Transferrin as a Possible Treatment for Anemia of Inflammation in the Critically Ill

  • M. BoshuizenEmail author
  • G. Li Bassi
  • N. P. Juffermans
Part of the Annual Update in Intensive Care and Emergency Medicine book series (AUICEM)


Previously termed ‘anemia of chronic diseases’, anemia developing as a consequence of inflammation is now called anemia of inflammation. In this chapter, we describe the prevalence and etiology of anemia of inflammation. Therapeutic strategies for anemia of inflammation that are currently under development are discussed, with a special emphasis on the rationale of transferrin as a novel therapy for anemia of inflammation.


  1. 1.
    Vincent JL, Baron JF, Reinhart K, et al. Anemia and blood transfusion in critically ill patients. JAMA. 2002;288:1499–507.Google Scholar
  2. 2.
    Walsh TS, Lee RJ, Maciver CR, et al. Anemia during and at discharge from intensive care: the impact of restrictive blood transfusion practice. Intensive Care Med. 2006;32:100–9.CrossRefGoogle Scholar
  3. 3.
    Corwin HL, Gettinger A, Pearl RG, et al. The CRIT Study: anemia and blood transfusion in the critically ill—current clinical practice in the United States. Crit Care Med. 2004;32:39–52.CrossRefGoogle Scholar
  4. 4.
    Sihler KC, Napolitano LM. Anemia of inflammation in critically ill patients. J Intensive Care Med. 2008;23:295–302.CrossRefGoogle Scholar
  5. 5.
    Lasocki S, Baron G, Driss F, et al. Diagnostic accuracy of serum hepcidin for iron deficiency in critically ill patients with anemia. Intensive Care Med. 2010;36:1044–8.CrossRefGoogle Scholar
  6. 6.
    Prakash D. Anemia in the ICU: anemia of chronic disease versus anemia of acute illness. Crit Care Clin. 2012;28:333–43.CrossRefGoogle Scholar
  7. 7.
    Pieracci FM, Barie PS. Diagnosis and management of iron-related anemias in critical illness. Crit Care Med. 2006;34:1898–905.CrossRefGoogle Scholar
  8. 8.
    Ganz T. Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation. Blood. 2003;102:783–8.CrossRefGoogle Scholar
  9. 9.
    Truman-Rosentsvit M, Berenbaum D, Spektor L, et al. Ferritin is secreted via 2 distinct nonclassical vesicular pathways. Blood. 2018;131:342–52.CrossRefGoogle Scholar
  10. 10.
    Ritchie RF, Palomaki GE, Neveux LM, et al. Reference distributions for the negative acute-phase serum proteins, albumin, transferrin and transthyretin: a practical, simple and clinically relevant approach in a large cohort. J Clin Lab Anal. 1999;13:273–9.CrossRefGoogle Scholar
  11. 11.
    Weiss G, Goodnough LT. Anemia of chronic disease. N Engl J Med. 2005;352:1011–23.CrossRefGoogle Scholar
  12. 12.
    Holst LB, Haase N, Wetterslev J, et al. Lower versus higher hemoglobin threshold for transfusion in septic shock. N Engl J Med. 2014;371:1381–91.CrossRefGoogle Scholar
  13. 13.
    Cassat JE, Skaar EP. Iron in infection and immunity. Cell Host Microbe. 2013;13:509–19.CrossRefGoogle Scholar
  14. 14.
    Hébert PC, et al. TRICC Trial—a multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. N Engl J Med. 1999;340:409–17.CrossRefGoogle Scholar
  15. 15.
    Murphy GJ, Pike K, Rogers CA, et al. Liberal or restrictive transfusion after cardiac surgery. N Engl J Med. 2015;372:997–1008.CrossRefGoogle Scholar
  16. 16.
    Carson JL, Terrin ML, Noveck H, et al. Liberal or restrictive transfusion in high-risk patients after hip surgery. N Engl J Med. 2011;365:2453–62.CrossRefGoogle Scholar
  17. 17.
    Pieracci FM, Stovall RT, Jaouen B, et al. A multicenter, randomized clinical trial of IV iron supplementation for anemia of traumatic critical illness. Crit Care Med. 2014;42:2048–57.CrossRefGoogle Scholar
  18. 18.
    Shah A, Roy NB, McKechnie S, et al. Iron supplementation to treat anaemia in adult critical care patients: a systematic review and meta-analysis. Crit Care. 2016;20:306.CrossRefGoogle Scholar
  19. 19.
    Litton E, Baker S, Erber WN, et al. Intravenous iron or placebo for anaemia in intensive care: the IRONMAN multicentre randomized blinded trial. Intensive Care Med. 2016;42:1715–22.CrossRefGoogle Scholar
  20. 20.
    Pieracci FM, Henderson P, Rodney JRM, et al. Randomized, double-blind, placebo-controlled trial of effects of enteral iron supplementation on anemia and risk of infection during surgical critical illness. Surg Infect. 2009;10:9–19.CrossRefGoogle Scholar
  21. 21.
    Garrido-Martín P, Nassar-Mansur MI, de la Llana-Ducrós R, et al. The effect of intravenous and oral iron administration on perioperative anaemia and transfusion requirements in patients undergoing elective cardiac surgery: a randomized clinical trial. Interact Cardiovasc Thorac Surg. 2012;15:1013–8.CrossRefGoogle Scholar
  22. 22.
    Madi-Jebara SN, Sleilaty GS, Achouh PE, et al. Postoperative intravenous iron used alone or in combination with low-dose erythropoietin is not effective for correction of anemia after cardiac surgery. J Cardiothorac Vasc Anesth. 2004;18:59–63.CrossRefGoogle Scholar
  23. 23.
    Rohde JM, Dimcheff DE, Blumberg N, et al. Health care-associated infection after red blood cell transfusion: a systematic review and meta-analysis. JAMA. 2014;311:1317–26.CrossRefGoogle Scholar
  24. 24.
    Corwin HL, Gettinger A, Pearl RG, et al. Efficacy of recombinant human erythropoietin in critically ill patients a randomized controlled trial. JAMA. 2002;288:2827–35.CrossRefGoogle Scholar
  25. 25.
    Drueke TB, Locatelli F, Clyne N, et al. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med. 2006;355:333–40.CrossRefGoogle Scholar
  26. 26.
    Tonia T, Mettler A, Robert N, et al. Erythropoietin or darbepoetin for patients with cancer. Cochrane Database Syst Rev. 2012;2012:CD003407.Google Scholar
  27. 27.
    Marik PE, Corwin HL. Efficacy of red blood cell transfusion in the critically ill: a systematic review of the literature. Crit Care Med. 2008;36:2667–74.CrossRefGoogle Scholar
  28. 28.
    Schipperus M, Rijnbeek B, Reddy M, et al. CNTO328 (Anti-IL-6 mAb) Treatment is associated with an increase in hemoglobin (Hb) and decrease in hepcidin levels in renal cell carcinoma (RCC). Blood. 2009;114:1551 (abst).Google Scholar
  29. 29.
    Song S-NJ, Iwahashi M, Tomosugi N, et al. Comparative evaluation of the effects of treatment with tocilizumab and TNF-a inhibitors on serum hepcidin, anemia response and disease activity in rheumatoid arthritis patients. Arthritis Res Ther. 2013;15:1.Google Scholar
  30. 30.
    Song SNJ, Tomosugi N, Kawabata H, et al. Down-regulation of hepcidin resulting from long-term treatment with an anti-IL-6 receptor antibody (tocilizumab) improves anemia of inflammation in multicentric Castleman disease. Blood. 2010;116:3627–34.CrossRefGoogle Scholar
  31. 31.
    Isaacs JD, Harari O, Kobold U, et al. Effect of tocilizumab on haematological markers implicates interleukin-6 signalling in the anaemia of rheumatoid arthritis. Arthritis Res Ther. 2013;15:R204.CrossRefGoogle Scholar
  32. 32.
    Schwoebel F, van Eijk LT, Zboralski D, et al. The effects of the anti-hepcidin Spiegelmer NOX-H94 on inflammation-induced anemia in cynomolgus monkeys. Blood. 2013;121:2311–5.CrossRefGoogle Scholar
  33. 33.
    Van Eijk LT, John ASE, Schwoebel F, et al. Effect of the antihepcidin Spiegelmer lexaptepid on inflammation-induced decrease in serum iron in humans. Blood. 2014;124:2643–6.CrossRefGoogle Scholar
  34. 34.
    Sasu BJ, Cooke KS, Arvedson TL, et al. Antihepcidin antibody treatment modulates iron metabolism and is effective in a mouse model of inflammation-induced anemia. Blood. 2010;115:3616–24.CrossRefGoogle Scholar
  35. 35.
    Poli M, Girelli D, Campostrini N, et al. Heparin: a potent inhibitor of hepcidin expression in vitro and in vivo Heparin: a potent inhibitor of hepcidin expression in vitro and in vivo. Blood. 2010;117:997–1004.CrossRefGoogle Scholar
  36. 36.
    Steinbicker AU, Sachidanandan C, Vonner AJ, et al. Inhibition of bone morphogenetic protein signaling attenuates anemia associated with inflammation. Blood. 2011;117:4915–24.CrossRefGoogle Scholar
  37. 37.
    Chung MCM. Stucture and function of transferrin. Biochem Educ. 1984;12:146–54.CrossRefGoogle Scholar
  38. 38.
    Crichton RR, Charloteaux-wauters M. Iron transport and storage. Eur J Biochem. 1987;164:485–506.CrossRefGoogle Scholar
  39. 39.
    Parkkinen J, von Bonsdorff L, Ebeling F, Sahlstedt L. Function and therapeutic development of apotransferrin. Vox Sang. 2002;83(Suppl 1):321–6.CrossRefGoogle Scholar
  40. 40.
    Prakash M. Role of non-transferrin-bound iron in chornic renal failure and other disease conditions. Ren Physiol. 2007;17:188–93.Google Scholar
  41. 41.
    von Bonsdorff L, Tölö H, Lindeberg E, et al. Development of a pharmaceutical apotransferrin product for iron binding therapy. Biologicals. 2001;29:27–37.CrossRefGoogle Scholar
  42. 42.
    Hayashi A, Wada Y, Suzuki T, Shimizu A. Studies on familial hypotransferrinemia: unique clinical course and molecular pathology. Am J Hum Genet. 1993;53:201–13.PubMedPubMedCentralGoogle Scholar
  43. 43.
    Boshuizen M, van der Ploeg K, von Bonsdorff L, et al. Therapeutic use of transferrin to modulate anemia and conditions of iron toxicity. Blood Rev. 2017;31:400–5.CrossRefGoogle Scholar
  44. 44.
    Li Bassi G, Rigol M, Marti JD, et al. A novel porcine model of ventilator-associated pneumonia caused by oropharyngeal challenge with Pseudomonas aeruginosa. Anesthesiology. 2014;120:1205–15.CrossRefGoogle Scholar
  45. 45.
    Sibila O, Agustí C, Torres A, et al. Experimental Pseudomonas aeruginosa pneumonia: evaluation of the associated inflammatory response. Eur Respir J. 2007;30:1167–72.CrossRefGoogle Scholar
  46. 46.
    Luna CM, Baquero S, Gando S, et al. Experimental severe Pseudomonas aeruginosa pneumonia and antibiotic therapy in piglets receiving mechanical ventilation. Chest. 2007;132:523–31.CrossRefGoogle Scholar
  47. 47.
    Hod EA, Zhang N, Sokol SA, et al. Transfusion of red blood cells after prolonged storage produces harmful effects that are mediated by iron and inflammation. Blood. 2015;115:4284–93.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • M. Boshuizen
    • 1
    • 2
    Email author
  • G. Li Bassi
    • 3
  • N. P. Juffermans
    • 1
    • 2
  1. 1.Department of Intensive Care MedicineAmsterdam UMC, University of AmsterdamAmsterdamThe Netherlands
  2. 2.Laboratory of Experimental Intensive Care and AnesthesiologyAmsterdam UMC, University of AmsterdamAmsterdamThe Netherlands
  3. 3.Department of Pulmonary and Critical Care MedicineThorax Institute, Hospital ClinicBarcelonaSpain

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