), there have been no reports on the very long-term usage of TPE as the sole systemic treatment intervention. We report the case of a male patient, originally diagnosed with limited systemic scleroderma (lcSSc) in early 1990, who has been undergoing regular plasmapheresis treatments for more than 22 years, beginning in late 1993. Prior to commencing treatment, the patient exhibited symptoms including severe gastro esophageal reflux disease (GERD) with esophagitis, frequent Raynaud's attacks, reduced lung function, and chronic chilling. With the exception of mild residual Raynaud's, all of the patient's symptoms reversed after three years of regular TPE treatments and he remains in complete remission. While the typical explanation for the therapeutic benefits seen with TPE focuses on temporary reduction of circulating antibodies or other pathogenic factors, we propose instead an explanation based on abnormal blood rheology as a novel disease pathogenesis model for SSc.

Elevated Low-Shear Blood Viscosity is Associated with Decreased Pulmonary Blood Flow in Children with Univentricular Heart Defects.

After the Fontan procedure, patients with univentricular hearts can experience long-term complications due to chronic low-shear non-pulsatile pulmonary blood flow. We sought to evaluate hemorheology and its relationship to hemodynamics in children with univentricular hearts. We hypothesized that low-shear blood viscosity and red blood cell (RBC) aggregation would be associated with increased pulmonary vascular resistance (PVR) and decreased pulmonary blood flow (PBF). We performed a cross-sectional analysis of 62 children undergoing cardiac catheterization-20 with isolated atrial septal defect (ASD), 22 status post Glenn procedure (Glenn), and 20 status post Fontan procedure (Fontan). Shear-dependent blood viscosity, RBC aggregation and deformability, complete blood count, coagulation panel, metabolic panel, fibrinogen, and erythrocyte sedimentation rate were measured. PVR and PBF were calculated using the Fick equation. Group differences were analyzed by ANOVA and correlations by linear regression. Blood viscosity at all shear rates was higher in Glenn and Fontan, partially due to normocytic anemia in ASD. RBC aggregation and deformability were similar between all groups. Low-shear viscosity negatively correlated with PBF in Glenn and Fontan only (R (2) = 0.27, p < 0.001); it also negatively correlated with pulmonary artery pressure in Glenn (R (2) = 0.15, p = 0.01), and positively correlated with PVR in Fontan (R (2) = 0.28, p = 0.02). Our data demonstrate that elevated low-shear blood viscosity is associated with negative hemodynamic perturbations in a passive univentricular pulmonary circulation, but not in a pulsatile biventricular pulmonary circulation.

Prediction of the level and duration of shear stress exposure that induces subhemolytic damage to erythrocytes.

BACKGROUND: Current generation mechanical circulatory assist devices are designed to minimize high shears to blood for prolonged durations to avoid hemolysis. However, red blood cells (RBC) demonstrate impaired capacity to deform when exposed to shear stress (SS) well below the "hemolytic threshold". OBJECTIVE: We endeavored to identify how changes in the magnitude and duration of SS exposure alter RBC deformability and subsequently develop a model to predict erythrocyte subhemolytic damage. METHODS: RBC suspensions were exposed to discrete magnitudes of SS (1-64 Pa) for specific durations (1-64 s), immediately prior to RBC deformability being measured. Analyses included exploring the maximal RBC deformation (EImax) and SS required for half EImax (SS1/2). A surface-mesh was interpolated onto the raw data to predict impaired RBC deformability. RESULTS: When SS was applied at <16Pa, limited changes were observed. When RBC were exposed to 32 Pa, mild impairments in EImax and SS1/2 occurred, although 64 Pa caused a dramatic impairment of RBC deformability. A clear relation between SS duration and magnitude was determined, which could predict impaired RBC deformability. CONCLUSION: The present results provide a model that may be used to predict whether RBC deformability is decreased following exposure to a given level and duration of SS, and may guide design of future generations of mechanical circulatory assist devices.

Effects of neutral polymers on the mechanics of red blood cell adhesion onto coated glass surfaces.

BACKGROUND: Cell-cell and cell-surface adhesion modulated by water-soluble polymers continues to be of current interest, especially since prior reports have indicated a role for depletion-mediated attractive forces. OBJECTIVE: To determine the effects of concentration and molecular mass of the neutral polymer dextran (40 kDa to 28 MDa) on the adhesion of human red blood cells (RBC) to coated glass coverslips. METHODS: Confocal-reflection interference contrast microscopy (C-IRM), in conjunction with phase contrast imaging, was utilized to measure the adhesion dynamics and contact mechanics of RBC during the initial stages of cell contact with several types of substrates. RESULTS: Adhesion is markedly increased in the presence of dextran with a molecular mass ⩾ 70 kDa. This increased adhesiveness is attributed to reduced surface concentration of the large polymers and hence increased attractive forces due to depletion interaction. The equilibrium deformation of adhering RBC was modeled as a truncated sphere and the calculated adhesion energies were in close agreement with theoretical results. CONCLUSIONS: These results clearly demonstrate that polymer depletion can promote RBC adhesion to artificial surfaces and suggest that this phenomenon may play a role in other specific and non-specific cell-cell interactions, such as rouleau formation and RBC-endothelial cell adhesion.

Chronic transfusion therapy improves but does not normalize systemic and pulmonary vasculopathy in sickle cell disease.

Tricuspid regurgitant (TR) jet velocity and its relationship to pulmonary hypertension has been controversial in sickle cell disease (SCD). Plasma free hemoglobin is elevated in SCD patients and acutely impairs systemic vascular reactivity. We postulated that plasma free hemoglobin would be negatively associated with both systemic and pulmonary endothelial function, assessed by flow-mediated dilation (FMD) of the brachial artery and TR jet velocity, respectively. Whole blood viscosity, plasma free hemoglobin, TR jet, and FMD were measured in chronically transfused SCD pre- and posttransfusion (N = 25), in nontransfused SCD (N = 26), and in ethnicity-matched control subjects (N = 10). We found increased TR jet velocity and decreased FMD in nontransfused SCD patients compared with the other 2 groups. TR jet velocity was inversely correlated with FMD. There was a striking nonlinear relationship between plasma free hemoglobin and both TR jet velocity and FMD. A single transfusion in the chronically transfused cohort improved FMD. In our patient sample, TR jet velocity and FMD were most strongly associated with plasma free hemoglobin and transfusion status (transfusions being protective), and thus consistent with the hypothesis that intravascular hemolysis and increased endogenous erythropoiesis damage vascular endothelia.

GLUT1 reductions exacerbate Alzheimer's disease vasculo-neuronal dysfunction and degeneration.

The glucose transporter GLUT1 at the blood-brain barrier (BBB) mediates glucose transport into the brain. Alzheimer's disease is characterized by early reductions in glucose transport associated with diminished GLUT1 expression at the BBB. Whether GLUT1 reduction influences disease pathogenesis remains, however, elusive. Here we show that GLUT1 deficiency in mice overexpressing amyloid ß-peptide (Aß) precursor protein leads to early cerebral microvascular degeneration, blood flow reductions and dysregulation and BBB breakdown, and to accelerated amyloid ß-peptide (Aß) pathology, reduced Aß clearance, diminished neuronal activity, behavioral deficits, and progressive neuronal loss and neurodegeneration that develop after initial cerebrovascular degenerative changes. We also show that GLUT1 deficiency in endothelium, but not in astrocytes, initiates the vascular phenotype as shown by BBB breakdown. Thus, reduced BBB GLUT1 expression worsens Alzheimer's disease cerebrovascular degeneration, neuropathology and cognitive function, suggesting that GLUT1 may represent a therapeutic target for Alzheimer's disease vasculo-neuronal dysfunction and degeneration.

Abnormal blood rheology and chronic low grade inflammation: possible risk factors for accelerated atherosclerosis and coronary artery disease in Lewis negative subjects.

OBJECTIVE: To test the hypothesis that abnormal hemorheology and chronic low-grade inflammation are more prevalent in Lewis negative individuals, possibly contributing to premature atherosclerosis. METHODS AND RESULTS: We enrolled 223 healthy subjects (154 females, mean age: 64yrs). Conventional risk factors, markers of inflammation and hemorheological profiles were measured; Lewis blood group was determined by serology. Conventional risk factors (age, gender, BMI, blood pressure, lipid profile, smoking habit) did not differ among Lewis phenotypes. However, markers of inflammation (WBC, hs-CRP, ESR) were significantly elevated and rheological parameters (RBC aggregation, plasma viscosity) were abnormal in Lewis negative subjects, especially when compared to the Le(a-b+) group. CONCLUSIONS: With a prevalence of 33% in select populations, our data support the hypothesis that Le(a-b-) represents a pro-inflammatory phenotype that may contribute to the elevated cardiovascular risk in this group.

Impact of glycocalyx structure on red cell-red cell affinity in polymer suspensions.

A theoretical framework based on macromolecular depletion has been utilized in order to examine the energetics of red blood cell interactions. Three different glycocalyx structures are considered and cell-cell affinities are calculated by superposition of depletion, steric and electrostatic interactions. The theoretical model predicts a non-monotonic dependence of the interaction energies on polymer size. Further, our results indicate that the glycocalyx segment distribution has a large impact on adhesion energies between cells: a linear segment distribution induces the strongest adhesion between cells followed by pseudo-tail and uniform distributions. Our approach confirms the concept of a depletion mechanism for RBC aggregation, and also provides new insights that may eventually help to understand and quantify cellular factors that control red blood cell interactions in health and disease.