PDF herunterladen
CC BY-NC-ND 4.0 · Thromb Haemost
DOI: 10.1055/s-0043-1775965
Stroke, Systemic or Venous Thromboembolism

Differential Effects of Erythropoietin Administration and Overexpression on Venous Thrombosis in Mice

Sven Stockhausen 
1   Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Ludwig-Maximilians-Universität, Munich, Germany
2   German Center for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany
3   Walter-Brendel Center of Experimental Medicine, Ludwig-Maximilians-Universität, Munich, Germany
,
Badr Kilani
1   Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Ludwig-Maximilians-Universität, Munich, Germany
2   German Center for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany
3   Walter-Brendel Center of Experimental Medicine, Ludwig-Maximilians-Universität, Munich, Germany
,
Irene Schubert
1   Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Ludwig-Maximilians-Universität, Munich, Germany
2   German Center for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany
3   Walter-Brendel Center of Experimental Medicine, Ludwig-Maximilians-Universität, Munich, Germany
,
Anna-Lena Steinsiek
4   Department of cardiology, German Heart Center, Munich, Germany.
,
Sue Chandraratne
1   Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Ludwig-Maximilians-Universität, Munich, Germany
2   German Center for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany
3   Walter-Brendel Center of Experimental Medicine, Ludwig-Maximilians-Universität, Munich, Germany
,
Franziska Wendler
1   Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Ludwig-Maximilians-Universität, Munich, Germany
2   German Center for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany
3   Walter-Brendel Center of Experimental Medicine, Ludwig-Maximilians-Universität, Munich, Germany
,
Luke Eivers
1   Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Ludwig-Maximilians-Universität, Munich, Germany
2   German Center for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany
3   Walter-Brendel Center of Experimental Medicine, Ludwig-Maximilians-Universität, Munich, Germany
,
Marie-Luise von Brühl
1   Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Ludwig-Maximilians-Universität, Munich, Germany
2   German Center for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany
3   Walter-Brendel Center of Experimental Medicine, Ludwig-Maximilians-Universität, Munich, Germany
,
Steffen Massberg
1   Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Ludwig-Maximilians-Universität, Munich, Germany
2   German Center for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany
3   Walter-Brendel Center of Experimental Medicine, Ludwig-Maximilians-Universität, Munich, Germany
,
Ilka Ott
4   Department of cardiology, German Heart Center, Munich, Germany.
,
Konstantin Stark
1   Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Ludwig-Maximilians-Universität, Munich, Germany
2   German Center for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany
3   Walter-Brendel Center of Experimental Medicine, Ludwig-Maximilians-Universität, Munich, Germany
› Institutsangaben Funding This project is supported by the ERC starting grant T-MEMORE project 947611 (K.S.). This study was supported by the Deutsche Forschungsgemeinschaft through the collaborative research center 1123 project A07 (K.S., S.M.) and the collaborative research center 914 project B02 (K.S., S.M.). We thank for the support by the grant from the Deutsche Gesellschaft für Kardiologie project DGK09/2020 and the Förderprogramm für Forschung und Lehre (FöFoLe) project 1123 (S.S).
› Weitere Informationen
   Lizenzen und Reprints


Abstract

Background Deep vein thrombosis (DVT) is a common condition associated with significant mortality due to pulmonary embolism. Despite advanced prevention and anticoagulation therapy, the incidence of venous thromboembolism remains unchanged. Individuals with elevated hematocrit and/or excessively high erythropoietin (EPO) serum levels are particularly susceptible to DVT formation. We investigated the influence of short-term EPO administration compared to chronic EPO overproduction on DVT development. Additionally, we examined the role of the spleen in this context and assessed its impact on thrombus composition.

Methods We induced ligation of the caudal vena cava (VCC) in EPO-overproducing Tg(EPO) mice as well as wildtype mice treated with EPO for two weeks, both with and without splenectomy. The effect on platelet circulation time was evaluated through FACS analysis, and thrombus composition was analyzed using immunohistology.

Results We present evidence for an elevated thrombogenic phenotype resulting from chronic EPO overproduction, achieved by combining an EPO-overexpressing mouse model with experimental DVT induction. This increased thrombotic state is largely independent of traditional contributors to DVT, such as neutrophils and platelets. Notably, the pronounced prothrombotic effect of red blood cells (RBCs) only manifests during chronic EPO overproduction and is not influenced by splenic RBC clearance, as demonstrated by splenectomy. In contrast, short-term EPO treatment does not induce thrombogenesis in mice. Consequently, our findings support the existence of a differential thrombogenic effect between chronic enhanced erythropoiesis and exogenous EPO administration.

Conclusion Chronic EPO overproduction significantly increases the risk of DVT, while short-term EPO treatment does not. These findings underscore the importance of considering EPO-related factors in DVT risk assessment and potential therapeutic strategies.

Keywords

deep vein thrombosis - red blood cells - spleen - erythropoietin - sterile inflammation - fibrin

Authors' Contribution

K.S., S.M., and S.S. conceived and designed the experiments. S.S., I.S., A.-L.S., and S.C. planned and performed histological and immunohistochemical analysis. B.K., I.S., A.-L.S., F.W., and M.v.B. did surgery for IVC flow reduction in mice. F.W. injected EPO into C57Bl/6J mice. I.S. performed splenectomy on mice. I.S. determined platelet circulation time. B.K. performed platelet clearance essay in liver and spleen FACS experiments. I.O. provided Tg(EPO) mice. S.S. and K.S. wrote the manuscript. All the authors reviewed and edited the manuscript.


Supplementary Material



Publikationsverlauf

Eingereicht: 17. September 2022

Angenommen: 06. August 2023

Artikel online veröffentlicht:
16. Oktober 2023

© 2023. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Ramsey G, Lindholm PF. Thrombosis risk in cancer patients receiving red blood cell transfusions. Semin Thromb Hemost 2019; 45 (06) 648-656
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 2 Kumar MA, Boland TA, Baiou M. et al. Red blood cell transfusion increases the risk of thrombotic events in patients with subarachnoid hemorrhage. Neurocrit Care 2014; 20 (01) 84-90
    CrossrefPubMedGoogle Scholar
  • 3 Goel R, Patel EU, Cushing MM. et al. Association of perioperative red blood cell transfusions with venous thromboembolism in a North American Registry. JAMA Surg 2018; 153 (09) 826-833
    CrossrefPubMedGoogle Scholar
  • 4 Wang C, Le Ray I, Lee B, Wikman A, Reilly M. Association of blood group and red blood cell transfusion with the incidence of antepartum, peripartum and postpartum venous thromboembolism. Sci Rep 2019; 9 (01) 13535
    CrossrefPubMedGoogle Scholar
  • 5 Donahue BS. Red cell transfusion and thrombotic risk in children. Pediatrics 2020; 145 (04) e20193955
    CrossrefPubMedGoogle Scholar
  • 6 Dicato M. Venous thromboembolic events and erythropoiesis-stimulating agents: an update. Oncologist 2008; 13 (Suppl. 03) 11-15
    CrossrefPubMedGoogle Scholar
  • 7 Bennett CL, Silver SM, Djulbegovic B. et al. Venous thromboembolism and mortality associated with recombinant erythropoietin and darbepoetin administration for the treatment of cancer-associated anemia. JAMA 2008; 299 (08) 914-924
    CrossrefPubMedGoogle Scholar
  • 8 Chievitz E, Thiede T. Complications and causes of death in polycythaemia vera. Acta Med Scand 1962; 172: 513-523
    CrossrefPubMedGoogle Scholar
  • 9 Gordeuk VR, Prchal JT. Vascular complications in Chuvash polycythemia. Semin Thromb Hemost 2006; 32 (03) 289-294
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 10 Ballestri S, Romagnoli E, Arioli D. et al. Risk and management of bleeding complications with direct oral anticoagulants in patients with atrial fibrillation and venous thromboembolism: a narrative review. Adv Ther 2023; 40 (01) 41-66
    CrossrefPubMedGoogle Scholar
  • 11 von Brühl ML, Stark K, Steinhart A. et al. Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo. J Exp Med 2012; 209 (04) 819-835
    CrossrefPubMedGoogle Scholar
  • 12 Lowe GD, Lee AJ, Rumley A, Price JF, Fowkes FG. Blood viscosity and risk of cardiovascular events: the Edinburgh Artery Study. Br J Haematol 1997; 96 (01) 168-173
    CrossrefPubMedGoogle Scholar
  • 13 Vogel J, Kiessling I, Heinicke K. et al. Transgenic mice overexpressing erythropoietin adapt to excessive erythrocytosis by regulating blood viscosity. Blood 2003; 102 (06) 2278-2284
    CrossrefPubMedGoogle Scholar
  • 14 Ruschitzka FT, Wenger RH, Stallmach T. et al. Nitric oxide prevents cardiovascular disease and determines survival in polyglobulic mice overexpressing erythropoietin. Proc Natl Acad Sci U S A 2000; 97 (21) 11609-11613
    CrossrefPubMedGoogle Scholar
  • 15 Bogdanova A, Mihov D, Lutz H, Saam B, Gassmann M, Vogel J. Enhanced erythro-phagocytosis in polycythemic mice overexpressing erythropoietin. Blood 2007; 110 (02) 762-769
    CrossrefPubMedGoogle Scholar
  • 16 Mebius RE, Kraal G. Structure and function of the spleen. Nat Rev Immunol 2005; 5 (08) 606-616
    CrossrefPubMedGoogle Scholar
  • 17 Boxer MA, Braun J, Ellman L. Thromboembolic risk of postsplenectomy thrombocytosis. Arch Surg 1978; 113 (07) 808-809
    CrossrefPubMedGoogle Scholar
  • 18 Khan PN, Nair RJ, Olivares J, Tingle LE, Li Z. Postsplenectomy reactive thrombocytosis. Proc Bayl Univ Med Cent 2009; 22 (01) 9-12
    CrossrefPubMedGoogle Scholar
  • 19 Thomsen RW, Schoonen WM, Farkas DK, Riis A, Fryzek JP, Sørensen HT. Risk of venous thromboembolism in splenectomized patients compared with the general population and appendectomized patients: a 10-year nationwide cohort study. J Thromb Haemost 2010; 8 (06) 1413-1416
    CrossrefPubMedGoogle Scholar
  • 20 Kato GJ. Vascular complications after splenectomy for hematologic disorders. Blood 2009; 114 (26) 5404
    CrossrefPubMedGoogle Scholar
  • 21 Sewify EM, Sayed D, Abdel Aal RF, Ahmad HM, Abdou MA. Increased circulating red cell microparticles (RMP) and platelet microparticles (PMP) in immune thrombocytopenic purpura. Thromb Res 2013; 131 (02) e59-e63
    CrossrefPubMedGoogle Scholar
  • 22 Frey MK, Alias S, Winter MP. et al. Splenectomy is modifying the vascular remodeling of thrombosis. J Am Heart Assoc 2014; 3 (01) e000772
    CrossrefPubMedGoogle Scholar
  • 23 Bratosin D, Mazurier J, Tissier JP. et al. Cellular and molecular mechanisms of senescent erythrocyte phagocytosis by macrophages. A review. Biochimie 1998; 80 (02) 173-195
    CrossrefPubMedGoogle Scholar
  • 24 Taher AT, Musallam KM, Karimi M. et al. Splenectomy and thrombosis: the case of thalassemia intermedia. J Thromb Haemost 2010; 8 (10) 2152-2158
    CrossrefPubMedGoogle Scholar
  • 25 Seki M, Arashiki N, Takakuwa Y, Nitta K, Nakamura F. Reduction in flippase activity contributes to surface presentation of phosphatidylserine in human senescent erythrocytes. J Cell Mol Med 2020; 24 (23) 13991-14000
    CrossrefPubMedGoogle Scholar
  • 26 Whelihan MF, Mann KG. The role of the red cell membrane in thrombin generation. Thromb Res 2013; 131 (05) 377-382
    CrossrefPubMedGoogle Scholar
  • 27 Frietsch T, Maurer MH, Vogel J, Gassmann M, Kuschinsky W, Waschke KF. Reduced cerebral blood flow but elevated cerebral glucose metabolic rate in erythropoietin overexpressing transgenic mice with excessive erythrocytosis. J Cereb Blood Flow Metab 2007; 27 (03) 469-476
    CrossrefPubMedGoogle Scholar
  • 28 Mitchell O, Feldman DM, Diakow M, Sigal SH. The pathophysiology of thrombocytopenia in chronic liver disease. Hepat Med 2016; 8: 39-50
    CrossrefPubMedGoogle Scholar
  • 29 Lv Y, Lau WY, Li Y. et al. Hypersplenism: history and current status. Exp Ther Med 2016; 12 (04) 2377-2382
    CrossrefPubMedGoogle Scholar
  • 30 Wagner KF, Katschinski DM, Hasegawa J. et al. Chronic inborn erythrocytosis leads to cardiac dysfunction and premature death in mice overexpressing erythropoietin. Blood 2001; 97 (02) 536-542
    CrossrefPubMedGoogle Scholar
  • 31 Klatt C, Krüger I, Zey S. et al. Platelet-RBC interaction mediated by FasL/FasR induces procoagulant activity important for thrombosis. J Clin Invest 2018; 128 (09) 3906-3925
    CrossrefPubMedGoogle Scholar
  • 32 Shibata J, Hasegawa J, Siemens HJ. et al. Hemostasis and coagulation at a hematocrit level of 0.85: functional consequences of erythrocytosis. Blood 2003; 101 (11) 4416-4422
    CrossrefPubMedGoogle Scholar
  • 33 Babu E, Basu D. Platelet large cell ratio in the differential diagnosis of abnormal platelet counts. Indian J Pathol Microbiol 2004; 47 (02) 202-205
    PubMedGoogle Scholar
  • 34 Formenti F, Beer PA, Croft QP. et al. Cardiopulmonary function in two human disorders of the hypoxia-inducible factor (HIF) pathway: von Hippel-Lindau disease and HIF-2alpha gain-of-function mutation. FASEB J 2011; 25 (06) 2001-2011
    CrossrefPubMedGoogle Scholar
  • 35 Ashraf HM, Javed A, Ashraf S. Pulmonary embolism at high altitude and hyperhomocysteinemia. J Coll Physicians Surg Pak 2006; 16 (01) 71-73
    PubMedGoogle Scholar
  • 36 Smallman DP, McBratney CM, Olsen CH, Slogic KM, Henderson CJ. Quantification of the 5-year incidence of thromboembolic events in U.S. Air Force Academy cadets in comparison to the U.S. Naval and Military Academies. Mil Med 2011; 176 (02) 209-213
    CrossrefPubMedGoogle Scholar
  • 37 Li M, Tang X, Liao Z. et al. Hypoxia and low temperature upregulate transferrin to induce hypercoagulability at high altitude. Blood 2022; 140 (19) 2063-2075
    CrossrefPubMedGoogle Scholar
  • 38 McDonald TP, Clift RE, Cottrell MB. Large, chronic doses of erythropoietin cause thrombocytopenia in mice. Blood 1992; 80 (02) 352-358
    CrossrefPubMedGoogle Scholar
  • 39 Jaïs X, Ioos V, Jardim C. et al. Splenectomy and chronic thromboembolic pulmonary hypertension. Thorax 2005; 60 (12) 1031-1034
    CrossrefPubMedGoogle Scholar
  • 40 Watters JM, Sambasivan CN, Zink K. et al. Splenectomy leads to a persistent hypercoagulable state after trauma. Am J Surg 2010; 199 (05) 646-651
    CrossrefPubMedGoogle Scholar
  • 41 Visudhiphan S, Ketsa-Ard K, Piankijagum A, Tumliang S. Blood coagulation and platelet profiles in persistent post-splenectomy thrombocytosis. The relationship to thromboembolism. Biomed Pharmacother 1985; 39 (06) 264-271
    PubMedGoogle Scholar
  • 42 McDonald TP, Cottrell MB, Clift RE, Cullen WC, Lin FK. High doses of recombinant erythropoietin stimulate platelet production in mice. Exp Hematol 1987; 15 (06) 719-721
    PubMedGoogle Scholar
  • 43 Shikama Y, Ishibashi T, Kimura H, Kawaguchi M, Uchida T, Maruyama Y. Transient effect of erythropoietin on thrombocytopoiesis in vivo in mice. Exp Hematol 1992; 20 (02) 216-222
    PubMedGoogle Scholar
  • 44 Jackson CW, Edwards CC. Biphasic thrombopoietic response to severe hypobaric hypoxia. Br J Haematol 1977; 35 (02) 233-244
    CrossrefPubMedGoogle Scholar
  • 45 McDonald TP. Platelet production in hypoxic and RBC-transfused mice. Scand J Haematol 1978; 20 (03) 213-220
    CrossrefPubMedGoogle Scholar
  • 46 Rolović Z, Basara N, Biljanović-Paunović L, Stojanović N, Suvajdzić N, Pavlović-Kentera V. Megakaryocytopoiesis in experimentally induced chronic normobaric hypoxia. Exp Hematol 1990; 18 (03) 190-194
    PubMedGoogle Scholar
  • 47 Wolf RF, Peng J, Friese P, Gilmore LS, Burstein SA, Dale GL. Erythropoietin administration increases production and reactivity of platelets in dogs. Thromb Haemost 1997; 78 (06) 1505-1509
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 48 Fraser JK, Tan AS, Lin FK, Berridge MV. Expression of specific high-affinity binding sites for erythropoietin on rat and mouse megakaryocytes. Exp Hematol 1989; 17 (01) 10-16
    PubMedGoogle Scholar
  • 49 Sasaki H, Hirabayashi Y, Ishibashi T. et al. Effects of erythropoietin, IL-3, IL-6 and LIF on a murine megakaryoblastic cell line: growth enhancement and expression of receptor mRNAs. Leuk Res 1995; 19 (02) 95-102
    CrossrefPubMedGoogle Scholar
  • 50 McBane II RD, Gonzalez C, Hodge DO, Wysokinski WE. Propensity for young reticulated platelet recruitment into arterial thrombi. J Thromb Thrombolysis 2014; 37 (02) 148-154
    CrossrefPubMedGoogle Scholar
  • 51 Buttarello M, Mezzapelle G, Freguglia F, Plebani M. Reticulated platelets and immature platelet fraction: clinical applications and method limitations. Int J Lab Hematol 2020; 42 (04) 363-370
    CrossrefPubMedGoogle Scholar
  • 52 Guthikonda S, Alviar CL, Vaduganathan M. et al. Role of reticulated platelets and platelet size heterogeneity on platelet activity after dual antiplatelet therapy with aspirin and clopidogrel in patients with stable coronary artery disease. J Am Coll Cardiol 2008; 52 (09) 743-749
    CrossrefPubMedGoogle Scholar
  • 53 Goel MS, Diamond SL. Adhesion of normal erythrocytes at depressed venous shear rates to activated neutrophils, activated platelets, and fibrin polymerized from plasma. Blood 2002; 100 (10) 3797-3803
    CrossrefPubMedGoogle Scholar
  • 54 Hermand P, Gane P, Huet M. et al. Red cell ICAM-4 is a novel ligand for platelet-activated alpha IIbbeta 3 integrin. J Biol Chem 2003; 278 (07) 4892-4898
    CrossrefPubMedGoogle Scholar
  • 55 Orbach A, Zelig O, Yedgar S, Barshtein G. Biophysical and biochemical markers of red blood cell fragility. Transfus Med Hemother 2017; 44 (03) 183-187
    CrossrefPubMedGoogle Scholar
  • 56 Helms CC, Marvel M, Zhao W. et al. Mechanisms of hemolysis-associated platelet activation. J Thromb Haemost 2013; 11 (12) 2148-2154
    CrossrefPubMedGoogle Scholar
  • 57 Villagra J, Shiva S, Hunter LA, Machado RF, Gladwin MT, Kato GJ. Platelet activation in patients with sickle disease, hemolysis-associated pulmonary hypertension, and nitric oxide scavenging by cell-free hemoglobin. Blood 2007; 110 (06) 2166-2172
    CrossrefPubMedGoogle Scholar
  • 58 Gambaryan S, Subramanian H, Kehrer L. et al. Erythrocytes do not activate purified and platelet soluble guanylate cyclases even in conditions favourable for NO synthesis. Cell Commun Signal 2016; 14 (01) 16
    CrossrefPubMedGoogle Scholar
  • 59 Krauss S. Haptoglobin metabolism in polycythemia vera. Blood 1969; 33 (06) 865-876
    CrossrefPubMedGoogle Scholar
  • 60 Vignoli A, Gamba S, van der Meijden PEJ. et al. Increased platelet thrombus formation under flow conditions in whole blood from polycythaemia vera patients. Blood Transfus 2022; 20 (02) 143-151
    PubMedGoogle Scholar
  • 61 Lawrence JH. The control of polycythemia by marrow inhibition; a 10-year study of 172 patients. J Am Med Assoc 1949; 141 (01) 13-18
    CrossrefPubMedGoogle Scholar
  • 62 Pearson TC, Wetherley-Mein G. Vascular occlusive episodes and venous haematocrit in primary proliferative polycythaemia. Lancet 1978; 2 (8102) 1219-1222
    CrossrefPubMedGoogle Scholar
  • 63 Fazekas JF, Nelson D. Cerebral blood flow in polycythemia vera. AMA Arch Intern Med 1956; 98 (03) 328-331
    CrossrefPubMedGoogle Scholar
  • 64 Thomas DJ, Marshall J, Russell RW. et al. Effect of haematocrit on cerebral blood-flow in man. Lancet 1977; 2 (8045) 941-943
    CrossrefPubMedGoogle Scholar
  • 65 D'Emilio A, Battista R, Dini E. Treatment of primary proliferative polycythaemia by venesection and busulphan. Br J Haematol 1987; 65 (01) 121-122
    CrossrefPubMedGoogle Scholar
  • 66 Taylor JE, Henderson IS, Stewart WK, Belch JJ. Erythropoietin and spontaneous platelet aggregation in haemodialysis patients. Lancet 1991; 338 (8779) 1361-1362
    CrossrefPubMedGoogle Scholar
  • 67 Zwaginga JJ, IJsseldijk MJ, de Groot PG. et al. Treatment of uremic anemia with recombinant erythropoietin also reduces the defects in platelet adhesion and aggregation caused by uremic plasma. Thromb Haemost 1991; 66 (06) 638-647
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 68 Fabris F, Cordiano I, Randi ML. et al. Effect of human recombinant erythropoietin on bleeding time, platelet number and function in children with end-stage renal disease maintained by haemodialysis. Pediatr Nephrol 1991; 5 (02) 225-228
    CrossrefPubMedGoogle Scholar
  • 69 Akizawa T, Kinugasa E, Kitaoka T, Koshikawa S. Effects of recombinant human erythropoietin and correction of anemia on platelet function in hemodialysis patients. Nephron J 1991; 58 (04) 400-406
    CrossrefPubMedGoogle Scholar
  • 70 Viganò G, Benigni A, Mendogni D, Mingardi G, Mecca G, Remuzzi G. Recombinant human erythropoietin to correct uremic bleeding. Am J Kidney Dis 1991; 18 (01) 44-49
    CrossrefPubMedGoogle Scholar
  • 71 Rios JA, Hambleton J, Viele M. et al. Viability of red cells prepared with S-303 pathogen inactivation treatment. Transfusion 2006; 46 (10) 1778-1786
    CrossrefPubMedGoogle Scholar
  • 72 Khandelwal S, van Rooijen N, Saxena RK. Reduced expression of CD47 during murine red blood cell (RBC) senescence and its role in RBC clearance from the circulation. Transfusion 2007; 47 (09) 1725-1732
    CrossrefPubMedGoogle Scholar
  • 73 Bosman GJ, Werre JM, Willekens FL, Novotný VM. Erythrocyte ageing in vivo and in vitro: structural aspects and implications for transfusion. Transfus Med 2008; 18 (06) 335-347
    CrossrefPubMedGoogle Scholar
  • 74 Crosby WH. Normal functions of the spleen relative to red blood cells: a review. Blood 1959; 14 (04) 399-408
    CrossrefPubMedGoogle Scholar
  • 75 Varin R, Mirshahi S, Mirshahi P. et al. Whole blood clots are more resistant to lysis than plasma clots–greater efficacy of rivaroxaban. Thromb Res 2013; 131 (03) e100-e109
    CrossrefPubMedGoogle Scholar
  • 76 Carvalho FA, Connell S, Miltenberger-Miltenyi G. et al. Atomic force microscopy-based molecular recognition of a fibrinogen receptor on human erythrocytes. ACS Nano 2010; 4 (08) 4609-4620
    CrossrefPubMedGoogle Scholar
  • 77 Wohner N, Sótonyi P, Machovich R. et al. Lytic resistance of fibrin containing red blood cells. Arterioscler Thromb Vasc Biol 2011; 31 (10) 2306-2313
    CrossrefPubMedGoogle Scholar