Transfusion Medicine Reviews xxx (2015) xxx–xxx

Contents lists available at ScienceDirect

Transfusion Medicine Reviews

journal homepage: www.tmreviews.com

Preoperative Autologous Blood Donation: Waning Indications in an Era of

Improved Blood Safety
Ralph Vassallo a,⁎, Mindy Goldman b, Marc Germain c, Miguel Lozano d, for the BEST Collaborative
a
Blood Systems, Inc, Scottsdale, AZ
b
Canadian Blood Services, Ottowa, ON, Canada
c
Medical Affairs, Héma-Québec, Québec, QC, Canada
d
Hemotherapy Section, Hospital Clinic de Barcelona, Barcelona, Spain

a r t i c l e i n f o a b s t r a c t

Available online xxxx A downward trend in preoperative autologous donation (PAD) continues in Europe and the Americas, with many
jurisdictions only funding medically necessary collections at present. This is the result of decreasing real and
Keywords: perceived residual risks of allogeneic transfusion-transmitted disease and the declining need for transfusion due
Autologous blood transfusion to patient blood management, which have also led to escalating logistical and cost constraints for PAD programs.
Blood donors We outline collection trends in North America, Europe, and Latin America and review the benefits, risks, effective-
Patient blood management
ness, and safety of PAD. Important elements of informed consent follow from these points. Evidence-based medical
criteria for PAD and autologous transfusion are discussed as are methods to optimize autologous collection timing
to regenerate donated red cells. Recommendations for identification of patients whose risk-to-benefit ratio
suggests substantial benefit compared with other autologous blood salvage and anemia management alternatives
conclude the review.
© 2015 Elsevier Inc. All rights reserved.

Contents

Preoperative Autologous Donation Trends . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

Benefits and Risks of PAD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Preoperative Autologous Donation Informed Consent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Effectiveness of PAD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Criteria and Procedure-Specific Guidelines for PAD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Transfusion Triggers for Autologous Blood . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Timing of PAD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Safety Concerns With PAD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Preoperative Autologous Donation Cost-Effectiveness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Summary and Recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Conflict of Interest. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

Despite recent decreases in red blood cell (RBC) demand, demo-
graphic projections in highly developed countries predict that, by
2050, the population 60 years and older will have nearly doubled while
the proportion of individuals 15 to 59 years old declines by almost
20% relative to the year 2000 [1]. This will result in a contracting donor
population just as more elderly patients require transfusion-dependent
⁎ Corresponding author at: Ralph Vassallo, MD, FACP, EVP/Chief Medical & Scientific
Officer, Blood Systems, Inc, 6210 E Oak St, Scottsdale, AZ 85257.
E-mail address: rvassallo@bloodsystems.org (R. Vassallo).
procedures. Therefore, efforts to assure the availability of blood remain
relevant. There has also been increasing awareness of potential compli-
cations of transfusion, and many institutions have developed blood con-
servation strategies to optimize use of allogeneic blood transfusion
alternatives in the perioperative setting. Autologous blood conservation
techniques including perioperative autologous cell salvage (PACS),
acute normovolemic hemodilution (ANH), and preoperative autologous
donation (PAD) may be elements of these blood conservation programs.
Preoperative autologous donation enjoyed a great surge in popularity
in the 1980s and early 1990s with the emergence of transfusion-

http://dx.doi.org/10.1016/j.tmrv.2015.04.001
0887-7963/© 2015 Elsevier Inc. All rights reserved.

Please cite this article as: Vassallo R, et al, Preoperative Autologous Blood Donation: Waning Indications in an Era of Improved Blood Safety,
Transfus Med Rev (2015), http://dx.doi.org/10.1016/j.tmrv.2015.04.001
2 R. Vassallo et al. / Transfusion Medicine Reviews xxx (2015) xxx–xxx
transmitted HIV and hepatitis C. At the peak of public concern, as many
as 8.5% of RBCs collected in the United States were obtained from autol-
ogous donors [2]. Since the mid 1990s, however, US autologous donation
volumes have declined, precipitously so since 2001. Although autologous
blood collection was never as prevalent in Canada or Europe as in the
United States, these jurisdictions have also seen a substantial decline in
use. The emergence of nontransfusion alternatives driven by patient
blood management programs and demonstration of the safety of lower
transfusion thresholds in a number of landmark randomized controlled
trials (RCTs) has further eroded the indications for PAD [3–7]. We review
PAD collection trends in the United States, Canada, and European and
Latin American countries as well as the advantages, disadvantages, safe-
ty, and efficacy of PAD in an era of significantly improved blood safety.
Preoperative Autologous Donation Trends
From the US 2011 National Blood Utilization and Collection Survey,
Figure 1 illustrates the progressive decline in US collections [8]. In
2011, approximately 113 000 autologous whole blood (WB) units
were collected (just b 30% in hospitals) and approximately 4000 RBC
units by single- or multiple-unit apheresis. The mean number of units
collected per patient was 1.3. Nearly 45% of collected units were not
transfused. Autologous units represented less than 0.75% of all RBCs col-
lected in the United States in 2011. More recent North American blood
providers' data are shown in Figure 2.
Even in European countries still transfusing significant volumes of
autologous blood, Figure 3 shows the significant downward trend in
the percentage of autologous units collected since 2001. Stringent autol-
ogous collection guidelines are in place in Denmark, Finland, Ireland, the
Netherlands, Norway, Poland, and Sweden, where less than 0.02% of do-
nations were provided by autologous donors in 2008 [9]. Within Latin
America, of the 13 countries reporting data to the Pan-American Health
Organization, Cuba, El Salvador, Honduras, and Nicaragua drew 0.02% or
less of RBCs from autologous donors in 2011 [10]. With the exception of
Argentina and Brazil (whose fraction of autologous units in the blood
supply has remained relatively stable around 2.5% and 1.4%, respective-
ly), since 2007, there has also been a downward collection trend in most
of the remaining countries (Fig 4).
Benefits and Risks of PAD
Potential benefits of PAD are listed in Table 1. When PAD was first in-
troduced, advocates focused on the elimination of allogeneic infectious
disease transmission. Because of improvements in donor testing, risks
of HIV, hepatitis C virus (HCV), and hepatitis B virus (HBV) transmissions
Fig 1. Historic US autologous collection volumes and fraction of collected RBCs.
Please cite this article as: Vassallo R, et al, Preoperative Autologous Blood Donation: Waning Indications in an Era of Improved Blood Safety,
Transfus Med Rev (2015), http://dx.doi.org/10.1016/j.tmrv.2015.04.001
have decreased dramatically. In the United States, these are approxi-
mately 1 per 1 470000 units for HIV, 1 per 1 150000 for HCV, and 1 per
765 000 to 1 010 000 units for HBV [11,12]. Corresponding rates in
Canada are reported as approximately 1 per 8 000 000 units for HIV, 1
per 6700000 for HCV, and 1 per 1700000 units for HBV [13]. However,
in Southern Europe, HBV residual risk still remains high, estimated
in Italy at 1 per 71942 and, in Spain, 1 in 177 305 transfusions [14,15].
Patients may have an erroneous impression of these risks for a variety
of reasons, including inaccurate transfusion consent forms, inadequate
explanations from treating physicians or other health professionals in-
volved in the PAD process, and commonly held misperceptions of trans-
fusion risk in the general public. Without an accurate representation of
risk, patients may perceive an inappropriately higher value for PAD [16].
Another cited benefit of PAD is related to supplementation of the
allogeneic blood supply. This would benefit all patients due to wider
availability of allogeneic blood. There are also benefits for the autologous
donor in particular because his or her surgery is less likely to be delayed
due to inadequate blood availability. However, as detailed in the PAD
trends below, the number of allogeneic units actually saved by transfu-
sion of autologous blood is very small, with negligible impact on overall
blood availability. In an environment of overall decline in blood use,
outside of holiday shortages, postponement of surgery is increasingly
uncommon [8].
A third possible benefit of PAD is avoidance of transfusion-related
immunomodulation (TRIM) effects associated with allogeneic transfu-
sion. Particularly in retrospective studies, allogeneic transfusion has
been associated with an increased risk of perioperative infection, cancer
progression and relapse, and overall mortality. The existence and magni-
tude of this effect have been the subject of intense debate. Despite the
conduct of a number of RCTs, no TRIM effect attributable to allogeneic
white blood cells has been unequivocally demonstrable. It was concluded
in a review of the many relevant studies that more widespread use of PAD
could not be recommended for TRIM prevention [17]. Immune-mediated
complications have, however, been reported with autologous transfusion,
including febrile nonhemolytic transfusion reactions (FNHTRs), allergic
reactions, and transfusion-related acute lung injury (TRALI) [18]. The
risk of bacterial infection does not appear to be reduced in patients receiv-
ing autologous, as opposed to allogeneic transfusions [19].
In the late 1980s and 1990s, there was substantial media attention
on the risks of transfusion-transmissible diseases. Inquiries into the
management of the blood system took place in many jurisdictions.
This fueled public concern about the safety of transfusion and encour-
aged patients to ask their physicians about autologous blood. Given
the extremely low risk of transfusion-transmissible diseases at present,
public confidence in the blood system has improved substantially.
 R. Vassallo et al. / Transfusion Medicine Reviews xxx (2015) xxx–xxx 3

Fig 2. Autologous fraction of collected RBCs from selected North American blood providers.

A rare but unequivocally medically justifiable reason for PAD is the
provision of units for patients with high-prevalence or multiple com-
mon alloantibodies, for whom the allogeneic blood supply may not be
able to adequately support their transfusion needs.
Potential risks of PAD are summarized in Table 2. Several studies
have demonstrated that individuals who have contributed autologous
units more often receive transfusions from any source, compared to
those who have not done so. This is in part linked to poor timing of
PAD, with patients arriving at their surgery with lower preoperative
hemoglobin levels (see section on timing of PAD below). Physicians
may also erroneously conclude that autologous transfusion is without
risk, so that units donated should be reinfused, regardless of clinical
need. In reality, as described above, PAD does not eliminate the risk of
some immunologic complications, bacterial contamination, or mis-
transfusion. Occasionally, donated units may be unavailable for transfu-
sion due to technical or administrative problems, and patients may
require allogeneic transfusions.
Patients who participate in PAD assume all the risks associated with
blood donation. Although donation has proven to be feasible in these
donors in spite of many underlying illnesses that would normally lead
to deferral from allogeneic donation, reaction rates are higher in
autologous than in allogeneic donors (see “Safety Concerns with PAD”
section below). Donors undergoing semielective surgery for cardiovas-
cular problems may be at particularly high risk for complications.
Scheduling of PAD donations may lead to delays in surgery and consid-
erable donor inconvenience because PAD is usually offered only in
selected donor collection sites.
Even for incontrovertible PAD indications such as the need for rare
blood, the frequency of wastage approaches 45% [8]. In addition,
because only the red cell component is usually transfused and adminis-
trative costs are higher than those with allogeneic donation, the cost
per unit of blood transfused is many times higher than for allogeneic
transfusion [20].
Criteria for autologous donation often do not defer donors with
transfusion-transmitted infectious risks. Therefore, autologous donors
have higher infectious disease marker reactivity rates than allogeneic
first-time donors [21]. For this reason and others related to less
stringent donor and testing criteria, crossover of autologous units into
the allogeneic blood supply almost never occurs, even when donors
meet allogeneic donation criteria.

Fig 3. Selected European countries' autologous fraction of collected RBCs.

Please cite this article as: Vassallo R, et al, Preoperative Autologous Blood Donation: Waning Indications in an Era of Improved Blood Safety,
Transfus Med Rev (2015), http://dx.doi.org/10.1016/j.tmrv.2015.04.001
4 R. Vassallo et al. / Transfusion Medicine Reviews xxx (2015) xxx–xxx
Fig 4. Selected Latin American countries' autologous fraction of collected RBCs.
When virally infected patients bank units on hospital shelves, there
are serious consequences if these units are transfused to the wrong re-
cipient [22]. A 1992 US survey revealed that 0.9% of responding transfu-
sion services had erroneously issued an autologous unit and nearly 60%
of these units were transfused [23]. Canadian data from the same era
show a similarly higher error rate in autologous blood shipment and
transfusion, in part related to the greater complexity of the autologous
donation process [24]. Some North American and European hospitals
choose not to bank infected units because of the ever-present risk of
misadministration. Virally infected donors are not considered for autol-
ogous donation in the UK and several other European and Latin
American countries. At least in the case of US HIV-infected patients
who are protected from discrimination by the Americans with Disabil-
ities Act, such strategies could result in litigation, creating an ethical di-
lemma for blood bank physicians [25,26].
Preoperative Autologous Donation Informed Consent
During informed consent for PAD, a number of key elements should be
part of the discussion (Table 3). These include a thorough description of
the patient's obligations in the collection process, including the criticality
of donation timing and the need for iron and, possibly, erythropoietin
supplementation. The material risks and benefits of PAD, along with alter-
natives such as preoperative anemia management and alternative autolo-
gous blood salvage techniques such as PACS and ANH, should also be
detailed. Lastly, mention should be made of the potential for unit loss
during processing, unit outdate, and discard if transfusion is not required
as well as the possibility that allogeneic blood may still need to be trans-
fused. Adequate time for questions and provision of written resources to
facilitate full understanding should conclude the conversation.
Effectiveness of PAD
The clinical effectiveness of PAD encompasses the procedure-
specific likelihood that an individual will avoid allogeneic transfusion,
Table 1
Potential benefits of autologous blood donation
1. Eliminates already low risk of transmitting allogeneic viral, parasitic, and
bacterial diseases
2. Preserves the allogeneic blood supply during shortages
3. Decreases likelihood of procedural delay during shortages, raising patient
priority near autologous unit expiration
4. Reduces or abolishes risk of many allogeneic immunologic and allergic adverse
reactions and eliminates risk of alloimmunization
5. Promotes transfusion acceptance in patients at psychological risk for refusal of blood
6. May fulfill rare blood needs for patients with high-frequency or multiple
alloantibodies
Please cite this article as: Vassallo R, et al, Preoperative Autologous Blood Donation: Waning Indications in an Era of Improved Blood Safety,
Transfus Med Rev (2015), http://dx.doi.org/10.1016/j.tmrv.2015.04.001
balanced by adverse events occurring as a result of autologous donation.
Cost-effectiveness is a separate measurement, subject to zero tolerance
societal biases justifying expenditures in the name of blood safety con-
sidered excessive in other health care settings. Yet another important
measure is efficiency, that is, whether the postdonation hemoglobin
(Hb) returns to baseline before a procedure. Inefficient PAD may in-
crease the likelihood of adverse events by inducing or exacerbating pre-
operative anemia.
Measuring clinical effectiveness can be difficult because of the dissim-
ilarity of patients undergoing the same ostensible procedure. Studies
must be large to balance patient comorbidities and must limit procedural
variations affecting transfusion risk, for example, primary unilateral vs
bilateral or redo joint replacement. Retrospective and cohort studies
are subject to many sources of bias. These include lack of blinding; non-
uniform transfusion thresholds (influenced by local practice and often
higher with “safer” autologous blood); and a lack of adjustment for im-
portant modifiers such as adjunct therapies (erythropoietin [EPO],
ANH, PACS, and fibrinolytic inhibitors), patient comorbidity, and critical
procedural variables (procedural diversity, surgeon proficiency, and use
of blood-sparing operative techniques). Accordingly, the most reliable
data come from well-designed RCTs.
A 2001 Cochrane review identified 14 evaluable RCTs encompassing
orthopedic (6), colorectal (4), hepatic (2), cardiac (1), and maxillofacial
(1) surgery [27]. Pooled analysis identified a 68% relative reduction in
allogeneic blood use (relative risk of transfusion, 0.32; 95% confidence in-
terval, 0.22-0.47) and a 44% absolute reduction (risk difference, −0.44;
95% confidence interval, − 0.68 to − 0.21). The risk of receiving any
transfusion after PAD, however, was significantly increased by 24%.
Overall, 78% of patients donating autologous units received those units
with or without additional allogeneic blood. The highest relative reduc-
tion in allogeneic blood use occurred in maxillofacial and cardiac surgery
(98% and 94%, respectively), with 79% relative reduction in orthopedic
procedures and 52% relative reduction in oncologic surgery. Preoperative
Table 2
Potential risks associated with autologous blood donation
1. Increases risk of perioperative anemia and transfusion events (and sometimes
hypovolemia), unnecessarily exposing some patients to otherwise avoidable
reactions
2. Potential unit loss due to administrative issues, cold agglutinins, and leukoreduction
filtration failure or other production losses; complex logistics increase risk of late
unit delivery or outdating at hospitals
3. Adds risk of significant donation reactions for patients with cardiopulmonary and
other disease states; additional risk of thrombosis if EPO is administered
4. Increasing donor inconvenience with fewer available sites at greater distances as
collection volumes decline
5. An expensive resource, exceeding generally accepted cost per QALY
6. Catastrophic consequences for misadministration of marker-positive banked units
 R. Vassallo et al. / Transfusion Medicine Reviews xxx (2015) xxx–xxx
Table 3
Elements of PAD informed consent
1. Clearly stated, procedure-specific estimate of absolute reduction in the
allotransfusion rate with variable numbers of banked units (eg, a “1 in 3 chance
of benefit if you can donate 2 units” rather than an unqualified relative estimate
like “62% relative reduction” [from 53% to 20%] in allotransfusion)
2. Magnitude of benefit expected, ie, avoidable residual risks of HIV, hepatitis,
and “rarer pathogens”; severe allergic reactions; antibody-mediated TRALI;
and alloimmunization
3. Risks of PAD including the risks of blood donation, bacterial contamination of the
unit, and increased likelihood of a transfusion event with its consequent risk of
transfusion-associated circulatory overload, mistransfusion of ABO-incompatible
blood, and other rare events
4. Alternatives to PAD or allogeneic blood such as preoperative anemia management,
PACS, and ANH
5. Optimal scheduling of donations and potential for loss of unit(s) during processing
or transport
6. Need for iron supplementation and side effects of iron therapy (and side effects
of EPO, if used)
7. Expected wastage rate, ie, likelihood that unit(s) may not be needed and inability
to be used for allogeneic transfusion
8. Possibility that allogeneic units may still need to be transfused in addition to
autologous unit(s)
autologous donation resulted in a mean decrement in preoperative Hb of
approximately 1.1 g/dL compared with patients not donating autologous
units. The increase in PAD participant transfusion events likely occurred
because lower preoperative Hb values resulted in transfusion triggers
being reached sooner and more often after intraoperative blood loss
and because more liberal transfusion triggers were used with autologous
units due to the perception of their relative safety. There were no differ-
ences in rates of infection or thrombosis between patient groups. Even
these RCTs were of generally low methodological quality, subject to pub-
lication bias with few small negative trials being reported, inadequate
randomization, lack of blinding, and a primary outcome (decision to
transfuse) dependent upon subjective practice variation. These studies
generally used very liberal transfusion triggers (Hb, b 10 g/dL), suggest-
ing that, in the face of more recently accepted restrictive triggers (b7-8
g/dL), absolute reductions in allogeneic blood use are likely no longer
quite so high and even higher autologous unit wastage will occur.
These will inevitably lead to further erosion in PAD's cost-effectiveness,
which has already fallen significantly below values reported in the
1990s due to dramatic improvements in infectious disease testing.
A mathematical model based on data from almost 4000 patients en-
rolled in 21 studies compared PAD to ANH and PACS, concluding that re-
turn of 50% or more of shed RBCs was superior to PAD in efficiency and
effectiveness, both of which were superior to ANH [28]. Preoperative
autologous donation was superior only in the subgroup of individuals
able to donate the equivalent of 4 units (usually with the aid of EPO
and/or by double RBC donation); ANH approached relevance only
when very low intraoperative hemoglobin values (~6 g/dL) were toler-
able [28].
Criteria and Procedure-Specific Guidelines for PAD
A classic North American criterion identifies PAD candidates as those
routinely requiring preoperative crossmatch due to a greater than or
equal to 10% procedural likelihood of allogeneic transfusion. Spanish
guidelines currently recommend a greater than 30% to 50% likelihood,
and on the way to virtual abolishment of PAD in the UK, where it is now
indicated only in patients requiring rare blood or refusing allogeneic trans-
fusion, a 50% likelihood had been recommended as an interim step [29,30].
There are several specific procedure-related recommendations to be
gleaned from the admittedly flawed literature. Groups who routinely do
not benefit from autologous donation include nonanemic primary hip
and knee arthroplasty patients [31–41]; those undergoing simple
laminectomy and, perhaps, noninstrumented spinal fusion [42,43];
transverse rectus abdominus muscle flap breast reconstruction
Please cite this article as: Vassallo R, et al, Preoperative Autologous Blood Donation: Waning Indications in an Era of Improved Blood Safety,
Transfus Med Rev (2015), http://dx.doi.org/10.1016/j.tmrv.2015.04.001
5
[44,45]; partial hepatectomy [46]; nonanemic bone marrow donors
[47]; and bimaxillary repositioning osteotomy [48].
A number of international guidelines have attempted to identify
high-yield patient populations for PAD. The 2007 British Committee for
Standards in Haematology recommendations state that PAD is not rec-
ommended unless the clinical circumstances include rare blood groups
where allogeneic units are difficult to obtain, patients at serious psycho-
logical risk if blood transfusion is thought likely or who refuse to consent
to allogeneic transfusion, and children undergoing scoliosis surgery [49].
The 2011 Dutch Institute for Healthcare Improvement Blood Transfusion
Guidelines recommend that PAD requires good indications to avoid
wastage, that iron supplementation begins 1 month before the proce-
dure, and that EPO support should be considered [50]. However, they
concluded that due to complex logistics, relatively high costs, lack of safe-
ty, and plasma wastage, there should be a restrictive policy for PAD, with
the few clear indications including situations where compatible blood is
not available and when previous RBC transfusions have resulted in unex-
plained hemolysis. Finally, the 2013 update of the “Seville Document”
(the Spanish Consensus Statement on Alternatives to Allogeneic Blood
Transfusion) mentions that PAD is indicated when compatible allogeneic
blood is difficult to find, for patients who refuse allotransfusion and in
elective surgical procedures for which transfusion risk is greater than
30% to 50% (usually with a preoperative Hb b14.5 g/dL) [29]. They note
that the risk of receiving allogeneic blood is further reduced in autolo-
gous donors receiving EPO plus iron for surgical procedures requiring
predeposit of greater than or equal to 3 autologous units. Specific proce-
dural recommendations include the use of PAD in orthopedic surgical
procedures generally requiring the transfusion of greater than or equal
to 3 RBCs, in patients undergoing surgery for colorectal, prostatic, or he-
patic cancer resection when accompanied by erythropoiesis-stimulating
agents and for cardiac procedures with cardiopulmonary bypass, but not
for surgical procedures generally requiring the transfusion of less than or
equal to 2 RBCs.
Transfusion Triggers for Autologous Blood
It has been suggested that lower postoperative Hb values are associat-
ed with a number of poorer postoperative functional outcomes, including
walking distance [51,52], arm exercise tolerance [53], and quality-of-life
scores [54]. Others have not found this association [55–60].
To some degree, lower postoperative Hb values may reflect lower
preoperative values, more complicated operative procedures, or both.
Each may be associated with poorer outcomes, the former because
anemia is a surrogate measure of overall health and the latter because
complications may be proportional to the complexity of surgical inter-
vention. Thus, in retrospective or cohort studies, lack of well-balanced
groups and the inability to comprehensively adjust for comorbidities
may erroneously associate lower Hb values with worsened functional
recovery. Prospective RCTs are thus required to identify causation vs
mere association.
Two RCTs have shed light on this contention. In more than 2000 hip
fracture repair patients randomized to an Hb transfusion trigger of 8 vs
10 g/dL, there was no difference in the hospital length of stay, propor-
tion of patients able to walk independently, or scores for fatigue and ac-
tivities of daily living between the 2 groups at 30 or 60 days [6]. A
smaller study of 120 hip fracture repair patients randomized to these
same transfusion triggers found no consistent differences in hospital
length of stay; functional independence during hospitalization; or
scores for ambulation, dizziness, and fatigue earlier in the postoperative
period on days 1 through 3 [61]. In light of the many retrospective and
observational studies unable to identify functional recovery differences
and even stronger data from these RCTs, postoperative Hb values above
accepted transfusion trigger values of 7 to 8 g/dL are not likely to result
in impaired functional recovery. These transfusion triggers should be
equally applied to patients receiving autologous as well as allogeneic
blood because there appears to be no benefit to hypertransfusion.
6 R. Vassallo et al. / Transfusion Medicine Reviews xxx (2015) xxx–xxx
Unnecessary transfusion events carry significant risk for adverse events,
even with autologous units lacking many allogeneic infectious and im-
munologic risks.
Timing of PAD
Maximally efficient PAD is timed so patients regenerate most or all of
their donated RBC volume before procedural losses. This increases the
maximum allowable blood loss before more RBCs are needed to main-
tain circulating oxygen-carrying capacity and avoids allogeneic RBC ex-
posure with moderate blood loss. Efficiency is particularly important
when intervention-related bleeding is less likely to lower the postopera-
tive Hb value below a predefined transfusion trigger in the absence of iat-
rogenic anemia. As AABB standards allow lower predonation Hb values
for autologous than allogeneic donors, as low as 11 g/dL, smaller donors
may arrive for procedures with Hb values less than 9.5 g/dL [62]. This, in
part, underlies the 24% increased likelihood of any transfusion event in
patients undergoing PAD in the Cochrane review (unweighted overall
exposure 77.9% vs 55.8% in those not undergoing PAD) [27].
A mean of 36 days (20-59) was needed to regenerate the RBCs in a
550-mL blood donation in healthy male volunteers not taking iron sup-
plements, with little regeneration seen within the first 5 to 10 days [63].
Mean time to 80% recovery of the postdonation Hb concentration in the
HEIRS study varied from 25 to more than 168 days, depending upon
sex, serum ferritin, and the use of iron supplements [64]. Recovery is likely
to be further delayed in an older donor with chronic disease and elevated
hepcidin levels, which impair erythropoietic iron metabolism. In a 2007
German study, the interval required to regenerate the RBCs from 1 or 2
preoperative donations was proportional to the initial Hb [65–67].
Patients with lower Hb values appear to up-regulate EPO production
more vigorously than those with higher values, resulting in enhanced
erythropoiesis and a more rapid return toward baseline Hb. The volume
of regenerated RBCs was also directly proportional to the interval
between last PAD and the operative procedure. In light of all these data,
it has been recommended that autologous collections should cease no
less than 4 weeks before surgery [67]. In addition, a more profound and
rapid initial decline in Hb by apheresis double RBC or WB donations
separated by 72 hours will increase the likelihood of a return to the
predonation Hb baseline by the day of the procedure. Double RBC dona-
tion appears to be as safe as serial WB donation, but results in a higher
preoperative Hb as would be expected from a longer interval before sur-
gery and more profound Hb decline afforded by a single collection [66,68].
An analysis of 21 published studies revealed that less than 30% of
patients' last donations occurred more than 21 days before surgery (and
b 10% more than 28 days) [28]. AABB standards still allow autologous col-
lections as little as 72 hours preceding operation [62]. Collections timed
this closely to operation essentially transform PAD into a subacute form
of hemodilution and increase the likelihood of banked blood transfusion.
Finally, a mathematical model suggested that intraoperative RBC
salvage and reinfusion of 50% of shed RBCs would have led to greater
tolerable intraoperative blood loss in the majority of approximately
1100 autologous donors except in the very small subgroup with
below-normal Hbs who regenerated their entire RBC loss or more by
aggressive, ideally timed donation(s) [69].
Safety Concerns With PAD
Certain donors are at particular risk for adverse events related to do-
nation or blood storage and are not eligible to donate (eg, those with
significantly compromised cardiopulmonary status or intermittent
bacteremia). In a study of more than 4.1 million American Red Cross
donations (218 190 autologous donations meeting all safety criteria),
the rate of postdonation hospitalization (mean, 1.9 days) was almost
12 times the allogeneic donor rate at 1 in 16 783 for autologous donors
vs 1 in 198119 for allogeneic donors [70]. Among another 5660 American
Red Cross autologous donations, the 15.7% of donors not meeting
Please cite this article as: Vassallo R, et al, Preoperative Autologous Blood Donation: Waning Indications in an Era of Improved Blood Safety,
Transfus Med Rev (2015), http://dx.doi.org/10.1016/j.tmrv.2015.04.001
allogeneic donor safety criteria experienced significantly more vasova-
gal and other severe reactions than those meeting criteria (4.3% vs
2.7%), and all 4 serious reactions occurred in this subgroup (angina
and stroke) [71].
Another group of US investigators compared 10200 autologous with
219 307 allogeneic donations and reported no differences in mild,
moderate, or severe reaction rates among donors from 4 blood centers,
but these rates were not age adjusted [72]. Upon comparison of rates
of vasovagal reactions in a subset of this group (2091 autologous donors
and 4737 allogeneic donors from one center), unadjusted rates for mild,
moderate, severe, and all reactions were again not significantly different.
However, compared by age group, the rates of all reactions combined
were significantly higher in autologous compared with allogeneic donors
[73]. Within this latter study's autologous subgroup of 652 first-time do-
nors, 37.8% of those reacting at their initial donation experienced repeat
reactions. This may be contrasted with a reported rate of 27.4% repeat
reactors among 18 700 allogeneic, generally younger ARC first-time
donors, a demographic group far more prone to vasovagal reactions [74].
This disparity may be related to the decreased interdonation intervals
allowed with autologous donation as well as the impaired health status
of autologous donors.
Finally, in the United States in 2012, there were an average of 80
injuries and 1 fatality per 100 million vehicle-miles traveled [75]. At a
very conservative 20-mile roundtrip distance by car to and from a
collection site, this represents an avoidable risk of 1 per 62000 autolo-
gous donor trips. This is far higher than the aggregate residual risk of
avoidable transfusion-related infections, the predominant factor in
persuading patients to participate in PAD.
Preoperative Autologous Donation Cost-Effectiveness
A number of studies have reported estimates of the societal cost
of autologous blood donation. All these articles were published
more than a decade ago, when residual rates of many transfusion-
transmitted viral infections were an order of magnitude more common
than they are now. Table 4 lists the ranges of US dollars spent per
quality-adjusted life year (QALY) saved. The value traditionally consid-
ered to justify a health intervention has ranged from a static $50 000
per QALY to the World Health Organization proposal for assessment at
3 times a country's per capita gross domestic product, which, in the
United States in 2013, would be estimated at $158 400 [81]. The cost-
benefit ratio of PAD is primarily driven by the avoidable residual rate
of infectious diseases and the fraction of autologous units that are
discarded (currently nearly 50% and likely to rise dramatically as physi-
cians adopt lower, evidence-based transfusion triggers). Thus, costs per
QALY are likely far higher in 2014 than values reported in the mid
1990s, with even the most transfusion-prone procedures such as revi-
sion hip replacement, likely to exceed $160000 per QALY.
Table 4
Cost-effectiveness of PAD
Orthopedic procedures [20,76]
Bilateral/revision total hip replacement $40 000-$241 000
Primary total hip replacement $235 000-$740 000
Primary total knee replacement $1147 000-$1 467 000
Cardiovascular procedures [20,77,78]
Coronary artery bypass graft $494 000-$1785 000
Urologic procedures [20,79]
Radical prostatectomy $531 000-$1813 000
Transurethral prostate resection $23 643 000
Gynecologic procedures [20,80]
Total abdominal hysterectomy/bilateral $1358 000-$2 179 000
salpingo-oophorectomy
Radical hysterectomy/lymph node dissection $1029 000
 R. Vassallo et al. / Transfusion Medicine Reviews xxx (2015) xxx–xxx
Summary and Recommendations
Over the last several years and in many countries, there has been a
steady decline in the use of PAD. This decline can be explained by a com-
bination of several factors, including a decreasing real and perceived
risk of disease transmission through allogeneic transfusion, the adop-
tion of better patient blood management practices that have reduced
the need for perioperative transfusion, and the increasing logistical
and cost constraints of PAD programs.
Given PAD's limitations, automatic referral of all patients scheduled
for particular procedures is unwarranted and should be discouraged. In-
dividualized identification of patients whose risk-to-benefit ratio sug-
gests substantial benefit should be the norm. Meticulous attention to
procedural timing is also required to maximize RBC regeneration
while avoiding unit loss through outdating.
Accordingly, akin to the British Committee for Standards in
Haematology and Spanish Consensus recommendations, we recom-
mend that PAD be considered exclusively for patients with RBC alloan-
tibodies necessitating rare blood unavailable in volumes likely to be
required; those at serious psychological risk for refusal of necessary
allotransfusion; and, possibly, selected healthy individuals planning
procedures with at least a 50% risk of requiring 3 or more units of
RBCs [29,49]. Qualifying donors must be able to donate several units
and collections must be timed to allow at least 3 to 4 weeks between
the last donation and the scheduled procedure for significant benefit
to accrue. Anecdotal observations of varying geographical popularity
of PAD have been attributed to practitioner preference. Efforts to edu-
cate physicians on the shifting risk-benefit balance in an era of im-
proved blood safety may eliminate unnecessary practice variation.
There is a need for further study of the relative effectiveness of PAD
compared with aggressive preoperative anemia management and PACS,
especially in an era of restrictive triggers for blood administration. How-
ever, funding for the RCT required to definitively assess costs and out-
comes associated with these differing approaches is unlikely given the
observed ongoing decline in the collection of autologous blood in virtu-
ally every country.
Unless novel infectious diseases emerge, which are not amenable to
screening or pathogen inactivation technologies, there is little likeli-
hood of a resurgence of PAD. In nondeveloping countries, continued im-
provements in blood product safety, perioperative salvage technologies,
blood ordering and administration practices, and system-driven periop-
erative planning will likely obsolete the need for PAD for all but a very
few patients requiring rare blood. The limited use of PAD in favor of
more cost-effective alternatives that result in equal (or better) out-
comes will likely benefit society by more evidence-based allocation of
scarce health care resources.
Conflict of Interest
The authors have no conflicts of interest to disclose.
Acknowledgments
The authors gratefully acknowledge the assistance of Drs Paolo
Rebulla and Silvano Wendel in identifying regional PAD usage data
and for reviewing the manuscript. The valuable input from members
of the BEST Collaborative is also appreciated.
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