The Erythrocyte–ROS Axis in Thrombosis and Hemostasis

Abstract

Thrombosis and hemostasis are critical processes that maintain vascular integrity, yet imbalances can lead to life-threatening cardiovascular events. Traditionally, erythrocytes were considered passive bystanders in coagulation, but emerging evidence highlights their active role in thrombogenesis, particularly through redox biology. Erythrocytes generate reactive oxygen and nitrogen species (RONS) via Hb autoxidation, NADPH oxidase activation, and external uptake from other blood components. This oxidative environment induces structural and functional modifications, including increased rigidity, phosphatidylserine exposure, microvesicle release, and enhanced adhesion to endothelial cells and platelets, all contributing to a prothrombotic phenotype. Hemorheological alterations such as increased aggregation and decreased deformability further exacerbate blood stasis and thrombus formation. Oxidative stress also accelerates hemolysis, releasing free Hb and heme, which trigger inflammatory responses and endothelial dysfunction, further amplifying thrombogenic potential. Additionally, erythrocyte-derived microvesicles act as carriers of procoagulant factors, enhancing thrombin generation and fibrin network formation. These mechanisms underscore the erythrocyte–ROS axis as a crucial determinant of thrombosis. Despite these insights, the full scope of erythrocyte-mediated redox signaling in thrombotic processes remains incompletely understood. This review discusses the multifaceted impact of erythrocyte oxidative stress on thrombosis and hemostasis, exploring its implications in cardiovascular diseases, metabolic disorders, and hematological conditions. Understanding these pathways may lead to novel therapeutic approaches targeting erythrocyte redox homeostasis to mitigate thrombotic risk and improve patient outcomes.

Keywords

erythrocytes - oxidative stress - redox signaling - thrombosis - hemostasis

^* These authors contributed equally to this article.

^** These authors share last authorship to this article.

Publication History

Received: 28 February 2025

Accepted: 15 May 2025

Article published online:
30 May 2025

• References

• 1 Sierra C, Moreno M, García-Ruiz JC. The physiology of hemostasis. Blood Coagul Fibrinolysis 2022; 33 (Suppl. 01) S1-S2
• 2 Raskob GE, Angchaisuksiri P, Blanco AN. et al; ISTH Steering Committee for World Thrombosis Day. Thrombosis: a major contributor to global disease burden. Arterioscler Thromb Vasc Biol 2014; 34 (11) 2363-2371
• 3 Potere N, Abbate A, Kanthi Y. et al. Inflammasome signaling, thromboinflammation, and venous thromboembolism. JACC Basic Transl Sci 2023; 8 (09) 1245-1261
• 4 Yang M, Silverstein RL. Targeting cysteine oxidation in thrombotic disorders. Antioxidants 2024; 13 (01) 83
• 5 Becatti M, Emmi G, Silvestri E. et al. Neutrophil activation promotes fibrinogen oxidation and thrombus formation in Behçet disease. Circulation 2016; 133 (03) 302-311
• 6 Bettiol A, Argento FR, Fini E. et al. ROS-driven structural and functional fibrinogen modifications are reverted by interleukin-6 inhibition in Giant cell arteritis. Thromb Res 2023; 230: 1-10
• 7 Wu H, Wang Y, Zhang Y. et al. Breaking the vicious loop between inflammation, oxidative stress and coagulation, a novel anti-thrombus insight of nattokinase by inhibiting LPS-induced inflammation and oxidative stress. Redox Biol 2020; 32: 101500
• 8 Nencini F, Bettiol A, Argento FR. et al. Post-translational modifications of fibrinogen: implications for clotting, fibrin structure and degradation. Mol Biomed 2024; 5 (01) 45
• 9 Sies H, Berndt C, Jones DP. Oxidative stress. Annu Rev Biochem 2017; 86: 715-748
• 10 Wójcik P, Gęgotek A, Žarković N, Skrzydlewska E. Oxidative stress and lipid mediators modulate immune cell functions in autoimmune diseases. Int J Mol Sci 2021; 22 (02) 723
• 11 Bettiol A, Alibaz-Oner F, Direskeneli H. et al. Vascular Behçet syndrome: from pathogenesis to treatment. Nat Rev Rheumatol 2023; 19 (02) 111-126
• 12 Emmi G, Bettiol A, Niccolai E. et al. Butyrate-rich diets improve redox status and fibrin lysis in Behçet's syndrome. Circ Res 2021; 128 (02) 278-280
• 13 Gallo A, Le Goff W, Santos RD. et al. Hypercholesterolemia and inflammation—cooperative cardiovascular risk factors. Eur J Clin Invest 2025; 55 (01) e14326
• 14 Gajos G, Siniarski A, Natorska J. et al. Polyhedrocytes in blood clots of type 2 diabetic patients with high cardiovascular risk: association with glycemia, oxidative stress and platelet activation. Cardiovasc Diabetol 2018; 17 (01) 146
• 15 Fernández-Sánchez A, Madrigal-Santillán E, Bautista M. et al. Inflammation, oxidative stress, and obesity. Int J Mol Sci 2011; 12 (05) 3117-3132
• 16 Shao C, Wang J, Tian J, Tang YD. Coronary artery disease: from mechanism to clinical practice. Adv Exp Med Biol 2020; 1177: 1-36
• 17 Beura SK, Dhapola R, Panigrahi AR, Yadav P, Reddy DH, Singh SK. Redefining oxidative stress in Alzheimer's disease: targeting platelet reactive oxygen species for novel therapeutic options. Life Sci 2022; 306: 120855
• 18 Zhang X, Yu S, Li X. et al. Research progress on the interaction between oxidative stress and platelets: another avenue for cancer?. Pharmacol Res 2023; 191: 106777
• 19 Ursini F, Maiorino M, Forman HJ. Redox homeostasis: the golden mean of healthy living. Redox Biol 2016; 8: 205-215
• 20 Whittaker A, Sofi F, Luisi ML. et al. An organic Khorasan wheat-based replacement diet improves risk profile of patients with acute coronary syndrome: a randomized crossover trial. Nutrients 2015; 7 (05) 3401-3415
• 21 Whittaker A, Dinu M, Cesari F. et al. A Khorasan wheat-based replacement diet improves risk profile of patients with type 2 diabetes mellitus (T2DM): a randomized crossover trial. Eur J Nutr 2017; 56 (03) 1191-1200
• 22 Fiorillo C, Becatti M, Attanasio M. et al. Evidence for oxidative stress in plasma of patients with Marfan syndrome. Int J Cardiol 2010; 145 (03) 544-546
• 23 Obeagu EI, Igwe MC, Obeagu GU. Oxidative stress's impact on red blood cells: unveiling implications for health and disease. Medicine (Baltimore) 2024; 103 (09) e37360
• 24 Gillespie AH, Doctor A. Red blood cell contribution to hemostasis. Front Pediatr 2021; 9: 629824
• 25 Bettiol A, Galora S, Argento FR. et al. Erythrocyte oxidative stress and thrombosis. Expert Rev Mol Med 2022; 24: e31
• 26 Zhang X, Lin Y, Xin J. et al. Red blood cells in biology and translational medicine: natural vehicle inspires new biomedical applications. Theranostics 2024; 14 (01) 220-248
• 27 Kuhn V, Diederich L, Keller IV TCS. et al. Red blood cell function and dysfunction: redox regulation, nitric oxide metabolism, anemia. Antioxid Redox Signal 2017; 26 (13) 718-742
• 28 Grenier JMP, El Nemer W, De Grandis M. Red blood cell contribution to thrombosis in polycythemia vera and essential thrombocythemia. Int J Mol Sci 2024; 25 (03) 1417
• 29 Mackman N. The red blood cell death receptor and thrombosis. J Clin Invest 2018; 128 (09) 3747-3749
• 30 Schreijer AJ, Reitsma PH, Cannegieter SC. High hematocrit as a risk factor for venous thrombosis. Cause or innocent bystander?. Haematologica 2010; 95 (02) 182-184
• 31 Enblom A, Lindskog E, Hasselbalch H. et al. High rate of abnormal blood values and vascular complications before diagnosis of myeloproliferative neoplasms. Eur J Intern Med 2015; 26 (05) 344-347
• 32 Gerds AT, Mesa R, Burke JM. et al. Association between elevated white blood cell counts and thrombotic events in polycythemia vera: analysis from REVEAL. Blood 2024; 143 (16) 1646-1655
• 33 Warny M, Helby J, Birgens HS, Bojesen SE, Nordestgaard BG. Arterial and venous thrombosis by high platelet count and high hematocrit: 108 521 individuals from the Copenhagen General Population Study. J Thromb Haemost 2019; 17 (11) 1898-1911
• 34 Becatti M, Marcucci R, Mannucci A. et al. Erythrocyte membrane fluidity alterations in sudden sensorineural hearing loss patients: the role of oxidative stress. Thromb Haemost 2017; 117 (12) 2334-2345
• 35 Wolberg AS, Aleman MM, Leiderman K, Machlus KR. Procoagulant activity in hemostasis and thrombosis: Virchow's triad revisited. Anesth Analg 2012; 114 (02) 275-285
• 36 Aarts PA, van den Broek SA, Prins GW, Kuiken GD, Sixma JJ, Heethaar RM. Blood platelets are concentrated near the wall and red blood cells, in the center in flowing blood. Arteriosclerosis 1988; 8 (06) 819-824
• 37 Mughal TI, Vaddi K, Sarlis NJ, Verstovsek S. Myelofibrosis-associated complications: pathogenesis, clinical manifestations, and effects on outcomes. Int J Gen Med 2014; 7: 89-101
• 38 Doche E, Sulowski C, Guigonis JM. et al; Retro-MATISSE Collaborators. How clot composition influences fibrinolysis in the acute phase of stroke: a proteomic study of cerebral thrombi. Stroke 2024; 55 (07) 1818-1829
• 39 Baskurt OK, Meiselman HJ. Erythrocyte aggregation: basic aspects and clinical importance. Clin Hemorheol Microcirc 2013; 53 (1-2): 23-37
• 40 Nader E, Skinner S, Romana M. et al. Blood rheology: key parameters, impact on blood flow, role in sickle cell disease and effects of exercise. Front Physiol 2019; 10: 1329
• 41 Rampling MW, Meiselman HJ, Neu B, Baskurt OK. Influence of cell-specific factors on red blood cell aggregation. Biorheology 2004; 41 (02) 91-112
• 42 Zhang K, Wang P, Huang W. et al. Integrated landscape of plasma metabolism and proteome of patients with post-traumatic deep vein thrombosis. Nat Commun 2024; 15 (01) 7831
• 43 Yu FT, Armstrong JK, Tripette J, Meiselman HJ, Cloutier G. A local increase in red blood cell aggregation can trigger deep vein thrombosis: evidence based on quantitative cellular ultrasound imaging. J Thromb Haemost 2011; 9 (03) 481-488
• 44 Becatti M, Marcucci R, Gori AM. et al. Erythrocyte oxidative stress is associated with cell deformability in patients with retinal vein occlusion. J Thromb Haemost 2016; 14 (11) 2287-2297
• 45 Wautier MP, Héron E, Picot J, Colin Y, Hermine O, Wautier JL. Red blood cell phosphatidylserine exposure is responsible for increased erythrocyte adhesion to endothelium in central retinal vein occlusion. J Thromb Haemost 2011; 9 (05) 1049-1055
• 46 Zhou Z, Mahdi A, Tratsiakovich Y. et al. Erythrocytes from patients with type 2 diabetes induce endothelial dysfunction via arginase I. J Am Coll Cardiol 2018; 72 (07) 769-780
• 47 Mahdi A, Wodaje T, Kövamees O. et al. The red blood cell as a mediator of endothelial dysfunction in patients with familial hypercholesterolemia and dyslipidemia. J Intern Med 2023; 293 (02) 228-245
• 48 Radosinska J, Vrbjar N. The role of red blood cell deformability and Na,K-ATPase function in selected risk factors of cardiovascular diseases in humans: focus on hypertension, diabetes mellitus and hypercholesterolemia. Physiol Res 2016; 65 (Suppl. 01) S43-S54
• 49 Connes P, Alexy T, Detterich J, Romana M, Hardy-Dessources MD, Ballas SK. The role of blood rheology in sickle cell disease. Blood Rev 2016; 30 (02) 111-118
• 50 Hierso R, Waltz X, Mora P. et al. Effects of oxidative stress on red blood cell rheology in sickle cell patients. Br J Haematol 2014; 166 (04) 601-606
• 51 Kucukal E, Ilich A, Key NS, Little JA, Gurkan UA. Red blood cell adhesion to heme-activated endothelial cells reflects clinical phenotype in sickle cell disease. Am J Hematol 2018; . Epub ahead of print.
• 52 Connes P, Lamarre Y, Waltz X. et al. Haemolysis and abnormal haemorheology in sickle cell anaemia. Br J Haematol 2014; 165 (04) 564-572
• 53 Smith JD, Rowe JA, Higgins MK, Lavstsen T. Malaria's deadly grip: cytoadhesion of Plasmodium falciparum-infected erythrocytes. Cell Microbiol 2013; 15 (12) 1976-1983
• 54 Tengbom J, Kontidou E, Collado A. et al. Differences in endothelial function between patients with type 1 and type 2 diabetes: effects of red blood cells and arginase. Clin Sci (Lond) 2024; 138 (15) 975-985
• 55 Hess JR. Measures of stored red blood cell quality. Vox Sang 2014; 107 (01) 1-9
• 56 Weisel JW, Litvinov RI. Red blood cells: the forgotten player in hemostasis and thrombosis. J Thromb Haemost 2019; 17 (02) 271-282
• 57 Yan M, Xu M, Li Z. et al. TMEM16F mediated phosphatidylserine exposure and microparticle release on erythrocyte contribute to hypercoagulable state in hyperuricemia. Blood Cells Mol Dis 2022; 96: 102666
• 58 Zahedpanah M, Azarkeivan A, Aghaieepour M. et al. Erythrocytic phosphatidylserine exposure and hemostatic alterations in β-thalassemia intermediate patients. Hematology 2014; 19 (08) 472-476
• 59 Qadri SM, Bissinger R, Solh Z, Oldenborg PA. Eryptosis in health and disease: a paradigm shift towards understanding the (patho)physiological implications of programmed cell death of erythrocytes. Blood Rev 2017; 31 (06) 349-361
• 60 Tkachenko A, Havránek O. Redox status of erythrocytes as an important factor in eryptosis and erythronecroptosis. Folia Biol (Praha) 2023; 69 (04) 116-126
• 61 Whelihan MF, Zachary V, Orfeo T, Mann KG. Prothrombin activation in blood coagulation: the erythrocyte contribution to thrombin generation. Blood 2012; 120 (18) 3837-3845
• 62 Whelihan MF, Lim MY, Mooberry MJ. et al. Thrombin generation and cell-dependent hypercoagulability in sickle cell disease. J Thromb Haemost 2016; 14 (10) 1941-1952
• 63 Vomero M, Finucci A, Barbati C. et al. Increased eryptosis in patients with primary antiphospholipid syndrome (APS): a new actor in the pathogenesis of APS. Clin Exp Rheumatol 2021; 39 (04) 838-843
• 64 Perkkiö J, Wurzinger LJ, Schmid-Schönbein H. Fåhraeus-Vejlens effect: margination of platelets and leukocytes in blood flow through branches. Thromb Res 1988; 50 (03) 357-364
• 65 Vallés J, Santos MT, Aznar J. et al. Platelet-erythrocyte interactions enhance alpha(IIb)beta(3) integrin receptor activation and P-selectin expression during platelet recruitment: down-regulation by aspirin ex vivo. Blood 2002; 99 (11) 3978-3984
• 66 Falanga A, Marchetti M, Evangelista V. et al. Polymorphonuclear leukocyte activation and hemostasis in patients with essential thrombocythemia and polycythemia vera. Blood 2000; 96 (13) 4261-4266
• 67 Kroll MH, Schafer AI. Biochemical mechanisms of platelet activation. Blood 1989; 74 (04) 1181-1195
• 68 Helms CC, Marvel M, Zhao W. et al. Mechanisms of hemolysis-associated platelet activation. J Thromb Haemost 2013; 11 (12) 2148-2154
• 69 Jiang D, Houck KL, Murdiyarso L. et al. RBCs regulate platelet function and hemostasis under shear conditions through biophysical and biochemical means. Blood 2024; 144 (14) 1521-1531
• 70 Morel O, Jesel L, Freyssinet JM, Toti F. Cellular mechanisms underlying the formation of circulating microparticles. Arterioscler Thromb Vasc Biol 2011; 31 (01) 15-26
• 71 Koch CG, Li L, Sessler DI. et al. Duration of red-cell storage and complications after cardiac surgery. N Engl J Med 2008; 358 (12) 1229-1239
• 72 Zecher D, Cumpelik A, Schifferli JA. Erythrocyte-derived microvesicles amplify systemic inflammation by thrombin-dependent activation of complement. Arterioscler Thromb Vasc Biol 2014; 34 (02) 313-320
• 73 Van Der Meijden PE, Van Schilfgaarde M, Van Oerle R, Renné T, ten Cate H, Spronk HM. Platelet- and erythrocyte-derived microparticles trigger thrombin generation via factor XIIa. J Thromb Haemost 2012; 10 (07) 1355-1362
• 74 Charpentier A, Lebreton A, Rauch A. et al. Microparticle phenotypes are associated with driver mutations and distinct thrombotic risks in essential thrombocythemia. Haematologica 2016; 101 (09) e365-e368
• 75 Gkaliagkousi E, Nikolaidou B, Gavriilaki E. et al. Increased erythrocyte- and platelet-derived microvesicles in newly diagnosed type 2 diabetes mellitus. Diab Vasc Dis Res 2019; 16 (05) 458-465
• 76 Smith SA, Travers RJ, Morrissey JH. How it all starts: initiation of the clotting cascade. Crit Rev Biochem Mol Biol 2015; 50 (04) 326-336
• 77 Assayag EB, Bornstein N, Shapira I. et al. Inflammation-sensitive proteins and erythrocyte aggregation in atherothrombosis. Int J Cardiol 2005; 98 (02) 271-276
• 78 Saldanha C. Fibrinogen interaction with the red blood cell membrane. Clin Hemorheol Microcirc 2013; 53 (1-2): 39-44
• 79 Litvinov RI, Farrell DH, Weisel JW, Bennett JS. The platelet integrin αIIbβ3 differentially interacts with fibrin versus fibrinogen. J Biol Chem 2016; 291 (15) 7858-7867
• 80 Semenov AN, Lugovtsov AE, Shirshin EA. 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. Biomolecules 2020; 10 (10) 1448
• 81 Becatti M, Mannucci A, Argento FR. et al. Super-resolution microscopy reveals an altered fibrin network in cirrhosis: the key role of oxidative stress in fibrinogen structural modifications. Antioxidants 2020; 9 (08) 737
• 82 Landi E, Mugnaini M, Vatansever T. et al. Advancing thrombosis research: a novel device for measuring clot permeability. Sensors (Basel) 2024; 24 (12) 3764
• 83 Gitto S, Fiorillo C, Argento FR. et al. Oxidative stress-induced fibrinogen modifications in liver transplant recipients: unraveling a novel potential mechanism for cardiovascular risk. Res Pract Thromb Haemost 2024; 8 (06) 102555
• 84 Fini E, Argento FR, Borghi S. et al. Fibrinogen structural changes and their potential role in endometriosis-related thrombosis. Antioxidants 2024; 13 (12) 1456
• 85 Sun Y, Le H, Lam WA, Alexeev A. Probing interactions of red blood cells and contracting fibrin platelet clots. Biophys J 2023; 122 (21) 4123-4134
• 86 Gersh KC, Nagaswami C, Weisel JW. Fibrin network structure and clot mechanical properties are altered by incorporation of erythrocytes. Thromb Haemost 2009; 102 (06) 1169-1175
• 87 Ermolinskiy PB, Maksimov MK, Muravyov AV, Lugovtsov AE, Scheglovitova ON, Priezzhev AV. Forces of interaction of red blood cells and endothelial cells at different concentrations of fibrinogen: measurements with laser tweezers in vitro. Clin Hemorheol Microcirc 2024; 86 (03) 303-312
• 88 Litvinov RI. Fibrin opens the “gate” for leukocytes in the endothelium. Thromb Res 2018; 162: 101-103
• 89 Cines DB, Lebedeva T, Nagaswami C. et al. Clot contraction: compression of erythrocytes into tightly packed polyhedra and redistribution of platelets and fibrin. Blood 2014; 123 (10) 1596-1603
• 90 Sies H, Jones DP. Reactive oxygen species (ROS) as pleiotropic physiological signalling agents. Nat Rev Mol Cell Biol 2020; 21 (07) 363-383
• 91 Kehrer JP, Klotz LO. Free radicals and related reactive species as mediators of tissue injury and disease: implications for health. Crit Rev Toxicol 2015; 45 (09) 765-798
• 92 Napolitano G, Fasciolo G, Venditti P. Mitochondrial management of reactive oxygen species. Antioxidants 2021; 10 (11) 1824
• 93 Adams L, Franco MC, Estevez AG. Reactive nitrogen species in cellular signaling. Exp Biol Med (Maywood) 2015; 240 (06) 711-717
• 94 Gwozdzinski L, Pieniazek A, Gwozdzinski K. The roles of oxidative stress and red blood cells in the pathology of the varicose vein. Int J Mol Sci 2024; 25 (24) 13400
• 95 Möller MN, Orrico F, Villar SF. et al. Oxidants and antioxidants in the redox biochemistry of human red blood cells. ACS Omega 2022; 8 (01) 147-168
• 96 Orrico F, Laurance S, Lopez AC. et al. Oxidative stress in healthy and pathological red blood cells. Biomolecules 2023; 13 (08) 1262
• 97 Umbreit J. Methemoglobin‐‐it's not just blue: a concise review. American journal of hematology 2007; 82 (02) 134-144
• 98 George A, Pushkaran S, Konstantinidis DG. et al. Erythrocyte NADPH oxidase activity modulated by Rac GTPases, PKC, and plasma cytokines contributes to oxidative stress in sickle cell disease. Blood 2013; 121 (11) 2099-2107
• 99 Attanzio A, Frazzitta A, Cilla A, Livrea MA, Tesoriere L, Allegra M. 7-Keto-cholesterol and cholestan-3beta, 5alpha, 6beta-triol induce eryptosis through distinct pathways leading to NADPH oxidase and nitric oxide synthase activation. Cell Physiol Biochem 2019; 53 (06) 933-947
• 100 Webb AJ, Milsom AB, Rathod KS. et al. Mechanisms underlying erythrocyte and endothelial nitrite reduction to nitric oxide in hypoxia: role for xanthine oxidoreductase and endothelial nitric oxide synthase. Circ Res 2008; 103 (09) 957-964
• 101 Fens MH, Larkin SK, Oronsky B, Scicinski J, Morris CR, Kuypers FA. The capacity of red blood cells to reduce nitrite determines nitric oxide generation under hypoxic conditions. PLoS One 2014; 9 (07) e101626
• 102 Al-Shehri SS. Reactive oxygen and nitrogen species and innate immune response. Biochimie 2021; 181: 52-64
• 103 Ozüyaman B, Grau M, Kelm M, Merx MW, Kleinbongard P. RBC NOS: regulatory mechanisms and therapeutic aspects. Trends Mol Med 2008; 14 (07) 314-322
• 104 Mahdi A, Cortese-Krott MM, Kelm M, Li N, Pernow J. Novel perspectives on redox signaling in red blood cells and platelets in cardiovascular disease. Free Radic Biol Med 2021; 168: 95-109
• 105 Dejam A, Hunter CJ, Pelletier MM. et al. Erythrocytes are the major intravascular storage sites of nitrite in human blood. Blood 2005; 106 (02) 734-739
• 106 Sun CW, Yang J, Kleschyov AL. et al. Hemoglobin β93 cysteine is not required for export of nitric oxide bioactivity from the red blood cell. Circulation 2019; 139 (23) 2654-2663
• 107 Orrico F, Lopez AC, Saliwonczyk D. et al. The permeability of human red blood cell membranes to hydrogen peroxide is independent of aquaporins. J Biol Chem 2022; 298 (01) 101503
• 108 Nemkov T, Stefanoni D, Bordbar A. et al; Recipient Epidemiology and Donor Evaluation Study III Red Blood Cell–Omics (REDS-III RBC-Omics) Study. Blood donor exposome and impact of common drugs on red blood cell metabolism. JCI Insight 2021; 6 (03) e146175
• 109 Arese P, Mannuzzu L, Turrini F. Pathophysiology of favism. Folia Haematol Int Mag Klin Morphol Blutforsch 1989; 116 (05) 745-752
• 110 Cortese-Krott MM. The reactive species interactome in red blood cells: oxidants, antioxidants, and molecular targets. Antioxidants 2023; 12 (09) 1736
• 111 Reisz JA, Wither MJ, Dzieciatkowska M. et al. Oxidative modifications of glyceraldehyde 3-phosphate dehydrogenase regulate metabolic reprogramming of stored red blood cells. Blood 2016; 128 (12) e32-e42
• 112 van 't Erve TJ, Wagner BA, Ryckman KK, Raife TJ, Buettner GR. The concentration of glutathione in human erythrocytes is a heritable trait. Free Radic Biol Med 2013; 65: 742-749
• 113 Einsele H, Clemens MR, Remmer H. Effect of ascorbate on red blood cell lipid peroxidation. Free Radic Res Commun 1985; 1 (01) 63-67
• 114 Czubak K, Antosik A, Cichon N, Zbikowska HM. Vitamin C and Trolox decrease oxidative stress and hemolysis in cold-stored human red blood cells. Redox Rep 2017; 22 (06) 445-450
• 115 May JM, Qu ZC, Mendiratta S. Protection and recycling of alpha-tocopherol in human erythrocytes by intracellular ascorbic acid. Arch Biochem Biophys 1998; 349 (02) 281-289
• 116 Gärtner A, Weser U. Erythrocuprein (Cu2Zn2 superoxide dismutase) is the major copper protein of the red blood cell. FEBS Lett 1983; 155 (01) 15-18
• 117 Manzanares W, Dhaliwal R, Jiang X, Murch L, Heyland DK. Antioxidant micronutrients in the critically ill: a systematic review and meta-analysis. Crit Care 2012; 16 (02) R66
• 118 Nassi N, Ponziani V, Becatti M, Galvan P, Donzelli G. Anti-oxidant enzymes and related elements in term and preterm newborns. Pediatr Int 2009; 51 (02) 183-187
• 119 Kopp TI, Vogel U, Dragsted LO, Tjonneland A, Ravn-Haren G. Association between single nucleotide polymorphisms in the antioxidant genes CAT, GR and SOD1, erythrocyte enzyme activities, dietary and life style factors and breast cancer risk in a Danish, prospective cohort study. Oncotarget 2017; 8 (38) 62984-62997
• 120 Costa NA, Cunha NB, Gut AL. et al. Erythrocyte SOD1 activity, but not SOD1 polymorphisms, is associated with ICU mortality in patients with septic shock. Free Radic Biol Med 2018; 124: 199-204
• 121 Orrico F, Möller MN, Cassina A, Denicola A, Thomson L. Kinetic and stoichiometric constraints determine the pathway of H₂O₂ consumption by red blood cells. Free Radic Biol Med 2018; 121: 231-239
• 122 Cohen G, Hochstein P. Glutathione peroxidase: the primary agent for the elimination of hydrogen peroxide in erythrocytes. Biochemistry 1963; 2: 1420-1428
• 123 Ogasawara Y, Ohminato T, Nakamura Y, Ishii K. Structural and functional analysis of native peroxiredoxin 2 in human red blood cells. Int J Biochem Cell Biol 2012; 44 (07) 1072-1077
• 124 Harper VM, Oh JY, Stapley R. et al. Peroxiredoxin-2 recycling is inhibited during erythrocyte storage. Antioxid Redox Signal 2015; 22 (04) 294-307
• 125 Manta B, Hugo M, Ortiz C, Ferrer-Sueta G, Trujillo M, Denicola A. The peroxidase and peroxynitrite reductase activity of human erythrocyte peroxiredoxin 2. Arch Biochem Biophys 2009; 484 (02) 146-154
• 126 Terada T, Oshida T, Nishimura M. et al. Study on human erythrocyte thioltransferase: comparative characterization with bovine enzyme and its physiological role under oxidative stress. J Biochem 1992; 111 (05) 688-692
• 127 Lind C, Gerdes R, Schuppe-Koistinen I, Cotgreave IA. Studies on the mechanism of oxidative modification of human glyceraldehyde-3-phosphate dehydrogenase by glutathione: catalysis by glutaredoxin. Biochem Biophys Res Commun 1998; 247 (02) 481-486
• 128 Einarson TR, Acs A, Ludwig C, Panton UH. Prevalence of cardiovascular disease in type 2 diabetes: a systematic literature review of scientific evidence from across the world in 2007-2017. Cardiovasc Diabetol 2018; 17 (01) 83
• 129 Catan A, Turpin C, Diotel N. et al. Aging and glycation promote erythrocyte phagocytosis by human endothelial cells: potential impact in atherothrombosis under diabetic conditions. Atherosclerosis 2019; 291: 87-98
• 130 Wautier JL, Paton RC, Wautier MP. et al. Increased adhesion of erythrocytes to endothelial cells in diabetes mellitus and its relation to vascular complications. N Engl J Med 1981; 305 (05) 237-242
• 131 Sun J, Han K, Xu M. et al. Blood viscosity in subjects with type 2 diabetes mellitus: roles of hyperglycemia and elevated plasma fibrinogen. Front Physiol 2022; 13: 827428
• 132 Mohammedi K, Bellili-Muñoz N, Marklund SL. et al. Plasma extracellular superoxide dismutase concentration, allelic variations in the SOD3 gene and risk of myocardial infarction and all-cause mortality in people with type 1 and type 2 diabetes. Cardiovasc Diabetol 2015; 14: 845
• 133 Ren Y, Li Z, Li W. et al. Arginase: biological and therapeutic implications in diabetes mellitus and its complications. Oxid Med Cell Longev 2022; 2022: 2419412
• 134 Yang J, Zheng X, Mahdi A. et al. Red blood cells in type 2 diabetes impair cardiac post-ischemic recovery through an arginase-dependent modulation of nitric oxide synthase and reactive oxygen species. JACC Basic Transl Sci 2018; 3 (04) 450-463
• 135 Ma CX, Ma XN, Guan CH, Li YD, Mauricio D, Fu SB. Cardiovascular disease in type 2 diabetes mellitus: progress toward personalized management. Cardiovasc Diabetol 2022; 21 (01) 74
• 136 Tsimikas S, Witztum JL. Oxidized phospholipids in cardiovascular disease. Nat Rev Cardiol 2024; 21 (03) 170-191
• 137 Forsyth AM, Braunmüller S, Wan J, Franke T, Stone HA. The effects of membrane cholesterol and simvastatin on red blood cell deformability and ATP release. Microvasc Res 2012; 83 (03) 347-351
• 138 Shahzad S, Hasan A, Faizy AF, Mateen S, Fatima N, Moin S. Elevated DNA damage, oxidative stress, and impaired response defense system inflicted in patients with myocardial infarction. Clin Appl Thromb Hemost 2018; 24 (05) 780-789
• 139 Becatti M, Marcucci R, Bruschi G. et al. Oxidative modification of fibrinogen is associated with altered function and structure in the subacute phase of myocardial infarction. Arterioscler Thromb Vasc Biol 2014; 34 (07) 1355-1361
• 140 Becatti M, Fiorillo C, Gori AM. et al. Platelet and leukocyte ROS production and lipoperoxidation are associated with high platelet reactivity in Non-ST elevation myocardial infarction (NSTEMI) patients on dual antiplatelet treatment. Atherosclerosis 2013; 231 (02) 392-400
• 141 Tengbom J, Humoud R, Kontidou E. et al. Red blood cells from patients with ST-elevation myocardial infarction and elevated C-reactive protein levels induce endothelial dysfunction. Am J Physiol Heart Circ Physiol 2024; 327 (06) H1431-H1441
• 142 Kaminski K, Bonda T, Wojtkowska I. et al. Oxidative stress and antioxidative defense parameters early after reperfusion therapy for acute myocardial infarction. Acute Card Care 2008; 10 (02) 121-126
• 143 Calvieri C, Tanzilli G, Bartimoccia S. et al. Interplay between oxidative stress and platelet activation in coronary thrombus of STEMI patients. Antioxidants 2018; 7 (07) 83
• 144 Laridan E, Martinod K, De Meyer SF. Neutrophil extracellular traps in arterial and venous thrombosis. Semin Thromb Hemost 2019; 45 (01) 86-93
• 145 Varjú I, Longstaff C, Szabó L. et al. DNA, histones and neutrophil extracellular traps exert anti-fibrinolytic effects in a plasma environment. Thromb Haemost 2015; 113 (06) 1289-1298
• 146 Apple CG, Miller ES, Kannan KB. et al. Prolonged chronic stress and persistent iron dysregulation prevent anemia recovery following trauma. J Surg Res 2021; 267: 320-327
• 147 Reeves BN, Moliterno AR. Thrombosis in myeloproliferative neoplasms: update in pathophysiology. Curr Opin Hematol 2021; 28 (05) 285-291
• 148 Haghpanah S, Karimi M. Cerebral thrombosis in patients with β-thalassemia: a systematic review. Blood Coagul Fibrinolysis 2012; 23 (03) 212-217
• 149 Hamali HA. Hypercoagulability in sickle cell disease: a thrombo-inflammatory mechanism. Hemoglobin 2023; 47 (06) 205-214
• 150 O'Neill DE, Graham MM. Anemia, cardiovascular disease, and frailty in the older adult. Can J Cardiol 2022; 38 (06) 715-717
• 151 Goel H, Hirsch JR, Deswal A, Hassan SA. Anemia in cardiovascular disease: marker of disease severity or disease-modifying therapeutic target?. Curr Atheroscler Rep 2021; 23 (10) 61
• 152 Salisbury AC, Alexander KP, Reid KJ. et al. Incidence, correlates, and outcomes of acute, hospital-acquired anemia in patients with acute myocardial infarction. Circ Cardiovasc Qual Outcomes 2010; 3 (04) 337-346
• 153 Wischmann P, Kuhn V, Suvorava T. et al. Anaemia is associated with severe RBC dysfunction and a reduced circulating NO pool: vascular and cardiac eNOS are crucial for the adaptation to anaemia. Basic Res Cardiol 2020; 115 (04) 43
• 154 Yang J, Gonon AT, Sjöquist PO, Lundberg JO, Pernow J. Arginase regulates red blood cell nitric oxide synthase and export of cardioprotective nitric oxide bioactivity. Proc Natl Acad Sci U S A 2013; 110 (37) 15049-15054
• 155 Jang T, Poplawska M, Cimpeanu E, Mo G, Dutta D, Lim SH. Vaso-occlusive crisis in sickle cell disease: a vicious cycle of secondary events. J Transl Med 2021; 19 (01) 397
• 156 Martino S, Arlet JB, Odièvre MH. et al. Deficient mitophagy pathways in sickle cell disease. Br J Haematol 2021; 193 (05) 988-993
• 157 Moriconi C, Dzieciatkowska M, Roy M. et al. Retention of functional mitochondria in mature red blood cells from patients with sickle cell disease. Br J Haematol 2022; 198 (03) 574-586
• 158 Esperti S, Nader E, Stier A. et al. Increased retention of functional mitochondria in mature sickle red blood cells is associated with increased sickling tendency, hemolysis and oxidative stress. Haematologica 2023; 108 (11) 3086-3094
• 159 Bou-Fakhredin R, Rivella S, Cappellini MD, Taher AT. Pathogenic mechanisms in thalassemia I: ineffective erythropoiesis and hypercoagulability. Hematol Oncol Clin North Am 2023; 37 (02) 341-351
• 160 Reuter S, Gupta SC, Chaturvedi MM, Aggarwal BB. Oxidative stress, inflammation, and cancer: how are they linked?. Free Radic Biol Med 2010; 49 (11) 1603-1616
• 161 Mitchell JD, Laurie M, Xia Q. et al. Risk profiles and incidence of cardiovascular events across different cancer types. ESMO Open 2023; 8 (06) 101830
• 162 Finke D, Heckmann MB, Frey N, Lehmann LH. Cancer—a major cardiac comorbidity with implications on cardiovascular metabolism. Front Physiol 2021; 12: 729713
• 163 Tefferi A, Vardiman JW. Myelodysplastic syndromes. N Engl J Med 2009; 361 (19) 1872-1885
• 164 Zhang M, Liu M, Yang L. et al. Increased ferroptosis of erythrocytes is associated with myelodysplastic syndromes. Ann Hematol 2024; 103 (10) 4009-4020
• 165 Xu Y, Li K, Zhao Y, Zhou L, Liu Y, Zhao J. Role of ferroptosis in stroke. Cell Mol Neurobiol 2023; 43 (01) 205-222
• 166 An Y, Xu M, Yan M. et al. Erythrophagocytosis-induced ferroptosis contributes to pulmonary microvascular thrombosis and thrombotic vascular remodeling in pulmonary arterial hypertension. J Thromb Haemost 2025; 23 (01) 158-170
• 167 Lee AJ, Kim SG, Nam JY, Yun J, Ryoo HM, Bae SH. Clinical features and outcomes of JAK2 V617F-positive polycythemia vera and essential thrombocythemia according to the JAK2 V617F allele burden. Blood Res 2021; 56 (04) 259-265
• 168 Vannucchi AM, Barbui T, Cervantes F. et al; ESMO Guidelines Committee. Philadelphia chromosome-negative chronic myeloproliferative neoplasms: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2015; 26 (Suppl. 05) v85-v99
• 169 Hovav T, Goldfarb A, Artmann G, Yedgar S, Barshtein G. Enhanced adherence of beta-thalassaemic erythrocytes to endothelial cells. Br J Haematol 1999; 106 (01) 178-181
• 170 Dąbrowski Z, Dybowicz AJ, Marchewka A. et al. Elongation index of erythrocytes, study of activity of chosen erythrocyte enzymes, and the levels of glutathione, malonyldialdehyde in polycythemia vera (PV). Clin Hemorheol Microcirc 2011; 47 (03) 169-176
• 171 Lacroix R, Dubois C, Leroyer AS, Sabatier F, Dignat-George F. Revisited role of microparticles in arterial and venous thrombosis. J Thromb Haemost 2013; 11 (Suppl. 01) 24-35
• 172 de Castro J, Hernández-Hernández A, Rodríguez MC, Llanillo M, Sánchez-Yagüe J. Comparison of changes in erythrocyte and platelet fatty acid composition and protein oxidation in advanced non-small cell lung cancer. Cancer Invest 2006; 24 (04) 339-345
• 173 Myers JN, Schäffer MW, Korolkova OY, Williams AD, Gangula PR, M'Koma AE. Implications of the colonic deposition of free hemoglobin-α chain: a previously unknown tissue by-product in inflammatory bowel disease. Inflamm Bowel Dis 2014; 20 (09) 1530-1547
• 174 Bragg MA, Breaux WA, M'Koma AE. Inflammatory bowel disease-associated colorectal cancer: translational and transformational risks posed by exogenous free hemoglobin alpha chain, a by-product of extravasated erythrocyte macrophage erythrophagocytosis. Medicina (Kaunas) 2023; 59 (07) 1254
• 175 Kim K, Bae ON, Koh SH. et al. High-dose vitamin C injection to cancer patients may promote thrombosis through procoagulant activation of erythrocytes. Toxicol Sci 2015; 147 (02) 350-359
• 176 Bujak K, Wasilewski J, Osadnik T. et al. The prognostic role of red blood cell distribution width in coronary artery disease: a review of the pathophysiology. Dis Markers 2015; 2015: 824624
• 177 Nam JS, Ahn CW, Kang S, Kim KR, Park JS. Red blood cell distribution width is associated with carotid atherosclerosis in people with type 2 diabetes. J Diabetes Res 2018; 2018: 1792760
• 178 Miwa S, Inouye M, Ohmura C, Mitsuhashi N, Onuma T, Kawamori R. Relationship between carotid atherosclerosis and erythrocyte membrane cholesterol oxidation products in type 2 diabetic patients. Diabetes Res Clin Pract 2003; 61 (02) 81-88
• 179 Nwose EU, Richards RS, Kerr RG, Tinley R, Jelinek H. Oxidative damage indices for the assessment of subclinical diabetic macrovascular complications. Br J Biomed Sci 2008; 65 (03) 136-141
• 180 Paquette M, Bernard S, Baass A. Hemoglobin concentration, hematocrit and red blood cell count predict major adverse cardiovascular events in patients with familial hypercholesterolemia. Atherosclerosis 2021; 335: 41-46
• 181 Escate R, Padró T, Suades R. et al. High miR-133a levels in the circulation anticipates presentation of clinical events in familial hypercholesterolaemia patients. Cardiovasc Res 2021; 117 (01) 109-122
• 182 Cubedo J, Suades R, Padro T. et al. Erythrocyte-heme proteins and STEMI: implications in prognosis. Thromb Haemost 2017; 117 (10) 1970-1980
• 183 Lai T, Liang Y, Guan F, Hu K. Trends in hemoglobin-to-red cell distribution width ratio and its prognostic value for all-cause, cancer, and cardiovascular mortality: a nationwide cohort study. Sci Rep 2025; 15 (01) 7685
• 184 Coradduzza D, Medici S, Chessa C. et al. Assessing the predictive power of the hemoglobin/red cell distribution width ratio in cancer: a systematic review and future directions. Medicina (Kaunas) 2023; 59 (12) 2124
• 185 Krongsut S, Piriyakhuntorn P. Unlocking the potential of HB/RDW ratio as a simple marker for predicting mortality in acute ischemic stroke patients after thrombolysis. J Stroke Cerebrovasc Dis 2024; 33 (09) 107874
• 186 Wang J, Chen Z, Yang H, Li H, Chen R, Yu J. Relationship between the hemoglobin-to-red cell distribution width ratio and all-cause mortality in septic patients with atrial fibrillation: based on propensity score matching method. J Cardiovasc Dev Dis 2022; 9 (11) 400