Biorheology - Volume 51, issue 2-3

Article Type: Other

DOI: 10.3233/BIR-140666

Citation: Biorheology, vol. 51, no. 2-3, pp. 81-81, 2014

Authors: Hardeman, Max | Alexy, Tamas | Brouwer, Bram | Connes, Philippe | Jung, Friedrich | Kuipers, Harm | Baskurt, Oguz K.

Article Type: Research Article

Abstract: Recombinant human erythropoietin (rHuEPO) is an agent commonly used by athletes with the aim to improve performance in endurance sports. However, the scientific community continues to debate the risks, benefits and its mechanism of action when used as a doping agent. This paper provides a brief overview on the pros and cons of rHuEPO use, as discussed by a group of scientist with diverse background, at the 17th Conference of the European Society for Clinical Hemorheology and Microcirculation in Pecs, Hungary. Among multiple topics, panel members challenged the common belief that the increased circulating hemoglobin concentration is the simple key …to the improved sporting performance. Rather, hemorheologists developed the concept of optimal hematocrit (Hct), a Hct value that represents the optimal balance between the oxygen transport capacity of blood and blood viscosity. While guideline-directed transfusion therapy is advantageous under pathological conditions, such as severe anemia related to chronic kidney disease, its beneficial effects on endurance in healthy athletes remains questionable. Further studies are warranted in the field evaluating the effects of rHuEPO that are independent of increasing hemoglobin concentration, such as peripheral vasodilation and tissue metabolic changes. Show more

Keywords: Erythropoetin, blood rheology, exercise, sports, optimal haematocrit

DOI: 10.3233/BIR-140655

Citation: Biorheology, vol. 51, no. 2-3, pp. 83-90, 2014

Authors: Neu, Björn | Meiselman, Herbert J.

Article Type: Research Article

Abstract: If a surface is in contact with a solution containing macromolecules or proteins, and the loss of configurational entropy of these molecules at the surface is not balanced by adsorption energy, a polymer-poor layer will develop near the surface. If two such layers overlap, an attractive force develops due to the osmotic pressure difference between these depletion zones and the bulk phase. Recent studies have shown that depletion interaction plays a major role in red blood cell (RBC) aggregation and hence it is a major determinate of blood flow stability; depletion interaction also markedly affects RBC adhesion to vascular endothelial …cells. Understanding and quantitating factors that regulate depletion in vivo are thus of importance, yet made difficult since only very small changes of the cell surface (e.g., glycocalyx thickness) such as seen during RBC aging can lead to massive changes of depletion interaction and hence cell–cell adhesion. It is suggested that insight into the in vivo relevance of depletion mechanisms may lead to an improved understanding of how and why blood flow is altered in many diseases, and may also provide new biomarkers (e.g., surface properties) that will aid in the development of novel or improved diagnostic and therapeutic tools. Show more

Keywords: Aggregation, adhesion, cell affinity, polymer depletion

DOI: 10.3233/BIR-140656

Citation: Biorheology, vol. 51, no. 2-3, pp. 91-97, 2014

Authors: Cooke, Brian M. | Stuart, John | Nash, Gerard B.

Article Type: Review Article

Abstract: During development inside red blood cells (RBCs), Plasmodium falciparum malaria parasites export a number of proteins beyond the confines of their own plasma membrane where they associate with the RBC membrane skeleton. Here they participate in protein–protein interactions with both RBC proteins and other parasite proteins and assemble into complex multi-component structures known as knobs. These interactions cause profound changes to the rheological properties of RBCs, particularly increased cell resistance to deformation and increased adhesiveness, which underpin the severe and often fatal clinical manifestations of falciparum malaria. Here, we bring together recent insights that have been made into understanding the …molecular mechanisms that underlie these parasite-induced alterations to RBCs. We describe some of the well-established methods that have been used to quantify the altered rheological properties of parasitized RBCs (PRBCs) and discuss emerging techniques that have already begun to advance our knowledge of the molecular basis of this important human disease. Finally, we suggest potential new avenues for rheological anti-malaria therapy. Show more

Keywords: Red blood cell, plasmodium, cell mechanics, adhesion

DOI: 10.3233/BIR-140654

Citation: Biorheology, vol. 51, no. 2-3, pp. 99-119, 2014

Authors: Simmonds, Michael J. | Detterich, Jon A. | Connes, Philippe

Article Type: Review Article

Abstract: Since the identification of the elusive endothelium-derived relaxing factor as nitric oxide (NO), much attention has been devoted to understanding its physiological effects. NO is a free radical with many roles, and owing to its neutral charge and high diffusion capacity, it appears NO is involved in every mammalian biological system. Most attention has been focused on the NO generating pathways within the endothelium; however, the recent discovery of a NO synthase (NOS)-like enzyme residing in red blood cells (RBC) has increased our understanding of the blood flow and oxygen delivery modulation by RBC. In the present review, pathways of …NO generation are summarized, with attention to those residing within RBC. While the bioactivity of RBC-derived NO is still debated due to its generation within proximity of NO scavengers, current theories for NO export from RBC are explored, which are supported by recent findings demonstrating an extracellular response to RBC-derived NO. The importance of NO in the active regulation of RBC deformability is discussed in the context of the subsequent effects on blood fluidity, and the complex interplay between blood rheology and NO are summarized. This review provides a summary of recent advances in understanding the role played by RBC in NO equilibrium and vascular regulation. Show more

Keywords: Erythrocyte, nitric oxide synthase, nitrite, vascular function

DOI: 10.3233/BIR-140653

Citation: Biorheology, vol. 51, no. 2-3, pp. 121-134, 2014

Authors: Muravyov, Alexei | Tikhomirova, Irina

Article Type: Research Article

Abstract: The exposure of red blood cells (RBC) to some hormones (epinephrine, insulin and glucagon) and agonists of α- and β-adrenergic receptors (phenylephrine, clonidine and isoproterenol) may modify RBC aggregation (RBCA). Prostaglandin E1 (PGE1 ) significantly decreased RBCA, and PGE2 had a similar but lesser effect. Adenylyl cyclase (AC) stimulator forskolin added to RBC suspension, caused a decrease of RBCA. More marked lowering of RBCA occurred after RBC treatment by dB-cAMP. Phosphodiesterase (PDE) inhibitors markedly reduced RBCA. Ca2+ influx stimulated by A23187 was accompanied by an increase of RBCA. The blocking of Ca2+ entry into the RBC …by verapamil or the chelation of Ca2+ by EGTA led to a significant RBCA decrease. Lesser changes of aggregation were found after RBC incubation with protein kinase C stimulator phorbol 12-myristate 13-acetate (PMA). A significant inhibitory effect of tyrosine protein kinase (TPK) activator cisplatin on RBCA was revealed, while selective TPK inhibitor, lavendustin, eliminated the above mentioned effect. Taken together, the data demonstrate that changes in RBCA are connected with activation of different intracellular signaling pathways. We suggest that alterations in RBCA are mainly associated with the crosstalk between the adenylyl cyclase-cAMP system and Ca2+ control mechanisms. Show more

Keywords: Erythrocyte aggregation, adenylyl cyclase, phosphodiesterases, intracellular signaling pathways, intracellular calcium, protein kinases

DOI: 10.3233/BIR-140664

Citation: Biorheology, vol. 51, no. 2-3, pp. 135-145, 2014

Authors: Alexy, Tamas | James, Amanda Marie | Searles, Charles D.

Article Type: Research Article

Abstract: Atherosclerosis, the leading cause of morbidity and mortality in developed nations, is a chronic inflammatory disease of arteries. In large and medium-sized vessels, the atherosclerotic burden is focal and non-random, despite the systemic nature of risk factors. This observation has prompted numerous studies over the past two decades that have evaluated the relationship between blood flow, endothelial function and plaque localization. The recent discovery of microRNAs (miRNAs) that are sensitive to distinct flow conditions has added a new layer of complexity to the pathophysiology of atherosclerosis, but may ultimately help us better understand the disease process. In this manuscript we …will briefly review the most commonly used in vitro and in vivo model systems developed to study the relationship between flow, endothelial function and plaque development. We will also provide a brief summary of shear sensitive miRNAs that have been shown to modulate inflammatory signaling pathways and atherosclerotic burden through changes in the endothelial gene expression. Show more

Keywords: MiRNA, shear stress, atherosclerosis

DOI: 10.3233/BIR-140657

Citation: Biorheology, vol. 51, no. 2-3, pp. 147-158, 2014

Authors: Rabai, Miklos | Detterich, Jon A. | Wenby, Rosalinda B. | Hernandez, Tatiana M. | Toth, Kalman | Meiselman, Herbert J. | Wood, John C.

Article Type: Research Article

Abstract: Sickle cell disease (SCD) is characterized by decreased erythrocyte deformability, microvessel occlusion and severe painful infarctions of different organs. Ektacytometry of SCD red blood cells (RBC) is made difficult by the presence of rigid, poorly-deformable irreversibly sickled cells (ISC) that do not align with the fluid shear field and distort the elliptical diffraction pattern seen with normal RBC. In operation, the computer software fits an outline to the diffraction pattern, then reports an elongation index (EI) at each shear stress based on the length and width of the fitted ellipse: EI=(length−width)/(length+width). Using a commercial ektacytometer (LORCA, Mechatronics Instruments, The Netherlands) …we have approached the problem of ellipse fitting in two ways: (1) altering the height of the diffraction image on a computer monitor using an aperture within the camera lens; (2) altering the light intensity level (gray level) used by the software to fit the image to an elliptical shape. Neither of these methods affected deformability results (elongation index-shear stress relations) for normal RBC but did markedly affect results for SCD erythrocytes: (1) decreasing image height by 15% and 30% increased EI at moderate to high stresses; (2) progressively increasing the light level increased EI over a wide range of stresses. Fitting data obtained at different image heights using the Lineweaver–Burke routine yielded percentage ISC results in good agreement with microscopic cell counting. We suggest that these two relatively simple approaches allow minimizing artifacts due to the presence of rigid discs or ISC and also suggest the need for additional studies to evaluate the physiological relevance of deformability data obtained via these methods. Show more

Keywords: Laser diffraction ellipsometry, diffraction pattern, sickle cell disease, irreversible sickled cells, sickle erythrocytes

DOI: 10.3233/BIR-140660

Citation: Biorheology, vol. 51, no. 2-3, pp. 159-170, 2014

Authors: Simmonds, Michael J. | Atac, Nazli | Baskurt, Oguz K. | Meiselman, Herbert J. | Yalcin, Ozlem

Article Type: Research Article

Abstract: BACKGROUND: Previous studies have demonstrated that red blood cells (RBC) either lyse or at least experience mechanical damage following prolonged exposure to high shear stress (≥100 Pa). Conversely, prolonged shear stress exposure within the physiological range (5–20 Pa, 300 s) was recently reported to improve RBC deformability. This study investigated the relationships between shear stress and RBC deformability to determine the breakpoint between beneficial vs. detrimental exposure to shear stress (i.e., “subhemolytic threshold”). A second aim of the study was to determine whether the frequency of intermittent application of shear stress influenced the subhemolytic threshold. METHODS: RBC were exposed …to various levels of shear stress (0–100 Pa) in a Couette type shearing system for 300 s. RBC deformability was then immediately measured via ektacytometry. Parallel experiments were conducted at the same shear stresses, except the application time differed while keeping constant the total exposure time: shear stress was applied either for 30 s and repeated 10 times (10×30 s) or applied for 15 s and repeated 20 times (20×15 s). RESULTS: For a range of donors, the subhemolytic threshold with constant shear stress application was between 30–40 Pa. When physiological shear stress was applied in an intermittent manner, more frequent applications tended to improve (i.e., increase) RBC deformability. However, when supra-physiological shear stress was applied, both continuous and intermittent protocols damaged RBC. Changes of RBC mechanical behavior occurred without increases of hemoglobin in the suspending media, thus attesting to the absence of hemolysis. CONCLUSION: Shear stress has a biphasic effect on the mechanical properties of RBC, with the duration and rate of exposure appearing to have minimal impact on the subhemolytic threshold when compared with the magnitude of applied shear stress. Show more

Keywords: Mechanical damage, red blood cell, deformability, shear stress, exposure time

DOI: 10.3233/BIR-140665

Citation: Biorheology, vol. 51, no. 2-3, pp. 171-185, 2014

Authors: Compagnoni, S.C. | Schulzki, T. | Thoeny, S. | Reinhart, W.H.

Article Type: Research Article

Abstract: BACKGROUND: Parenteral nutrition (PN) is a hyperosmolar solution composed of glucose, amino acids and a lipid emulsion, which is often used despite well-known side effects and complications. OBJECTIVES: In this study the hypothesis was tested that PN could affect hemorheology. METHODS: The influence of increasing plasma concentrations (0, 4, 10 and 25%) of the 3-in-1-mixture of PN on various rheological parameters were studied in vitro. The influence of the individual components was studied with plasma concentrations of 10, 10 and 5%, respectively. Hematological and coagulation tests were performed. Blood viscosity and red blood cell (RBC) aggregation were measured …and platelet aggregation in flowing blood was assessed with a PFA-100 instrument. RESULTS: It was found that PN induced RBC shrinkage, which was partially reversible. It reduced RBC aggregation measured by low shear viscosity or RBC sedimentation. Platelet aggregation was strongly inhibited. Coagulation tests were not affected. Investigations with the single components of PN showed that the RBC shrinkage was mainly caused by the amino acid solution and the inhibition of platelet aggregation by all 3 components. The lipid emulsion in higher plasma concentrations led to echinocytosis, indicating that the lipids interact with the outer half of the membrane lipid bilayer. CONCLUSIONS: High concentrations of PN affect blood rheology in several ways. The strongest effect was an inhibition of platelet aggregation, which may have a clinical relevance. Other effects such as RBC shrinkage and decreased RBC aggregation occurred only at high PN concentrations, which are reached in vivo at the infusion site. Show more

Keywords: Aggregation, erythrocyte, morphology, platelet, viscosity

DOI: 10.3233/BIR-140652

Citation: Biorheology, vol. 51, no. 2-3, pp. 187-196, 2014

Authors: Koltai, Katalin | Papp, Judit | Kenyeres, Peter | Feher, Gergely | Tibold, Antal | Alexy, Tamas | Marton, Zsolt | Kesmarky, Gabor | Toth, Kalman

Article Type: Research Article

Abstract: BACKGROUND: Sex-specific response to antiplatelet medications have been reported in several previous studies. OBJECTIVE: We investigated a possible connection between gender differences in hemorheological parameters and in vitro platelet aggregation in vascular patients treated with widely used antiplatelet agents. METHODS: In vitro platelet aggregation was assessed in 2687 patients treated with 100 mg acetylsalicylic acid (ASA), 1047 patients treated with 75 mg clopidogrel and 311 patients on dual antiplatelet therapy (100 mg aspirin and 75 mg clopidogrel) according to the method of Born. In subgroups of patients fibrinogen concentration, whole blood and plasma viscosity, red blood cell aggregation …and hematocrit were simultaneously measured. The subjects were divided into groups according to their gender. RESULTS: ADP induced platelet aggregation was significantly higher in women in the case of ASA treatment (p<0.001). No gender differences could be observed in platelet function in patients treated with clopidogrel or on dual antiplatelet therapy. Hematocrit and whole blood viscosity were significantly higher in men in all groups (p<0.001), while no significant gender differences were observed in red blood cell aggregation indices in either group. Fibrinogen concentration was significantly higher in women than in men among patients treated with 100 mg ASA (p<0.05), but not in the other groups. CONCLUSIONS: Significantly higher fibrinogen concentration found in aspirin treated women than men may play a role in higher ADP induced platelet aggregation. Gender differences in response to monotherapy suggest that benefits from combination therapy may be greater in females. The clinical relevance of higher ADP induced platelet aggregation in women treated with ASA needs further investigation. Show more

Keywords: Aspirin, thienopyridines, viscosity, fibrinogen, erythrocyte aggregation, optical aggregometry

DOI: 10.3233/BIR-140661

Citation: Biorheology, vol. 51, no. 2-3, pp. 197-206, 2014

Authors: Jung, F. | Krüger, A. | Pindur, G. | Sternitzky, R. | Franke, R.P. | Gori, T.

Article Type: Research Article

Abstract: BACKGROUND: The role of the microcirculation in the pathophysiology and symptoms of peripheral arterial obliterative disease (PAOD) has been progressively emphasized during the past decades. Under resting conditions, already, the tissue oxygen partial pressure in the m. tibialis anterior (pO2im ) is reduced to about 50% compared to healthy subjects. METHODS: In the framework of this study the pO2im of patients with PAOD stage II according to Fontaine (n=16) in the m. tibialis anterior was measured under resting conditions and during walking on a treadmill in comparison to healthy subjects (n=10). RESULTS: Under resting conditions the pO2im …only marginally differed between PAOD patients and healthy subjects. But during exercise the pO2im dropped significantly more severely in PAOD patients and a return to baseline values could only be reached when the treadmill was stopped and the patients stood still. The pO2im minima correlated clearly with the clinical symptom of calf pain. CONCLUSION: The data revealed that the pO2im values were lower in PAOD patients and dropped significantly faster during walking compared to the pO2im values in healthy subjects. The pO2im decrease correlated with the calf pain occurring when the pO2im values approached or fell below 10 mmHg. Show more

Keywords: Tissue oxygen partial pressure, peripheral arterial occlusive disease, treadmill test

DOI: 10.3233/BIR-140651

Citation: Biorheology, vol. 51, no. 2-3, pp. 207-214, 2014

Authors: Cho, Minhee | Shin, Sehyun | Kwon, Hyuck Moon | Chung, Hyemoon | Lee, Byoung Kwon

Article Type: Research Article

Abstract: Myocardial ischemia may be present even when there is no significant stenosis of the epicardial coronary artery, or after coronary angioplasty for significant coronary artery disease. This phenomenon is related to disturbance of the coronary microcirculation or vasomotor tone. The aim of this study was to determine the influence of clinical and RBC hemorheological factors, such as RBC deformability and aggregation, on myocardial perfusion in patients with type 2 diabetes mellitus (DM) when compared to patients without DM, presenting with stable angina or acute coronary syndrome. Myocardial perfusion was graded using the myocardial blush grade (MBG) which describes the relative …“blush” or intensity of the radio-opacity of myocardial tissue observed after an epicardial coronary injection of contrast medium during coronary angiography. MBG was counted before any medical or mechanical intervention, and in the myocardial territory without anatomical flow limitation (<50% of luminal narrowing on coronary angiogram), in order to remove the direct influence of anatomical stenosis. Myocardial perfusion in this region was associated with diabetes, renal function, LV diastolic function, inflammatory biomarkers such as hs-CRP, fibrinogen and ESR, but not with the clinical presentation. Among the hemorheological parameters, reduced myocardial perfusion was linked to increased RBC aggregation, but not to variation in RBC deformability. In conclusion, myocardial perfusion was affected by diabetes, left ventricular diastolic function, and inflammatory activity indicated by clinical parameters, and by the hemorheological factor RBC aggregation. Show more

Keywords: Myocardial perfusion, diabetes, acute coronary syndrome, RBC aggregation

DOI: 10.3233/BIR-140659

Citation: Biorheology, vol. 51, no. 2-3, pp. 215-226, 2014

Authors: Muthard, Ryan W. | Diamond, Scott L.

Article Type: Research Article

Abstract: Millions of clotting tests each year require recalcification of blood treated with sodium citrate, a calcium chelator that prevents prothrombinase assembly. We validated a converging trifurcated microfluidic device to measure platelet and fibrin accumulation following on-chip recalcification of citrated whole blood. Recalcification was accomplished by sheathing the blood with Ca2+ buffer. Fluorescein rapidly diffused across the buffer-blood interface (achieving 62.5% of maximum centerline concentration within ~4 cm of flow), while albumin remained relatively unchanged in blood due to its lower diffusivity (<20% decrease). Since Ca2+ diffuses faster than fluorescein, full recalcification of whole blood was achieved within ~1 …cm of flow prior to encountering a collagen/tissue surface. Platelet and fibrin were reduced by 87.3% and 99.0%, respectively, when the sheath buffer was Ca2+ -free. A 30-min preincubation of citrated whole blood prior to on-chip recalcification increased platelet (159%) and fibrin (86.6%) deposition, compared to 5-min preincubation, likely due to factor XIIa generation in citrated blood. The P2Y1 inhibitor, MRS-2179, was delivered by diffusion into flowing blood and inhibited platelet deposition on collagen with a calculated IC50 of 0.155 μM. On-chip recalcification and drug dosing of citrated blood allows for assays of platelet function in a whole blood milieu under flow. Show more

Keywords: Thrombosis, citrate, fibrin, platelet

DOI: 10.3233/BIR-140658

Citation: Biorheology, vol. 51, no. 2-3, pp. 227-237, 2014