Blood substitutes can address the unmet medical needs of some patients with hematologic disorders

Issue: July 25, 2008

ByPaul M. Ness, MD

Recent articles and editorials in the Journal of the American Medical Association and HemOnc Today have documented the safety concerns with hemoglobin-based oxygen carriers. Data from the evolving clinical trials have suggested a profile of adverse effects, perhaps due to nitric oxide scavenging, that have led some clinicians to suggest that there is no role for hemoglobin-based oxygen carriers, more commonly called a blood substitute, since current blood supplies are so safe.

Although it is certainly true that the current risks for infectious disease transmission have been minimized by a battery of tests for HIV and hepatitis B and C viruses, alleviating some of the concerns of patients and their physicians about transfusion risks, emerging viruses and other infectious agents will always be a concern until we have a reliable system of pathogen reduction for blood components. Likewise, the growing concerns about the immunomodulatory effects of blood and the possibility of adverse effects of blood that has been stored for its currently acceptable shelf-life of 42 days suggest that transfusion alternatives such as blood substitutes should not be so readily dismissed.

Paul M. Ness, MD
Paul M. Ness

It is even more unfortunate that the critics of blood substitutes have forgotten that there are groups of patients for whom currently available red cell components are not an acceptable option and for whom a hemoglobin-based oxygen carrier (HBOC) may actually have an acceptable risk–benefit ratio. Although the blood substitutes under clinical development would not be acceptable, either medically or financially, for the otherwise healthy patient who is inappropriately concerned about the safety risks of blood that may be needed for an elective surgery procedure, there are patient groups for whom the mortality without red cell transfusions remains unacceptably high and for whom some form of blood substitute may be life-saving.

Patients in need of blood substitutes

One example of a forgotten transfusion recipient would be the patient who presents with severe anemia due to autoimmune hemolysis in which the readily available red cell supply is serologically incompatible. It is not uncommon that these patients may also present with reticulocytopenia, worsening the anemia in a short time. In many cases, these patients have had previous pregnancies or transfusions putting them at risk for alloantibody formation and adverse hemolytic transfusion reactions. This scenario has often resulted in a reluctance of even experienced hematologists to provide incompatible blood, sometimes mistaking the apparent signs of clinical stability that can mask the rapid deterioration that can occur suddenly with hemoglobin levels of less than 3 g/dL. The availability of a blood substitute that could provide hemoglobin support while the serologic complexities are being resolved could be life-saving for these patients.

Another clinical scenario well known to hematologists is the patient with sickle cell anemia who presents with worsening anemia in the face of an acute chest syndrome or other clinical crisis requiring transfusion. Although most patients with sickle cell anemia tolerate their baseline hemoglobin status of 6 g/dL to 8 g/dL, it is not uncommon for these patients to have transient worsening of anemia where the hemoglobin may fall below 4 g/dL. Many patients with sickle cell anemia present with multiple alloantibodies resulting from previous transfusions; some of these patients also have unusual alloantibodies often directed to uncommon phenotypes in the Rh blood system where only rare blood would be compatible. In these situations, it may be impossible to identify the source of the incompatibility quickly or to locate suitable units of blood that would be compatible. A blood substitute could provide precious time to support these patients while the workup ensues and the search for rare blood is taking place.

A third group of patients who would benefit from a blood substitute are religious objectors, most commonly Jehovah’s Witnesses. It has been well documented in the medical literature that patients who refuse blood as their hemoglobin falls below 5 g/dL have increased mortality in association with medical illnesses, trauma or surgical interventions where transfusion would often be recommended. Although religious objectors will not permit transfusion with red cell concentrates, many of these patients will accept a blood substitute manufactured from human red cells after an informed discussion as a matter of conscience.

Balance risk and benefit

Although it remains unclear whether an HBOC or other forms of blood substitute will have an acceptable risk–benefit profile to justify common use for all potential red cell recipients, it is clear to hematologists and transfusion medicine specialists that there are patient groups who currently will die in the absence of available blood support and whose medical care would be enhanced by some form of blood substitute. It is important that we recognize the unmet medical needs of these patients before we dismiss the concept of a blood substitute. What will be important is to continue to address the challenge by assessing the risks for evolving blood substitutes in the context of the benefit to the patient groups, to which they would be applied, recognizing that some patients will have a high risk for mortality in their absence.

Paul M. Ness, MD, is a member of the Board of Directors of Northfield Laboratories, a company developing Polyheme as an HBOC for clinical use. He is also Director of Transfusion Medicine at Johns Hopkins University and a member of the HemOnc Today Editorial Board.

For more information:

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Conley CL, Lippman SM, Ness PM. Autoimmune hemolytic anemia with reticulocytopenia: A medical emergency. J Am Med Assoc. 1980;244:1685.

HemOnc Today. Hemoglobin-based blood substitutes: increased risk and no clinical benefit. May 10, 2008.

HemOnc Today. Hemoglobin-based blood substitutes increase risk for death, MI. June 25, 2008.

Klein HG, Anderson D, Bernardi MJ, et al. Pathogen inactivation: making decisions about new technologies: report of a consensus conference. Transfusion. 2007;47:2338-2347.

Koch CG, Ku L, Sessler DI, et al. Duration of red-cell storage and complications after cardiac surgery. N Engl J Med. 2008;358:1229-1239.

Lanzkron S, Moliterno AR, Norris EJ, et al. Polymerized human Hb use in acute chest syndrome: a case report. Transfusion. 2002;42:1422-1427.

Natanson C, Kern SJ, Lurie P, et al. Cell-free hemoglobin-based blood substitutes and risk of myocardial infarction and death. JAMA. 2008;doi:10.1001/jama.299.jrv80007.

Ness PM. How do I encourage clinicians to transfuse mismatched blood to patients with autoimmune hemolytic anemia in urgent situations? Transfusion. 2006;46:1859-1862.