Pediatric Hematology/Oncology and ImmunopathologyPediatric Hematology/Oncology and ImmunopathologyВопросы гематологии/онкологии и иммунопатологии в педиатрии1726-17082414-9314Fund Doctors, Innovations, Science for Children65910.24287/1726-1708-2022-21-3-136-141LITERATURE REVIEWОБЗОР ЛИТЕРАТУРЫRed blood cells contribution in blood coagulationВлияние эритроцитов на свертывание кровиChabinI. A.ЧабинИ. А.
Russian Federation

Moscow

Москва

PodoplelovaN. A.ПодоплеловаН. А.
Russian Federation

Nadezhda A. Podoplelova, PhD, leading researcher of the Laboratory of Cell Hemostasis and Thrombosis

1 Samory Mashela St., Moscow 117997, Russia

Подоплелова Надежда Александровна, ведущий научный сотрудник лаборатории клеточного гемостаза и тромбоза

117997, Москва, ул. Саморы Машела, 1

podoplelovan@yandex.ruPanteleevM. A.ПантелеевМ. А.
Russian Federation

Moscow

Москва

Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of Ministry of Healthcare of the Russian FederationФГБУ «Национальный медицинский исследовательский центр детской гематологии, онкологии и иммунологии им. Дмитрия Рогачева» Минздрава РоссииSechenov First Moscow State Medical University (Sechenov University)ФГАОУ ВО Первый Московский государственный медицинский университет им. И.М. Сеченова Минздрава России (Сеченовский Университет)Center for Theoretical Problems of Physicochemical Pharmacology, Russian Academy of SciencesФГБУН Центр теоретических проблем физико-химической фармакологии РАН151020222131361411510202215102022Copyright ©; 2022, «D. Rogachev NMRCPHOI»Copyright ©; 2022, ФГБУ «НМИЦ ДГОИ им. Дмитрия Рогачева» Минздрава России2022«D. Rogachev NMRCPHOI»ФГБУ «НМИЦ ДГОИ им. Дмитрия Рогачева» Минздрава Россииhttps://creativecommons.org/licenses/by/4.0https://hemoncim.com/jour/article/view/659

For a long time, red blood cells have been known to have a procoagulant effect on hemostatic system. This effect was usually ascribed to either general increase of blood viscosity due to increased hematocrit value, RBCs' transport-enhancing effect on platelets adhesion under flow conditions. It is known that red blood cells can have a procoagulant effect on the hemostasis system. This effect is usually explained either by a general increase in blood viscosity due to an increase in hematocrit, or by the effect of red blood cells on the transport of platelets to the vessel wall and their further adhesion. However, recent studies indicate that the role of red blood cells in blood coagulation is much wider. In this review, we will consider the main mechanisms currently known, through which red blood cells can influence the processes of hemostasis and thrombosis in normal and pathological conditions.

Известно, что эритроциты могут оказывать прокоагулянтное действие на систему гемостаза. Этот эффект обычно объясняют либо общим повышением вязкости крови из-за увеличения гематокрита, либо влиянием эритроцитов на транспорт тромбоцитов к стенке сосуда и их дальнейшую адгезию. Однако исследования последних лет указывают на то, что роль эритроцитов в свертывании крови гораздо шире. В данном обзоре мы рассмотрим основные механизмы, известные на данный момент, посредством которых эритроциты могут влиять на процессы гемостаза и тромбоза в норме и патологии.

red blood cellsblood coagulationthrombosisэритроцитысвертывание кровитромбоз1. Toss F., Nordström A., Nordström P. Association between hematocrit in late adolescence and subsequent myocardial infarction in Swedish men. Int J Cardiol 2013; 168: 3588–93.Toss F., Nordström A., Nordström P. Association between hematocrit in late adolescence and subsequent myocardial infarction in Swedish men. Int J Cardiol 2013; 168: 3588–93.2. Sabatine M.S., Morrow D.A., Giugliano R.P., Burton P.B.J., Murphy S.A., McCabe C.H., et al. Association of hemoglobin levels with clinical outcomes in acute coronary syndromes. Circulation 2005; 111: 2042–9.Sabatine M.S., Morrow D.A., Giugliano R.P., Burton P.B.J., Murphy S.A., McCabe C.H., et al. Association of hemoglobin levels with clinical outcomes in acute coronary syndromes. Circulation 2005; 111: 2042–9.3. Gagnon D.R., Zhang T.J., Brand F.N., Kannel W.B. Hematocrit and the risk of cardiovascular disease – the Framingham study: a 34-year follow-up. Am Heart J 1994; 127: 674–82.Gagnon D.R., Zhang T.J., Brand F.N., Kannel W.B. Hematocrit and the risk of cardiovascular disease – the Framingham study: a 34-year follow-up. Am Heart J 1994; 127: 674–82.4. Danesh J., Collins R., Peto R., Lowe G.D.O. Haematocrit, viscosity, erythrocyte sedimentation rate: meta-analyses of prospective studies of coronary heart disease. Eur Heart J 2000; 21: 515–20.Danesh J., Collins R., Peto R., Lowe G.D.O. Haematocrit, viscosity, erythrocyte sedimentation rate: meta-analyses of prospective studies of coronary heart disease. Eur Heart J 2000; 21: 515–20.5. Verduzco L.A., Nathan D.G. Sickle cell disease and stroke. Blood 2009; 114: 5117–25.Verduzco L.A., Nathan D.G. Sickle cell disease and stroke. Blood 2009; 114: 5117–25.6. Stein P.D., Beemath A., Meyers F.A., Skaf E., Olson R.E. Deep Venous Thrombosis and Pulmonary Embolism in Hospitalized Patients with Sickle Cell Disease. Am J Med 2006; 119: 897.e7–e11.Stein P.D., Beemath A., Meyers F.A., Skaf E., Olson R.E. Deep Venous Thrombosis and Pulmonary Embolism in Hospitalized Patients with Sickle Cell Disease. Am J Med 2006; 119: 897.e7–e11.7. Novelli E.M., Huynh C., Gladwin M.T., Moore C.G., Ragni M.V. Pulmonary embolism in sickle cell disease: a case–control study. J Thromb Haemost 2012; 10: 760–6.Novelli E.M., Huynh C., Gladwin M.T., Moore C.G., Ragni M.V. Pulmonary embolism in sickle cell disease: a case–control study. J Thromb Haemost 2012; 10: 760–6.8. Folsom A.R., Tang W., Roetker N.S., Kshirsagar A.V., Derebail V.K., Lutsey P.L., et al. Prospective study of sickle cell trait and venous thromboembolism incidence. J Thromb Haemost 2015; 13: 2–9.Folsom A.R., Tang W., Roetker N.S., Kshirsagar A.V., Derebail V.K., Lutsey P.L., et al. Prospective study of sickle cell trait and venous thromboembolism incidence. J Thromb Haemost 2015; 13: 2–9.9. Schilling R.F., Gangnon R.E., Traver M.I. Delayed adverse vascular events after splenectomy in hereditary spherocytosis. J Thromb Haemost 2008; 6: 1289–95.Schilling R.F., Gangnon R.E., Traver M.I. Delayed adverse vascular events after splenectomy in hereditary spherocytosis. J Thromb Haemost 2008; 6: 1289–95.10. Hill A., Kelly R.J., Hillmen P. Thrombosis in paroxysmal nocturnal hemoglobinuria. Blood 2013; 121: 4985–96.Hill A., Kelly R.J., Hillmen P. Thrombosis in paroxysmal nocturnal hemoglobinuria. Blood 2013; 121: 4985–96.11. Wannez A., Devalet B., Chatelain B., Chatelain C., Dogné J.M., Mullier F. Extracellular Vesicles in Red Blood Cell Concentrates: An Overview. Transfus Med Rev 2019; 33: 125–30.Wannez A., Devalet B., Chatelain B., Chatelain C., Dogné J.M., Mullier F. Extracellular Vesicles in Red Blood Cell Concentrates: An Overview. Transfus Med Rev 2019; 33: 125–30.12. Turpin C., Catan A., Meilhac O., Bourdon E., Canonne-Hergaux F., Rondeau P. Erythrocytes: Central Actors in Multiple Scenes of Atherosclerosis. Int J Mol Sci 2021; 22 (11): 5843. DOI: 10.3390/ijms22115843Turpin C., Catan A., Meilhac O., Bourdon E., Canonne-Hergaux F., Rondeau P. Erythrocytes: Central Actors in Multiple Scenes of Atherosclerosis. Int J Mol Sci 2021; 22 (11): 5843. DOI: 10.3390/ijms2211584313. Dintenfass L. Inversion of the Fahraeus-Lindqvist phenomenon in blood flow through capillaries of diminishing radius. Nature 1967; 215: 1099–100.Dintenfass L. Inversion of the Fahraeus-Lindqvist phenomenon in blood flow through capillaries of diminishing radius. Nature 1967; 215: 1099–100.14. Baskurt O.K., Yalcin O., Ozdem S., Armstrong J.K., Meiselman H.J. Modulation of endothelial nitric oxide synthase expression by red blood cell aggregation. Am J Physiol Heart Circ Physiol 2004; 286 (1): H222–9. DOI: 10.1152/ajpheart.00532.2003Baskurt O.K., Yalcin O., Ozdem S., Armstrong J.K., Meiselman H.J. Modulation of endothelial nitric oxide synthase expression by red blood cell aggregation. Am J Physiol Heart Circ Physiol 2004; 286 (1): H222–9. DOI: 10.1152/ajpheart.00532.200315. Flamm M.H., Diamond S.L. Multiscale systems biology and physics of thrombosis under flow. Ann Biomed Eng 2012; 40: 2355–64.Flamm M.H., Diamond S.L. Multiscale systems biology and physics of thrombosis under flow. Ann Biomed Eng 2012; 40: 2355–64.16. Duke W.W. The Relation of Blood Platelets to Hemorrhagic Disease: Description of a Method for Determining the Bleeding Time and Coagulation Time and Report of Three Cases of Hemorrhagic Disease Relieved by Transfusion. JAMA 1983; 250: 1201–9.Duke W.W. The Relation of Blood Platelets to Hemorrhagic Disease: Description of a Method for Determining the Bleeding Time and Coagulation Time and Report of Three Cases of Hemorrhagic Disease Relieved by Transfusion. JAMA 1983; 250: 1201–9.17. Clyne N., Berglund B., Egberg N. Treatment with recombinant human erythropoietin induces a moderate rise in hematocrit and thrombin antithrombin in healthy subjects. Thromb Res 1995; 79: 125–9.Clyne N., Berglund B., Egberg N. Treatment with recombinant human erythropoietin induces a moderate rise in hematocrit and thrombin antithrombin in healthy subjects. Thromb Res 1995; 79: 125–9.18. Tokish J.M., Kocher M.S., Hawkins R.J. Ergogenic aids: a review of basic science, performance, side effects, and status in sports. Am J Sports Med 2004; 32: 1543–53.Tokish J.M., Kocher M.S., Hawkins R.J. Ergogenic aids: a review of basic science, performance, side effects, and status in sports. Am J Sports Med 2004; 32: 1543–53.19. Byrnes J.R., Wolberg A.S. Red blood cells in thrombosis. Blood 2017; 130: 1795–9.Byrnes J.R., Wolberg A.S. Red blood cells in thrombosis. Blood 2017; 130: 1795–9.20. Jensen A.S., Idorn L., Thomsen C., Von Der Recke P., Mortensen J., Sørensen K.E., et al. Prevalence of cerebral and pulmonary thrombosis in patients with cyanotic congenital heart disease. Heart 2015; 101: 1540–6.Jensen A.S., Idorn L., Thomsen C., Von Der Recke P., Mortensen J., Sørensen K.E., et al. Prevalence of cerebral and pulmonary thrombosis in patients with cyanotic congenital heart disease. Heart 2015; 101: 1540–6.21. De Stefano V., Za T., Rossi E., Vannucchi A.M., Ruggeri M., Elli E., et al. Recurrent thrombosis in patients with polycythemia vera and essential thrombocythemia: incidence, risk factors, and effect of treatments. Haematologica 2008; 93: 372–80.De Stefano V., Za T., Rossi E., Vannucchi A.M., Ruggeri M., Elli E., et al. Recurrent thrombosis in patients with polycythemia vera and essential thrombocythemia: incidence, risk factors, and effect of treatments. Haematologica 2008; 93: 372–80.22. Leone G., Sica S., Chiusolo P., Teofili L., De Stefano V. Blood cells diseases and thrombosis. Haematologica 2001; 86: 1236–44.Leone G., Sica S., Chiusolo P., Teofili L., De Stefano V. Blood cells diseases and thrombosis. Haematologica 2001; 86: 1236–44.23. Lowe G.D.O., Lee A.J., Rumley A., Price J.F., Fowkes F.G.R. Blood viscosity and risk of cardiovascular events: the Edinburgh Artery Study. Br J Haematol 1997; 96: 168–73.Lowe G.D.O., Lee A.J., Rumley A., Price J.F., Fowkes F.G.R. Blood viscosity and risk of cardiovascular events: the Edinburgh Artery Study. Br J Haematol 1997; 96: 168–73.24. Rampling M.W. The binding of fibrinogen and fibrinogen degradation products to the erythrocyte membrane and its relationship to haemorheology. Acta Biol Med Ger 1981; 40: 373–8.Rampling M.W. The binding of fibrinogen and fibrinogen degradation products to the erythrocyte membrane and its relationship to haemorheology. Acta Biol Med Ger 1981; 40: 373–8.25. Pries A.R., Neuhaus D., Gaehtgens P. Blood viscosity in tube flow: dependence on diameter and hematocrit. Am J Physiol 1992; 263 (6 Pt 2): H1770–8. DOI: 10.1152/ajpheart.1992.263.6.H1770Pries A.R., Neuhaus D., Gaehtgens P. Blood viscosity in tube flow: dependence on diameter and hematocrit. Am J Physiol 1992; 263 (6 Pt 2): H1770–8. DOI: 10.1152/ajpheart.1992.263.6.H177026. Lanotte L., Mauer J., Mendez S., Fedosov D.A., Fromental J.M., Claveria V., et al. Red cells’ dynamic morphologies govern blood shear thinning under microcirculatory flow conditions. Proc Natl Acad Sci U S A 2016; 113: 13289–94.Lanotte L., Mauer J., Mendez S., Fedosov D.A., Fromental J.M., Claveria V., et al. Red cells’ dynamic morphologies govern blood shear thinning under microcirculatory flow conditions. Proc Natl Acad Sci U S A 2016; 113: 13289–94.27. Weisel J.W., Litvinov R.I. Red blood cells: the forgotten player in hemostasis and thrombosis. J Thromb Haemost 2019; 17: 271–82.Weisel J.W., Litvinov R.I. Red blood cells: the forgotten player in hemostasis and thrombosis. J Thromb Haemost 2019; 17: 271–82.28. Piety N.Z., Reinhart W.H., Pourreau P.H., Abidi R., Shevkoplyas S.S. Shape matters: the effect of red blood cell shape on perfusion of an artificial microvascular network. Transfusion 2016; 56: 844–51.Piety N.Z., Reinhart W.H., Pourreau P.H., Abidi R., Shevkoplyas S.S. Shape matters: the effect of red blood cell shape on perfusion of an artificial microvascular network. Transfusion 2016; 56: 844–51.29. Alamin A.A. The Role of Red Blood Cells in Hemostasis. Semin Thromb Hemost 2021; 47: 26–31.Alamin A.A. The Role of Red Blood Cells in Hemostasis. Semin Thromb Hemost 2021; 47: 26–31.30. Owen J.S., Bruckdorfer K.R., Day R.C., McIntyre N. Decreased erythrocyte membrane fluidity and altered lipid composition in human liver disease. J Lipid Res 1982; 23: 124–32.Owen J.S., Bruckdorfer K.R., Day R.C., McIntyre N. Decreased erythrocyte membrane fluidity and altered lipid composition in human liver disease. J Lipid Res 1982; 23: 124–32.31. Crawford N. Structural and Molecular Properties of Platelet Membrane Systems. Platelet Membr Glycoproteins 1985: 13–49.Crawford N. Structural and Molecular Properties of Platelet Membrane Systems. Platelet Membr Glycoproteins 1985: 13–49.32. Whelihan M.F., Mann K.G. The role of the red cell membrane in thrombin generation. Thromb Res 2013; 131: 377–82.Whelihan M.F., Mann K.G. The role of the red cell membrane in thrombin generation. Thromb Res 2013; 131: 377–82.33. Shi J., Shi Y., Waehrens L.N., Rasmussen J.T., Heegaard C.W., Gilbert G.E. Lactadherin detects early phosphatidylserine exposure on immortalized leukemia cells undergoing programmed cell death. Cytometry A 2006; 69: 1193–201. DOI: 10.1002/cyto.a.20345Shi J., Shi Y., Waehrens L.N., Rasmussen J.T., Heegaard C.W., Gilbert G.E. Lactadherin detects early phosphatidylserine exposure on immortalized leukemia cells undergoing programmed cell death. Cytometry A 2006; 69: 1193–201. DOI: 10.1002/cyto.a.2034534. Freikman I., Fibach E. Distribution and shedding of the membrane phosphatidylserine during maturation and aging of erythroid cells. Biochim Biophys Acta 2011; 1808: 2773–80.Freikman I., Fibach E. Distribution and shedding of the membrane phosphatidylserine during maturation and aging of erythroid cells. Biochim Biophys Acta 2011; 1808: 2773–80.35. Whelihan M.F., Zachary V., Orfeo T., Mann K.G. Prothrombin activation in blood coagulation: the erythrocyte contribution to thrombin generation. Blood 2012; 120: 3837–45.Whelihan M.F., Zachary V., Orfeo T., Mann K.G. Prothrombin activation in blood coagulation: the erythrocyte contribution to thrombin generation. Blood 2012; 120: 3837–45.36. Iwata H., Kaibara M., Dohmae N., Takio K., Himeno R., Kawakami S. Purification, identification, and characterization of elastase on erythrocyte membrane as factor IX-activating enzyme. Biochem Biophys Res Commun 2004; 316: 65–70.Iwata H., Kaibara M., Dohmae N., Takio K., Himeno R., Kawakami S. Purification, identification, and characterization of elastase on erythrocyte membrane as factor IX-activating enzyme. Biochem Biophys Res Commun 2004; 316: 65–70.37. Ward S.E., O’Sullivan J.M., O’Donnell J.S. The relationship between ABO blood group, von Willebrand factor, and primary hemostasis. Blood 2020; 136: 2864.Ward S.E., O’Sullivan J.M., O’Donnell J.S. The relationship between ABO blood group, von Willebrand factor, and primary hemostasis. Blood 2020; 136: 2864.38. Stojanovski B.M., Pelc L.A., Zuo X., Pozzi N., Di Cera E. Enhancing the anticoagulant profile of meizothrombin. Biomol Concepts 2018; 9: 169–75.Stojanovski B.M., Pelc L.A., Zuo X., Pozzi N., Di Cera E. Enhancing the anticoagulant profile of meizothrombin. Biomol Concepts 2018; 9: 169–75.39. Morel O., Jesel L., Freyssinet J.-M., Toti F. Cellular mechanisms underlying the formation of circulating microparticles. Arterioscler Thromb Vasc Biol 2011; 31: 15–26.Morel O., Jesel L., Freyssinet J.-M., Toti F. Cellular mechanisms underlying the formation of circulating microparticles. Arterioscler Thromb Vasc Biol 2011; 31: 15–26.40. Leal J.K.F., Adjobo-Hermans M.J.W., Bosman G.J.C.G.M. Red blood cell homeostasis: Mechanisms and effects of microvesicle generation in health and disease. Front Physiol 2018; 9: 703. DOI: 10.3389/fphys.2018.00703Leal J.K.F., Adjobo-Hermans M.J.W., Bosman G.J.C.G.M. Red blood cell homeostasis: Mechanisms and effects of microvesicle generation in health and disease. Front Physiol 2018; 9: 703. DOI: 10.3389/fphys.2018.0070341. Van der Meijden P.E.J, van Schilfgaarde M., van Oerle R., Renné T., ten Cate H., Spronk H.M.H. Plateletand erythrocyte-derived microparticles trigger thrombin generation via factor XIIa. J Thromb Haemost 2012; 10: 1355–62. DOI: 10.1111/j.1538-7836.2012.04758.xVan der Meijden P.E.J, van Schilfgaarde M., van Oerle R., Renné T., ten Cate H., Spronk H.M.H. Plateletand erythrocyte-derived microparticles trigger thrombin generation via factor XIIa. J Thromb Haemost 2012; 10: 1355–62. DOI: 10.1111/j.1538-7836.2012.04758.x42. Allan D., Limbrick A.R., Thomas P., Westerman M.P. Release of spectrin-free spicules on reoxygenation of sickled erythrocytes. Nature 1982; 295: 612–3.Allan D., Limbrick A.R., Thomas P., Westerman M.P. Release of spectrin-free spicules on reoxygenation of sickled erythrocytes. Nature 1982; 295: 612–3.43. Forest A., Pautas E., Ray P., Bonnet D., Verny M., Amabile N., et al. Circulating microparticles and procoagulant activity in elderly patients. J Gerontol A Biol Sci Med Sci 2010; 65: 414–20. DOI: 10.1093/gerona/glp187Forest A., Pautas E., Ray P., Bonnet D., Verny M., Amabile N., et al. Circulating microparticles and procoagulant activity in elderly patients. J Gerontol A Biol Sci Med Sci 2010; 65: 414–20. DOI: 10.1093/gerona/glp18744. Zecher D., Cumpelik A., Schifferli J.A. Erythrocyte-derived microvesicles amplify systemic inflammation by thrombin-dependent activation of complement. Arterioscler Thromb Vasc Biol 2014; 34: 313–20.Zecher D., Cumpelik A., Schifferli J.A. Erythrocyte-derived microvesicles amplify systemic inflammation by thrombin-dependent activation of complement. Arterioscler Thromb Vasc Biol 2014; 34: 313–20.45. Kim Y., Goodman M.D., Jung A.D., Abplanalp W.A., Schuster R.M., Caldwell C.C., et al. Microparticles from aged packed red blood cell units stimulate pulmonary microthrombus formation via P-selectin. Thromb Res 2020; 185: 160–6.Kim Y., Goodman M.D., Jung A.D., Abplanalp W.A., Schuster R.M., Caldwell C.C., et al. Microparticles from aged packed red blood cell units stimulate pulmonary microthrombus formation via P-selectin. Thromb Res 2020; 185: 160–6.46. Klatt C., Krüger I., Zey S., Krott K.J., Spelleken M., Gowert N.S., et al. Platelet-RBC interaction mediated by FasL/FasR induces procoagulant activity important for thrombosis. J Clin Invest 2018; 128: 3906–25.Klatt C., Krüger I., Zey S., Krott K.J., Spelleken M., Gowert N.S., et al. Platelet-RBC interaction mediated by FasL/FasR induces procoagulant activity important for thrombosis. J Clin Invest 2018; 128: 3906–25.47. Vallés J., Teresa Santos M., Aznar J., Martínez M., Moscardó A., Piñón M., et al. Platelet-erythrocyte interactions enhance aIIbb3 integrin receptor activation and P-selectin expression during platelet recruitment: Down-regulation by aspirin ex vivo. Blood 2002; 99: 3978–84.Vallés J., Teresa Santos M., Aznar J., Martínez M., Moscardó A., Piñón M., et al. Platelet-erythrocyte interactions enhance aIIbb3 integrin receptor activation and P-selectin expression during platelet recruitment: Down-regulation by aspirin ex vivo. Blood 2002; 99: 3978–84.48. Hermand P., Gane P., Huet M., Jallu V., Kaplan C., Sonneborn H.H., et al. Red cell ICAM-4 is a novel ligand for platelet-activated aIIbb3 integrin. J Biol Chem 2003; 278: 4892–8.Hermand P., Gane P., Huet M., Jallu V., Kaplan C., Sonneborn H.H., et al. Red cell ICAM-4 is a novel ligand for platelet-activated aIIbb3 integrin. J Biol Chem 2003; 278: 4892–8.49. Reimers R., Sutera S., Joist J. Potentiation by Red Blood Cells of Shear-Induced Platelet Aggregation: Relative Importance of Chemical and Physical Mechanisms. Blood 1984; 64: 1200–6.Reimers R., Sutera S., Joist J. Potentiation by Red Blood Cells of Shear-Induced Platelet Aggregation: Relative Importance of Chemical and Physical Mechanisms. Blood 1984; 64: 1200–6.50. Villagra J., Shiva S., Hunter L.A., Machado R.F., Gladwin M.T., Kato G.J. Platelet activation in patients with sickle disease, hemolysis-associated pulmonary hypertension, and nitric oxide scavenging by cell-free hemoglobin. Blood 2007; 110: 2166–72.Villagra J., Shiva S., Hunter L.A., Machado R.F., Gladwin M.T., Kato G.J. Platelet activation in patients with sickle disease, hemolysis-associated pulmonary hypertension, and nitric oxide scavenging by cell-free hemoglobin. Blood 2007; 110: 2166–72.51. Nakai K., Ohta T., Sakuma I., Akama K., Kobayashi Y., Tokuyama S., et al. Inhibition of endothelium-dependent relaxation by hemoglobin in rabbit aortic strips: comparison between acellular hemoglobin derivatives and cellular hemoglobins. J Cardiovasc Pharmacol 1996; 28: 115–23.Nakai K., Ohta T., Sakuma I., Akama K., Kobayashi Y., Tokuyama S., et al. Inhibition of endothelium-dependent relaxation by hemoglobin in rabbit aortic strips: comparison between acellular hemoglobin derivatives and cellular hemoglobins. J Cardiovasc Pharmacol 1996; 28: 115–23.52. Schnog J.J.B., Jager E.H., van der Dijs F.P.L., Duits A.J., Moshage H., Muskiet F.D., et al. Evidence for a metabolic shift of arginine metabolism in sickle cell disease. Ann Hematol 2004; 83: 371–5.Schnog J.J.B., Jager E.H., van der Dijs F.P.L., Duits A.J., Moshage H., Muskiet F.D., et al. Evidence for a metabolic shift of arginine metabolism in sickle cell disease. Ann Hematol 2004; 83: 371–5.53. Rother R.P., Bell L., Hillmen P., Gladwin M.T. The clinical sequelae of intravascular hemolysis and extracellular plasma hemoglobin: a novel mechanism of human disease. JAMA 2005; 293: 1653–62.Rother R.P., Bell L., Hillmen P., Gladwin M.T. The clinical sequelae of intravascular hemolysis and extracellular plasma hemoglobin: a novel mechanism of human disease. JAMA 2005; 293: 1653–62.54. Wautier J.L., Wautier M.P. Molecular basis of erythrocyte adhesion to endothelial cells in diseases. Clin Hemorheol Microcirc 2013; 53: 11–21.Wautier J.L., Wautier M.P. Molecular basis of erythrocyte adhesion to endothelial cells in diseases. Clin Hemorheol Microcirc 2013; 53: 11–21.55. Wautier M.P., Héron E., Picot J., Colin Y., Hermine O., Wautier J.L. Red blood cell phosphatidylserine exposure is responsible for increased erythrocyte adhesion to endothelium in central retinal vein occlusion. J Thromb Haemost 2011; 9: 1049–55.Wautier M.P., Héron E., Picot J., Colin Y., Hermine O., Wautier J.L. Red blood cell phosphatidylserine exposure is responsible for increased erythrocyte adhesion to endothelium in central retinal vein occlusion. J Thromb Haemost 2011; 9: 1049–55.56. Watkins N.A., Du L.M., Scott J.P., Ouwehand W.H., Hillery C.A. Single-chain antibody fragments derived from a human synthetic phage-display library bind thrombospondin and inhibit sickle cell adhesion. Blood 2003; 102: 718–24.Watkins N.A., Du L.M., Scott J.P., Ouwehand W.H., Hillery C.A. Single-chain antibody fragments derived from a human synthetic phage-display library bind thrombospondin and inhibit sickle cell adhesion. Blood 2003; 102: 718–24.57. Hillery C.A., Du M.C., Montgomery R.R., Scott J.P. Increased adhesion of erythrocytes to components of the extracellular matrix: Isolation and characterization of a red blood cell lipid that binds thrombospondin and laminin. Blood 1996; 87: 4879–86.Hillery C.A., Du M.C., Montgomery R.R., Scott J.P. Increased adhesion of erythrocytes to components of the extracellular matrix: Isolation and characterization of a red blood cell lipid that binds thrombospondin and laminin. Blood 1996; 87: 4879–86.58. Sergueeva A., Miasnikova G., Shah B.N., Song J., Lisina E., Okhotin D.J., et al. Prospective study of thrombosis and thrombospondin-1 expression in Chuvash polycythemia. Haematologica 2017; 102: e166–9.Sergueeva A., Miasnikova G., Shah B.N., Song J., Lisina E., Okhotin D.J., et al. Prospective study of thrombosis and thrombospondin-1 expression in Chuvash polycythemia. Haematologica 2017; 102: e166–9.59. Silvain J., Collet J.P., Nagaswami C., Beygui F., Edmondson K.E., Bellemain-Appaix A., et al. Composition of coronary thrombus in acute myocardial infarction. J Am Coll Cardiol 2011; 57: 1359–67.Silvain J., Collet J.P., Nagaswami C., Beygui F., Edmondson K.E., Bellemain-Appaix A., et al. Composition of coronary thrombus in acute myocardial infarction. J Am Coll Cardiol 2011; 57: 1359–67.60. Gersh K.C., Nagaswami C., Weisel J.W. Fibrin network structure and clot mechanical properties are altered by incorporation of erythrocytes. Thromb Haemost 2009; 102: 1169–75.Gersh K.C., Nagaswami C., Weisel J.W. Fibrin network structure and clot mechanical properties are altered by incorporation of erythrocytes. Thromb Haemost 2009; 102: 1169–75.61. Kattula S., Byrnes J.R., Martin S.M., Holle L.A., Cooley B.C., Flick M.J., et al. Factor XIII in plasma, but not in platelets, mediates red blood cell retention in clots and venous thrombus size in mice. Blood Adv 2018; 2: 25–35.Kattula S., Byrnes J.R., Martin S.M., Holle L.A., Cooley B.C., Flick M.J., et al. Factor XIII in plasma, but not in platelets, mediates red blood cell retention in clots and venous thrombus size in mice. Blood Adv 2018; 2: 25–35.62. Cines D.B., Lebedeva T., Nagaswami C., Hayes V., Massefski W., Litvinov R.I., et al. Clot contraction: compression of erythrocytes into tightly packed polyhedra and redistribution of platelets and fibrin. Blood 2014; 123: 1596–603.Cines D.B., Lebedeva T., Nagaswami C., Hayes V., Massefski W., Litvinov R.I., et al. Clot contraction: compression of erythrocytes into tightly packed polyhedra and redistribution of platelets and fibrin. Blood 2014; 123: 1596–603.63. Tutwiler V., Litvinov R.I., Lozhkin A.P., Peshkova A.D., Lebedeva T., Ataullakhanov F.I., et al. Kinetics and mechanics of clot contraction are governed by the molecular and cellular composition of the blood. Blood 2016; 127: 149–59.Tutwiler V., Litvinov R.I., Lozhkin A.P., Peshkova A.D., Lebedeva T., Ataullakhanov F.I., et al. Kinetics and mechanics of clot contraction are governed by the molecular and cellular composition of the blood. Blood 2016; 127: 149–59.64. Tutwiler V., Litvinov R.I., Protopopova A., Nagaswami C., Villa C., Woods E., et al. Pathologically stiff erythrocytes impede contraction of blood clots. J Thromb Haemost 2021; 19: 1990–2001.Tutwiler V., Litvinov R.I., Protopopova A., Nagaswami C., Villa C., Woods E., et al. Pathologically stiff erythrocytes impede contraction of blood clots. J Thromb Haemost 2021; 19: 1990–2001.65. Peshkova A., Malyasyov D., Bredikhin R., Le Minh G., Andrianova I., Tutwiler V., et al. Reduced Contraction of Blood Clots in Venous Thromboembolism Is a Potential Thrombogenic and Embologenic Mechanism. TH Open 2018; 2 (1): e104–15. DOI: 10.1055/s-0038-1635572Peshkova A., Malyasyov D., Bredikhin R., Le Minh G., Andrianova I., Tutwiler V., et al. Reduced Contraction of Blood Clots in Venous Thromboembolism Is a Potential Thrombogenic and Embologenic Mechanism. TH Open 2018; 2 (1): e104–15. DOI: 10.1055/s-0038-1635572