The Impact of COVID-19 on Cellular Factors Influencing Red Blood Cell Aggregation Examined in Dextran: Possible Causes and Consequences

Several studies have indicated that COVID-19 can lead to alterations in blood rheology, including an increase in red blood cell aggregation. The precise mechanisms behind this phenomenon are not yet fully comprehended. The latest findings suggest that erythrocyte aggregation significantly influences microcirculation, causes the formation of blood clots in blood vessels, and even damages the endothelial glycocalyx, leading to endothelial dysfunction. The focus of this research lies in investigating the cellular factors influencing these changes in aggregation and discussing potential causes and implications in the context of COVID-19 pathophysiology. For this purpose, the aggregation of erythrocytes in a group of 52 patients with COVID-19 pneumonia was examined in a 70 kDa Dextran solution, which eliminates the influence of plasma factors. Using image analysis, the velocities and sizes of the formed aggregates were investigated, determining their porosity. This study showed that the process of erythrocyte aggregation in COVID-19 patients, independent of plasma factors, leads to the formation of more compact, denser, three-dimensional aggregates. These aggregates may be less likely to disperse under circulatory shear stress, increasing the risk of thrombotic events. This study also suggests that cellular aggregation factors can be responsible for the thrombotic disorders observed long after infection, even when plasma factors have normalized. The results and subsequent broad discussion presented in this study can contribute to a better understanding of the potential complications associated with increased erythrocyte aggregation.

[1]  Blaine R. Roberts,et al.  Multiplatform analyses reveal distinct drivers of systemic pathogenesis in adult versus pediatric severe acute COVID-19 , 2023, Nature Communications.

[2]  M. Anstead,et al.  Predictors and outcomes of acute pulmonary embolism in COVID-19; insights from US National COVID cohort collaborative , 2023, Respiratory Research.

[3]  A. Hernández-Machado,et al.  A mathematical model of fibrinogen-mediated erythrocyte–erythrocyte adhesion , 2023, Communications Biology.

[4]  P. Verhamme,et al.  Risk of venous thromboembolic events after COVID-19 infection: a systematic review and meta-analysis , 2023, Journal of Thrombosis and Thrombolysis.

[5]  J. Steinacker,et al.  SARS-CoV-2 Altered Hemorheological and Hematological Parameters during One-Month Observation Period in Critically Ill COVID-19 Patients , 2022, International journal of molecular sciences.

[6]  B. Scola,et al.  SARS-CoV-2 Spike Protein Induces Hemagglutination: Implications for COVID-19 Morbidities and Therapeutics and for Vaccine Adverse Effects , 2022, bioRxiv.

[7]  M. Bosek,et al.  Relationship between red blood cell aggregation and dextran molecular mass , 2022, Scientific Reports.

[8]  H. Daabo,et al.  Role of Oxidative Stress in Pathogenesis and Severity of COVID-19 Infection: Case-Control Study in Iraq , 2022, Journal of Life and Bio Sciences Research.

[9]  M. Bosek,et al.  Study of Albumin Oxidation in COVID-19 Pneumonia Patients: Possible Mechanisms and Consequences , 2022, International journal of molecular sciences.

[10]  J. Rosmalen,et al.  Persistence of somatic symptoms after COVID-19 in the Netherlands: an observational cohort study , 2022, The Lancet.

[11]  J. Detterich,et al.  Physical Properties of Blood and their Relationship to Clinical Conditions , 2022, Frontiers in Physiology.

[12]  G. Barshtein Biochemical and Biophysical Properties of Red Blood Cells in Disease , 2022, Biomolecules.

[13]  J. Bester,et al.  Pathophysiological Changes in Erythrocytes Contributing to Complications of Inflammation and Coagulation in COVID-19 , 2022, Frontiers in Physiology.

[14]  M. Fu,et al.  Vascular Endothelial Glycocalyx Damage and Potential Targeted Therapy in COVID-19 , 2022, Cells.

[15]  V. Sumantran,et al.  Revisiting dextran effect on red blood cell to understand the importance of rouleaux distribution and red blood cell-endothelial cell adhesion , 2022, Biomass Conversion and Biorefinery.

[16]  H. Predel,et al.  Even patients with mild COVID‐19 symptoms after SARS‐CoV‐2 infection show prolonged altered red blood cell morphology and rheological parameters , 2022, Journal of cellular and molecular medicine.

[17]  A. Priezzhev,et al.  Problems of Red Blood Cell Aggregation and Deformation Assessed by Laser Tweezers, Diffuse Light Scattering and Laser Diffractometry , 2022, Photonics.

[18]  L. Bruce,et al.  Reticulocyte Maturation and Variant Red Blood Cells , 2022, Frontiers in Physiology.

[19]  D. Barreca,et al.  Implication of COVID-19 on Erythrocytes Functionality: Red Blood Cell Biochemical Implications and Morpho-Functional Aspects , 2022, International journal of molecular sciences.

[20]  F. Dentali,et al.  Upper extremity deep vein thrombosis in COVID-19: Incidence and correlated risk factors in a cohort of non-ICU patients , 2022, PloS one.

[21]  Y. Bertrand,et al.  Increased blood viscosity and red blood cell aggregation in patients with COVID‐19 , 2021, American journal of hematology.

[22]  S. Bhatia,et al.  CD147-spike protein interaction in COVID-19: Get the ball rolling with a novel receptor and therapeutic target , 2021, Science of The Total Environment.

[23]  G. Silvestri,et al.  FIBRINOGEN-RBC INTERACTIONS PLAY A KEY ROLE IN COVID-19-ASSOCIATED ENDOTHELIAL DYSFUNCTION , 2021, Chest.

[24]  R. Dorey,et al.  Vm-related extracellular potentials observed in red blood cells , 2021, Scientific Reports.

[25]  D. Fedosov,et al.  Erythrocyte sedimentation: Effect of aggregation energy on gel structure during collapse. , 2021, Physical review. E.

[26]  K. Davidson,et al.  Postdischarge thromboembolic outcomes and mortality of hospitalized patients with COVID-19: the CORE-19 registry , 2021, Blood.

[27]  J. Prchal,et al.  How Do Red Blood Cells Die? , 2021, Frontiers in Physiology.

[28]  Alessia Remigante,et al.  Band 3 protein function and oxidative stress in erythrocytes , 2021, Journal of cellular physiology.

[29]  P. Joly,et al.  Impact of COVID‐19 on red blood cell rheology , 2021, British journal of haematology.

[30]  M. Yamaoka-Tojo Vascular Endothelial Glycocalyx Damage in COVID-19 , 2020, International journal of molecular sciences.

[31]  B. Chernyak,et al.  COVID-19 and Oxidative Stress , 2020, Biochemistry (Moscow).

[32]  J. Mehta,et al.  COVID‐19, thromboembolic risk, and Virchow's triad: Lesson from the past , 2020, Clinical cardiology.

[33]  L. Carrozzi,et al.  Lower limb deep vein thrombosis in COVID-19 patients admitted to intermediate care respiratory units , 2020, Thrombosis Research.

[34]  P. Buehler,et al.  Evidence of Structural Protein Damage and Membrane Lipid Remodeling in Red Blood Cells from COVID-19 Patients , 2020, Journal of proteome research.

[35]  H. Pavenstädt,et al.  Microvascular dysfunction in COVID-19: the MYSTIC study , 2020, Angiogenesis.

[36]  A. Priezzhev,et al.  Assessment of Fibrinogen Macromolecules Interaction with Red Blood Cells Membrane by Means of Laser Aggregometry, Flow Cytometry, and Optical Tweezers Combined with Microfluidics , 2020, Biomolecules.

[37]  I. Cosic,et al.  RRM Prediction of Erythrocyte Band3 Protein as Alternative Receptor for SARS-CoV-2 Virus , 2020, Applied Sciences.

[38]  R. Zennadi,et al.  Oxidative Stress and Thrombosis during Aging: The Roles of Oxidative Stress in RBCs in Venous Thrombosis , 2020, International journal of molecular sciences.

[39]  Loay H Abdelnour,et al.  COVID 19 infection presenting as motor peripheral neuropathy , 2020, Journal of the Formosan Medical Association.

[40]  M. Fenech,et al.  Effects of red blood cell aggregation on microparticle wall adhesion in circular microchannels. , 2019, Medical engineering & physics.

[41]  A. Shahesmaeili,et al.  The correlation between blood oxidative stress and sialic acid content in diabetic patients with nephropathy, hypertension, and hyperlipidemia , 2019, Diabetology International.

[42]  J. Weisel,et al.  Red blood cells: the forgotten player in hemostasis and thrombosis , 2019, Journal of thrombosis and haemostasis : JTH.

[43]  G. Karniadakis,et al.  Cytoskeleton Remodeling Induces Membrane Stiffness and Stability Changes of Maturing Reticulocytes. , 2018, Biophysical journal.

[44]  Thomas Podgorski,et al.  The buckling instability of aggregating red blood cells , 2017, Scientific Reports.

[45]  E. Pretorius,et al.  Effects of IL-1β, IL-6 and IL-8 on erythrocytes, platelets and clot viscoelasticity , 2016, Scientific Reports.

[46]  A. Gori,et al.  Erythrocyte oxidative stress is associated with cell deformability in patients with retinal vein occlusion , 2016, Journal of thrombosis and haemostasis : JTH.

[47]  Daniel M Tartakovsky,et al.  Shear-induced nitric oxide production by endothelial cells , 2016, bioRxiv.

[48]  M. Jacob,et al.  Degradation of the endothelial glycocalyx in clinical settings: searching for the sheddases , 2015, British journal of clinical pharmacology.

[49]  D. Janz,et al.  The role of red blood cells and cell-free hemoglobin in the pathogenesis of ARDS , 2015, Journal of Intensive Care.

[50]  Sung Yang,et al.  Effects of Aggregation on Blood Sedimentation and Conductivity , 2015, PloS one.

[51]  E. Nwose,et al.  Association of abnormal erythrocyte morphology with oxidative stress and inflammation in metabolic syndrome. , 2015, Blood cells, molecules & diseases.

[52]  N. Salehi-Nik,et al.  Nitric oxide secretion by endothelial cells in response to fluid shear stress, aspirin, and temperature. , 2015, Journal of biomedical materials research. Part A.

[53]  Maciej Bosek,et al.  Kinetics of red blood cell rouleaux formation studied by light scattering , 2015, Journal of biomedical optics.

[54]  M. Abkarian,et al.  Red blood cell: from its mechanics to its motion in shear flow , 2014, International journal of laboratory hematology.

[55]  Dileep Kumar,et al.  Erythrocyte membrane bound and plasma sialic acid during aging , 2013, Biologia.

[56]  S. Svetina,et al.  Aggregation of red blood cells: From rouleaux to clot formation , 2013, 1310.1483.

[57]  S. Rizvi,et al.  Erythrocyte Sialic Acid Content during Aging in Humans: Correlation with Markers of Oxidative Stress , 2012, Disease markers.

[58]  H. Meiselman,et al.  A local increase in red blood cell aggregation can trigger deep vein thrombosis: evidence based on quantitative cellular ultrasound imaging , 2011, Journal of thrombosis and haemostasis : JTH.

[59]  R. Fåhraeus The influence of the rouleau formation of the erythrocytes on the rheology of the blood. , 2009, Acta medica Scandinavica.

[60]  O. Baskurt,et al.  RBC Aggregation: More Important than RBC Adhesion to Endothelial Cells as a Determinant of In Vivo Blood Flow in Health and Disease , 2008, Microcirculation.

[61]  S. Svetina,et al.  Morphology of small aggregates of red blood cells. , 2008, Bioelectrochemistry.

[62]  Herbert J Meiselman,et al.  Nitric oxide generation by endothelial cells exposed to shear stress in glass tubes perfused with red blood cell suspensions: role of aggregation. , 2008, American journal of physiology. Heart and circulatory physiology.

[63]  S. Yedgar,et al.  Role of red blood cell flow behavior in hemodynamics and hemostasis , 2007, Expert review of cardiovascular therapy.

[64]  A. Pribush,et al.  The mechanism of the dextran-induced red blood cell aggregation , 2007, European Biophysics Journal.

[65]  J. Tarbell,et al.  Mechanotransduction and the glycocalyx , 2006, Journal of internal medicine.

[66]  Lance L. Munn,et al.  Influence of erythrocyte aggregation on leukocyte margination in postcapillary expansions: A lattice Boltzmann analysis , 2006 .

[67]  O. Baskurt,et al.  Graded alterations of RBC aggregation influence in vivo blood flow resistance. , 2004, American journal of physiology. Heart and circulatory physiology.

[68]  O. Baskurt,et al.  Blood rheology and hemodynamics. , 2003, Seminars in thrombosis and hemostasis.

[69]  J. Vincent,et al.  Alterations of red blood cell shape and sialic acid membrane content in septic patients , 2003, Critical care medicine.

[70]  J. Loscalzo,et al.  Nitric oxide and its relationship to thrombotic disorders , 2003, Journal of thrombosis and haemostasis : JTH.

[71]  I. Cicha,et al.  Changes of RBC aggregation in oxygenation-deoxygenation: pH dependency and cell morphology. , 2003, American journal of physiology. Heart and circulatory physiology.

[72]  Kevin Kendall,et al.  Adhesion and aggregation of fine particles , 2001 .

[73]  V. Prochorov,et al.  Parameters of red blood cell aggregation as correlates of the inflammatory state. , 2001, American journal of physiology. Heart and circulatory physiology.

[74]  G. Guiffant,et al.  Effects of red blood cell hyperaggregation on the rat microcirculation blood flow. , 1998, Acta physiologica Scandinavica.

[75]  J. F. Richardson,et al.  Sedimentation and fluidisation: Part I , 1997 .

[76]  A. Rumley,et al.  Blood viscosity and risk of cardiovascular events: the Edinburgh Artery Study , 1997, British journal of haematology.

[77]  A. Simon,et al.  Influence of Sialic Acid on Erythrocyte Aggregation in Hypercholesterolemi , 1996, Thrombosis and Haemostasis.

[78]  A. Pries,et al.  Biophysical aspects of blood flow in the microvasculature. , 1996, Cardiovascular research.

[79]  Bruce E. Logan,et al.  Settling Velocities of Fractal Aggregates , 1996 .

[80]  M W Rampling,et al.  Decrease in erythrocyte glycophorin sialic acid content is associated with increased erythrocyte aggregation in human diabetes. , 1992, Clinical science.

[81]  I. Marcu,et al.  Contribution of the erythrocytes physical qualities (deformability and aggregability) to the viscoelastic properties of the blood clot in patients with acute cerebral thrombosis. , 1983, Neurologie et psychiatrie.

[82]  J. Oncley,et al.  The contribution of sialic acid to the surface charge of the erythrocyte. , 1962, The Journal of biological chemistry.

[83]  World Health Organization,et al.  Clinical management of severe acute respiratory infection (SARI) when COVID-19 disease is suspected. Interim guidance , 2020, Pediatria i Medycyna Rodzinna.

[84]  M. Girasole,et al.  Morphological changes induced in erythrocyte by amyloid beta peptide and glucose depletion: A combined atomic force microscopy and biochemical study. , 2019, Biochimica et biophysica acta. Biomembranes.

[85]  P. Nithiarasu,et al.  Red blood cell (RBC) aggregation and its influence on non-Newtonian nature of blood in microvasculature , 2017 .

[86]  E. Kaliviotis Mechanics of the red blood cell network , 2015 .

[87]  M. Spengler,et al.  Lipid peroxidation affects red blood cells membrane properties in patients with systemic lupus erythematosus. , 2014, Clinical hemorheology and microcirculation.

[88]  O. Baskurt,et al.  Erythrocyte aggregation: basic aspects and clinical importance. , 2013, Clinical hemorheology and microcirculation.

[89]  Carlos Lenz Cesar,et al.  Electrical properties of the red blood cell membrane and immunohematological investigation , 2011, Revista brasileira de hematologia e hemoterapia.

[90]  N. Chesler,et al.  Shear stress regulation of nitric oxide production in uterine and placental artery endothelial cells: experimental studies and hemodynamic models of shear stresses on endothelial cells. , 2010, The International journal of developmental biology.

[91]  D. Meyerstein,et al.  The mechanism of erythrocyte sedimentation. Part 1: Channeling in sedimenting blood. , 2010, Colloids and surfaces. B, Biointerfaces.

[92]  O. Baskurt,et al.  Nitric oxide generation in red blood cells induced by mechanical stress. , 2010, Clinical hemorheology and microcirculation.

[93]  C. Thornton,et al.  Red cell aggregation as a factor influencing margination and adhesion of leukocytes and platelets. , 2008, Clinical hemorheology and microcirculation.

[94]  O. Baskurt,et al.  Hemodynamic effects of red blood cell aggregation. , 2007, Indian journal of experimental biology.

[95]  M W Rampling,et al.  Influence of cell-specific factors on red blood cell aggregation. , 2004, Biorheology.

[96]  O. Baskurt,et al.  Modulation of endothelial nitric oxide synthase expression by red blood cell aggregation. , 2004, American journal of physiology. Heart and circulatory physiology.

[97]  A. Deviatkin,et al.  [Clinical implications of impaired microcirculation and hemodynamics in acute respiratory viral infections and their pharmacological correction]. , 2003, Klinicheskaia meditsina.

[98]  G. Mchedlishvili,et al.  Local RBC aggregation disturbing blood fluidity and causing stasis in microvessels. , 2002, Clinical hemorheology and microcirculation.

[99]  Alicja,et al.  The fractal dimension of red blood cell aggregates in dextran 70 solutions , 2001 .

[100]  H. Goldsmith,et al.  Effect of red blood cells and their aggregates on platelets and white cells in flowing blood. , 1999, Biorheology.

[101]  E. Vicaut,et al.  Red blood cell aggregation and microcirculation in rat cremaster muscle. , 1994, International journal of microcirculation, clinical and experimental.

[102]  T L Fabry,et al.  Mechanism of erythrocyte aggregation and sedimentation. , 1987, Blood.

[103]  A. Ehrly Erythrocyte aggregation in clinical medicine. , 1986, Klinische Wochenschrift.

[104]  R. Skalak Aggregation and disaggregation of red blood cells. , 1984, Biorheology.