An Examination of Ethical Issues Raised in the Pretreatment of Normal Volunteer Granulocyte Donors With Granulocyte Colony-Stimulating Factor

Medical ethics, or bioethics, focuses on ethical issues arising in areas of biological and medical interactions. Ethical and moral dilemmas can arise from any interaction or situation where there is conflict, confusion, or uncertainty between recognized moral principles and rules. For example, monetary payment for organ or blood donations, the collection and storage of umbilical cord blood stem cells, the allocation of scarce blood resources, and the administration of hematopoietic growth factors to otherwise healthy blood and bone marrow donors, to name only a few, are areas which have created a number of ethical issues in recent years. Table 1 details several of the main principles of biomedical ethics that can be applied in the assessment and analysis of bioethical issues.

Careful consideration of some of the ethical issues surrounding the treatment of healthy donors with hematopoietic growth factors, such as granulocyte colony-stimulating factor (G-CSF), is warranted and is the focus of this article. Ethical questions that need to be examined include the following: Does the potential benefit to the recipient justify the unknown risks to the medicated granulocyte donor? Who should act as an advocate for donors so that their interests are protected? What is the role and quality of informed consent for donors undergoing G-CSF administration? Is monetary compensation appropriate for donors administered G-CSF as part of a research protocol? In this article we concentrate on the use of G-CSF for the collection of granulocytes from the normal donor, discuss the ethical questions involved, and, based on ethical principles and our ethical assessments, provide recommendations for an ethically supportable use of G-CSF in normal blood donors.

Historically, the use of drugs (eg, ferrous sulfate) in normal blood donors to enhance blood component collection has been a long-accepted practice, and repeat whole blood donors (particularly female donors) have been encouraged to supplement their diets with ferrous sulfate to replace iron stores lost during donation.1–3 Corticosteroids and hydroxyethyl starch are routinely administered to granulocyte donors to enhance collection.3 More recently, G-CSF and granulocyte-macrophage colony-stimulating factor have been administered to enhance the collection of granulocytes or peripheral blood stem cells (PBSC) from normal donors.3,4 Erythropoietin and thrombopoietin are being investigated to increase the yield of whole blood/red cell donations and apheresis platelet collections, respectively.3,5 Stem cell factor is also being investigated as a potential agent to enhance the collection of PBSC.6 

Despite the prevalence and enthusiasm for their use, these drugs can have significant side effects. Ferrous sulfate causes upper and lower gastrointestinal symptoms in up to one third of individuals. Chronic ferrous sulfate use can potentially lead to iron overload. A further indirect hazard associated with ferrous sulfate is accidental iron poisoning in children.7 The side effects of corticosteroids include headache, flushing, insomnia, euphoria, palpitation, epigastric acidity, alteration of blood glucose levels, and potential osteopenia (when used acutely or chronically).3 Hydroxyethyl starch has reportedly caused febrile reactions, increased blood volume with resulting edema, hypertension, and headache, as well as allergic reactions, ranging in severity from urticaria to anaphylaxis. These secondary effects may require treatment of otherwise healthy blood donors with a variety of analgesics and diuretics.

Although the administration of G-CSF to healthy granulocyte or PBSC donors has not yet been approved by the US Food and Drug Administration, its use has been reported in more than 500 normal donors to date. The majority of donors pretreated with G-CSF report side effects, including bone pain, myalgias, arthralgias, headache, fever, chills, gastrointestinal discomfort, paresthesias, chest pain, edema, and fatigue (Table 2).8–14 Many otherwise healthy donors required additional treatment for these secondary side effects (Table 2).8–14 Both Anderlini et al11 and Stroncek et al15 found that G-CSF administration was immediately associated with mild abnormalities of serum enzymes and potassium levels. Their findings confirmed previously documented, transient, dose-dependent changes in serum electrolyte and enzyme levels, presumably due to marrow expansion, but which were considered to be clinically unimportant.16 Another effect of G-CSF administration to normal donors is mild thrombocytopenia, which becomes more marked after PBSC collection and is reported to resolve within several weeks following the procedure.8,10,11,15,17 The authors are also aware of at least one anecdotal case of splenic rupture in an otherwise normal individual who received G-CSF for PBSC collection (Scott Rowley, MD, oral communication, October 1997).

Several studies have reviewed the effects of G-CSF in immunosuppressed individuals, patients with connective tissue diseases, patients with underlying malignancy, and patients undergoing treatment for neutropenia.16,18–20 Ophthalmologic complications, including retinal hemorrhage and acute iritis, as well as thyroid dysfunction, osteopenia/osteoporosis, and splenomegaly, have occurred in some of these patients. Potentially, donors may be unaware that they harbor such an underlying illness and may be at increased risk for such complications.19 

The long-term effects of G-CSF administration to healthy donors are less well documented. Concerns regarding the potential risk of development of hematopoietic abnormalities, such as myeloproliferative disorders or stem cell exhaustion, exist. However, only 2 studies to date have examined this issue. One study evaluated 3 volunteers 5 years after administration of G-CSF.21 Peripheral blood and bone marrow aspiration specimens were evaluated in these volunteers, as well as karyotype analysis using G-banding techniques and fluorescence in situ hybridization probes specific for chromosome 7 abnormalities. Each volunteer was found to have a normal karyotype, normal peripheral blood findings, and normal bone marrow studies 5 years after receiving 1 course of G-CSF. Another study evaluated 19 PBSC donors who were pretreated with G-CSF before 2 donation periods 1 year apart.22 One year after the administration of G-CSF, the donors' peripheral blood counts were normal and unchanged. Furthermore, the number of stem cells expressing the CD34 antigen in volunteers pretreated with G-CSF 1 year after a similar pretreatment and PBSC collection was similar. Clearly, too few data have been collected to evaluate accurately the potential long-term risk of G-CSF administration to the normal donor. In reality, relatively little is known regarding the short- and long-term effects of G-CSF in healthy donors.

Living tissue and organ donation involves persons who willingly violate their own bodily integrity to assist in the treatment of others. These donors provide a range of “products,” from blood cells to gametes, to whole organs. Regarding such donations the American Medical Association has stated that there should be “adequate safeguards to ensure that the health of donors and recipients is in no way jeopardized. . . .” 2 To assure a donor's safety, drugs administered to donors to assist or enhance donation must be investigated thoroughly before their widespread use outside of experimental protocols. As noted above, in the case of G-CSF administration, only a small number of studies have examined the short-term effects on healthy donors, and there have been virtually no long-term studies or follow-up.8–22 Furthermore, some investigators suggest that the careful observation and monitoring of at least 2000 donors for a minimum of 10 years after completion of drug administration is required to define adequately the risk of hematopoietic malignancy among this group.24 

Not only are the long-term side effects of G-CSF in the healthy donor unclear, but so are the side effects of multiple granulocyte or stem cell donations. Investigators have noted that after multiple platelet donations, some donors demonstrate a permanently lowered baseline peripheral platelet count.25 Is it possible that with the increasing use of G-CSF donors who donate on multiple occasions risk permanent reductions of their granulocyte or PBSC counts?

Potential risks to granulocyte or PBSC donors are not always easy to identify, whereas benefits to recipients (eg, allogeneic bone marrow/stem cell transplantation) are more easily identified and include possible extension of life, improved quality of life, return of functional capacity, and alleviation of suffering.14,26,27 

In the case of allogeneic granulocyte collection, corticosteroids and hydroxyethyl starch have been used to prime donors and enhance the total number of granulocytes collected.2 However, investigators have shown that low-dosage (3–6 μg/kg) G-CSF prestimulation allows the harvest of as much as a fivefold increase in the number of normal granulocytes when compared with the use of corticosteroids and hydroxyethyl starch.12,28 Historically, adequate and effective support of the severely neutropenic, infected patient by granulocyte transfusion was thought to be severely limited due to the minimal number of functioning granulocytes transfused. The use of G-CSF priming may overcome this earlier limitation of therapy and provide an effective addition to the armamentarium in the treatment of neutropenic patients.13,28 

Despite both known and theoretical patient benefits, as noted, the effects of pretreatment of donors with colony-stimulating factors are unclear because solid clinical data are lacking. This is ethically problematic. Until adequate and longitudinal safety and efficacy studies have been performed, the health of donors could be jeopardized.

Advocacy has a central role in promoting and safeguarding the well-being of patients and clients, but the concept of the transfusion medicine physician in the role of donor or patient advocate has received little attention in the literature.29,30 At various times transfusion medicine physicians are called on to advocate for various groups or individuals (eg, the needs of potential transfusion recipients and the welfare and best interests of potential donors). Transfusion medicine physicians are likely to fulfill their duties to transfusion recipients, donors, or other physicians based on whether they are blood center–based, hospital-based, or both. Traditionally, blood centers and blood banks have filled the need for blood components based on patient-centered needs. Currently, patient needs are met by actively recruiting normal individuals to donate, and this practice often involves the use of marketing strategies, donor incentives, and public pleas on behalf of patients in need. Risks to the donor have been perceived to be few, and the donor has been viewed as an almost inexhaustible renewable source of hematopoietic cells.

Apropos to this discussion, the transfusion medicine physician may be asked, or pressured, to administer growth factors to donors to optimize granulocyte yields. As noted above, these donors may be subject to side effects and other poorly defined short- and long-term risks. The transfusion medicine physician is thus faced with competing or conflicting ethical claims of protecting the donor, encouraging the donation, respecting the needs of the recipient, and respecting/honoring the physician-patient relationship.

The role of advocate helps to explain the multiple interests that the transfusion medicine physician should try to create, promote, and safeguard. The goals of an advocate in transfusion medicine might be as delineated in Table 3.31 

In the case of granulocyte donation, the transfusion medicine physician must be able to balance these competing influences in order to discuss the known and unknown risks directly with the potential donor. This physician-donor dialogue must remain objective so that the prospective donor can make an autonomous informed decision about whether to undergo growth factor–stimulated donation. This respect for an individual's ability to be a part of the decision-making process has been referred to as “enhanced autonomy.” 32 

Because of the known and unknown risks to donors, transfusion medicine physicians may have additional obligations to advocate for donors and to promote their best interests. To foster a mutually participatory relationship between the transfusion medicine physician and the donor, the points in Table 4 should be considered.33 

The transfusion medicine physician is not only a medical expert in transfusion, but is also a manager, an educator, and a clinical researcher, who must consider and balance the interests of donors, recipients, and other physicians. Thus, the role of advocate (for donor or recipient) must—and should—fall primarily on the shoulders of the transfusion medicine physician. How to balance these multiple roles and potential conflicts of interest are challenges faced by transfusion medicine physicians.

In the bioethics literature, the major elements of informed consent usually identified are detailed in Table 5.34 In a discussion about pretreatment of normal volunteer donors with G-CSF, all 4 elements have relevance for informed consent by donors, although the first element (competence/decisional capacity) may be the least problematic, because given a fairly large pool of healthy adult volunteers, there are no medical reasons nor is there justification for using pediatric donors or adult donors with impaired cognitive abilities.

Regarding the correlative elements of disclosure of information and the comprehension of that information, a concern on the part of transfusion medicine physicians will be how much information about the nature, purpose, risks, benefits, and alternatives is sufficient for the donor to make an informed choice? An extremely demanding criterion of full and complete disclosure could make informed consent impossible to obtain for pretreatment of normal volunteer blood donors.35 On the other hand, an “event model” or criterion36 that reduces informed consent to providing persons with “information material to the decision” 37 and symbolized by a consent form with its detailed recital of risks and benefits seems too minimalistic.

The fourth element of informed consent (voluntariness) raises concerns about coercion, manipulation, control, and any undue pressure or influence that may be placed on the donor. In general, donors should make a substantially free and voluntary choice about real options (eg, to donate or not to donate). The crucial objective is to create a situation in which donors can make a voluntary decision about a procedure that clearly has no medical benefit for them, but which may carry other kinds of benefit (eg, increased self-esteem). In creating this context for consent, it should be noted that not all pressure or influence is incompatible with voluntariness; human interactions can never be totally free of pressures that one person consciously or unconsciously places on another.38 Whether the pressure or influence is inappropriate or illegitimate depends both on the intentions and actions of the person exerting the pressure and on the context in which the pressure is exerted.39 Thus, the voluntariness of the donor could be compromised by such situations as the donor feeling a strong need to please the recipient on whom the donor depends for a continued good, or an enticement of financial compensation to potential donors who have few other opportunities for income.

The issues of pressure and influence correlate with the known as well as hidden motivations of the donor. Why does a prospective donor wish to donate blood components? A motive of authentic altruism is more likely to support and preserve a free and voluntary consent. A donor's motives that include profit and financial gain, for example (if financial compensation is available and used as an influence), could signal a compromise in the voluntariness of the consent. The ethical goal of informed consent is to uphold and maximize the 4 basic elements listed in Table 5 through a process that ensures the donor's participation in the decision and that empowers donors by educating and involving them in pretreatment protocols. This envisioned “process model” of informed consent is appropriately described as conversation, dialogue, open discussion, education, and even negotiation.40 In this context, the questions of what and how much information to disclose remain important and essential but are actually secondary to the process of helping the person understand and comprehend the information.

One of the significant, practical concerns for the process of informed consent is helping the prospective donor understand the risks and dangers associated with donation. Certainly, if pretreatment regimens and donation were completely safe and risk-free, there would be little hesitation in accepting donations from free and uncoerced individuals. But few activities in human life, both inside and outside the field of medicine, are risk-free. At issue is the identification, anticipation, and calculation of the risks to the donor, both to assure adequate disclosure to the prospective donor and (as discussed) to attempt to determine whether the benefits to the recipients justify the risks to the donors. Although taking risks to help others is generally considered to be heroic, worthy of great praise, and not a sign of psychopathology41 (and from a religious perspective can be viewed as “an act of supreme charity,” 42 blood component collection centers and their professionals have a responsibility to provide an objective evaluation of risks, vis-à-vis potential benefits, and to assure that the risk-benefit ratio is reasonable. Although, ultimately, respect for a donor's autonomy requires that people be allowed to make their own choices, even when it seems that they are not doing what is best for themselves, transfusion medicine physicians and other health care professionals are not excused from promoting and protecting the donor's best interests by anticipating and weighing the burdens, risks, and harms of pretreatments and interventions.

The issues surrounding whether to compensate blood, tissue, and organ donors have long been debated, and it is not the intent of this article to exhaustively review this area.43–48 Because volunteer donors derive no known therapeutic benefit from their donation, their motivations are routinely grounded in psychological or altruistic reasons.

In the United States, blood, tissue, and organ donors do not usually receive monetary compensation for their gift. Many believe that the act of financially rewarding donors for the inconvenience and hardship of the donation process negates the spirit of an altruistic donation, despite the potentially significant invasiveness of some tissue and organ retrieval procedures, including the administration of general anesthesia in some cases.41,43,47 However, donors in the United States rarely donate without some reward. Living tissue donors, including whole blood donors, may receive paid time away from work, free medical examinations, free tickets to events, recognition dinners, and increased self-esteem through positive verbal reinforcement.43–51 Nonmonetary donor incentives have generally not been considered powerful or coercive enough to overshadow the altruism of voluntary donation, although recent studies are challenging this belief.52,53 

Arguments in favor of significant financial remuneration to tissue and organ donors include the possible increased availability of scarce, potentially lifesaving resources.49,54 For example, paying organ donors has been compared to paying persons in high-risk occupations, such as fire fighting, in which persons subject themselves to significant risk of bodily pain and injury in return for monetary compensation.54 

Whether the altruism of potential donors can be compromised by offering too great a financial reward for their donation also continues to be debated.43,44,55,56 Financial pressures on the donor, it is argued may obviate a true voluntary choice and may be viewed as financial coercion, especially if directed to the desperately poor.57,58 It is possible that the donor pool could become overrepresented by a socioeconomically disadvantaged population whose blood and tissue donations are passed on to wealthier groups.

The recipient's safety is often cited as a reason to avoid monetary reimbursement for blood, tissue, or organs. Voluntary donation is believed by many to be the safest method of obtaining necessary resources.51 This belief may stem from the historical association between paid blood donation and posttransfusion hepatitis.48 Voluntary donors, it is argued, have no reason to give false information about risk factors regarding lifestyle. This concern may have greater weight today in light of the acquired immunodeficiency syndrome epidemic. However, with current infectious disease testing and donor screening procedures, there is some evidence that paid donation, by itself, does not increase the risk of transfusion-transmitted infections.59 

Another argument opposing financial compensation is that the pool of volunteer donors may decrease. Woo60 found that the availability of paid, unrelated organ donors from India has led to a decrease in patient requests for living-related organ donation among renal failure patients in Singapore. Alternatively, a strictly volunteer system also has unique problems, and the question of whether a paid donor system can coexist with a volunteer system has not been completely answered.

In contrast to the relative lack of significant financial donor compensation for vital blood, tissue, or organs is the compensation offered for gamete donation, particularly egg donation. Egg donors are subjected to hormonal manipulation to prime the donor to produce numerous mature eggs during one cycle, followed by general anesthesia and a moderately invasive laparoscopic procedure to retrieve the ova.61 Some believe that the risks endured by egg donors justify the monetary reimbursement, which may be upwards of $2000 per donation.61 To prevent this practice from being viewed as the buying and selling of human tissue, such payments have often been described as “reasonable compensation for time and trouble.” However, egg donation, as opposed to the life-saving potential of vital tissue or organ donation, is considered something of a luxury and, therefore, altruism may not be enough to recruit egg donors.

The retrieval of hematopoietic cells (eg, granulocytes) from a G-CSF–primed donor may be intermediate in morbidity between organ and egg donation but, nevertheless, the risks are generally greater than that of routine whole blood donation. This may be particularly true for the repeat or long-term donor (eg, granulocyte donations). Although altruistic donation is an ideal, the exposure of donors to an increasing array of drugs with significant known and unknown side effects is likely to add fuel to the debate on donor compensation.

Currently, the short-term side effects of G-CSF are being defined, and although its use appears to be relatively safe, additional studies are clearly needed to delineate further both the short- and long-term side effects of G-CSF use in the normal donor. The clinical efficacy of G-CSF–mobilized PBSC collected from the allogeneic donor is being established and is supported in the bone marrow transplantation literature. In contrast, the clinical efficacy of G-CSF–mobilized granulocytes has not been established and requires additional study.

We recommend the establishment of a donor registry to collect short- and long-term safety data on the use of hematopoietic growth factors in normal donors to allow for rapid expansion of knowledge regarding the safety of these growth factors. The concept of such a registry has also been promoted by others.62 Until safety and efficacy issues surrounding the use of hematopoietic growth factors are resolved and their use in normal blood donors is approved by the US Food and Drug Administration, the use of these agents in normal donors should be considered experimental, and each use detailed in formal research protocols reviewed and overseen by an institutional review board. We also recommend that the re-examination of the informed consent process for blood component donation, in general, be considered, with special attention given to the promotion or use of other hematinics or drugs (ferrous sulfate, corticosteroids, hydroxyethyl starch, etc).

The transfusion medicine physician's relationship to donors, patients, and other physicians should be further defined, delineated, and detailed. This could be achieved within the context of a national professional organization, such as the Ethics Committee of the American Association of Blood Banks, the Committee on Practice of the American Society of Hematologists, or other appropriate national medical organizations. In doing so, the role of an advocate in transfusion medicine should be further defined and position statements drafted.

Although we are not advocating direct monetary compensation for blood donation, in general, until the risks associated with the administration of colony-stimulating factors to normal donors have been fully defined, monetary compensation may be considered appropriate as part of an institutional review board–approved research protocol. Similar to research subjects enrolled in many experimental protocols, G-CSF–stimulated granulocyte donors may also qualify for monetary compensation under current institutional review board guidelines in order to collect further data in a timely manner and to compensate donors for their time and trouble. The recipients of blood components (eg, granulocytes) obtained as part of such institutional review board–approved research protocols should also be afforded full informed consent prior to transfusion.

As innovative methods and techniques for collecting blood components become available, these ethical issues will continue to have an impact on transfusion medicine. Specialists in transfusion medicine must assume their rightful and important role in addressing these issues.