Erythropoiesis-stimulating Agents

Thomas Turgeon, M.D., MPH, FRCSC
Winnipeg, MB

Blood loss and the potential need for allogeneic transfusion continue to be a significant challenge for orthopaedic patients. Allogeneic blood transfusion continues to carry associated risks. The use of preoperative autologous donation (PAD) in cases at higher risk of blood loss, generally leads to increased anaemia at the time of surgery1. PAD is associated with increased need for transfusion (both PAD and allogeneic), adverse transfusion reactions and wastage of unused units2-6. Erythropoiesis-stimulating agents, developed for anaemia due to a variety of conditions, have been used extensively to assist in the management of patients undergoing elective orthopaedic surgery with preoperative anaemia.


There are a few Erythropoiesis-stimulating agents currently in production. All work in the same fashion by stimulating the erythropoietin (Epo) hormone receptor in red bone marrow resulting in increased production of red blood cells. The most commonly used agents are human Epo produced using recombinant DNA technology. Two newer synthetic agents are currently produced, but neither has been studied to any extent in elective orthopaedic patients. Dosing of Epo is listed by the manufacturers as 600IU/kg; however, most treatment protocols and studies use 40,000IU per patient with 20,000IU used in smaller patients or those that prove sensitive to the drug. The drug is indicated for the treatment of preoperative anaemia for haemoglobin values between 100 and 130. Several clinical studies have used a range of 100-140 with a goal of reaching 150 on the day of surgery, but this is not the recommendation within the product monographs7-9. The use of Epo is generally augmented with iron supplementation.

The majority of the orthopaedic research on Epo comes from the hip and knee arthroplasty literature. Numerous treatment protocols combining Epo with PAD have been found to be beneficial in reducing transfusion rates10-12. Several randomized trials have been performed on the effects of Epo. Feagan, et al. compared placebo, 20,000 and 40,000IU of Epo started four weeks preoperatively in 408 total hip patients. With both low and high dose Epo, the allogeneic transfusion rate was significantly reduced to 23% and 11%, respectively, versus 45% in the placebo control13. Karkouti, et al. compared adding Epo to their standard of care versus no Epo treament. Dosing of Epo was 20,000IU for subjects 14.

Several studies have compared the interventions of Epo versus PAD, although most have started Epo within only two weeks of surgery. Bezwada, et al. found that the combination of Epo and PAD was the most effective with an 11% allogeneic transfusion rate in the combined group and 28% and 33% in the two single treatment arms7. Most subjects were given PAD units intra-operatively regardless of clinical need and results were further complicated by the use of re-infusion drains and cell-saver units for selected cases. Another small study of 50 total knee patients found the risk of allogeneic transfusion was 28% for Epo versus 6% for PAD15. A third study found no difference in transfusion rates between Epo and PAD, but did find PAD subjects that required transfusion needed nearly twice the volume of blood products8.

There are a few concerns about the use of Epo in elective patients. An increased risk of thromboembolic events has been documented in the spine literature16,17. There have also been concerns about hypertension exacerbations. Cost of the medication continues to be an issue. In Canada, the price of Epo per dose ranges between $400 and $500. The price per unit of blood in Canada, both PAD and allogeneic, is in a similar range to a single Epo dose. A cost analysis in the United States found that PAD with additional allogeneic blood was the most cost-effective option, but this study used a PAD cost significantly lower than that seen in Canada, likely due to differences in blood testing protocols.

Epo continues to be an important adjunct to elective orthopaedic surgery. Its role in relation to PAD is not entirely clear; however, in patients with preoperative anaemia Epo definitely has a role in minimizing the need for allogeneic blood transfusion.


  1. Goodnough L.T. Autologous blood donation. Crit Care. 2004;8 Suppl 2:S49-52.
  2. Transfusion alert: use of autologous blood. National Heart, Lung, and Blood Institute Expert Panel on the use of Autologous Blood. Transfusion. 1995 Aug;35(8):703-11.
  3. Billote D.B., Glisson S.N., Green D., Wixson R.L. A prospective, randomized study of preoperative autologous donation for hip replacement surgery. J Bone Joint Surg Am. 2002 Aug;84-A(8):1299-304.
  4. Henry D.A., Carless P.A., Moxey A.J., O'Connell D., Forgie M.A., Wells P.S., et al. Pre-operative autologous donation for minimising perioperative allogeneic blood transfusion. Cochrane Database Syst Rev. 2002(2):CD003602.
  5. Popovsky M.A., Whitaker B., Arnold N.L. Severe outcomes of allogeneic and autologous blood donation: frequency and characterization. Transfusion. 1995 Sep;35(9):734-7.
  6. Stowell C.P., Chandler H., Jove M., Guilfoyle M., Wacholtz M.C. An open-label, randomized study to compare the safety and efficacy of perioperative epoetin alfa with preoperative autologous blood donation in total joint arthroplasty. Orthopedics. 1999 Jan;22(1 Suppl):s105-12.
  7. Bezwada H.P., Nazarian D.G., Henry D.H., Booth R.E., Jr. Preoperative use of recombinant human erythropoietin before total joint arthroplasty. J Bone Joint Surg Am. 2003 Sep;85-A(9):1795-800.
  8. Hardwick M.E., Morris B.M., Colwell C.W., Jr. Two-dose epoetin alfa reduces blood transfusions compared with autologous donation. Clin Orthop Relat Res. 2004 Jun(423):240-4.
  9. Keating E.M., Callaghan J.J., Ranawat A.S., Bhirangi K., Ranawat C.S. A randomized, parallel-group, open-label trial of recombinant human erythropoietin vs preoperative autologous donation in primary total joint arthroplasty: effect on postoperative vigor and handgrip strength. J Arthroplasty. 2007 Apr;22(3):325-33.
  10. Rashiq S., Jamieson-Lega K., Komarinski C., Nahirniak S., Zinyk L., Finegan B. Allogeneic blood transfusion reduction by risk-based protocol in total joint arthroplasty. Can J Anaesth. 2010 Apr;57(4):343-9.
  11. Gonzalez-Porras J.R., Colado E., Conde M.P., Lopez T., Nieto M.J., Corral M. An individualized pre-operative blood saving protocol can increase pre-operative haemoglobin levels and reduce the need for transfusion in elective total hip or knee arthroplasty. Transfus Med. 2009 Feb;19(1):35-42.
  12. Martinez V., Monsaingeon-Lion A., Cherif K., Judet T., Chauvin M., Fletcher D. Transfusion strategy for primary knee and hip arthroplasty: impact of an algorithm to lower transfusion rates and hospital costs. Br J Anaesth. 2007 Dec;99(6):794-800.
  13. Feagan B.G., Wong C.J., Kirkley A., Johnston D.W., Smith F.C., Whitsitt P., et al. Erythropoietin with iron supplementation to prevent allogeneic blood transfusion in total hip joint arthroplasty. A randomized, controlled trial. Ann Intern Med. 2000 Dec 5;133(11):845-54.
  14. Karkouti K., McCluskey S.A., Evans L., Mahomed N., Ghannam M., Davey R. Erythropoietin is an effective clinical modality for reducing RBC transfusion in joint surgery. Can J Anaesth. 2005 Apr;52(4):362-8.
  15. Deutsch A., Spaulding J., Marcus R.E. Preoperative epoetin alfa vs autologous blood donation in primary total knee arthroplasty. J Arthroplasty. 2006 Aug;21(5):628-35.
  16. Parr A.M., Wang M.Y. Preoperative erythropoietin prior to spinal surgery increases DVT risk. Neurosurgery. 2010 Feb;66(2):N16.
  17. Stowell C.P., Jones S.C., Enny C., Langholff W., Leitz G. An open-label, randomized, parallel-group study of perioperative epoetin alfa versus standard of care for blood conservation in major elective spinal surgery: safety analysis. Spine (Phila Pa 1976). 2009 Nov 1;34(23):2479-85.

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