Skip to main content
Log in

Potential Clinical Applications of Recombinant Human Haemoglobin in Blood Conservation

  • Review Article
  • Published:
BioDrugs Aims and scope Submit manuscript

Abstract

Haemoglobin solutions have been tried as blood substitutes for decades with little success. Problems with early haemoglobin solutions include instability of the haemoglobin tetramer in the plasma, resulting in dissociation of the protein into dimers, as well as excessively high oxygen affinity for clinical oxygen transport capabilities. Newer haemoglobin solutions are currently under development and may prove adequate to transport oxygen while avoiding excessive toxicity However, these compounds pose other difficulties, including a short plasma half-life and the potential for systemic hypertension due to nitric oxide binding.

Several haemoglobin solutions are now undergoing human testing for potential clinical use. Haemoglobin can be harvested from outdated packed red blood cell units and chemically altered for use in clinical scenarios. Likewise, bovine haemoglobin may be obtained and modified for use as a blood substitute. While both these approaches may yield clinically useful oxygen carrying solutions, neither is completely free from infectious risk. The use of recombinant technology to produce a genetically altered haemoglobin from Escherichia coli allows avoidance of infectious risks and a functional haemoglobin which does not need further chemical modification. Use of this first generation of recombinant human haemoglobin as a blood substitute may be limited due to its short half-life of <12 hours, but clinical uses such as replacement fluid for acute normovolaemic haemodilution during the perioperative period may allow significant blood savings for patients and the potential to avoid patient exposure to allogeneic transfusions.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Winslow RM. Hemoglobin-based red cell substitutes. Baltimore (MD): The Johns Hopkins University Press, 1992

    Google Scholar 

  2. Amberson WR, Jennings JJ, Rhode CM. Clinical experience with hemoglobin-saline solutions. Am J Physiol 1949; 1: 469–89

    CAS  Google Scholar 

  3. Newman RJ, Podolsky D. Bad blood. U.S. News & World Report 1994 Jun 27: 68–78

  4. Williams AE, Thomson RA, Schreiber GB, et al. Estimates of infectious disease risk factors in US blood donors. JAMA 1997; 277: 967–72

    Article  PubMed  CAS  Google Scholar 

  5. Valeri CR, Hirsch NM. Restoration in vivo of erthyrocyte aden-osine triphosphate, 2,3-diphosphoglycerate, potassium ion, and sodium ion concentrations following the transfusion of acid-citrate-dextrose-stored human red blood cells. J Lab Clin Med 1969; 73: 722–33

    PubMed  CAS  Google Scholar 

  6. Howland WS, Schweizer O. Physiologic compensation for storage lesion of bank blood. Anesth Analg 1965; 44: 8–16

    Article  PubMed  CAS  Google Scholar 

  7. Myhre BA. Fatalities from blood transfusion. JAMA 1980; 244: 1333–5

    Article  PubMed  CAS  Google Scholar 

  8. Lackritz EM, Satten GA, Aberle-Grasse J, et al. Estimated risk of transmission of the human immunodeficiency virus by screened blood in the United States. N Engl J Med 1995; 333: 1721–5

    Article  PubMed  CAS  Google Scholar 

  9. Landers DF, Hill GE, Wong KC, et al. Blood transfusion-induced immunomodulation. Anesth Analg 1996; 82: 187–204

    PubMed  CAS  Google Scholar 

  10. Gascon P, Zoumbos NC, Young NS. Immunologic abnormalities in patients receiving multiple blood transfusions. Ann Int Med 1984; 100: 173–7

    PubMed  CAS  Google Scholar 

  11. Murphy P, Heal JM, Blumberg N. Infection or suspected infection after hip replacement surgery with autologous or homologous blood transfusions. Transfusion 1991; 31: 212–7

    Article  PubMed  CAS  Google Scholar 

  12. Schriemer PA, Longnecker DE, Mintz PD. The possible immunosuppressive effects of perioperative blood transfusion in cancer patients. Anesthesiology 1988; 68: 422–8

    Google Scholar 

  13. Waymack JP, Warden GD, Alexander JW, et al. Effect of blood transfusion and anesthesia on resistance to bacterial peritonitis. J Surg Res 1987; 42: 528–35

    Article  PubMed  CAS  Google Scholar 

  14. Wu HS, Little AG. Perioperative blood transfusions and cancer recurrence. J Clin Oncol 1988; 6: 1348–54

    PubMed  CAS  Google Scholar 

  15. Blumberg N, Heal JM, Murphy P, et al. Association between transfusion of whole blood and recurrence of cancer. BMJ [Clin Res] 1986; 293: 530–3

    Article  CAS  Google Scholar 

  16. Blumberg N, Heal JM. Transfusion and recipient immune function. Arch Pathol Lab Med 1989; 113: 246–53

    PubMed  CAS  Google Scholar 

  17. Bradley JA. The blood transfusion effect: experimental aspects. Immunol Lett 1991; 29: 127–32

    Article  PubMed  CAS  Google Scholar 

  18. MacFarlane BJ, Marx L, Anquist K, et al. Analysis of a protocol for an autologous blood transfusion program for total joint replacement surgery. Can J Surg 1988; 31: 126–9

    PubMed  CAS  Google Scholar 

  19. Kruskall MS, Popovsky MA, Pacini DG, et al. Autologous versus homologous donors: evaluation of markers for infectious disease. Transfusion 1988; 28: 286–8

    Article  PubMed  CAS  Google Scholar 

  20. Etchason J, Petz L, Keeler E, et al. The cost effectiveness of preoperative autologous blood donations. N Engl J Med 1995; 332: 719–24

    Article  PubMed  CAS  Google Scholar 

  21. Casthely PA, Yoganathan T, Salem M, et al. Phlebotomy via the pulmonary artery catheter introducer for intraoperative autotransfusion. J Cardiothorac Anesth 1990; 4: 43–5

    Article  PubMed  CAS  Google Scholar 

  22. Whitten CW, Allison PM, Latson TW, et al. Evaluation of laboratory coagulation and lytic parameters resulting from autologous whole blood transfusion during primary aortocoronary artery bypass grafting. J Clin Anesth 1996; 8: 229–35

    Article  PubMed  CAS  Google Scholar 

  23. Landow L. Perioperative hemodilution. Can J Surg 1987; 30: 321–5

    PubMed  CAS  Google Scholar 

  24. Feldman JM, Roth JV, Bjoraker DG. Maximum blood savings by acute normovolemic hemodilution. Anesth Analg 1995; 80: 108–13

    PubMed  CAS  Google Scholar 

  25. Weiskopf RB. Mathematical analysis of isovolemic hemodilution indicates that it can decrease the need for allogeneic blood transfusion. Transfusion 1995; 35: 37–41

    Article  PubMed  CAS  Google Scholar 

  26. Ness PM, Bourke DL, Walsh PC. A randomized trial of perioperative hemodilution versus transfusion of preoperatively deposited autologous blood in elective surgery. Transfusion 1992; 32: 226–30

    Article  PubMed  CAS  Google Scholar 

  27. Klimberg IW. Autotransfusion and blood conservation in urologic oncology. Semin Surg Oncol 1989; 5: 286–92

    Article  PubMed  CAS  Google Scholar 

  28. Jones JW, Rawitscher RE, McLean TR, et al. Benefit from combining blood conservation measures in cardiac operations. Ann Thorac Surg 1991; 51: 541–4

    Article  PubMed  CAS  Google Scholar 

  29. Bland LA, Villarino ME, Arduino MJ, et al. Bactëriologic and endotoxin analysis of salvaged blood used in autologous transfusions during cardiac operations. J Thorac Cardiovasc Surg 1992; 103: 582–8

    PubMed  CAS  Google Scholar 

  30. Rabiner SF, Helbert SR, Lopas H. Evaluation of stroma-free hemoglobin for use as a plasma expander. J Exp Med 1967; 126: 1127–42

    Article  PubMed  CAS  Google Scholar 

  31. Amberson W, Flexner J, Steggerda FR, et al. On the use of Ringer-Locke solutions containing hemoglobin as a substitute for normal blood in mammals. J Cell Comp Physiol 1937; 5: 359–82

    Article  Google Scholar 

  32. Hoffman SJ, Looker DL, Roehrich JM, et al. Expression of fully functional tetrameric human hemoglobin in Escherichia coli. Proc Natl Acad Sci 1990; 87: 8521–5

    Article  PubMed  CAS  Google Scholar 

  33. Klocke RA. Effect of alterations in oxygen binding to hemoglobin on oxygen delivery. Pulm Crit Care Update 1990; 6: 1–7

    Google Scholar 

  34. Klocke RA. Oxygen transport and 2, 3-diphosphoglycerate (DPG). Chest 1972; 62Suppl. 2: 79S–85S

    PubMed  Google Scholar 

  35. Bunn HF. Differences in the interaction of 2,3-diphosphoglycerate with certain mammalian hemoglobins. Science 1971; 172: 1049–50

    Article  PubMed  CAS  Google Scholar 

  36. Anonymous. BSE-bovine spongiform encephalopathy (’mad cow disease’). J R Soc Health 1996; 116: 322-33

  37. Cullen M, Bellis M, Tocque K. Bovine spongiform encephalopathy. Public health officials are confused over whether to eat beef [letter; comment]. BMJ 1996; 313: 1146

    Article  PubMed  CAS  Google Scholar 

  38. Dealler S. A matter for debate: the risk of bovine spongiform encephalopathy to humans posed by blood transfusion in the UK [see comments]. Transfus Med 1996; 6: 217–22

    Article  PubMed  CAS  Google Scholar 

  39. Looker D, Abbott-Brown D, Cozart P, et al. A human recombinant haemoglobin designed for use as a blood substitute. Nature 1992; 356: 258–60

    Article  PubMed  CAS  Google Scholar 

  40. Viele MK, Weiskopf RB, Fisher D. Recombinant human hemoglobin does not affect renal function in humans: analysis of safety and pharmacokinetics. Anesthesiology 1997; 86: 848–58

    Article  PubMed  CAS  Google Scholar 

  41. Lessen R, Williams MJ, Seltzer JL, et al. A safety study of recombinant human hemoglobin for intraoperative transfusion therapy. Anesth Analg 1996; 81: S–275

    Google Scholar 

  42. Leone BJ, Chuey C, Gleason D, et al. Can recombinant human hemoglobin make ANH more effective? An initial feasibility and safety study. Anesth Analg 1996; 81: S–274

    Google Scholar 

  43. Rand PW, Lacombe E, Hunt HE, et al. Viscosity of normal human blood under normothermic and hypothermic conditions. J Appl Physiol 1964; 19: 117–22

    PubMed  CAS  Google Scholar 

  44. Hint H. The pharmacology of dextran and the physiological background for the clinical use of Rheomacrodex and Macrodex. Acta Anaesth Belgica 1968; 2: 119–38

    Google Scholar 

  45. Messmer KFW. Acceptable hematocrit levels in surgical patients. World J Surg 1987; 11: 41–6

    Article  PubMed  CAS  Google Scholar 

  46. Nelson AH, Fleisher LA, Rosenbaum SH. Relationship between postoperative anemia and cardiac morbidity in highrisk vascular patients in the intensive care unit. Crit Care Med 1993; 21: 860–6

    Article  PubMed  CAS  Google Scholar 

  47. Spahn DR, Smith LR, McRae RL, et al. Effects of acute isovolemic hemodilution and anesthesia on regional function in left ventricular myocardium with compromised coronary blood flow. Acta Anaesth Scand 1992; 36: 628–36

    Article  PubMed  CAS  Google Scholar 

  48. Spahn DR, Smith LR, Veronee CD, et al. Acute isovolemic hemodilution and blood transfusion: effects on regional function and metabolism in myocardium with compromised coronary blood flow. J Thorac Cardiovasc Surg 1993; 105: 694–704

    PubMed  CAS  Google Scholar 

  49. Spahn DR, Smith LR, Schell RM, et al. Importance of severity of coronary artery disease for the tolerance to normovolemic hemodilution: comparison of single versus multivessel stenoses in a canine model. J Thorac Cardiovasc Surg 1994; 108: 231–9

    PubMed  CAS  Google Scholar 

  50. Spahn DR, Fielding RM, Gillespie R, et al. Cardiovascular effects of recombinant human hemoglobin (rHbl.l) in a normovolemic canine model of hemodilution [abstract]. Br J Anaesth 1993; 71: 761P

    Google Scholar 

  51. Cole DJ, Schell RM, Drummond JC, et al. Focal cerebral ischemia in rats: effect of hemodilution with alpha-alpha cross-linked hemoglobin on brain injury and edema. Can J Neurol Sei 1993; 20: 30–6

    CAS  Google Scholar 

  52. Cole DJ, Schell RM, Drummond JC, et al. Focal cerebral ischemia in rats. Effect of hypervolemic hemodilution with diaspirin cross-linked hemoglobin versus albumin on brain injury and edema. Anesthesiology 1993; 78: 335–42

    Article  PubMed  CAS  Google Scholar 

  53. Cole DJ, Schell RM, Drummond JC. Diaspirin crosslinked hemoglobin (DCLHb): effect of hemodilution during focal cerebral ischemia in rats. Artif Cells Blood Substit Immobil Biotechnol 1994; 22: 813–8

    Article  PubMed  CAS  Google Scholar 

  54. Schreiber GB, Busch MP, Kleinman SH, et al. The risk of tranfusion-transmitted viral infections. N Engl J Med 1996; 334: 1685–90

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Bruce J. Leone.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Leone, B.J. Potential Clinical Applications of Recombinant Human Haemoglobin in Blood Conservation. BioDrugs 11, 211–221 (1999). https://doi.org/10.2165/00063030-199911030-00007

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00063030-199911030-00007

Keywords

Navigation