Objectives: Whereas administration of erythropoietin (EPO) acutely after myocardial infarction (MI) reduces infarct size and chronic EPO therapy attenuates post-MI remodeling, the safety of chronic EPO therapy following MI is unknown. Therefore, we examined the thrombogenic effects of a chronic EPO therapy after MI. Methods: Rats underwent coronary occlusion followed by reperfusion. They were assigned to one of the following groups: EPO-A, single injection of EPO 5,000 U/kg at the time of reperfusion; EPO-C, injection of EPO 5,000 U/kg at the time of reperfusion followed by 300 U/kg/week; PBS-C, injection of vehicle only. After eight weeks of treatment they were exposed to a validated prethrombotic test based on partial stenosis of the inferior vena cava. Results: As compared to the rats receiving vehicle only, the rats treated with EPO exhibited a significant reduction in MI size (28.7 ± 2.1% and 25.8 ± 1.9 vs. 39.8 ± 3.0% in EPO-A, EPO-C and PBS-C, respectively; p < 0.05). Whereas the hematocrit was significantly increased in EPO-C (59.7 ± 2.0% vs. 44.7 ± 0.9% in EPO-A, p < 0.001), the proportion of rats in which a thrombus occurred was similar in all groups (p = 0.52). Conclusion: Chronic EPO therapy added to the single high dose of EPO injected acutely did not induce venous pro-thrombotic effect in rats.

1.
Calvillo L, Latini R, Kajstura J, Leri A, Anversa P, Ghezzi P, Salio M, Cerami A, Brines M: Recombinant human erythropoietin protects the myocardium from ischemia-reperfusion injury and promotes beneficial remodeling. Proc Natl Acad Sci USA 2003;100:4802–4806.
2.
Joyeux-Faure M, Godin-Ribuot D, Ribuot C: Erythropoietin and myocardial protection: what’s new? Fundam Clin Pharmacol 2005;19:439–446.
3.
Moon C, Krawczyk M, Ahn D, Ahmet I, Paik D, Lakatta EG, Talan MI: Erythropoietin reduces myocardial infarction and left ventricular functional decline after coronary artery ligation in rats. Proc Natl Acad Sci USA 2003;100:11612–11617.
4.
Moon C, Krawczyk M, Paik D, Lakatta EG, Talan MI: Cardioprotection by recombinant human erythropoietin following acute experimental myocardial infarction: dose response and therapeutic window. Cardiovasc Drugs Ther 2005;19:243–250.
5.
Parsa CJ, Kim J, Riel RU, Pascal LS, Thompson RB, Petrofski JA, Matsumoto A, Stamler JS, Koch WJ: Cardioprotective effects of erythropoietin in the reperfused ischemic heart: a potential role for cardiac fibroblasts. J Biol Chem 2004;279:20655–29662.
6.
Parsa CJ, Matsumoto A, Kim J, Riel RU, Pascal LS, Walton GB, Thompson RB, Petrofski JA, Annex BH, Stamler JS: A novel protective effect of erythropoietin in the infarcted heart. J Clin Invest 2003;112:999–1007.
7.
van der Meer P, Voors AA, Lipsic E, van Gilst WH, van Veldhuisen DJ: Erythropoietin in cardiovascular diseases. Eur Heart J 2004;25:285–291.
8.
Cai Z, Manalo DJ, Wei G, Rodriguez ER, Fox-Talbot K, Lu H, Zweier JL, Semenza GL: Hearts from rodents exposed to intermittent hypoxia or erythropoietin are protected against ischemia-reperfusion injury. Circulation 2003;108:79–85.
9.
Lipsic E, van der Meer P, Henning RH, Suurmeijer AJ, Boddeus KM, van Veldhuisen DJ, van Gilst WH, Schoemaker RG: Timing of erythropoietin treatment for cardioprotection in ischemia/reperfusion. J Cardiovasc Pharmacol 2004;44:473–479.
10.
Tramontano AF, Muniyappa R, Black AD, Blendea MC, Cohen I, Deng L, Sowers JR, Cutaia MV, El-Sherif N: Erythropoietin protects cardiac myocytes from hypoxia-induced apoptosis through an Akt-dependent pathway. Biochem Biophys Res Commun 2003;308:990–994.
11.
van der Meer P, Lipsic E, Henning RH, Boddeus K, van der Velden J, Voors AA, van Veldhuisen DJ, van Gilst WH, Schoemaker RG: Erythropoietin induces neovascularization and improves cardiac function in rats with heart failure after myocardial infarction. J Am Coll Cardiol 2005;46:125–133.
12.
Prunier F, Pfister O, Hadri L, Liang L, Del Monte F, Liao R, Hajjar RJ: Delayed erythropoietin therapy reduces post-MI cardiac remodeling only at a dose that mobilizes endothelial progenitor cells. Am J Physiol Heart Circ Physiol 2007;292:H522–H529.
13.
Taylor JE, McLaren M, Henderson IS, Belch JJ, Stewart WK: Prothrombotic effect of erythropoietin in dialysis patients. Nephrol Dial Transplant 1992;7:235–239.
14.
Taylor JE, Belch JJ, McLaren M, Henderson IS, Stewart WK: Effect of erythropoietin therapy and withdrawal on blood coagulation and fibrinolysis in hemodialysis patients. Kidney Int 1993;44:182–190.
15.
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;78:1505–1509.
16.
Biesma DH, Bronkhorst PJ, de Groot PG, van de Wiel A, Kraaijenhagen RJ, Marx JJ: The effect of recombinant human erythropoietin on hemostasis, fibrinolysis, and blood rheology in autologous blood donors. J Lab Clin Med 1994;124:42–47.
17.
Malyszko J, Malyszko JS, Borawski J, Rydzewski A, Kalinowski M, Azzadin A, Mysliwiec M, Buczko W: A study of platelet functions, some hemostatic and fibrinolytic parameters in relation to serotonin in hemodialyzed patients under erythropoietin therapy. Thromb Res 1995;77:133–143.
18.
Viron B, Jaar B, Verdy E, Mignon F: Erythropoietin-induced protein S deficiency and vena cava thrombosis. Nephrol Dial Transplant 1992;7:979.
19.
Bohlius J, Wilson J, Seidenfeld J, Piper M, Schwarzer G, Sandercock J, Trelle S, Weingart O, Bayliss S, Djulbegovic B: Recombinant human erythropoietins and cancer patients: updated meta-analysis of 57 studies including 9353 patients. J Natl Cancer Inst 2006;98:708–714.
20.
Pottier P, Planchon B, Truchaud F, Leftheriotis G, Herbert JM, Bressolette L, Trewick D, Passuti N: Development of an experimental model of pre-thrombosis in rats based on Wessler’s principle using a calibrated venous stasis. Blood Coagul Fibrinolysis 2003;14:3–9.
21.
Pottier P, Planchon B, Truchaud F, Leftheriotis G, Herbert JM, Bressollette L, Passuti N: Efficacy of pentasaccharide on a prethrombosis model based on a calibrated stasis by the increase in up-stream venous pressure. Blood Coagul Fibrinolysis 2003;14:587–591.
22.
Rafiee P, Shi Y, Su J, Pritchard KA Jr, Tweddell JS, Baker JE: Erythropoietin protects the infant heart against ischemia-reperfusion injury by triggering multiple signaling pathways. Basic Res Cardiol 2005;100:187–197.
23.
Wald MR, Borda ES, Sterin-Borda L: Mitogenic effect of erythropoietin on neonatal rat cardiomyocytes: signal transduction pathways. J Cell Physiol 1996;167:461–468.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.