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Journal of Clinical Apheresis 21: 132–141 (2006)

Complications of Donor Apheresis

Jeffrey L. Winters*
Department of Laboratory Medicine and Pathology and Division of Transfusion Medicine, Mayo
Clinic College of Medicine, Mayo Clinic, Rochester, Minnesota

A decreasing blood donor pool in the presence of increasing blood transfusion demands has resulted in the
need to maximally utilize each blood donor. This has led to a trend in the increasing use of automated blood
collections. While apheresis donation shares many reactions and injuries with whole blood donation, because
of the differences, unique complications also exist. Overall, evidence in the literature suggests that the fre-
quency of reactions to apheresis donation is less than that seen in whole blood donation, though the risk of
reactions requiring hospitalization is substantially greater. The most common apheresis-specific reaction is
hypocalcemia due to citrate anticoagulation, which, while usually mild, has the potential for severely injuring
the donor. Other reactions to apheresis donation are uncommon (e.g., hypotension) or rare (e.g., air
embolism). More worrisome, and in need of additional study, are the long-term effects of apheresis donation.
Recent evidence suggests that repeated apheresis platelet donations may adversely effect thrombopoiesis as
well as bone mineralization. Granulocyte donation has also been implicated in unexpected long-term con-
sequences. J. Clin. Apheresis 21: 132–141, 2006.  2005 Wiley-Liss, Inc.

Key words: granulocyte donation; platelet donation; plasma donation; citrate toxicity; hypocalcemia; air
embolism; G-CSF; thrombocytopenia

INTRODUCTION whole blood donation. As with whole blood dona-

tion, McLeod et al. found that first time donors were
With the trend toward maximal utilization of
more likely to have reactions than repeat donors.
blood donors in these times of a decreasing donor
Reactions were found to be more frequent among
pool and expanding blood usage, there is a shift to-
platelet donors (12%) than either plasma (5.9%) or
ward automated blood collections. These collection
granulocyte donors (9.4%). The authors hypothesized
methods share many of the same reactions and inju-
that this was due to a greater frequency of first time
ries seen with whole blood donation but also have
donors in the plateletpheresis group. McLeod et al. [1]
unique complications due to the collection method
also noticed that the instrument used for the collec-
and the frequency at which donation can occur. This
tion influenced reaction rates. Donors collected with
article provides an overview of the frequency and
the Fenwal CS3000 had fewer reactions than those
severity of reactions to apheresis donation in com-
collected with the COBE Spectra or Haemonetics
parison to those seen with whole blood donation, a
instruments. The authors postulated that this was due
discussion of the common and uncommon reactions
to a lower citrate infusion rate with the Fenwal
seen with apheresis donation, and a discussion of the
CS3000 that produced fewer citrate reactions. In
potential long-term consequences of donation.
addition, the CS3000 cannot perform single-needle
apheresis collection procedures while the other
instruments could. It was felt that the larger extra-
REACTIONS TO APHERESIS DONATION corporeal volumes seen with the single-needle proce-
The frequency of acute reactions among donors dures might have contributed to hypotensive
undergoing apheresis procedures was found by reactions [1].
McLeod et al. to be 2.18% in a multi-institutional
study [1]. In comparison, in a review of reactions Presented at the World Apheresis Association 10th Congress
among whole blood donors, Newman reported an hosted by the American Society for Apheresis at its 25th Annual
overall reaction rate to whole blood donation of 11 to Meeting, May 5–8, 2004, Miami Beach, Florida.
*Correspondence to: Jeffrey L. Winters, M.D., Mayo Clinic
21% [2]. The frequencies of different types of reactions Division of Transfusion Medicine, 200 1st Street SW, Rochester,
reported by McLeod and Newman are presented in MN 55905. E-mail:
Table I for comparison. As with the overall reaction Published online in Wiley InterScience
rate, the frequencies of the reactions observed with (
apheresis donation were less than that seen with DOI: 10.1002/jca.20039

Ó 2005 Wiley-Liss, Inc.

Complications of Donor Apheresis 133
TABLE I. Reaction Rates Among Apheresis [1] and Whole Blood solution into a donor would result in a calcium ion
[21] Donors concentration of 0.2 mmol/L, a level incompatible
Reaction Apheresis donations Whole blood with life. This does not occur, however, for a number
(%) donations of reasons. First, when blood returns from the
Hematoma or pain 1.15 9–16 apheresis instrument to the donor, the citrate present
Citrate toxicity 0.4 NA in the blood is diluted throughout total extracellular
Mild vasovagal 0.05 2–5 fluid, not just the intravascular space. In addition, the
Vasovagal with syncope 0.08 0.1–0.3 liver, kidneys, and muscles rapidly metabolize citrate,
releasing the bound calcium [5]. The body also re-
sponds to the decrease in ionized calcium by
A second study by Despotis et al. [3] looking at
increasing parathyroid hormone levels with mobili-
reactions to apheresis donations (platelet and leuko-
zation of calcium from skeletal stores as well as in-
cyte donations) at a single institution found a similar
creased absorption by the kidneys [6]. Interestingly,
overall reaction rate of 0.81%. These authors deter-
this compensatory mechanism may be limited with
mined the rate of very serious reactions, those
intact parathyroid hormone levels reaching their
requiring hospitalization, to be 0.01% (2 out of 19,736
maximum within 30 min of the start of collection
donations) [3]. This rate is 20 times greater than that
without a subsequent increase despite a continued
reported to occur with allogeneic whole blood dona-
decline of ionized calcium [7]. A final mechanism that
tion (1 out of 198,119 donations, 0.0005%) [4]. It,
compensates for the effects of citrate is that there also
therefore, appears that while the overall rate of
appears to be mobilization of ionized calcium bound
reactions in apheresis donors is less than that seen in
to serum albumin [8].
whole blood donation, the risk of more severe reac-
Despite compensatory mechanisms, citrate infu-
tions, those requiring hospitalization, is greater.
sion can result in the decrease in ionized calcium
Among all reactions, Despotis et al. [3] found
levels to a point where symptoms develop in the do-
associations between citrate and hypotensive reactions
nor. In a study of the effects of citrate on apheresis
and donor weight, female gender, and the collection
platelet donors, Bolan et al. found an average fall in
instrument used. For venipuncture related complica-
ionized calcium of 33% from baseline [7]. The result
tions, only female gender was associated as a risk
of such a decrease in ionized calcium is that the
factor. In this study [3], an interesting relationship was
excitability of nerve membranes increases to the point
noted with regard to citrate reactions and the instru-
where spontaneous depolarization can occur [5]. This
ment used for the collection. Despotis et al. noted that
produces the signs and symptoms of citrate toxicity
the relationship between donor weight and citrate
including perioral paresthesias, acral paresthesias,
reactions was different when comparing the COBE
shivering, light-headedness, twitching, and tremors.
Spectra and the Fenwal CS3000. Donors with lower
In addition, some patients also experience nausea and
weights had a higher probability of citrate reactions
vomiting. As the ionized calcium levels fall further,
on the Fenwal CS3000 while those with higher weights
these symptoms may progress to carpopedal spasm,
had a higher probability on the COBE Spectra. The
tetany, and seizure [5]. It is, therefore, important to
authors of this study [3] felt that this was due to the
elicit the presence of the early symptoms from the
methods by which these instruments determine the
donor so that interventions can occur prior to the
anticoagulant infusion rate.
more severe symptoms. Hypotension may also be
seen with citrate reactions [9] and may be due to the
CITRATE TOXICITY depressed myocardial function as well as to vascular
smooth muscle relaxation [10].
Hypocalcemia In addition to the symptoms described above,
Citrate is used as the primary anticoagulant in prolongation of the QT interval on electrocardiogram
donor apheresis procedures. The anticoagulant effect and fatal arrhythmia have been reported [5,11].
of citrate results from its ability to chelate calcium Laspina et al. reported prolongation of the QT
ions resulting in the calcium ions being unavailable to interval in 76 platelet donors examined during col-
participate in biological reactions such as the coagu- lection procedures [11]. While no adverse events oc-
lation cascade. Within the apheresis instrument, curred, the authors recommended that apheresis
plasma citrate concentrations reach 15 to 24 mmol/L, donors should be screened for a family history of long
lowering the calcium ion concentration below 0.2 to QT syndrome or sudden cardiac death in order to
0.3 mmol/L, the level necessary for clotting to occur avoid those donors who many have inherited this
[5]. This level of anticoagulation requires the infusion disorder and be at risk for fatal arrhythmia [11].
of approximately 500 mL of ACD-A solution and it Factors that have been found to influence the rate
would be expected that the infusion of this volume of of citrate reactions in donor and therapeutic apheresis
134 Winters

include alkalosis due to hyperventilation [5], the type [15]. In a comparison with a continuous infusion of
of anticoagulant solution used with ACD-A having calcium gluconate, prophylactically at the start of
more reactions than ACD-B [12], the rate of infusion HPC collection, or at the time of symptom develop-
of the anticoagulant solution [5], the amount of cit- ment, continuous infusion maintained higher calcium
rate infused [5], and the donor’s serum albumin level levels with insignificant changes seen in the other two
prior to the start of the collection procedure [8]. It has modes of administration [16].
also been reported that intermittent flow hemapher- Continuous infusion should not be necessary in
esis procedures tend to have a greater frequency of normal apheresis donation. When IV supplementa-
citrate reactions, as there is a higher rate of citrate tion is necessary, such as in severe reactions, the usual
infusion when the separation chamber is emptied, as dose of intravenous calcium is 10 ml of 10% calcium
compared to continuous apheresis procedures. gluconate IV infused over 10 to 15 minutes. Too rapid
The method by which an instrument calculates the of an infusion can result in hypotension and is to be
dose of anticoagulant also influences the rate of avoided [17].
reactions among certain donor subgroups [3]. The
COBE Spectra bases its rate of infusion on the do-
nor’s blood volume that is calculated by the instru- Hypomagnesemia
ment based upon donor height, weight, and gender.
Magnesium, just as calcium, is a divalent cation
This calculation may overestimate the blood volume
and, as a result, is also bound by citrate. Magnesium
in females and obese individuals, resulting in a rela-
is second in concentration only to calcium among
tive overdose of citrate in these donor populations [3].
divalent cations in the blood and is involved in a
The Fenwal CS3000 determines the dose of antico-
number of physiologic processes. Infusion of citrate
agulant based upon the blood draw rate. As a result,
in the setting of plateletpheresis has been found to
females with low body weights could receive a relative
decrease ionized magnesium by 30 to 40% [7,18].
overdose of citrate as their blood volume is not con-
Ionized magnesium levels have been shown to fall
sidered [3].
more rapidly than ionized calcium levels during cit-
The treatment of citrate reactions is relatively
rate infusion with a more prolonged recovery [18].
simple when the reactions are identified early. The
Hypomagnesemia can induce signs and symptoms
treatment includes slowing the re-infusion rate to al-
similar to hypocalcemia including muscle spasms,
low for dilution and metabolism of the citrate,
muscle weakness, decreased vascular tone, and im-
increasing donor blood to citrate ratio to decrease the
paired cardiac contractility. In addition, hypomag-
amount of citrate infused, giving oral calcium in the
nesemia can also impair calcium and potassium
form of calcium antacids, and giving intravenous
homeostasis, inhibiting the release of parathyroid
calcium [5].
hormone when markedly decreased [18]. As a result,
The administration of oral calcium carbonate and
individuals with low magnesium levels prior to
its effects on citrate toxicity have recently been
undergoing apheresis with citrate anticoagulation
examined by Bolan et al. [8,13] These authors found
may exhibit signs and symptoms of citrate toxicity
that the administration of 2 g of calcium carbonate
due to hypomagnesemia and not hypocalcemia. These
was associated with a statistically significant reduc-
symptoms may be unresponsive to the administration
tion in the severity of paresthesias [13]. Physiologi-
of calcium supplementation.
cally, this dose was also associated with the greatest
improvement in ionized and total calcium levels
among the doses examined (1, 2, and 4 g) [8]. While
improving paresthesias, in multivariate analysis, the Other Acute Effects of Citrate
oral administration of calcium was not associated The metabolism of citrate consumes hydrogen ions
with a reduction in overall symptom development and and results in a rise in the blood pH of donors during
did not effect the occurrence of more severe symp- apheresis platelet collections [7]. Metabolic alkalosis
toms [13]. has been reported to occur in therapeutic apheresis
The administration of intravenous calcium, in the patients with renal disease who cannot adequately
form of calcium gluconate or calcium chloride is excrete bicarbonate [19] and in those receiving
usually not necessary in donor procedures and, replacement fluids containing citrate, such as fresh
therefore, has not been studied in this setting. In frozen plasma [20]. As donors should have normal
hematopoietic progenitor cell (HPC) collections, the renal function and will not be receiving as great a
continuous infusion of either calcium gluconate or citrate load, significant metabolic alkalosis should not
calcium chloride has been found to prevent hypocal- occur [19].
cemic symptom development [14,15] with calcium The rise in blood pH seen with this metabolic
chloride maintaining higher ionized calcium levels alkalosis also results in a shift in hydrogen ions from
Complications of Donor Apheresis 135

intracellular locations in an attempt to compensate. higher incidence in women and the increasing fre-
This produces a concurrent flux of potassium into quency with age were related to a lower circulating
these cells to maintain electrical neutrality resulting in blood volume in these donor groups with a resulting
a fall in serum potassium levels. Bolan et al. noted a greater percentage of the donor’s blood being within
6% decline in serum potassium levels among apheresis the extracorporeal circuit during collection. This re-
platelet donors [7]. sulted in a greater drop in blood pressure during
collection leading to more vasovagal reactions.
Tomita et al. also noted that the incidence of these
reactions increased with increasing cycles during a
Hypotension during apheresis collections can re- collection. Based upon this, they theorized that
sult from a number of factors including intravascular hypocalcemia may also be involved in the onset of
volume depletion, vasovagal reactions, citrate reac- vasovagal reactions in apheresis donors [22].
tions, severe allergic reactions, and air embolism. In Hypovolemic and vasovagal reactions are treated
some cases, hypotension may be multifactorial. similarly. The procedure should be temporarily
With intravascular volume depletion, hypotension interrupted and a fluid bolus should be infused. If the
results due to the removal of blood that fills the reaction is due to hypovolemia, the blood pressure
extracorporeal circuit. This is characterized by in- should increase and the pulse rate should decrease in
creased vascular tone and cardiac output as the response to this intervention. If the reaction is due to
sympathetic nervous system attempts to compensate a vasovagal reaction, this may not occur. Additional
for the hypovolemia [5]. Increased cardiac output treatments for vasovagal reactions include placing the
occurs through an increase in heart rate as well as donor in Trendelenburg position (head down below
increased cardiac contractility. These reactions are the level of the heart), applying cold compresses to the
not common among hemapheresis donors as regula- forehead and neck, and reassuring the donor [5].
tory restrictions limit the extracorporeal volume to
10.5 mL/Kg [21] with most modern instruments
having an extracorporeal volume well below this,
except in the smallest of donors. Allergic reactions result from the release of vaso-
Another mechanism causing hypotension during active substances from mast cells and basophils when
apheresis procedures is the vasovagal reaction. In this IgE antibodies bound to their surface bind the anti-
reaction, hypovolemia results in a decrease in blood body’s target antigen. The release of these substances
pressure. The compensatory response for this volume produces a variety of symptoms by causing contrac-
depletion is to increase sympathetic nervous system tion of smooth muscle, increased vascular permeabil-
output with physiologic compensation as previously ity, and vasodilatation. Mast cells and basophils can
described. During a vasovagal reaction, however, also be activated by complement-derived factors such
parasympathetic output that normally counteracts as C3a and C5a, which can be produce by a variety of
sympathetic output increases, resulting in a slowing of mechanisms including antigen-IgG interactions. These
heart rate and decreased vascular tone [5]. This results types of reactions can range from mild urticarial
in hypotension. Factors that have been associated reactions to life-threatening anaphylactic reactions.
with vasovagal reactions in whole blood donors in- Signs and symptoms of these reactions include pruri-
clude younger age, low weight, first time donation, tus, urticaria, erythema, flushing, angioedema, upper
and inattentive collection staff [2]. airway obstruction, lower airway obstruction, hypo-
Tomita et al. examined the incidence of vasovagal tension, shock, nausea, vomiting, and diarrhea [23].
reactions among apheresis donors and whole blood Allergic reactions have been reported in donors
donors at the same collection center. They found the undergoing collections including platelet, plasma,
incidence of vasovagal reactions among female and granulocyte donors. Among platelet and plasma
apheresis donors and female whole blood donors to donors, reactions to ethylene oxide used to sterilize
be 1.25 and 4.17%, respectively. The rate among male the disposable sets have been described [24,25].
donors was 0.83 and 0.99%, respectively [22]. The rate These reactions have occurred predominantly in
among apheresis donors was substantially greater donors who have donated by apheresis numerous
than that reported by other authors [1,3] although an times. It is thought that during the procedures,
explanation was not apparent from the data reported. ethylene oxide present within the plastic binds to
Tomita et al. noted that the incidence of vasovagal proteins within the plasma with these serving as
reactions increased with age among apheresis donors, carrier molecules. The ethylene oxide becomes a
unlike what has been reported with whole blood hapten resulting in an immune response to the eth-
donors. This increasing incidence was especially true ylene oxide bound to the serum protein and pro-
in women [22]. Tomita et al. hypothesized that the duction of IgE antibodies. In most of the apheresis
136 Winters

donors who experienced allergic phenomenon, IgE maintained using saline. With less severe reactions,
antibodies to ethylene oxide were identified [25]. The epinephrine 0.3 to 0.5 mg can be given subcutaneously
reactions ranged from urticaria, flushing and peri- with the dose being repeated every 20 to 30 minutes for
orbital edema [25] to an anaphylactic reaction con- up to three doses. In addition, aminophylline 6 mg/Kg
sisting of wheezing, flushing, swelling of the lips, and can be given for bronchospasm. This loading dose
hypotension [24]. The overall rate of the reactions in should be followed by an infusion of 0.5 to 1 mg/Kg/
one study was 1.0% of platelet donors. Reactions hour. Volume expansion with normal saline or lactated
were most frequent with one plateletpheresis instru- Ringer’s solution can be given for hypotension. Oxygen
ment examined in that study, the Fenwal CS3000 as should be given for respiratory distress. For severe
compared to the Haemonetics V-50. The authors of reactions, epinephrine 0.5 mg can be given intrave-
the study felt that this was due to the fact that at the nously, with repeated dosing every 5 to 10 minutes.
start of processing with the CS3000, a mixture of Dopamine can also be given for hypotension unre-
saline and anticoagulant that was used to prime the sponsive to volume infusion. The airway must also be
disposable set was infused into the patient. This was protected and endotracheal intubation may be indi-
not the case with the V-50 where the priming solu- cated [23]. Obviously, the best course of action is to
tion was diverted to a waste bag. It was postulated avoid such reactions. Donors who have experienced
that this difference resulted in a bolus of ethylene such reactions should be deferred from future apheresis
oxide to the donor resulting in the reactions [25]. donation.
Attempts to prevent these reactions among donors
have included double priming the disposable set in
order to remove any ethylene oxide present as well BLEEDING
as using the oldest kits, with presumably the least
amount of ethylene oxide left, for these donors. Thrombocytopenia
Allergic type reactions have also been reported A platelet donor typically experiences an acute
among granulocyte donors. While ethylene oxide fall in platelet count of 20 to 29% following dona-
reactions could also occur in this group, another tion [29–31]. Among females, this decrease tends to
possible mechanism could be exposure to hydroxy- be greater [32,33]. Interestingly, the fall in platelet
ethyl starch. Granulocyte donors are exposed to hy- count does not correlate with the yield of the
droxyethyl starch, either low molecular weight or plateletpheresis procedure as more platelets are col-
high molecular weight, in order to enhance red cell lected than anticipated due to the mobilization of
sedimentation. While these substances are poor im- platelets from the spleen during collection [29].
munogens and have not been able to induce antibody Dettke et al. found the time required for a donor to
formation, allergic reactions have occurred in the return to baseline following a platelet donation to be
setting of HES use in hemapheresis [26] and as a four days in males with a delay in increase of
volume expander [27]. The mechanism behind the thrombopoietin levels and a corresponding delay in
production of these reactions is thought to be due to return to normal platelet counts in females [33]. In
the ability of HES to activate the alternate comple- donors undergoing alternate day collections, platelet
ment cascade. This would result in the production of count and apheresis yields have been shown to re-
C3a and C5a, both of which can cause mast cell and turn to baseline levels by day 10 of collection with
basophil histamine release [26]. Reactions reported to stabile counts and yields with subsequent collections
occur with HES include mild urticarial reactions as [34]. A rebound elevation in platelet count with in-
well as severe reactions with respiratory and cardiac creased platelet yield following repeat procedures
arrest. The rate of reactions in a study of patients has been reported [31]. In donors with low platelet
receiving HES for volume expansion was 0.085% with counts (150,000 to 180,000/mL), plateletpheresis
severe (anaphylactic) reactions occurring in 0.006% using prolonged collection times in order to achieve
[27]. Reactions have occurred with both high molec- adequate platelet product yields demonstrated no
ular weight (hetastarch) [27] and low molecular clinically significant problems in 291 procedures,
weight (pentastarch) [28] HES. Because of this risk, despite post-procedure platelet counts as low as
Dutcher et al. recommended that people with a his- 69,000/mL [32]. The results of these studies indicate
tory of any allergies be excluded from granulocyte that platelet counts return to normal levels promptly
donations [26]. following plateletpheresis, even in those undergoing
In all donor reactions, the procedure should be repeated procedures, and that bleeding complica-
stopped. The subsequent treatment of allergic reactions tions are uncommon.
depends upon their severity. Simple reactions, such as In granulocyte collections, platelets and significant
urticaria, can be treated with oral antihistamines. For numbers of red blood cells are also present in the
anaphylactic reactions, vascular access should be leukapheresis product. Typically, a drop in hemato-
Complications of Donor Apheresis 137

crit of 7% and a fall in platelet count of 22% occurs TABLE II. Relative Contraindications to Granulocyte Mobilization
after each granulocyte donation. This fall is due to the Regimens [37,47]
loss of these cells in the product as well as the dilu- Medication Condition
tional effects of volume expansion caused by the HES Corticosteroids Hypertension
used during the procedure [35]. In donors stimulated Diabetes
with G-CSF, however, there appears to be a greater Peptic ulcer disease
decrease in platelet count [36]. Healthy donors G-CSF Inflammatory conditions
receiving G-CSF for 10 days typically have a decline Gout
Risk factors for thrombosis
in platelet count starting at day 8 with significant
differences in counts at days 10 and 11. The mecha-
nism behind this effect is uncertain and may represent
Anticoagulant Induced Bleeding
changed platelet distribution, decrease platelet pro-
duction, or increased intravascular volume [37]. In Concern occasionally arises as to whether citrate
addition, recovery of platelet count also appears to be concentrations within the donor will cause bleeding.
prolonged requiring 7 to 10 days for recovery among As stated, in order to anticoagulate blood, calcium
stem cell donors versus 4 to 6 days among platelet levels less than 0.2 to 0.3 mmol/L must be achieved.
donors [38]. This level is achieved in the hemapheresis instrument
but not in the donor. Such a low ionized calcium level
is incompatible with life.
Hydroxyethyl Starch
The use of HES, either as volume replacement or as REACTIONS TO G-CSF AND CORTICOSTEROIDS
a sedimenting agent, has also been associated with USED IN GRANULOCYTE COLLECTION
changes in coagulation factor levels. Both high and
G-CSF can be used alone or in combination with
low molecular weight HES produce a prolongation of
steroids to enhance granulocyte collection yields.
the partial thromboplastin time (PTT) and a decrease
These medications can cause a number of side effects.
in fibrinogen levels when infused. This is thought to
Common side effects associated with corticosteroids
result from the dilutional effects produced as the col-
include headache, flushing, insomnia, euphoria, pal-
loidal action expands intravascular volume. High
pitations, epigastric acidity, and hyperglycemia [43].
molecular weight, but not low molecular weight HES,
Common side effects of G-CSF administration in-
is also associated with decreases in factor VIII activity,
clude bone pain, myalgias, arthralgias, headache,
factor VIII antigen, and Von Willebrand factor (vWF)
fever, chills, gastrointestinal discomfort, paresthesias,
antigen as well as prolongation of bleeding time [39]. It
chest pain, chills, and fatigue [43]. The side effects
is thought that this last effect is a result of the decrease
seen with G-CSF are common, occurring in 90% of
in vWF antigen levels and may represent an acquired
allogeneic donors receiving G-CSF for hematopoietic
Von Willebrand disease-like state. Because of these
progenitor cell mobilization [44]. They are usually
changes, a risk of coagulopathy exists with the use of
mild and treated symptomatically, such as the
high molecular weight HES as a sedimenting agent.
administration of mild analgesics for the bone pain
This risk appears to be dose dependent. In the setting
and headache. The side effects of G-CSF tend to be
of volume expansion in critical care, the maximum
dose related [44,45] with the exceptions being nausea/
dose of HES beyond which such complications can
vomiting and headache, with the former being more
occur is 20 mL/Kg/24-hour period. Doses up to 3,600
common in women and the latter being more com-
mL, however, have been given in the critical care set-
mon in those under 35 years old [45]. More significant
ting without difficulty [40]. The danger in hemapher-
side effects have been reported with G-CSF including
esis procedures is that multiple collections may be
splenic rupture, retinal hemorrhage, acute iritis, gouty
necessary over consecutive days. Since HES, especially
arthritis, and thrombotic events [37,43]. These are felt
high molecular weight HES, has a long half-life, this
to represent exacerbation of underlying donor ill-
may result in an accumulation.
nesses and donors should be evaluated for these in
determining suitability for donation (Table II). A
report has also appeared in which an allogeneic
Removal of Coagulation Factors peripheral blood hematopoietic progenitor cell donor
Plasma donation could theoretically result in experienced a life-threatening capillary leak syndrome
bleeding if donation resulted in the removal of characterized by hypoxemia, ascites, pericardial effu-
coagulation factors faster than the donor’s synthetic sion, pleural effusion, shock, and hepatocellular in-
ability. Studies of plasma donors have not supported jury following G-CSF administration and peripheral
this concern [41,42]. blood hematopoietic progenitor cell collection [46].
138 Winters

This was felt to be due to apheresis activating the loss of lymphocytes over the course of 24 platelet
large number of neutrophils produced by the G-CSF donations using modern hemapheresis equipment is
administration [46]. equivalent to the loss of lymphocytes in a single
whole blood donation [49]!
With plasma donations, similar concerns have been
expressed with regard to inducing deficiency in hu-
Air embolism is a rare complication of apheresis. It moral immunity. Theoretically, depletion of immuno-
results when more than 3 to 8 mL/kg of air enters the globulins faster than they can be replenished could
venous system through either a leak in the hemaph- occur, especially in frequent donors. Studies of long-
eresis instrument or the venous access. The symptoms term donors [41] as well as donors undergoing frequent
that characterize air embolism are dyspnea, tachyp- donations [42] have not supported these concerns.
nea, cyanosis, tachycardia, and hypotension. These
result from air entering the right ventricle and
pulmonary artery with obstruction of the right
ventricular output as well as pulmonary artery vaso-
constriction [48]. The reason for the rarity of this While studies have shown that platelet counts
complication is that all modern hemapheresis instru- recover quickly following platelet donation, studies
ments possess sensors that can detect air within the of the long-term effects of platelet donation on do-
extravascular circuit and stop the procedure. Should a nor platelet counts are limited. Stohlawetz et al.
significant volume of air embolism occur, however, examined levels of reticulated platelets, a measure of
the treatment consists of placing the donor in the thrombopoiesis, following platelet donation in first
Trendelenburg position on their left side. This traps time donors and those who had under gone dona-
the air in the apex of the right ventricle, away from tion every other week for 18 months [52]. First time
the pulmonary outflow tract, improving right ven- donors had significantly higher levels of reticulated
tricular function. With time, the air will dissolve. platelets and demonstrated a transient increase in
Entrance of a large volume of air or donor hemody- reticulated platelets on day 3. Frequent donors
namic instability may require surgical intervention demonstrated a more sustained rise in reticulated
with the placement of a pulmonary artery catheter to platelets but the level attained was significantly less
aspirate the air [48]. than that seen in first time donors [52]. No difference
in platelet counts was seen between the two groups
at any time period. These findings lead the authors
to postulate that frequent apheresis platelet donation
may lead to a ‘‘relative exhaustion of thrombopoie-
Plateletpheresis using early hemapheresis instru- sis’’ [52].
ments was associated with losses of donor lympho- Lazarus et al. retrospectively studied 939 donors
cytes as great as 5 to 10 · 109 per procedure [49]. who had donated 11,464 platelet donations over 4
Studies involving therapeutic lymphocytapheresis years. These authors found a significant and sustained
and chronic thoracic duct drainage demonstrated decrease in platelet count that directly correlated with
that abnormal cell mediated immunity could be apheresis platelet donation frequency [53]. In the
produced by the loss of 1 to 1.5 · 1011 lymphocytes subgroup of donors with the most donations, this
within a few weeks [49]. As a result of this and correlation was not seen but the authors postulated
studies showing decreased total lymphocytes, T that this was due to the deferral of donors with low
lymphocytes, and IgG levels 8 months after apher- counts. While regular donation resulted in lower
esis platelet donation, concerns about inducing im- platelet counts, clinically significant thrombocytope-
mune suppression arose. This prompted a regulatory nia was not seen [53].
response limiting the number of platelet apheresis These findings raise concerns that frequent
donations to 24 per year [21], the warning of po- apheresis platelet donations could produce throm-
tential plateletpheresis donors about the possibility bocytopenia. While the original limitations on the
of lymphocyte depletion [50], and some authors number of platelet donations per year may have
suggesting that donors should be deferred if their been implemented due to concerns over lymphocyte
lymphocyte counts were below 1.2 · 109/L [49]. depletion, these limits may still be valid in order to
More recent studies of donors donating with newer prevent the development of thrombocytopenia. The
hemapheresis instruments have shown no differences effect of current practices to collect double and triple
in lymphocyte counts, lymphocyte subsets, or IgG platelet products from a donor may further effect
levels when comparing non-donors, plateletpheresis long-term platelet counts and additional studies are
donors, and whole blood donors [51]. In fact, the needed.
Complications of Donor Apheresis 139
Bolan et al. noted that in addition to the acute While the short-term effects of G-CSF are pre-
metabolic effects of citrate infusion, sustained dominantly mild, the long-term effects of exposure to
changes in calcium metabolism, up to 24 hours after G-CSF are unknown. Concerns have been raised over
the completion of the procedure, are also seen [8]. the possibility of the development of hematologic
These changes included altered bone metabolism diseases such as myelodysplasia or chronic myeloge-
demonstrated by changes in alkaline phosphatase, nous leukemia in healthy donors exposed to this
osteocalcin, intact parathyroid hormone, and 1,25- medication [37,43]. This is due in part to the occur-
dihydroxyvitamin D levels and raised concerns rence of leukemic transformation after G-CSF ther-
about the potential for long-term effects on bone apy in 10 to 15% of patients with congenital
metabolism [8]. neutropenia [56–60]. In addition, such patients on
Dettke et al. in a recently published abstract long-term G-CSF therapy have also been reported to
examined apheresis platelet donors for evidence of develop osteopenia, splenomegaly, and cutaneous
such effects [54]. They compared the bone mineral vasculitis [56]. Studies with limited numbers of nor-
density of the femoral necks and lumbar spines of mal donors (3 to 281) and limited follow-up (12 to 60
apheresis donors with more than 100 donations (n months) have reported no abnormalities in granulo-
¼ 45) and those with less than 50 donations (n ¼ cyte and hematopoietic progenitor cell donors to date
40). Thirty-five percent of the donors with more [61–65]. Donors undergoing G-CSF stimulation for
than 100 donations exhibited significant osteopenia granulocyte collection should give informed consent
independent of the donors’ gender or age. Similar prior to stimulation and appropriate institutional re-
changes were not seen in those donors with less view should be obtained for use of G-CSF in this non-
than 50 donations [54]. Additional studies are FDA-approved role. Recommendations have also
obviously needed but these initial findings are of been made that donor registries should be created to
concern. monitor for long-term consequences of G-CSF stim-
ulation [37].


Overall, apheresis donations have acute reaction
Adverse effects due to long-term steroid treat-
rates less than those seen with whole blood donation
ment are well known and include the development
though the frequency of reactions requiring hospi-
of posterior subcapsular cataracts (PSC) [55]. As
talization appears to be greater. The acute effects of
these complications appear with chronic use, it has
donation are relatively mild and easily treated. Recent
been felt that the intermittent use of short-term
evidence suggests, however, that apheresis donation
steroid stimulation of granulocyte donors should
may produce adverse long-term effects in donors such
not be associated with such complications. Due to
as bone demineralization and cataract formation.
the presence of a PSC in an apheresis donor who
Additional research is needed to ascertain the risks of
had made numerous steroid stimulated granulocyte
long-term apheresis donation.
donations, Ghodsi and Strauss examined 11 gran-
ulocyte donors and 9 plateletpheresis donors mat-
ched for age and donation experience for the
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