Handchir Mikrochir Plast Chir 2013; 45(02): 108-119
DOI: 10.1055/s-0033-1334909
Übersichtsarbeit
© Georg Thieme Verlag KG Stuttgart · New York

Erythropoetin in der Plastischen Chirurgie

Erythropoietin in Plastic Surgery
C. I. Günter
1   Klinik und Poliklinik für Plastische Chirurgie und Handchirurgie, Klinikum rechts der Isar, Technische Universität München, München
,
F. Rezaeian
1   Klinik und Poliklinik für Plastische Chirurgie und Handchirurgie, Klinikum rechts der Isar, Technische Universität München, München
,
Y. Harder
1   Klinik und Poliklinik für Plastische Chirurgie und Handchirurgie, Klinikum rechts der Isar, Technische Universität München, München
,
J. A. Lohmeyer
1   Klinik und Poliklinik für Plastische Chirurgie und Handchirurgie, Klinikum rechts der Isar, Technische Universität München, München
,
S. Egert
2   Münchener Studienzentrum, Klinikum rechts der Isar, München
,
A. Bader
3   University of Leipzig Center for Biotechnology and Biomedicine Cell Techniques and Applied Stem Cell Biology, Leipzig
,
A. F. Schilling
1   Klinik und Poliklinik für Plastische Chirurgie und Handchirurgie, Klinikum rechts der Isar, Technische Universität München, München
,
H.-G. Machens
1   Klinik und Poliklinik für Plastische Chirurgie und Handchirurgie, Klinikum rechts der Isar, Technische Universität München, München
› Author Affiliations
Further Information

Publication History

eingereicht 09 August 2012

akzeptiert 28 January 2013

Publication Date:
29 April 2013 (online)

Zusammenfassung

Erythropoetin (EPO) ist ein körpereigenes Hormon, welches durch Fibroblasten des Nierenpa­renchyms produziert wird und die Ausdifferenzierung der Erythrozyten im Knochenmark steuert. Seit 30 Jahren wird es therapeutisch bei ­Anämien der terminalen Niereninsuffizienz, bei tumorinduzierten Anämien und vor der Eigenblutspende eingesetzt.

Mittlerweile konnte in einer großen Anzahl von Arbeiten demonstriert werden, dass EPO zudem eine Schlüsselrolle bei der Reaktion auf akute und chronische Gewebeschäden einnimmt. Es konnte gezeigt werden, dass EPO in einer Vielzahl von Geweben in der Akutphase nach Trauma synthetisiert wird. Es hemmt die initiale Entzündungsreaktion und die Apoptose, stimuliert die Stammzellrekrutierung und die Ausschüttung verschiedener Wachstumsfaktoren sowie die Angiogenese und die Re-Epithelialisierung. Unerwünschte Wirkungen von EPO sind u. a. Erhöhung der Thromboseneigung und des Blutdrucks sowie kürzere Überlebenszeiten von mit EPO behandelten Patienten mit Tumoranämien. Wissenschaftlich untersuchte Einsatzbereiche von EPO in dem Gebiete der plastischen Chirurgie sind: Lappenplastiken (lokale und freie), die Regeneration peripherer Nerven sowie die Wundheilungsförderung in thermischen Verletzungen und in chronischen Wunden.

Aktuell ist die Evidenzlage insbesondere für den konkreten klinischen Einsatz aufgrund mangelnder Ergebnisse von GCP (good clinical practice) -gerechten klinischen Studien jedoch ungenügend. Die Durchführung weiterer wissenschaftlich und formal anspruchsvoller Studien ist daher notwendig.

Abstract

EPO is an autologous hormone, which is known to regulate erythropoiesis. For 30 years it has been used for the therapy of diverse forms of anaemia, such as renal anaemia, tumour-related anaemias, etc. Meanwhile, a multitude of scientific publications were able to demonstrate its pro-regenerative effects after trauma. These include short-term effects such as the inhibition of the „primary injury response“ or apoptosis, and mid- and long-term effects for example the stimula­tion of stem cell recruitment, growth factor production, angiogenesis and re-epithelialisation. Known adverse reactions are increases of thromboembolic events and blood pressure, as well as a higher mortality in patients with tumour anaemias treated with EPO. Scientific investigations of EPO in the field of plastic surgery included: free and local flaps, nerve regeneration, wound healing enhancement after dermal thermal injuries and in chronic wounds.

Acute evidence for the clinical use of EPO in the field of plastic surgery is still not satisfactory, due to the insufficient number of Good Clinical Practice (GCP)-conform clinical trials. Thus, the initiation of more scientifically sound trials is ­indicated.

 
  • Literatur

  • 1 Jourdanet D. De l´anemie des altitudes et de l´anemie en general dans ses rapports avec la pression del l´atmosphere. 1863 Balliere, Paris
  • 2 Jelkmann W. EPO after a century of research: younger than ever. Eur J Haematol 2007; 78: 183-205
  • 3 Lee-Huang S. Cloning and expression of human erythropoietin cDNA in Escherichia coli. Proc Nat Acad Sci USA 1984; 81: 2708-2712
  • 4 Fachinformation 2011 NeoRecormon Multidose 50 000 IE, Roche Pharma AG, Grenzach-Wyhlen, Germany
  • 5 Bany-Mohammed FM, Slivka S, Hallman M. Recombinant Human Erythropoietin: Possible Role as an Antioxidant in Rabbits. Pediatric Research 1996; 40: 381-387
  • 6 Brines M, Cerami A. EPO-mediated tissue protection: reducing collateral damage from primary injury response. J Int Med 2008; 264: 405-432
  • 7 Um M, Lodish HF. Antiapoptotic effects of EPO in differentiated neuroblastoma SH-SY5Y cells require activation of both the STAT5 and AKT signaling pathways. J Biol Chem 2006; 281: 5648-5656
  • 8 Tramontano AF, Muniyappa R, Black AD et al. EPO protects cardiacmyocytes from hypoxia-induced apoptosis through an Akt-dependent pathway. Biochem Biophys Res Commun 2003; 308: 990-994
  • 9 Bahlmann FH, De Groot K, Spandau JM. EPO regulates endothelial progenitor cells. Blood 2004; 103: 921-926
  • 10 Arcasoy MO. The non-haematopoietic biological effects of erythropoietin. Brit J Haematology 2008; 141: 14-31
  • 11 Guneli E, Cardar Z, Islekel H et al. EPO protects the intestine against ischemia/reperfusion injury in rats. Mol Med 2007; 13: 509-517
  • 12 Sakanaka M, Wen TC, Matsuda S et al. In vivo evidence that EPO protects neurons from ischemic damage. Proc Natl Acad Sci USA 1998; 95: 4635
  • 13 Ehrenreich H, Weissenborn K, Prange H et al. Recombinant human erythropoietin in the treatment of acute ischemic stroke. Stroke 2009; 40: e647-e656
  • 14 Jelkmann W. Effects of EPO on brain function. Curr Pharmaceut Biotechnol 2004; 6: 65-79
  • 15 Parsa CJ, Matsumoto A, Kim J et al. A novel protective effect of EPO in the infarcted heart. J Clin Invest 2003; 112: 999-1007
  • 16 Sepodes B, Maio R, Pinto R et al. Recombinant human EPO protects the liver from hepatic ischemia-reperfusion injury in the rat. Transpl Int 2006; 19: 919-926
  • 17 Schmeding M, Boas-Knoop S, Lippert S et al. EPO promotes hepatic regeneration after extended liver resection in rats. J Gastroenterol Hepatol 2008; 23: 1125-1131
  • 18 Chatterjee PK. Pleiotropic renal actions of EPO. Lancet 2005; 365: 1890-1892
  • 19 Brines M, Grasso G, Fiordaliso F et al. EPO mediated tissue protection through an EPO and common beta-subunit heteroreceptor. Proc Natl Acad Sci USA 2004; 101: 14907
  • 20 Brines M, Patel NSA, Villa P et al. Nonerythropoietic, tissue-protective peptides derived from the tertiary structure of erythropoietin. Proc Natl Acad Sci USA 2008; 105: 10925
  • 21 Elliott S, Busse L, Bass MB et al. Anti-Epo receptor antibodies do not predict Epo receptor expression. Blood 2006; 107: 1892-1895
  • 22 Brown WM, Maxwell P, Graham AN et al. Erythropoietin receptor expression in non-small cell lung cancer: A question of antibody specificity. Stem Cells 2007; 25: 718-722
  • 23 Taylor JE, McLaren M, Henderson IS et al. Prothrombotic effect of erythropoietin in dialysis patients. Nephrol Dial Transplant 1992; 7: 235-239
  • 24 Tobu M, Iqbal O, Fareed D et al. Erythropoietin-induced thrombosis as a result of increased inflammation and thrombin activatable fibrinolytic inhibitor. Clin Appl Thromb Hemost 2004; 10: 225-232
  • 25 Lim VS, Kirchner PT, Fangman J et al. The safety and the efficacy of maintenance therapy of recombinant human erythropoietin in patients with renal insufficiency. Am J Kidney Dis 1989; 14: 496-506
  • 26 Schiffl H, Lang SM. Hypertension induced by recombinant human erythropoietin (rHU-EPO) can be prevented by indomethacin. Pathogenetic role of cytosolic calcium. Eur J Med Res 1997; 2: 97-100
  • 27 Ortega LM, Contreras G. Nefrologia. The clinical impact of the physiological effects of erythropoietin and erythropoietin-stimulating agents on the incidence of malignancy, and hypertension: beyond anaemia 2009; 29: 288-294 DOI: 10.3265/Nefrologia.2009.29.4.5282.
  • 28 Corwin HL, Gettinger A, Fabian TC et al. Efficacy and Safety of EPO alfa in Critically Ill patients. New Engl J Med 2007; 357: 965-976
  • 29 Aapro M, Osterwalder B, Scherhag A et al. Epoetin-beta treatment in patients with cancer chemotherapy-induced anaemia: the impact of initial haemoglobin and target haemoglobin levels on survival, tumour progression and thromboembolic events. Br J Cancer 2009; 101: 1961-1971
  • 30 Bohlius J, Schmidlin K, Brillant C et al. Erythropoietin or Darbepoetin for patients with cancer – meta-analysis based on individual patient data. Cochrane Database Syst Rev 2009; 3 CD007303
  • 31 Saray A, Ozakpinar R, Koc C et al. Effect of chronic and short-term EPO treatment on random flap survival in rats: an experimental study. Laryngoscope 2003; 113: 85-89
  • 32 Lehr HA, Leunig M, Menger MD et al. Dorsal skinfold chamber technique for intravital microscopy in nude mice. Am J Pathol 1993; 143: 1055-1062
  • 33 Harder Y, Amon M, Erni D et al. Evolution of ischemic tissue injury in a random pattern flap: a new mouse model using intravital microscopy. J Surg Res 2004; 121: 197-205
  • 34 Rezaeian F, Wettstein R, Manon M et al. EPO protects critically perfused flap tissue. Ann Surg 2008; 248: 919-929
  • 35 Rezaeian F, Wettstein R, Egger JF et al. EPO-induced upregulation of endothelial nitric oxide synthase but not vascular endothelial growth factor prevents musculocutaneus tissue from ischemic damage. Lab Invest 2010; 90: 40
  • 36 Harder Y, Amon M, Schramm R et al. EPO reduces necrosis in critically ischemic myocutaneous tissue by protecting nutritive perfusion in a dose-dependent manner. Surgery 2009; 145: 372-383
  • 37 Contaldo C, Meier C, Elsherbiny A et al. Human recombinant erythropoietin protects the striated muscle microcirculation of the dorsal skinfold from postischemic injury in mice. Am J Physiol Heart Circ Physiol 2007; 293: H274-H283
  • 38 Contaldo C, Elsherbiny A, Lindenblatt N et al. EPO enhances oxygenation in critically perfused tissue through modulation of nitric oxide synthase. Shock 2009; 31: 599-606
  • 39 Erbayraktar Z, Erbayraktar S, Yilmatz O et al. Nonerythropoietic Tissue Protective Compounds are highly effective facilitators of wound healing. Mol Med 2009; 15: 235-241
  • 40 Campana WM, Myers RR. EPO and EPO Receptors in the peripheral nervous system: changes after nerve injury. FASEB 2001;
  • 41 Campana WM, Myers RR. Exogenous EPO protects against dorsal root ganglion apoptosis and pain following peripheral nerve injury. Europ J Neurosci 2003; 18: 1497-1506
  • 42 Lykissas MG, Korompilias AV, Vekris MD et al. Axonal regeneration stimulated by EPO: An experimental study in rats. J Neuroscie methods 2007; 164: 107-115
  • 43 Hassan K, Simri W, Rubenchik I et al. Effect of EPO therapy on poly­neuropathy in predialitic patients. J Nephrol 2003; 16: 121-125
  • 44 Lohmeyer JA, Essmann E, Richerson SJ et al. Use of EPO as adjuvant therapy in nerve reconstruction. Langenbecks Arch Surg 2008; 393: 317-323
  • 45 Yin ZS, Zhang H, Gao W et al. EPO promotes functional recovery and enhances nerve regeneration after peripheral nerve injury in rats. Am J Neuroradiol 2010; 31: 509-515
  • 46 Robinson H, Monafo WW, Saver SM et al. The role of erythropoietin in the anemia of thermal injury. Ann Surg 1973; 178: 565-572
  • 47 Deitch EA, Sittig KM. A Serial Study of the Erythropoietic Response tp Thermal Injury. Ann Surg 1993; 217: 293-299
  • 48 Pajoumand M, Erstad EL, Camamo JM et al. Use of epoetin alfa in critically ill patients. Ann Pharmacotherapy 2004; 38: 1325-1326
  • 49 Galeano M, Altavilla D, Bitto A et al. Recombinant human EPO improves angiogenesis and wound healing in experimental burn wounds. Crit Care Med 2006; 34: 1139-1146
  • 50 Bader A, Machens HG. Recombinant human EPO plays a pivotal role as a topical stem cell activator to reverse effects of damage to the skin in aging and trauma. Rejun Res 2010; 13: 499
  • 51 Bader A, Ebert S, Giri S et al. Skin regeneration with conical and hair follicle structure of deep second-degree scalding injuries via combined expression of the EPO receptor and beta common receptor by local subcutaneous injection of nanosized rhEPO. Int J Nanomed 2012; 7: 1227-1237
  • 52 Dornseifer U, Machens HG, Bader A et al. Potential der topischen Anwendung von EPO zur Wundbehandlung. Poster, 40. Jahrestagung, DGPRÄC, 2009, Hannover
  • 53 Machens HG EPO in Burns, EuraCT Number: 2006-002886-38, Protocol Number: 0506, ISRCT Number: ISRCTN95777824
  • 54 Horch RE, Nord D, Augustin M et al. Ökonomische Aspekte in der chirurgischen Wundbehandlung. Chirurg 2008; 79: 518-525
  • 55 Buemi M, Galliano M, Sturiala A et al. Recombinant human EPO stimulates angiogenesis and healing of ischemic skin wounds. Shock 2004; 22: 169
  • 56 Galeano M, Altavilla D, Cucinotta D et al. Recombinant human EPO stimulates angiogenesis and wound healing in the genetically diabetic mouse. Diabetes 2004; 53: 2509
  • 57 Hamed S, Ullmann Y, Masoud M et al. Topical EPO promotes wound repair in diabetic rats. J Invest Dermatol 2010; 130: 287
  • 58 Bader A, Ebert S, Giri S et al. Interactive Role of Trauma Cytokines and EPO and their therapeutic potential for acute and chronic wounds. Rejun Res 2011; 14: 57-66
  • 59 Ferri C, Giuggioli D, Sebastiani M et al. Treatment of severe scleroderma skin ulcers with rhEPO. Clin Exp Dermatol 2007; 32: 287-290
  • 60 Keast DH, Fraser C. Treatment of chronic skin ulcers in individuals with anemia of chronic disease using rhEPO: a review of four cases. Osteotomy Wound Manage 2004; 50: 64-70
  • 61 Wolf RF, Peng J, Friese P et al. EPO potentiates thrombus development in a canine arteriovenous shunt model. Thromb Haemost 1997; 77: 1020-1024
  • 62 Lindenblatt N, Menger MD, Klar E et al. Darbepoeitin-Alpha does not promote microvascular thrombus formation in mice. Role of eNOS-dependent protection through platelet and endothelial cell deactivation. Art Thromb Vasc Biol 2007; online March 14 2007
  • 63 Hasegawa Y, Takamatsu J, Iwase T et al. Effects of rhEPO on thrombosis and fibrinolysis in autologous transfusion for hip surgery. Arch Orthop Trauma Surg 1999; 119: 384-387
  • 64 Sorg H, Kuhbier JW, Menger B et al. Die Rolle von EPO bei der Verbesserung der Wundheilung. Chirurg 2010; 81: 993-998
  • 65 Meistrell 3 ME, Botchkina GI, Wang H et al. Tumor necrosis factor is a brain damaging cytocine in cerebral ischemia. Shock 1997; 8: 341-348
  • 66 Yazihan N, Karakurt O, Ataoglu H. EPO reduces lopopolysaccharide-induced cell damage and midkine secretion inU937 huamn histiocytic lymphoma cells. Adv Ther 2008; 25: 502-514
  • 67 Cuzzocera S, Mazzon E, di Paola R et al. EPO reduces the degree of arthritis caused by type II collagen in the mouse. Arthritis Rheum 2005; 52: 949-950
  • 68 Wiese L, Hempel C, Penkowa M et al. Recombinant human EPO increases survival and reduces neuronal apoptosis in a murine model of malaria. Malar J 2008; 7: 3
  • 69 Viviani B, Gardoni F, Marinovich M. Cytokines and neuronal ion channels in health and disease. Int Rev Neurobiol 2007; 82: 247-263
  • 70 Beguin Y. EPO and Platelet production. Haematologica 1999; 84: 541-547
  • 71 Van der Meer P, Lipsic E, Henning RH et al. EPO induces neovascularisation and improves cardiac function in rats with heart failure after myocardial infaction. J Am Coll Cardiol 2005; 46: 125-133
  • 72 Silva M, Benito A, Sanz C. EPO can induce the expression of Bcl-XL through Stat 5 in EPO-dependent progenitor Cell ines. J Biol Chem 1999; 274: 22165-22169
  • 73 Kim I, Kim CH, Yim YS. Autocrine function of EPO in IGF-1-induced EPO biosynthesis. Neuroreport 2008; 19: 1699-1703
  • 74 Sharples EJ, Patel N, Brown P. EPO protects kidneys against the injury and dysfunction caused by iscemia-reperfusion. J Am Soc Nephrol 2004; 15: 2116-2124
  • 75 Silva M, Grillt D, Benito A. EPO can promote erythroid progenitor survival by repressing apoptosis through Bcl-XL and Bcl-2. Blood 1996; 88: 1576-1582
  • 76 Moore E, Bellomo R. EPO in acute kidney injury. Ann Intens Care 2011; 1: 3