Successful Management of Tendinopathy With Injections of the MMP-inhibitor Aprotinin

  • John Orchard
  • Andrew Massey
  • Richard Brown
  • Adéline Cardon-Dunbar
  • Jamie Hofmann
Symposium: Molecular and Clinical Developments in Tendinopathy


Aprotinin is a broad spectrum proteinase inhibitor (including matrix metalloproteinase [MMP] inhibitor) used for treating patellar and Achilles tendinopathies. One previous randomized control trial demonstrated aprotinin injections superior to both corticosteroid and saline injections in patellar tendinopathy (Level II), whereas results reported for aprotinin treatment in Achilles tendinopathy have been mixed. We performed a case review and followup questionnaire for 430 consecutive patients with tendinopathy treated by 997 aprotinin injections (30,000 KIU). A response rate of 72% was achieved with a minimum followup of 3 months (average, 12.2 months; range, 3–54 months). Seventy-six percent of patients had improved, 22% of patients reported no change, and 2% were worse. Sixty-four percent of patients thought aprotinin injections were helpful, while 36% believed they had neither a positive nor negative effect. Mid-Achilles tendinopathy patients (84% improvement) were more successfully treated than patellar tendinopathy patients (69% improvement). Despite stronger published evidence of benefit in patellar tendinopathy, clinical outcomes appeared better with aprotinin use in Achilles tendinopathies.

Level of Evidence: Level IV, case series. See the Guidelines for Authors for a complete description of levels of evidence.


Aprotinin Achilles Tendon Bovine Spongiform Encephalopathy Achilles Tendinopathy Rugby League 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Alfredson H, Lorentzon M, Backman S, Backman A, Lerner U. cDNA-arrays and real time quantitative PCR techniques in the investigation of chronic human Achilles tendinopathy. J Orthop Res. 2003;21:970–975.PubMedCrossRefGoogle Scholar
  2. 2.
    Apeler H, Peters J, Schröder W, Schneider KH, Lemm G, Hinz V, Rossouw GW, Dembowsky K. Expression, purification, biochemical and pharmacological characterization of a recombinant aprotinin variant. Arzneimittelforschung. 2004;54:483–497.PubMedGoogle Scholar
  3. 3.
    Aubin F, Javaudin L, Rochcongar P. Case report of aprotinin in Achilles tendinopathies with athletes [in French]. J Pharmacie Clinique. 1997;16:270–273.Google Scholar
  4. 4.
    Beierlein W, Scheule A, Dietrich W, Ziemer G. Forty years of clinical aprotinin use: a review of 124 hypersensitivity reactions. Annals of Thoracic Surgery. 2005;79:741–748.PubMedCrossRefGoogle Scholar
  5. 5.
    Berton A, Lorimier S, Emonard H, Laurent-Maquin D, Hornebeck W, Bellon G. Contribution of the plasmin/matrix metallopoteinase cascade to the retraction of human fibroblast populated collagen lattices. Mol Cell Biol Res Commun. 2000;3:173–180.PubMedCrossRefGoogle Scholar
  6. 6.
    Bojanov G, Belani KG. Aprotinin - an update for the perioperative physician. Ann Card Anaesth. 2005;8:75–80.PubMedGoogle Scholar
  7. 7.
    Brown R, Orchard J, Kinchington M, Hooper A, Nalder G. Aprotinin in the management of Achilles tendinopathy: a randomised controlled trial. Br J Sports Med. 2006;40:275–279.PubMedCrossRefGoogle Scholar
  8. 8.
    Brukner P, Khan K. Clinical Sports Medicine, 3rd ed. McGraw-Hill: Sydney; 2006.Google Scholar
  9. 9.
    Capasso G, Maffulli N, Testa V, Sgambato A. Preliminary results with peritendinous potease inhibitor injections in the management of Achilles tendinitis. J Sports Traumatol Rel Res. 1993;15:37–40.Google Scholar
  10. 10.
    Capasso G, Testa V, Maffulli N, Bifulco G. Aprotinin, corticosteroids and normosaline in the management of patellar tendinopathy in athletes: a prospective randomized study. Sports Exerc Injury. 1997;3:111–115.Google Scholar
  11. 11.
    Cederholm-Williams SA. Fibrin glue [letter]. BMJ. 1994;308:1570.PubMedGoogle Scholar
  12. 12.
    Chu SC, Yang SF, Lue KH, Hsieh YS, Wu CL, Lu KH. Regulation of gelatinases expression by cytokines, endotoxin, and pharmacological agents in the human osteoarthritic knee. Connect Tissue Res. 2004;45:142–150.PubMedCrossRefGoogle Scholar
  13. 13.
    Coleman C, Rigali V, Hammond J, Kluger J, Jeleniowski K, White C. Evaluating the safety implications of aprotinin use: the Retrospective Evaluation of Aprotinin in Cardio Thoracic Surgery (REACTS). J Thorac Cardiovasc Surg. 2007;133:1547–1552.PubMedCrossRefGoogle Scholar
  14. 14.
    Collen A, Hanemaaijer R, Lupu F, Quax P, van Lent N, Grimbergen J, Peters E, Koolwijk P, van Hinsbergh V. Membrane-type maxtrix metelloproteinase-mediated angiogenesis in a fibrin-collagen matrix. Blood. 2003;101:1810–1817.PubMedCrossRefGoogle Scholar
  15. 15.
    DaCruz D, Geeson M, Allen M, Phair I. Achilles paratendonitis: an evaluation of steroid injection. Br J Sports Med. 1988;22:64–65.PubMedCrossRefGoogle Scholar
  16. 16.
    Davis G, Pintar Allen KA, Salazar R, Maxwell SA. Matrix metalloproteinase-1 and -9 activation by plasmin regulates a novel endothelial cell-mediated mechanism of collagen gel contraction and capillary tube regression in three-dimensional collagen matrices. J Cell Sci. 2001;114:917–930.PubMedGoogle Scholar
  17. 17.
    de Mos M, van El B, DeGroot J, Jahr H, van Schie H, van Arkel E, Tol H, KHeijboer R, van Osch G, Verhaar J. Achilles tendinosis: changes in biochemical composition and collagen turnover rate. Am J Sports Med. 2007;35:1549–1556.PubMedCrossRefGoogle Scholar
  18. 18.
    Dietrich W, Späth P, Zühlsdorf M, Dalichau H, Kirchhoff PG, Kuppe H, Preiss DU, Mayer G. Anaphylactic reactions to aprotinin reexposure in cardiac surgery: relation to antiaprotinin immunoglobulin G and E antibodies. Anesthesiology. 2001;95:64–71.PubMedCrossRefGoogle Scholar
  19. 19.
    Dollery C, ed. Therapeutic Drugs. Edinburgh UK: Churchill Livingstone; 1991.Google Scholar
  20. 20.
    Druce J, Locarnini S, Birch C. Isolation of HIV-1 from experimentally contaminated multidose local anaesthetic vials. Med J Aus. 1995;162:513–515.Google Scholar
  21. 21.
    Fu S, Chan B, Wang W, Pau H, Chan K, Rolf C. Increased expression of matrix metalloproteinase 1 (MMP1) in 11 patients with patellar tendinosis. Acta Orthop Scand. 2002;73:658–662.PubMedCrossRefGoogle Scholar
  22. 22.
    Genety J, Pernin E. Utilisation du Zymofren® dans le traitement des tendinites chez le sportif. Cahiers Méd Lyonnais. 1971;47:135–139.Google Scholar
  23. 23.
    Gill SS, Gelbke MK, Mattson SL, Anderson MW, Hurwitz SR. Fluoroscopically guided low-volume peritendinous corticosteroid injection for Achilles tendinopathy. A safety study. J Bone Joint Surg Am. 2004;86:802–806.PubMedGoogle Scholar
  24. 24.
    Golker C, Whiteman M, Gugel K, Gilles R, Stadler P, Kovatch R, Lister D, Wisher M, Calcagni C, Hubner G. Reduction of the infectivity of scrapie agent as a model for BSE in the manufacturing process of Trasylol. Biologicals. 1996;24:103–111.PubMedCrossRefGoogle Scholar
  25. 25.
    Hausenloy D, Pagano D, Keogh B. Aprotinin—still courting controversy. Lancet. 2008;371:449–450.PubMedCrossRefGoogle Scholar
  26. 26.
    Ireland D, Harrall R, Curry V, Holloway G, Hackney R, Hazleman B, Riley G. Multiple changes in gene expression in chronic human Achilles tendinopathy. Matrix Biol. 2001;20:159–169.PubMedCrossRefGoogle Scholar
  27. 27.
    Komurcu M, Akkus O, Basbozkurt M, Gur E, Akkas N. Reduction of restrictive adhesions by local aprotinin application and primary sheath repair in surgically traumatized flexor tendons of the rabbit. J Hand Surg Am. 1997;22:826–832.PubMedCrossRefGoogle Scholar
  28. 28.
    Lee E, Vaughan DE, Parikh SH, Grodzinsky AJ, Libby P, Lark MW, Lee RT. Regulation of matrix metalloproteinases and plasminogen activator inhibitor-1 synthesis by plasminogen in clutured human vascular smooth muscle cells. Circ Res. 1996;78:44–49.PubMedGoogle Scholar
  29. 29.
    Lo I, Marchuk L, Hollinshead R, Hart D, Frank C. Matrix metalloproteinase and tissue inhibitor of matrix metalloproteinase mRNA levels are specifically altered in torn rotator cuff tendons. Am J Sports Med. 2004;32:1223–1229.PubMedCrossRefGoogle Scholar
  30. 30.
    Maffulli N, Testa V, Capasso G, Sullo A. Calcific insertional Achilles tendinopathy. Reattachment with bone anchors. Am J Sports Med. 2004;32:174–182.PubMedCrossRefGoogle Scholar
  31. 31.
    Magra M, Maffulli N. Matrix metalloproteases: a role in overuse tendinopathies. Br J Sports Med. 2005;39:789–791.PubMedCrossRefGoogle Scholar
  32. 32.
    Mangano D, Tudor I, Dietzel C. Group MSoPIR, Foundation IRaE. The risk associated with aprotinin in cardiac surgery. New Engl J Med. 2006;354:353–365.PubMedCrossRefGoogle Scholar
  33. 33.
    Mouton R, Finch D, Davies I, Binks A, Zacharowski K. Effect of aprotinin on renal dysfunction in patients undergoing on-pump and off-pump cardiac surgery: a retrospective observational study. Lancet. 2008;371:475–482.PubMedCrossRefGoogle Scholar
  34. 34.
    National Health and Medical Research Council Web site. National Statement on Ethical Conduct in Human Research. Available at: Accessed June 4, 2007.
  35. 35.
    Orchard J, Hofman J, Brown R. The risks of local aprotinin injections for treating chronic tendinopathy. Sport Health. 2005;23:24–28.Google Scholar
  36. 36.
    Orchard J, Massey A, Rimmer J, Hofman J, Brown R. Delay of 6 weeks between aprotinin injections for tendinopathy reduces risk of allergic reaction. J Sci Med Sport. 2007: Aug 11 epub ahead of print.Google Scholar
  37. 37.
    Rabago D, Best TM, Beamsley M, Patterson J. A systematic review of prolotherapy for chronic musculoskeletal pain. Clin J Sport Med. 2005;15:376–380.PubMedCrossRefGoogle Scholar
  38. 38.
    Rochcongar P, Thoribe B, Le Beux P, Jan J. Tendinopathie calcanéenne et sport : place des injections d’aprotinin. Sci Sports. 2005;20:261–267.CrossRefGoogle Scholar
  39. 39.
    Rukin NJ, Maffulli N. Systemic allergic reactions to aprotinin injection around the Achilles tendon. J Sci Med Sport. 2007;10:320–322.PubMedCrossRefGoogle Scholar

Copyright information

© The Association of Bone and Joint Surgeons 2008

Authors and Affiliations

  • John Orchard
    • 1
  • Andrew Massey
    • 2
  • Richard Brown
    • 3
  • Adéline Cardon-Dunbar
    • 4
  • Jamie Hofmann
    • 5
  1. 1.Sports Medicine at Sydney UniversityUniversity of SydneySydneyAustralia
  2. 2.University of BathBathUK
  3. 3.Brisbane Orthopaedic and Sports Medicine CentreBrisbaneAustralia
  4. 4.University of New South WalesSydneyAustralia
  5. 5.Free UniversityAmsterdamThe Netherlands

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