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A review of the haematopoietic stem cell donation experience: is there room for improvement?

Abstract

Donation of haematopoietic stem cells, either through BM or PBSC collection, is a generally safe procedure for healthy donors although adverse reactions are a definite risk. The invaluable source of donation and its central role in transplantation implies that every effort should be made to alleviate possible difficulties the donor encounters. The physical and psychological reactions to donation have been established for some time, but less is known about the factors that are associated with a poorer donation experience. In this article, we provide an overview of the physical and psychological donation experience and focus attention on demographic, physical and psychological factors that may influence this donation experience. Understanding that toxicity profiles vary with certain donor characteristics is crucial as this knowledge could influence practice in numerous ways including the modification of joining and recruitment policies and the improvement of supportive measures and donor follow-up procedures. Although this review deals with both unrelated and related donors (RDs), there is a relative paucity of regulation of RD care and we call for more attention to this area. Owing to the relative rarity of donation in each country, a global effort to collect donor outcome data is needed.

Introduction

Haematopoietic SCT is a curative procedure for life-threatening haematological diseases. The number of allogeneic SCTs has steadily increased by up to 10% annually on a global scale1, 2 with currently up to 30 000 allogeneic SCTs being performed every year in over 1000 transplant centres worldwide. During the last decade, PBSCs have replaced BM as the main source of haematopoietic stem cells. Furthermore, new conditioning regimens have led to an increased use of donor lymphocyte infusions. Surveys from Europe and the United States show that there are now more unrelated than related haematopoietic stem cell donations in these areas.1, 3

Although the donation process is generally considered safe, adverse reactions (ARs) are a known and definable risk. Optimizing the donation experience is important for several reasons. The act of donating BM or PBSC for haematopoietic cell transplantation is to submit to a procedure for which the individual will not derive any direct physical benefit. Thus, any harm that might result will not be offset by a benefit to the donor, except for the potential sense of satisfaction derived from an altruistic act.4 Therefore, care must be taken to minimize the potential of harm and donor registries should have donor safety as their first priority. In addition, stem cell donation requires us to balance the inherent tension between ensuring sufficient donors are registered while protecting the safety of donors. An excellent reputation of the donation process is needed if we want adequate numbers of donors on our registers. It will similarly allow transplant centre physicians to recognize that donors will be available and be well looked after.

The overall experience of the donor includes both physical and psychological aspects, from the time of their first contact with the registry until full recovery. In this review, we discuss the most common short-term physical and psychological reactions to the donation process and concentrate specifically on the factors that may influence these. We mention mechanisms that are already in place to ensure donor safety and consider possible strategies for the future.

Short-term physical ARs

PBSC donation involves four or five daily s.c. injections with G-CSF followed by leukapheresis. Although this is preferentially performed using peripheral venous access, a central venous catheter insertion might be needed if donors have inadequate veins. Common side effects of PBSC donation are summarized in Table 1.5, 6, 7, 8, 9, 10, 11, 12, 13, 14 Other complications can be related to the insertion of a catheter and the process of leukapheresis. The latter might cause symptomatic hypovolemia, and hypocalcaemia is common as a result of the use of citrate anticoagulation in the circuit. The discomfort following PBSC donation starts within 24–48 h of administration of G-CSF but resolves fairly quickly after collection is complete, with just over 10% of donors reporting discomfort at 1-week after collection.7 The discussion concerning the long-term safety of G-CSF has been published elsewhere15, 16 and falls outside the scope of this paper.

Table 1 Common side effects of PBSC and BM donation5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 17, 19, 21, 22

BM donation involves general or spinal anaesthesia followed by repeated insertion of large bore needles into the donor’s posterior iliac crests to remove up to 2 L of marrow. In many centres, autologous red cell units are collected before the harvest.17, 18, 19 Others see no need to collect autologous units arguing that red cell donation renders donors anaemic on the day of surgery, making transfusion—autologous or even allogeneic—more likely.20 In addition, red cell donations often expire because of postponement of the donation. The most common post-donation complications are summarized in Table 1.5, 7, 11, 17, 19, 21, 22 The average hospital stay is 8–72 h.17, 19, 21 At 1-month after donation, pain had resolved for 80% of donors11 and complete recovery was reported in 67% of donors.7 Although the peak symptom burden of PBSC donors does not differ from those reported by BM donors, the temporal patterns differ with some studies showing that discomfort peaks on day +5 of G-CSF for PBSC donors compared with 48-h after collection for BM donors.7, 23 The latter are likely to have a delayed recovery compared with PBSC donors.7, 21, 24, 25, 26 Despite considerable pain and physical limitations, general health scores remain high following BM donation.19

Prospective studies have reported an incidence of serious ARs (SARs) ranging from 1.34 to 2.38% in BM donors and from 0.6 to 1.1% in PBSC donors.6, 8, 11, 12, 27 SARs have not been well defined in all studies, which render incidences difficult to compare. A large retrospective analysis of data collected by the European Group for Blood and Marrow Transplantation (EBMT), reported 7.25 SARs per 10 000 and significantly less in BM than PBSC donors.28 This is, however, a retrospective study, questionnaire based and has very low overall rates of SARs so might represent underreporting. Most SARs have been reported as case reports or by retrospective studies, hence causality can usually not be determined.29 Some of these SARs, such as thrombotic and cardiovascular events or splenic rupture, may be explained by the biological effects of G-CSF15, 28, 29, 30, 31, 32 or are associated with the collection procedure used (harvest site pain with subsequent disability, anaesthesia or central venous catheter related).21, 27, 28, 29, 33 Halter et al.28 reported that the incidence of donor fatalities was 0.98 per 10 000 donors, all in related donors (RDs), one after a BM donation and four after peripheral blood donation. The cases reported included cardiac arrest and pulmonary embolus. In most of these donors, pre-existing medical conditions were identified post-mortem, highlighting the need for strict medical eligibility criteria and assessment of donors. Death in unrelated donors (URDs) is exceedingly rare with only one death reported to the World Marrow Donor Association (WMDA) between 2003 and 2012, caused by an extensive haemothorax secondary to traumatic jugular vein catheter insertion. Second donations of stem cells are not associated with an increased risk of donor complications, however, the need for adequate informed consent is clear.34

Literature on the topic of RD safety has been scarce5, 6, 13, 14, 21, 23, 24, 25, 33, 35, 36, 37 and ARs are not as well characterized in terms of frequency and severity compared with URDs. Current research suggests that the risks associated with donation seem to be higher for RDs compared with URDs.28 This increased risk has several explanations. The same transplant centre and occasionally the same physician caring for the recipient may evaluate the RD.38 This could represent potential conflict of interest in favour of the recipient. Transplant centres may use less stringent criteria to determine donor eligibility in RDs.36 To the benefit of the donor, an independent physician for donor clearance, follow-up and counselling ought to be provided.38, 39, 40 Children who are being evaluated as potential donors require special attention to their clinical, psychological and social needs. Often parents are expected to consent for their children, which may create additional conflict of interest situations.38, 41 In Europe, any potential donation of BM or PBSC from adults who lack the capacity to consent and children who lack the competence to consent, must be assessed by an Accredited Assessor.42 In addition, as data show better survival after URD transplantation when a young donor is used, this has led to clinicians choosing the youngest available URD. This is in contrast with RDs who often match the age of their recipients. These donor groups have specific issues (size issues in paediatric donors and increased end-organ dysfunction and cancer in older donors). As opposed to URDs, RDs are not self-selected, have personal motivations and are likely to be willing to take more risks and underreport conditions that could impact ARs. Studies comparing RD and URD outcomes are limited.43 Chang et al.43 reported that related marrow donors experience more acute physical pain, possibly resulting from higher stress levels being manifested by an increased vulnerability to pain. A study comparing RD and concurrently enrolled NMDP URD outcomes is planned.44

Mechanisms to ensure donor safety

URD safety is prioritized through published WMDA standards covering donor recruitment, consent, medical assessment, donor follow-up and a global collaborative effort in adverse event reporting.45, 46 No equivalent regulations currently exist for RD care.

Several mechanisms that aim to maintain donor safety are summarized in Table 2. The pre-donation history, which addresses risks both to the donor and the recipient, should focus on matters relevant to the anticipated donation, including psychological issues. In general, donors with moderate or severe organ impairment are deferred and this commonly includes those with coronary artery disease, renal or hepatic impairment.47 Many other medical conditions may prevent donation for the sake of donor safety. Potential donors ought to receive a full description of the procedure, its risks and potential alternatives at the time of their medical assessment. It is recommended that donors are counselled about the possibility of subsequent donations of stem cells or lymphocytes before their first donation.34 Special regulations exist for donors who are donating on research protocols,48 however, we do not discuss that here in detail as this is beyond the scope of this paper. The reporting of serious adverse events is mandatory for all WMDA-accredited registries, representing the vast majority of unrelated adult donations worldwide. Although most URD registers are collecting some degree of donor follow-up, there is no centralized system in place at the moment.

Table 2 Current mechanisms to optimize donor safety

Predictive factors for developing ARs

Studies assessing factors that influence the donation experience are limited. Table 3 lists donor and treatment-related characteristics that have been found to influence the donation experience.

Table 3 Factors influencing donor adverse reactions (in PBSC donation, BM donation or both)

Gender

Multiple studies have shown that female gender is associated with a higher risk of both apheresis and BM donation-related ARs compared with men.7, 8, 9, 10, 17, 41, 49, 50, 51 Women are also more likely to experience serious complications11, 50 and are almost twice as likely to require extended hospitalization.7, 8 The explanation for these findings is unclear, but is likely multifactorial. Research in other medical specialties has shown higher pain scores in various conditions in women.52 This might reflect a gender difference in the perception of pain52 and physical functioning.53 The increased incidence of fatigue in female BM donors could be explained by the lower post-donation Hb levels in women following BM donation with an average Hb drop in women from 12.8–13.6 to 10.3–11.1 g/dL (versus 15.2–15.4 to 12.4–13.4 g/dL in men).11, 17 Yuan et al.50 stated that a smaller total blood volume in women may partially explain the increased incidence of citrate toxicity, however, a multivariate analysis could not be performed in this study because of the low number of ARs. In addition, an increased incidence of ARs related to drugs in women, which may be explained by pharmacokinetic, immunological and hormonal differences, has been described.54 Other studies have found that women need a central line in 21% of cases versus 5% of men8 and are more likely to develop post-donation haematomas.50 This can be explained by the finding that female donors tend to have a smaller body size and smaller veins. They are therefore more prone to vascular injuries when access needles of the same gauge are used.

Age

Younger donors have not been shown to be at increased risk of experiencing complications during PBSC donation,7, 10, 50, 51 apart from headache and grades II–IV pain.7, 9 Furthermore, a positive correlation between younger donors and increased pre-syncopal and syncopal events as demonstrated in whole blood donors, has not been established in PBSC donation.50, 55, 56 This finding is surprising, given that the extracorporeal blood volume can exceed 20% of the donor’s blood volume during apheresis57 and most apheresis machines do not routinely provide saline infusions. Conversely, older PBSC donors were more likely to experience citrate-related toxicity and persistent toxicities at 1 week,7, 50 reflecting a slower recovery period than younger donors for all aspects of the donation process. This slower recovery is also described in older BM donors.7 The actual day of donation is generally tolerated better in older BM donors.7, 49 Young donors may have been less experienced with and more fearful of medical procedures in general.49

Weight

There have been no studies examining the influence of weight on ARs in BM donors. Many centres already have strict body mass index restrictions for BM donors because of procedural difficulties in heavier donors. There is some evidence that donors who are overweight or obese tend to have more pain following PBSC donation.7, 8, 10 This may be a consequence of a relatively higher dose of G-CSF received in this population10 as extracellular fluid and haematopoietic mass do not increase in direct proportion to weight.

Full blood count

There is no conclusive evidence of a link between baseline haematology results and ARs7, 10 and therefore no indication for monitoring white cell counts during G-CSF administration exists. In addition, the increase in spleen size secondary to G-CSF does not appear to be associated with higher peripheral blood white cell counts.58, 59

BM harvest procedure

A longer duration of BM harvest has been consistently associated with increased post-donation physical limitations and complications.11, 19 It is unclear whether it is the procedure’s duration per se that is a predictor or the product volume harvested. The volume of marrow harvested—which has been shown to be correlated with duration of the procedure19—predicted donor recovery in one study17 but not in others.19 The duration of harvest may also reflect the total number of puncture holes. Further effort should be directed to recording the number of bone punctures, developing a valid measure of ‘difficulty of harvest’ and studying whether they affect donors’ recovery.19 This matter is complicated by the knowledge that small volume marrow aspirations and multiple puncture sites optimize the yields of the BM harvest.60 There are few reports that compare general versus regional anaesthesia for BM harvesting.11, 18, 61, 62, 63 Local anaesthesia has reduced risk of trauma, because the patient is awake and vigilant, whereas general anaesthesia may produce a minor respiratory risk, because the donor has a secured airway.64 Most studies found no difference regarding numbers of adverse events during or after the procedure. This strongly suggests that the choice of anaesthesia depends on the donor or the anaesthetist’s preference.18 Jobs involving mild to moderate daily work activities have been associated with fewer of days off work following BM donation compared with jobs involving more heavy duties.17 Blood donors had more physical difficulty with donation; their previous experience with blood donation may have led them to underestimate the physical impact of BM donation.49 Being a blood donor is also correlated with higher number of days off work, this may be secondary to lower baseline Hb levels in those donors.17

Psychological aspects of donation

Most studies have focussed on the physical outcomes following donation and only few have assessed the psychological impact of donation. The psychological reactions following donation are generally positive.65 Common experiences are feeling like a better person as a result of donation65 and most subjects felt deep personal satisfaction and gratitude for an opportunity to donate.66 Donors felt they were actualizing a central trait in their identity67 and most donors would donate a second time.66, 68 Outcomes appear mainly reliant on the outcome in the recipient, physical ARs experienced during the donation process and the psychological state of ambivalence (Table 4).

Table 4 Factors influencing psychological outcomes

One study looking into reactions of unrelated BM donors when the recipient dies, concluded that death of the recipient produced feelings of grief and was often surprisingly intense, given the fact that the recipient was a stranger.69 Studies in RDs are complicated by the direct connection of donors with the patient. Poor outcomes can have devastating effects and ‘survivor’s guilt’ is well documented in the literature. A study in 23 BM donors found that donors whose sibling died had significantly higher scores on the Beck Depression Inventory—a validated depression scale—compared with those whose siblings remained alive.70 These are interesting findings given that most registries allow information exchange or contact between the donor and recipient after a certain period of time. Limiting information about the recipient may result in more positive psychological outcomes in these donors. However, other strategies such as psychological counselling services that relieve donor grief could be considered.

Butterworth et al.65 assessed the psychosocial effects of BM donation in 493 URDs. The donors experienced the donation as quite positive in general and they were more likely to think of themselves as a better person as a result of the donation. They also showed that donors with longer collection times or lower back pain were more likely to have less positive psychosocial outcomes. A large Canadian randomized trial assessed mood states and quality of life before donation and 1 week and 4 weeks following donation in BM and PBSC donors.25 Both the mood and quality of life scores were worse after BM donation, compared with PBSC donation. The authors commented that physical morbidity can affect mood and this is in keeping with a delayed physical recovery in BM versus PBSC donors.

The psychological condition of the donor should be assessed, in particular the donor’s motivations for considering donation. Switzer et al.49 reported that a psychological state of ambivalence was a better predictor of a negative donation experience than actual physical difficulty with donation. Persons especially at risk for pre-donation ambivalence were more educated, less likely to have been blood donors, less happy in general and less optimistic about the patient’s chances of survival.49, 71, 72, 73 Donors who are motivated by an intrinsic commitment to donate, rather than extrinsic pressure, are less ambivalent about donating.71 The same author reported ethnic variation in the donation experience. He found that Asian Americans were more ambivalent and more anxious than all other ethnic groups.73

RDs may have different motivations from URDs and may be subject to increased emotional and physical stress associated with donation.66 A more positive experience has been reported if there is a better emotional support from family, friends and hospital staff.74 Routine provision of psychosocial support to donors as well as recipients is therefore important.

Possible future strategies

Understanding that toxicity profiles vary with certain donor characteristics is important as this knowledge could influence practice in numerous ways including: modification of joining and recruitment policies, management of expectations and the improvement of supportive measures and donor follow-up procedures.

Donors who are found to be at high risk of ARs are excluded from donation. For example, the knowledge that G-CSF can cause flare-ups of autoimmune disease15 has led to stricter eligibility criteria concerning autoimmune diseases within many stem cell registers. Selection criteria may be altered in the future based on the awareness that toxicity profiles vary with certain donor characteristics. Recently, some registers have started to concentrate on the recruitment of male donors. Although this is often driven by increased availability and stem cell yields among males, it may also result in fewer ARs75, 76, 77, 78 and a reduced incidence of GVHD.79 Conversely, restricting the recruitment to male donors may influence the numbers of donors on the register and the overall HLA repertoire. Similarly, the finding that older donors are at a higher risk of experiencing SARs, could further enhance the trend towards registries recruiting younger donors. This practice is currently mainly driven by the finding that transplant outcomes are improved when using younger donors.80, 81, 82 Heavier donors have been found to experience more bone pain, although this was mainly classified as being mild. Restricting the recruitment to ‘lighter’ donors would carry an inherent conflict as several studies have shown that stem cell yields are positively correlated with donor weight.83, 84

The management of donors’ expectations can similarly be important, especially in donors at increased risk of ARs. High-risk groups ought to be made aware of this at the time of their medical assessment. For instance, regular blood donors who are asked to donate BM should be specifically informed about the increased risk of anaemia following donation and the likely need for iron replacement therapy. In addition, a more stringent short-term follow-up could be considered in donors who are at increased risk to allow early intervention. Some groups, such as obese PBSC donors, may benefit from pre-emptive analgesia.85

The physical state of ambivalence was found to be a better predictor of a negative donation experience, even more so than the actual physical difficulty with donation. Recruitment staff have a critical role, for example, in reducing ambivalence and consequently reducing donation difficulties among new recruits by clearly providing information to the donor concerning the medical risks of the donation. Strategies to enhance commitment at recruitment could involve a two-stage process, where the decision to join the register needs to be reaffirmed. Other options may include strategies where it is made easier for donors to opt out of the register.

Conclusion

Voluntary donation of BM or PBSC for haematopoietic cell transplantation is a well-established altruistic act, performed by thousands of healthy RDs or URDs throughout the world. Although allogeneic stem cell donation is a safe procedure with very low rates of serious ARs, the risk exists and every effort should be made to minimalize this. Several mechanisms to ensure donor safety are already in place and the increasing amount of data on factors that may increase the risk of ARs will further allow registries to tailor their donor care. Nevertheless, we have encountered some major limitations.

Although stem cell registers are the richest source of URD outcome data, only a fraction of these data are currently published. Most registers collect some level of donor outcome data but few have large-scale donor follow-up programs. Further effort should be directed to standardize operational definitions on post-donation physical and psychological outcomes and ARs and to develop a prospective global data collection.86 The EBMT has recently developed a reporting system for both RD and URD outcomes, but this is not a mandatory requirement yet and only covers EBMT centres. Furthermore, a continued effort to develop clinical trials is required. Future research areas of interest may include the development of an index that measures the ‘difficulty’ of a BM harvest procedure and the detection of certain harvest-related factors that are most strongly associated with poorer donor outcomes. Other areas are the use of validated general physical and psychological wellbeing questionnaires before donation and the impact of these scores on donor outcomes.

Another major restriction the community faces is the lack of international guidelines for RD care. Although the care of family donors has been carefully considered and managed in transplant centres internationally, there is currently a lack of standardized guidelines for the management of family donors40 (although some exceptions exist87). Although key ethical considerations between RDs and URDs differ, the underlying principles of family donor care are in many ways similar to those involving URDs. Further research needs to be directed at reviewing the feasibility of a model of RD care, which separates this from the transplant team’s responsibility. An increased collaboration between those caring for RD and URD is important and the WMDA and WBMT have started to provide some guidance in this area.40

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Billen, A., Madrigal, J. & Shaw, B. A review of the haematopoietic stem cell donation experience: is there room for improvement?. Bone Marrow Transplant 49, 729–736 (2014). https://doi.org/10.1038/bmt.2013.227

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Keywords

  • PBSC donation
  • BM donation
  • donation experience
  • influencing factors
  • recovery

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