C H A P T E R

62
Platelet Transfusion Medicine
Peter L. Perrotta,1 Jeremy Parsons,2 Henry M. Rinder,3 and Edward L. Snyder3
1
Department of Pathology, West Virginia University, Morgantown, West Virginia
2
Department of Transfusion Medicine, University of New Mexico, Albuquerque, New Mexico
3
Department of Laboratory Medicine, Yale University School of Medicine,
New Haven, Connecticut

I. INTRODUCTION II. PLATELET PREPARATION

Platelets maintain normal hemostasis through
their elaborate responses to vascular injury.
Accordingly, patients with low numbers of circulat-
ing platelets or functionally hyporeactive platelets
are at increased risk of spontaneous bleeding or
hemorrhage following traumatic injuries or during
surgical procedures. Thrombocytopenic bleeding was
a major cause of death in patients with acute leuke-
mia until platelet concentrates (PCs) became widely
available in the early 1970s.1 Before then, the only
source of viable platelets was freshly drawn whole
blood.2 Routine platelet transfusion therapy was
made possible in large part by the development of
gas-permeable plastic containers that facilitate the
collection, separation, and storage of platelets from
whole blood. Today, PCs are used extensively to
support patients who receive thrombocytopenia-
inducing, intensive therapies for hematologic malig-
nancies and solid tumors. Transfusion services strive
to maintain an adequate supply of PCs that is both
safe and efficacious to support patient needs.
Unfortunately, the constrained shelf-life of PCs
(5 days) makes it impractical for blood banks to
maintain large reserves of products. The safety of
platelet transfusions, in terms of the risk of viral and
bacterial transmission, has improved with advances
in donor selection and testing. Methods for inactivat-
ing contaminating bacteria and monitoring bacterial
growth are being implemented in many countries,
and this will further increase PC safety.
Platelets used in transfusion therapy are prepared
by centrifuging whole blood obtained from a single
blood donation or by apheresis using automated cell
separators. The processes used to separate platelets
from whole blood have evolved during the past sev-
eral decades to maximize the ield of platelets while
limiting the number of red and white blood cells.
Isolating platelets from other blood cells also allows
platelets to be stored under optimal conditions, which
are different from the conditions used to store other
blood components such as red blood cells and plasma.
A. Methods
1. Platelet Concentrates Prepared from Whole
Blood by Platelet-Rich Plasma and Buffy Coat
Methods
Blood is drawn through wide-bore, siliconized nee-
dles to minimize the activation of platelets and clotting
proteins. Removed blood is immediately mixed with
citrate anticoagulant. Before separation by centrifuga-
tion, whole blood must be left undisturbed at room
temperature for a short period because platelets are
activated during blood collection. Approximately
450 mL of whole blood is withdrawn during allogeneic
donation, which is then separated to yield a unit each
of red cells, platelets, and plasma. Platelets prepared in
this manner are often referred to as whole blood “ran-
dom donor” platelets (WB-RDP) because the human

Platelets, 3rd edition 1275 © 2013 Elsevier Inc. All rights reserved.
1276 62. PLATELET TRANSFUSION MEDICINE

leukocyte antigen (HLA) type of the donor is unknown
(i.e., of random HLA type). Each WB-RDP contains on
the order of 5.5 3 1010 platelets suspended in approxi-
mately 50
60 mL of the donor’s plasma. This volume
of suspending plasma is required to maintain platelet
viability during storage.
The two major methods used to isolate platelets
from whole blood are the platelet-rich plasma (PRP)
and the buffy coat (BC) methods (Fig. 62-1).3 Most PCs
in the United States are prepared by the PRP method,
whereas the BC method is preferred in Europe.
Anticoagulated blood is separated based on differen-
tial sedimentation, a process that is accelerated by cen-
trifugation. The sedimentation rate is most heavily
influenced by physical properties of cells (specific
gravity, size, and deformability) and the viscosity of
the medium. Separation times and speeds are opti-
mized to maximize platelet yields within shorter time
periods.
In the PRP technique, whole blood first undergoes a
low g force (“soft”) spin, which separates red cells
from PRP (Fig. 62-1A). Low-speed centrifugation
results in a supernatant (PRP) that contains the major-
ity of suspended platelets, 30
50% of the original
white cells, and few red cells. The PRP is transferred
to a satellite bag and centrifuged at a higher g force
(“hard” spin). The platelet-poor plasma supernatant is
removed, and the platelet pellet is gently resuspended
in residual plasma. Leaving the product undisturbed
for 1 hour prior to resuspension is intended to mini-
mize platelet aggregation and damage, although one
study found no difference in platelet characteristics or
in vivo platelet survival when comparing rest times of
0 minutes, 5 minutes, 1 hour, and 4 hours.4 The PRP
method yields approximately 5.0
7.5 3 1010 platelets,
or 60
75% of the platelets found in the whole blood
unit before separation. Multiple (e.g., four to six) PRP
units are combined to create a platelet “pool” that is
more convenient to transfuse than single PRP units.
Platelets pooled in blood banks must be transfused
within 4 hours of preparation because of the risks of
bacterial contamination during the pooling process.
When platelets are manufactured by the BC method,
whole blood is first centrifuged at high force (3000 g
for 7
10 minutes) to create a buffy coat layer where
platelets and leukocytes reside (Fig. 62-1B).
Higher-speed centrifugation separates cells somewhat
differently than slow-speed centrifugation. During
high-speed centrifugation, white cells initially sedi-
ment with red cells; platelets remain in the supernatant
plasma. Next, red cells are packed closely together and
rapidly fall to the bag bottom. This process forces
plasma and white cells upward to the plasma
interface. The platelets eventually accumulate on this
interface. The settling of platelets on the red cell inter-
face may explain the lesser degree of platelet activation

A +/– leukoreduction

Plasma
PRP

Soft Hard
Spin Spin

Whole blood Single-donor PC

B
Plasma or platelet
additive solution +/– leukoreduction

Plasma
Pool
buffy coats

Hard Soft
Spin Spin

Whole blood RBC Pooled PC

FIGURE 62-1 Preparation of platelet concentrates from anticoagulated whole blood by the (A) platelet-rich plasma and (B) buffy coat
techniques. (Reprinted from Reference 3, with permission; copyright 2010.)

VI. THERAPY TO INCREASE PLATELET NUMBERS AND/OR FUNCTION

 II. PLATELET PREPARATION
when platelets are prepared by the BC compared to
the PRP method.5 The resultant buffy coat, consisting
of platelets and white cells, is removed along with
small portions of the lower plasma layer and the upper
red cell layer. The BC is then centrifuged at low g force
to separate the platelets from leukocytes and red cells.
Top and bottom bag systems facilitate separation by
allowing the platelets in the buffy coat to remain rela-
tively undisturbed in the primary separation bag (with
the plasma and red cells removed from the top and
bottom ports, respectively).6 In practice, four to six
BCs are pooled, diluted in plasma, and centrifuged at
low speed. The resulting platelet-rich supernatant is
then transferred to a larger volume storage bag.
Random donor PCs can also be pooled at the collec-
tion facility to create “prestorage pooled whole blood
derived platelets.” ABO identical PCs are pooled in a
sterile closed system, leukocyte reduced, and tested for
bacteria prior to storage. The dose of one of these
pooled products is similar to that of an apheresis unit.
A study comparing prestorage pooled PCs with non-
pooled individual PCs found no differences in either
platelet quality as assessed by common measures of
platelet viability or in activation of the coagulation or
complement systems.7 Another study comparing these
products found statistically significant differences in
several in vitro tests of platelet degradation; however,
these changes were not considered clinically relevant
to transfusion therapy.8 Other studies have shown that
prestorage pooled WB-RDP are not associated with
any higher incidence of febrile transfusion reactions
than are WB-RDP that are not pooled prestorage.9
2. Single-Donor Platelet Concentrates Prepared by
Apheresis
Platelets collected by cell separators are generally
referred to as “platelets, apheresis” or “single-donor
platelets (SDP) by apheresis.” Donor blood removed
through a catheter in an arm vein is passed through an
apheresis instrument in which platelets are separated
from other cellular components by differential centrifu-
gation. Instruments are automated in that separation
parameters are determined by the instrument’s elec-
tronics based on input parameters, including the
donor’s weight, platelet count, and hematocrit. PRP is
separated from whole blood in the centrifuge; the
residual red cells and plasma are returned to the
donor. Most apheresis systems directly collect platelets
as PRP, whereas other systems yield a concentrated
platelet pellet that must be gently resuspended.
Approximately 4 or 5 L of donor blood is processed
during the 1.5- to 2-hour collection. Other systems
have been developed that can collect not only platelets
but also red cells and plasma during a single dona-
tion.10 Although platelet apheresis is well tolerated by
VI. THERAPY TO INCREASE PLATELET NUMBERS AND/OR FUNCTION
1277
most donors, adverse reactions related to citrate toxic-
ity (hypocalcemia) and hemodynamic instability can
occur.11 Interestingly, there is evidence of platelet acti-
vation in donors several days after platelets are col-
lected by apheresis.12 Moreover, repeated platelet
donations by apheresis result in the transient appear-
ance of mild platelet dysfunction in the donor.13
United States standards require that an apheresis
platelet product contain at least 3 3 1011 platelets sus-
pended in approximately 200 mL of the donor’s
plasma. Thus, one apheresis SDP approximates six
WB-RDP, but because of the variability in platelet col-
lection, the range is four to eight WB-RDP. Because of
increased machine efficiency, many blood centers can
collect two, or up to three, SDP doses (6
9 3 1011 pla-
telets) from a single apheresis procedure. Modern
instruments collect concentrated platelets that contain
few white cells—typically less than 1 3 106—and these
SDP are considered leukocyte-reduced by most stan-
dards. Plateletpheresis products are stored at 20
24o% C
for up to 5 days, identical to platelets prepared by
other methods. Apheresis-derived platelets, like BC-
and PRP-prepared PCs, contain few red cells, and red
cell cross-matching is therefore not necessary.
However, there are enough red cells in an SDP unit
that some physicians, in an attempt to prevent active
alloimmunization to the RhD antigen, would consider
providing Rh Immune Globulin to RhD negative reci-
pients who receive RhD positive SDP, especially
women of child-bearing potential. Transfusing aphere-
sis-derived platelets that are ABO incompatible typi-
cally does not produce measurable hemolysis in
adults.14 Some centers titer group O platelets to avoid
the uncommon situation in which the platelet donor
carries an exceptionally high-titer anti-A that could
cause hemolysis if infused to a group A recipient.15
This situation is more dangerous when group O aphe-
resis-derived platelets are given to group A infants
and small children.16
B. Quality Control
Institutions that prepare PC used for transfusion
therapy have quality control (QC) programs that detect
problems in the collection, processing, or storage of
these products.17 Guidelines for monitoring PC quality
vary slightly across different countries and are specific
for the preparation technique.18 Most standards
require measurements of platelet numbers, pH, and,
when products are labeled leukoreduced, white blood
cell count (Table 62-1). Platelet and white cell counts
reflect the efficiency of the particular platelet collection
and/or leukocyte reduction process utilized. The con-
centrations of platelets prepared from PRP
1278 62. PLATELET TRANSFUSION MEDICINE

TABLE 62-1 Standards for Platelet Concentrate Quality
Assurance
United States18
Whole Apheresis Whole
Blood Derived Blood
Derived Derived
Platelets (31010) $ 5.5 $ 30 PRP $ 0.02,
BC $ 0.005
Volume (mL) Not Not .40 mL per .40 mL per
specifieda specifieda 60 3 109
platelets platelets
White cells ,0.83b ,5.0b ,1.0a
(3106) to label
leukoreduced
pH .6.2 .6.2 6.4
7.4
a
Standard met if 90% of units tested fall within indicated values. Volume of plasma
sufficient to keep platelet pH . 6.2.
b
In 95% of units tested.
(150,000
450,000/μL) are less than those collected by
apheresis (.1,000,000/μL). As a QC tool, PC pH is
measured at the end of the storage period because a
pH below 6.2 or above 7.6 correlates with decreased
in vivo efficacy.19 The total volume of PCs is largely
based on the amount of plasma needed to maintain
product pH within an acceptable range during storage.
Temperature control charts on platelet incubators ver-
ify that the platelets were stored between 20 and 24 C.
1. Platelet Counting in Platelet Concentrates
The original methods employed to enumerate plate-
lets used small-volume chamber hemacytometers and
phase contrast microscopy. These techniques required
removal of red cells by lysis or sedimentation before
counting and were time-consuming, labor-intensive, and
highly variable with coefficients of variation exceeding
10%. Thus, automated hematology analyzers are com-
monly used by blood banks to determine platelet counts
in PCs in a more rapid and reproducible manner.
Although the precision and accuracy of most instru-
ments are generally considered acceptable, a multicenter
study conducted by the Biomedical Excellence for Safer
Transfusion (BEST) Collaborative group found signifi-
cant interanalyzer variability among instruments used to
count platelet numbers in PCs.20 There are several possi-
ble explanations for variability in PC platelet counting.
First, hematology analyzers are designed for whole
blood samples—not PRP—and thus are calibrated using
whole blood controls. Second, analytic errors can be
introduced when PC samples are diluted before analysis.
Third, platelet aggregates can form during product sam-
pling, which results in falsely low platelet counts.
2. Residual White Cell Counting in Platelet
Concentrates
Europe276 Centers that produce leukoreduced PCs must
Apheresis
ensure that a sufficient number of white cells have
Derived been removed from products.21 Automated hematol-
ogy analyzers are inappropriate for determining white
cell numbers in leukoreduced PCs because of their
$ 20
lack of sensitivity when trying to measure very low
WBC counts such as are seen in leukoreduced PCs.22
Most residual white cell counts are therefore per-
60 3 109
formed by manual chamber techniques using larger
volume chambers such as the 50 μL Nageotte-type
,1.0a
hemacytometer.23 While these “chamber” white cell
counts are considered acceptable for monitoring PC
quality, alternative approaches have been developed
6.4
7.4
that are more precise and accurate at the low white
cell counts found in leukoreduced PCs. These techni-
ques, which are not routinely employed by blood cen-
ters to verify adequate leukoreduced PCs, include flow
cytometry, microvolume fluorometry, and quantitative
polymerase chain reaction (PCR).24
III. PLATELET STORAGE AND STORAGE
INJURY
PCs undergo alterations during collection, proces-
sing, and storage that adversely affect their structure
and function. These changes, commonly referred to as
the platelet storage defect (PSD) or platelet storage
lesion (PSL), are important because they are
associated with decreased post-transfusion in vivo
survival.25 Several factors related to the collection,
processing, and storage of PCs that influence devel-
opment of the PSD have been identified
(Table 62-2).26 For example, centrifugation may dam-
age platelets by exposing them to conditions of high
shear stress. Shear stress may cause the release of
both cytosolic lactate dehydrogenase (LDH) and
platelet granule contents.27 Residual leukocytes and
platelets remain metabolically active during storage
and continue to consume nutrients and produce
potentially harmful metabolic products. Cellular
debris and proteolytic enzymes are also found in the
surrounding plasma. Interactions between stored pla-
telets and suspending plasma may activate clotting
factors and, thus, the coagulation system.
Stored PCs have been studied using a wide variety
of techniques including platelet morphology by
microscopy, pH, LDH, platelet activation markers,
osmotic recovery, platelet aggregation, and extent of
shape change (Table 62-3).28,29 Simple evaluations
include visually inspecting PCs before they are trans-
fused. Normal discoid platelets, when exposed to a

VI. THERAPY TO INCREASE PLATELET NUMBERS AND/OR FUNCTION

 III. PLATELET STORAGE AND STORAGE INJURY 1279
TABLE 62-2 Factors that Influence Development of the Platelet falls below about pH 6.2, the platelet undergoes a
Storage Defect disc-to-sphere transformation and the refraction of
Collection and Separation Storage Conditions and light is lost and the platelet “swirl” disappears. The
Techniques Processing lack of swirling may thus correlate with a less-than-
predicted post-transfusion platelet increment.31 In
Blood drawing flow rate Storage temperature
clinical practice, however, only platelet number, con-
Type of anticoagulant/preservative Storage duration centrate volume, supernatant pH, and white cell
solution number are routinely measured in PCs; these tests
Ratio of anticoagulant to whole Form and intensity of platelet likely reflect only a small subset of changes that occur
blood agitation during platelet storage. Many investigators believe
Time between whole blood Volume of suspending plasma that in vivo autologous recovery of radiolabeled plate-
collection and separation in PCs lets is the gold standard test of platelet viability and
Centrifugation forces Composition of storage
should be conducted when storage conditions and/or
(time and g force) container (permeability) platelet substitutes are evaluated.32 The survival
curves of transfused platelets, whether an allogeneic
Processing temperature Leukodepletion technique
PC prepared by a standard or novel technique,
should approximate those curves obtained when
unaltered autologous platelets are infused.
Standardized methods utilize radiolabeling of plate-
TABLE 62-3 In Vitro Tests of Platelet Concentrate Quality
lets with 51chromium or 111indium.33
PLATELET STRUCTURE

Cellular content (platelet count) A. Platelet Concentrate Storage Conditions

Visual inspection for swirling phenomena 1. Platelet Storage Temperature and Platelet Cold
Platelet morphology by microscopy Injury
Platelet size distribution by automated counters
PCs were originally stored refrigerated like red
blood cell units until it was determined that platelet
FUNCTIONAL TESTS function and viability are severely compromised when
Platelet aggregation, spontaneous and to agonists
stored at these colder temperatures.34 They are now
stored at 20
24 C, which markedly improves post-
Hypotonic shock response transfusion viability as compared to cold storage.35
Extent of shape change Alternatively, the viability of platelets stored at physio-
Thrombin-stimulated ATP release
logic temperatures (closer to 37 C) is lower than those
stored at 22 C. This observation may be related to the
METABOLIC STATUS normal high metabolic rate of platelets with rapid
Supernatant pH, pO2, pCO2, HCO3
adenosine triphosphate (ATP) turnover—a rate that
can be decreased by maintaining platelets at lower
Glucose consumption than physiologic temperatures.36
Lactate production Platelets stored at 4 C develop a sphere-like mor-
phology, which is evidence of irreversible physical
PLATELET ACTIVATION damage.37 Even when platelets are briefly exposed to
P-selectin (CD62P) surface expression temperatures less than 20 C for 24 hours, as may occur
Soluble P-selectin release to supernatant
during transport of platelets from a supplier to a hos-
pital, there are observable differences in platelet mor-
Platelet factor 4 and β-thromboglobulin phology. These shape changes may involve actin
Annexin V binding assembly.38,39 Furthermore, refrigerated platelets are
Lactate dehydrogenase release to supernatant
rapidly cleared from the circulation upon transfusion.
Evidence suggests that this clearance is mediated by
Platelet microparticle formation the integrin αMβ2 (Mac-1) on Kupffer cells in the liver
that recognize clustered glycoprotein (GP) Ib receptors
on chilled platelets, resulting in rapid platelet phago-
light source and the plastic storage bag is gently cytosis.40 The circulation of functional cooled platelets
rotated or squeezed, refract light and produce a in mice can be prolonged through enzymatic galacto-
visual “swirling” phenomenon that can be identified sylation of chilled platelets, which effectively blocks a
by trained personnel.30 If the pH of the unit of PC lectin that recognizes exposed β-N-acetylglucosamine

VI. THERAPY TO INCREASE PLATELET NUMBERS AND/OR FUNCTION

1280 62. PLATELET TRANSFUSION MEDICINE
(βGlcNAc) residues of N-linked glycans on GPIbα.41
However, post-transfusion survival of chilled platelets
in humans was not improved by galactosylation.42
2. Agitating Platelet Concentrates
PCs are routinely stored with continuous gentle agi-
tation in order to slow deterioration of in vitro mea-
sures of platelet function and structure.43 In addition,
agitation appears to prolong platelet survival following
transfusion.44 Horizontal agitation on a flat-bed agita-
tor is generally preferred over circular rolling “Ferris
wheel”-type agitation.45 Agitation is thought to
enhance the transport of gases like O2 through the
storage bag. There is evidence that PCs stored without
agitation experience upregulated glycolysis, which
may lead to increased lactic acid production and a fall
in PC pH. The BEST Collaborative group reported that
PCs could maintain a pH greater than 6.5 for up to
7 days storage after temporarily stopping agitation for
the 20
24 hours that might be required to ship a PC
from a blood supplier to a healthcare facility.46 These
findings suggest that the PC glycolytic rate returns to
lower levels after agitation is resumed.
B. Platelet Storage Containers
One of the most significant advances in platelet
transfusion therapy was the development of plastic,
gas-permeable storage containers that allow adequate
O2 and CO2 exchange. The earliest storage bags com-
posed of polyvinyl chloride (PVC) and a 2-diethylhexyl
phthalate (DEHP) plasticizer did not allow platelet
storage beyond 3 days. Aerobic metabolism was not
maintained, which resulted in lactic acid production, a
rapidly falling pH and, most importantly, poor in vivo
platelet recovery and survival.47 The next generation of
storage containers, composed of PVC and non-DEHP
plasticizers such as butyryl-tri-hexyl citrate, was more
gas permeable, allowing the storage of platelets for 5
days at 20
24 C, while maintaining acceptable degrees
of in vitro function and survival after transfusion.48
Containers composed of polyolefin with even greater
oxygen permeability have been shown to provide a
stable in vitro environment for PCs stored for up to
7 days.49
C. Metabolic Changes during Platelet Storage
The metabolic processes of human platelets continue
after they are removed from the body and stored as
PC.50 Moreover, the white cells found in PCs also main-
tain some metabolic activity. Thus, the pH of whole
blood begins to decline soon after collection at a rate
dependent on the buffering capacities of these cells and
the suspending solution. Decrements in pH are
VI. THERAPY TO INCREASE PLATELET NUMBERS AND/OR FUNCTION
relatively small within the first 14
24 hours after whole
blood collection because of the buffering capacity of
plasma and red cells. As in cold injury, platelets
exposed to a pH , 6.3 exhibit morphologic changes and
have diminished in vivo survival upon transfusion.
Most of the pH-related effects of stored platelets appear
permanent, although more modest damage may be par-
tially reversible.51 Thus, the amount of plasma required
in a PC is selected to ensure adequate buffering capac-
ity to maintain the pH of the PC . 6.2 during the stor-
age period. In general, 35 mL of plasma is sufficient for
a single WB-RDP unit, but 50
60 mL is typically pro-
vided in practice. Platelets stored at room temperature
have lower metabolic activity than platelets that circu-
late in vivo at body temperature and are therefore stored
at 22oC.52 Based on the propensity of platelets stored at
cooler temperatures to be cleared more quickly after
transfusion, several studies have examined the effects of
warming platelets to body temperature before transfu-
sion. The most recent of these found that heating autol-
ogous platelets stored at 22oC to 37oC provided no
benefit in platelet survival following transfusion.53
Finally, the detrimental effects on platelet metabolism
during storage appear at least partially reversible by
“rescuing” the platelets with fresh plasma.54
D. Anticoagulants
The anticoagulant-preservative solutions into which
whole blood is drawn typically contain either of two
formulations of citrate
phosphate
dextrose (CPD or
CP2D) or CPD with adenine (CPDA-1). The cardiotoxic
agent EDTA, used in the early days of platelet transfu-
sion, is inappropriate because EDTA-anticoagulated
platelets are rapidly removed from the circulation. The
concentration of citrate in CPD plasma is usually
20
22 mM. Apheresis platelets are generally collected
into solutions containing citric acid, trisodium citrate,
and dextrose (ACD-A). Dextrose provides a source of
energy, and phosphate serves as a buffer. Adenine,
which is added to blood collection bags to improve
red cell survival during storage by increasing cellular
ATP levels, does not appear to enhance platelet sur-
vival during storage. When pH levels and concentra-
tions of calcium ions are maintained lower than in the
physiologic state, platelets are less likely to become
activated, release their intracellular contents, and
undergo irreversible aggregation. The amount of cit-
rate found in PCs does not usually produce hypocalce-
mia or systemic anticoagulation in recipients of PCs
because the citrate is rapidly metabolized to bicarbon-
ate in the liver. However, patients with end-stage liver
disease are more prone to citrate toxicity, which can
cause transient hemodynamic depression.55
 III. PLATELET STORAGE AND STORAGE INJURY
E. Platelet Storage Solutions
PCs are typically stored suspended in autologous
plasma to better maintain pH and cell viability. However,
a number of platelet storage solutions (PSS) have been
developed that, like plasma, maintain platelet structure
and function.56 A major reason for developing PSSs is
that plasma not used to suspend platelets could be used
for other purposes.57 This was particularly true in the
1970s and 1980s, when large amounts of plasma were
needed to manufacture Factor VIII concentrates for
patients with hemophilia. In addition, patients transfused
with platelets stored in PSS may be less likely to experi-
ence allergic and febrile transfusion reactions and, possi-
bly, transfusion-related acute lung injury. Crystalloid
solutions that do not contain glucose or bicarbonate do
not maintain PC pH, and platelets stored in such solu-
tions therefore exhibit reduced in vivo recovery after
transfusion.58 Furthermore, at least some glucose is
required in the Krebs cycle for oxidative processes and in
glycolytic reactions that result in lactic acid production.
Most PSS are buffered salt solutions that contain var-
ious additives (e.g., gluconate and acetate), designed to
reduce oxygen consumption, glucose utilization, and
lactate production, and also to limit in vitro platelet acti-
vation.59 Acetate also participates in platelet metabolism
through the tricarboxylic acid (citrate) cycle and is oxi-
dized through the respiratory chain.60 The use of acetate
in PSS is thought to limit production of lactate and
hence to partially replace glucose as a substrate for
energy production.61 Removing plasma may decrease
the incidence of certain transfusion reactions, but post-
transfusion increments may be lower when platelets are
resuspended in additive solutions alone.62 Other inves-
tigators, however, have been unable to demonstrate a
difference in platelet recovery when PSS are used to
suspend platelets.63 More recently, a study examining
the use of a PSS found that apheresis platelets stored in
a mixture of 65% of a PSS and 35% plasma maintained
PC pH $ 6.9 for storage up to 5 days, while maintaining
platelet survival upon transfusion.64
PSS have been used for some time in Europe when
preparing buffy coat platelets,65 although they can also
be used to produce platelets by the PRP technique.
Various inhibitors of platelet and coagulation factor acti-
vation, such as theophylline, prostaglandin (PG) E1, and
aprotinin, have been added experimentally to PSS in
attempts to further preserve platelet function.66 PGE1 sti-
mulates adenyl cyclase, whereas theophylline inhibits
platelet phosphodiesterase; the net effect of both addi-
tives is increased cyclic adenosine monophosphate
(cAMP) availability. cAMP at least partially inhibits cal-
cium release from the dense tubular system membrane.67
Adding aprotinin, a broad-spectrum serine protease
inhibitor, and a thrombin inhibitor (e.g., hirudin) to
VI. THERAPY TO INCREASE PLATELET NUMBERS AND/OR FUNCTION
1281
PGE1/theophylline PSS has also been studied in
attempts to further improve in vitro platelet
preservation.68
The newer PSS appear more capable of maintaining
platelet integrity and metabolic properties than older
formulations. Improvements include adding cations like
K1 and Mg21 to a PSS, which reduces in vitro indicators
of platelet storage degradation (e.g., lower glucose
uptake, decreased lactate production) after 7 days of
storage; however, this was not accompanied by
improvements in platelet recovery following transfu-
sion.69 In a similar study, platelet recovery was lower
for PCs stored in a PSS containing cations than those
stored in plasma, despite maintenance of in vitro indica-
tors during storage.70 Most recently, little differences
were seen in the metabolic and cellular functions of pla-
telets stored with plasma alone compared to those
stored in 20/80 plasma/PAS mixture PSS that con-
tained higher levels of Mg21, K1, and glucose.71 The
Mg21 appears to better preserve the ability of stored
platelets to bind and aggregate to subendothelium.72 In
another study, the effectiveness of PSS was questioned
by investigators who found that autologous platelets
stored in a 20/80 mix of plasma/PSS had poorer post-
transfusion recovery than platelets stored in plasma.73
Thus, PSS may not be able to entirely replace plasma.
F. Platelet Activation during Storage
Platelets become activated during the preparation
process and during prolonged storage as assessed by
flow cytometric analysis of the platelet surface expres-
sion of the α-granule membrane protein P-selectin
(CD62P).74 Alternatively, soluble P-selectin can be
quantified in supernatant plasma.75 P-selectin surface
expression is one of the most commonly applied mea-
sures of platelet activation in PCs, and efforts have
been made to standardize these measurements.76
Other proteins found within platelet granules, such as
β-thromboglobulin, platelet factor-4, and serotonin,
have also been examined in stored PC.27 Annexin V
binding, which is used as a marker of phosphatidylser-
ine exposure on the platelet surface, has been exam-
ined as an alternative marker of platelet activation
within the context of platelet preparation and storage.
In general, annexin V binding increases during 5 days
of platelet storage at room temperature.77 However,
the degree of change in annexin V binding may be
related in part to the method used to prepare platelets
(e.g., PRP vs. apheresis-collected platelets).78
In any event, materials and methods used to collect,
prepare, and store PCs are generally designed to limit
platelet activation.79 Increased platelet activation gener-
ally correlates with other adverse changes that occur
during platelet storage. However, there is little evidence
1282 62. PLATELET TRANSFUSION MEDICINE
that the degree of platelet activation associated with
platelet preparation and storage impairs the ability of
transfused platelets to produce acceptable post-transfu-
sion recovery or to arrest bleeding. Studies have been
conducted to determine if activated, P-selectin-positive
platelets are preferentially removed from the circulation
in proportion to P-selectin surface expression. However,
these studies are limited by the difficulty in controlling
other factors (e.g., supernatant pH) that affect the sur-
vival of transfused platelets in the circulation.80
Michelson et al.81 demonstrated in a nonhuman pri-
mate model of platelet transfusion that transfused
degranulated platelets rapidly lose surface P-selectin
to the plasma pool but continue to circulate and func-
tion in vivo. This study demonstrated that platelet sur-
face P-selectin molecules, rather than degranulated
platelets, are rapidly cleared. These results were subse-
quently independently confirmed by Berger et al.,82
who found that the platelets of both wild-type and
P-selectin knockout mice had identical life spans.
When platelets were isolated, activated with thrombin,
and reinjected into mice, the rate of platelet clearance
was unchanged. The infused thrombin-activated plate-
lets rapidly lost their surface P-selectin in circulation,
and this loss was accompanied by the simultaneous
appearance of a 100-kDa P-selectin fragment in the
plasma. Storage of platelets at 4 C caused a significant
reduction in their life span in vivo, but again no signifi-
cant differences were observed between the two geno-
types. Thus, the results of Berger et al.82 confirm that
P-selectin does not mediate platelet clearance.
Furthermore, in a thrombocytopenic rabbit kidney
injury model, Krishnamurti et al.83 reported that throm-
bin-activated human platelets lose platelet surface P-selec-
tin in the (reticuloendothelial system-inhibited) rabbit
circulation, survive in the circulation just as long as fresh
human platelets, and, most important, are just as effective
as fresh human platelets at decreasing blood loss. Taken
together, these studies81
83 strongly suggest that the mea-
surement of platelet surface P-selectin in platelet concen-
trates stored in the blood bank should not be used as a
predictor of platelet survival or function in vivo.
However, platelet surface P-selectin could still be a useful
measure of QC during processing, storage, and manipula-
tion (filtration and washing). The reason is that, in con-
trast to the situation in vivo, the activation-dependent
increase in platelet surface P-selectin is not reversible over
time under standard blood banking conditions.84
G. Platelet
Derived Microparticle Formation in
Platelet Concentrates
Platelet-derived microparticles (PMPs), small parti-
cles derived from the membranes of intact platelets
also known as platelet-derived microvesicles, are
VI. THERAPY TO INCREASE PLATELET NUMBERS AND/OR FUNCTION
present in PC. PMPs are strongly procoagulant, and
there is evidence that they retain many of the biologic
properties of intact platelets (see Chapter 22). Various
mechanisms may contribute to PMP formation in PCs,
including direct mechanical injury and exposure to
stresses during component preparation. In addition,
PMPs are formed as a result of the inevitable platelet
activation that occurs during platelet processing and
storage—activation that partially depends on
interactions between platelets and the plastic storage
container.85 PMP formation in PCs is most conve-
niently quantified by flow cytometric methods based
on light-scattering properties and surface expression of
GPIb-IX or GPIIb-IIIa (integrin αIIbβ3).86
Differences in PMP formation observed when
platelets are prepared using different component
preparation techniques (e.g., apheresis vs. whole
blood-derived PC) appear to be related to separation
forces and anticoagulant concentrations.87 Platelets col-
lected by apheresis contain more PMPs than the donor’s
predonation plasma, and there is little increase in PMP
number during storage, suggesting PMP formation
resulted from the collection process.88 Thus, patients
transfused with PCs prepared using modern techniques
are exposed to significant numbers of PMPs. However,
it remains unclear to what degree these procoagulant
PMPs contribute to the hemostatic effectiveness of
transfused platelets. In addition, fragments of white
cells, endothelium, and platelets appear capable of pro-
voking primary alloimmunization to HLA antigens in a
transfusion recipient.89
H. Apoptotic Activity of Stored Platelets
Apoptosis, or programmed cell death, plays an
important role in many biological processes. During the
past decade, it has been recognized that anucleate plate-
lets undergo apoptotic-like changes in response to chem-
ical and physical stimulation.90 Platelets contain
enzymes that are central to apoptotic execution such as
caspase-3, and key elements of the mitochondrial death
pathway including cytochrome c, Apaf-1, and death reg-
ulators of the Bcl-2 family (see Chapter 3).91
94 Since pla-
telets are anucleate, it is hypothesized that this apoptotic
machinery originally resided in, and was programmed
by, nucleated megakaryocytes from which platelets are
derived. In vitro experiments demonstrate that platelet
apoptosis can be induced by calcium ionophores, other
platelet agonists, and following storage at room tempera-
ture under standard blood bank conditions. Platelet cas-
pase activity is enhanced during storage at 37 C;
however, inhibition of caspase activity does not improve
platelet viability at 37 C despite clear decreases in cas-
pase activity.95 Evidence of platelet apoptosis also exists
at the mitochondrial level in stored and experimentally
 IV. POSTCOLLECTION PROCESSING
stressed platelets.96,97 Understanding the role of apopto-
tic mechanisms in platelet survival (see Chapter 3) could
help to better understand the platelet storage lesion.
I. Cold Storage of Platelets
The constant need for platelet products and their
relatively short storage time at room temperature has
prompted investigation of processes of cold storage
that might prolong the shelf-life of platelets for trans-
fusion. Unfortunately, although these studies have
yielded important information on platelet physiology,
the ability of cold-stored platelets to function and sur-
vive after transfusion has not yet been borne out.
Cryopreservation of platelets using Trehalose stabili-
zation has been demonstrated to maintain thawed pla-
telets’ ability to regulate internal pH and related platelet
function.98 When Trehalose-stabilized freeze-dried out-
dated platelets were used in a murine wound model,
the preserved platelets induced wound healing to the
same degree as standard PC.99 In vitro examination of
Trehalose-treated platelets at 4oC showed that platelets
did not undergo as rapid apoptosis as untreated plate-
lets and were able to maintain aspects of function.100
However, studies of cryopreserved platelets currently
have not progressed beyond in vitro assessments.
Platelets stored at 4oC are rapidly removed from the
circulation after transfusion.101 The mechanism of this
clearance is thought to be due to clustering of the
platelet GPIbα receptors with a resulting increase in
exposure of galactose residues; the latter are recog-
nized by β2 integrin sialoglycoprotein receptors on
hepatic macrophages which bind to and clear the pla-
telets. This mechanism was confirmed in a murine
model of thrombocytopenia.102 It was initially thought
that galactosylation would block this interaction
because galactosylated platelets maintained in vitro
function after 14 days of cold storage and inhibited
in vitro macrophage recognition.103 However, when
UDP-galactose was added to platelets in a phase I trial
of storage at 4oC, this treatment did not prevent clear-
ance.42 It appears that capping the β-GlcNAc with
galactosylation will prevent clearance with very short-
term 4oC storage but is ineffective with the needed
long-term storage; the latter continues to increase
platelet-hepatic macrophage binding via both β2 integ-
rin and Ashwell
Morell receptors.104
IV. POSTCOLLECTION PROCESSING
A. Leukocyte Reduction of Platelet
Components
In many countries, platelets, like red blood cells, are
commonly leukoreduced. The United Kingdom
VI. THERAPY TO INCREASE PLATELET NUMBERS AND/OR FUNCTION
1283
implemented universal leukodepletion in 1999, largely
based on the theoretical benefit of reducing the risk of
variant Creutzfeldt
Jacob disease. The clearest bene-
fits of leukoreduction include decreasing the risks of
febrile nonhemolytic transfusion reactions, cytomega-
lovirus (CMV) transmission, and HLA alloimmuniza-
tion.105 Platelets are most commonly leukoreduced
soon after collection and before storage (prestorage
leukoreduction). “Poststorage” leukoreduction refers
to the less common practice of removing white cells
immediately before transfusion. Prestorage leukore-
duction can be performed when platelets are prepared
by either the PRP method or the BC method. For the
latter technique, BC concentrates are pooled and fil-
tered through a single filter, either on the day of pro-
cessing or after overnight storage. “Process”
leukoreduction refers to the ability to collect platelets,
by apheresis, with very little white cell contamination;
platelets collected by apheresis are considered prestor-
age leukoreduced.
Cotton wool was the first material used to remove
white blood cells from donated whole blood.106
Currently, the three most commonly used leukoreduc-
tion filters are composed of negatively charged polyes-
ter, positively charged polyester, and noncharged
polyurethane. Some polyester filters are constructed as
a nonwoven mesh, whereas polyurethane filters form
multilayer sponge networks. White blood cells are
removed from blood by filters through several mechan-
isms, including simple sieving/mechanical retention
based on cell size, direct adhesion of white cells to
fibers, and indirect adhesion through platelets.107
Earlier developed leukoreduction filters removed not
only leukocytes but also platelets, which adhered to the
polyester fiber surface. Fibers were later modified, for
example, by coating with polymers such as polyhy-
droxyethyl methacrylate/polystyrene, to minimize the
loss of platelets during blood filtration.108 Two filters
remain in widespread use—one to remove white cells
from red cell concentrates and another to remove
white cells from PC.
B. Gamma and Ultraviolet Irradiation of
Platelets
Residual white blood cells found in PCs can
cause transfusion-associated graft-versus-host disease
(TA-GVHD) in susceptible patients.109 This rare, albeit
usually fatal, reaction is prevented by gamma-irradiat-
ing PC before transfusion. Ionizing radiation inacti-
vates residual T cells found in PCs by damaging
nuclear DNA. Platelets that are stored for 1
5 days
and then irradiated with 5,000 cGy (1 rad 5 1 cGy)
maintain normal in vitro measures of platelet structure
1284 62. PLATELET TRANSFUSION MEDICINE
and function.110 More important clinically, irradiated
platelets (5,000 cGy) produce the expected platelet
increments and appear hemostatically effective when
transfused to thrombocytopenic patients.111 When irra-
diation is performed, the FDA requires that a dose of
2,500 cGy be delivered to the midplane of the irradia-
tion canister and that a minimum dose of 1,500 cGy be
delivered to any other point in the canister. This irradi-
ation dose effectively inactivates T cells and is well tol-
erated by both whole blood- and apheresis-derived
products in terms of in vivo platelet recovery or plate-
let survival.112 Moreover, gamma irradiation does not
harm in vitro measures of platelet function when aphe-
resis-derived platelets are irradiated and stored for up
to 7 days.113 However, gamma irradiation of platelets
does not destroy bacteria and cannot be used to pre-
vent bacterial proliferation in platelet components.
Exposing platelet transfusion recipients to foreign
major histocompatibility complex (MHC) antigens is a
major cause of platelet alloimmunization. This in turn
can lead to a platelet refractory state in which patients
do not respond to platelet transfusions. The Trial to
Prevent Alloimmunization to Platelets (TRAP) showed
that ultraviolet B (UVB) irradiation at 1,480 mJ/cm2
was equivalent to leukofiltration for decreasing the
incidence of platelet refractoriness in patients with
acute myelogenous leukemia.105 Animal experimenta-
tion has shown that UVB-irradiated leukocytes induce
a state of humoral immune tolerance in which recipi-
ents cannot respond to foreign MHC antigens.114 In
vitro studies have verified that medium-wavelength
(280
320 nm) UVB light inactivates leukocytes found
in PCs, but the necessary dose is related to the type
and size of the plastic container in which platelets are
stored. When exposed to 3,000 J/m2 UVB, PCs stored
for up to 5 days exhibit no adverse effects on pH or
aggregation responses.115 Higher doses of UVB irradia-
tion (100,000 J/m2) cause changes in platelet structure
and affect the expression of various platelet membrane
proteins including GPIb.116
C. Pathogen Reduction Technology
Pathogen reduction technologies (PRTs), largely
based on photochemical reactions, are being developed
to inactivate viruses and bacteria that may contaminate
blood products.117,118 An important feature of any pho-
tochemical treatment developed for platelet therapy is
its ability to leave platelet function intact so that post-
transfusion recovery and survival are not impaired.119
PRT methods under investigation include riboflavin
(vitamin B2) plus ultraviolet (UVA) irradiation,120,121
amotosalen-HCL (S-59) plus UVA irradiation,122
125
L-carnitine, and gamma irradiation.
126
VI. THERAPY TO INCREASE PLATELET NUMBERS AND/OR FUNCTION
There are relatively few recent studies examining
the use of riboflavin and UVA (Mirasol PRT,
CaridianBCT Biotechnologies, Lakewood, CO), possi-
bly related to the findings described later indicating
concerns on loss of platelet numbers and function in
stored PC treated by this technology. In one study,
most platelet properties were preserved equally well
after storage of PRT-treated concentrates versus PSS
alone.72 However, there is contrasting evidence sug-
gesting that treating PCs with this PRT can adversely
affect platelet-dependent clot strength and aggregation
after storage.127 Furthermore, platelet counts do not
appear to be as well preserved after Mirasol PRT treat-
ment, possibly related to enhancement of platelet
activation and metabolic activity 128
Transfusing platelets, in general, is associated with
a low incidence of adverse reactions, but there
remains a risk of serious reactions including acute
lung injury. The latter may be associated with neutro-
phil oxidase activity that is primed by generation of
biologically active compounds found in stored PC.
However, it does not appear that this priming activ-
ity is increased by either a PSS nor by the two main
PRT technologies, including Mirasol and one that uti-
lizes amotosalen and UVA (INTERCEPT, Cerus
Corporation, Concord, CA).129
A larger number of studies are available evaluating
both the in vitro and in vivo experience with INTERCEPT
PRT. This process was shown to be fully functional in
plasma storage of platelets, with complete inactivation of
bacteria in conventional random donor platelet units.130
Initial evaluations examining PRT in PC stored in plasma
demonstrated little effect of this PRT on platelet mor-
phology, hypotonic shock response, or shape change
over 5 days of storage, although the pH in the PC did
fall faster than in non-PRT-treated PC in plasma.131
Thus, subsequent studies have examined INTERCEPT
treatment in platelets stored with a PSS. In vitro studies
of INTERCEPT-treated buffy coat PCs demonstrated
superior in vitro platelet function and metabolic proper-
ties in PSS supplemented with Mg21 and K1.132 When
evaluating for a storage-induced increase in biologically
active components, investigators found that INTERCEPT
PRT did not affect the release of cytokines/chemokines
over 7 days of PC storage.133 Ex vivo studies of this PRT
versus conventional PCs stored for up to 7 days demon-
strated a drop in platelet numbers, likely related to the
inactivation process. However, under flow conditions,
platelet adhesive function was maintained similarly to
conventional PC. Early prospective transfusion studies
demonstrated a low incidence (,1%) of transfusion reac-
tions with this PRT process and a safety profile similar
to conventional (without PRT) PC transfusion.134
Hemoviligance studies of larger patient numbers con-
firmed this low incidence of transfusion reactions.135
 V. PLATELET TRANSFUSION THERAPY
Since INTERCEPT PRT is in use in several countries
within the EU, clinical assessments of efficacy and
safety from a large experience (B200,000 PC transfu-
sions) are now possible. A recent review found no
development of antibodies to neoantigens and no cyto-
toxic reactions to INTERCEPT-treated PCs.136 In fact,
there appears to be a reduced incidence of febrile and
allergic reactions since PRT was introduced; although
there is some platelet loss during the process, there
was no increase in the frequency of PC transfusion
when compared to historical controls. A second retro-
spective review of PRT-treated patients and historical
controls using data from the same database demon-
strated a similar decrease in the incidence of transfu-
sion reactions and, additionally, no increase in platelet
or red cell usage on a per patient basis following PRT
introduction.137 The latter finding was also demon-
strated in a review of a single institutional experience
in all transfused patients and in a subset of patients
with hematologic disease.138
Thus, there appears to be no identifiable adverse
impact of this PRT on component usage. These find-
ings are supported by a recent report demonstrating
that although the corrected count increment (CCI) in
transfused patients was slightly better in standard PC
versus PRT-PC (an expected finding given platelet loss
during the PRT process), there were no differences in
post-transfusion bleeding and overall red cell product
usage, nor was there an increased interval to the next
PC transfusion.139 INTERCEPT PRT side effects were
also studied in a subset of at-risk subjects, namely
patients receiving hematopoietic stem cell transplants
(HSCT) who are thought to have a higher incidence of
acute lung injury after PC transfusion.140 For HSCT
patients with lung injury, there was no difference in
mortality between those receiving PRT versus those
receiving standard PC support. However, these inves-
tigators also did not find a difference in the number of
days of platelet support or the number of platelet
transfusions between HSCT patients with and without
acute lung injury.
D. Volume-Reduced Platelet Concentrates
The total volume of PC prepared by the PRP tech-
nique is typically 40
60 mL. This volume is required
to maintain PC pH . 6.2 during 5 days of storage,
although smaller (35
40 mL) volumes of donor plasma
may be adequate.141 In certain clinical situations, it
may be necessary to reduce the volume of PC even fur-
ther. For example, ABO-incompatible plasma can
potentially harm neonates and small infants.142
Removing platelet-specific antibodies (e.g., anti-
HPA-1a) from platelets obtained from a mother who
VI. THERAPY TO INCREASE PLATELET NUMBERS AND/OR FUNCTION
1285
has delivered a child with neonatal alloimmune throm-
bocytopenia (NAT) may be indicated if the mother’s
platelets are to be transfused to the newborn as a
source of HPA-1a-negative platelets (see Chapter 46).
V. PLATELET TRANSFUSION THERAPY
The earliest reports of the potential benefits of plate-
let transfusions utilized freshly drawn whole blood as
a source of viable platelets.143 Bleeding times were
reduced and hemorrhage stopped when thrombocyto-
penic patients were transfused with whole blood.
Fresh whole blood, however, is neither a convenient
nor an optimal source of platelets, and thrombocytope-
nic bleeding remained a major cause of death in
patients with acute leukemia.1 PC became widely
available in the late 1960s and early 1970s when plastic
collection/storage containers were developed that
facilitated the separation of platelets from whole blood.
These new sources of concentrated and viable platelets
improved the outcomes of patients with hematologic
malignancies and solid tumors who received intensive
chemotherapy. Hematology/oncology patients are the
major recipients of PCs, although significant numbers
of PCs are utilized by trauma, general surgery, cardio-
thoracic surgery, and solid-organ transplant services.
Despite vast clinical experience with platelet transfu-
sion therapy, transfusion practices vary widely and
evidence-based guidelines are often not followed.144
Platelet transfusions are primarily used to treat or
prevent bleeding in patients with thrombocytopenia or
platelet function defects. The majority of PCs are trans-
fused to nonbleeding, thrombocytopenic patients as a
prophylactic precaution.145 The effectiveness of platelet
transfusions in bleeding thrombocytopenic patients
has been well established through an accumulation of
clinical experience, not through controlled trials. It is
generally agreed that increasing platelet counts to
40
50 3 109/L stops major bleeding. The benefit of
prophylactic platelet transfusions in preventing hemor-
rhage in thrombocytopenic patients with bone marrow
failure is more controversial. Importantly, the cause of
thrombocytopenia should be established before initiat-
ing platelet transfusions because platelets are often
ineffective in some thrombocytopenic conditions,
such as immune thrombocytopenic purpura (ITP)
(Chapter 40). In other conditions, such as thrombotic
thrombocytopenic purpura (Chapter 43) and heparin-
induced thrombocytopenia (Chapter 42), platelet trans-
fusions could be harmful. Patients with congenital or
acquired platelet function defects (Chapters 50 and 51)
will usually have normal numbers of circulating plate-
lets. However, since these platelets have decreased
1286 62. PLATELET TRANSFUSION MEDICINE
hemostatic capabilities, platelet transfusions can con-
trol or arrest bleeding in many circumstances.
A. General Considerations in Platelet
Transfusion Therapy
Each unit of WB-RDP platelets, prepared by either
the PRP or BC technique, typically contains more than
5.5 3 1010 platelets. When transfused, one WB-RDP
unit is expected to increase a recipient’s platelet count
by 5
10 3 109/L in the absence of conditions associ-
ated with decreased platelet survival such as fever,
sepsis, and splenomegaly. Historically, WB-RDPs have
been administered in “pools” of six units. Many hospi-
tals have decreased pool sizes to four or five WB-RDP
units because processes used to separate platelets from
whole blood have become more efficient; a WB-RDP
often contains .8
10 3 1010 platelets per concen-
trate.146 Single-donor platelets collected by apheresis
are highly concentrated and contain more than 3 3 1011
platelets, equivalent to four to eight average WB-RDP
units.
Testing requirements of platelet donors are the
same as for any blood donor and include ABO and Rh
(D) typing, as well as screens for human immunodefi-
ciency virus (HIV)-1, HIV-2, HTLVI/II, hepatitis B,
hepatitis C, VDRL, West Nile Virus, and Chagas.
A portion of donors are tested for cytomegalovirus
(CMV) IgG antibodies; products drawn from these
CMV seronegative donors are labeled “CMV nega-
tive.” PCs that are leukoreduced under carefully con-
trolled and monitored conditions are considered an
acceptable alternative to CMV seronegative products
to minimize the risk of CMV transmission in suscepti-
ble patient groups.147 Studies suggest that leukore-
duced apheresis platelet products also do not pose a
significant risk of transmitting CMV to patients given
a platelet transfusion following stem cell
transplantation.148
Many hospitals transfuse ABO-compatible or ABO-
identical platelets whenever possible because data sug-
gest that ABO-incompatible platelet transfusions (e.g.,
group A platelets to group O recipient) are associated
with decreased platelet survival.149 Transfusing plate-
lets that are incompatible with the recipient’s blood
type may also lead to increased levels of circulating
immune complexes, the effects of which are unclear.150
Most PCs contain few red cells, and red cell cross-
matching is unnecessary. However, there are sufficient
red cells in random donor PCs to cause RhD alloim-
munization in RhD-negative individuals.151 If Rh-nega-
tive random donor PCs are not available for an RhD-
negative patient, RhD-positive platelets can be trans-
fused followed by administration of Rh immune
VI. THERAPY TO INCREASE PLATELET NUMBERS AND/OR FUNCTION
globulin (RhIG) within 72 hours of transfusion. An
intravenous preparation is available to prevent RhD
alloimmunization, which is a safe and effective alterna-
tive to intramuscular RhIG preparations for thrombo-
cytopenic patients.152 Apheresis-derived platelets
contain very few red cells, and thus, some physicians
consider RhD immunoprophylaxis unnecessary in this
situation.153
The practical aspects of transfusing platelets are
similar to those used to transfuse other cellular blood
products. Both the platelet product and the intended
recipient must be accurately identified before starting
the transfusion. Vital signs should be taken before the
transfusion and then soon thereafter or if there is any
evidence of a transfusion reaction. Common signs of a
reaction include temperature elevations and changes
in blood pressure. Patients may develop symptoms
such as chills, pruritus, rash, and shortness of breath.
Platelets, like red cells and fresh-frozen plasma (FFP),
must be transfused at the bedside through an infusion
set that contains a filter (usually a screen filter with a
170
265 μm pore size) to remove fibrin clots and
larger debris that can form during storage. This is
required even if the blood components are filtered pre-
storage with a leukoreduction filter. Routine platelet
transfusions must be completed within 4 hours,
although most require less than 2 hours.
B. Prophylactic Platelet Transfusion
Decisions to transfuse any blood product, including
platelets, should not be made based purely on transfu-
sion “triggers.” The overall status of the patient (e.g.,
disease, medications, and coagulation status) must be
considered when determining the need for platelet
transfusions. Historically, many physicians have trans-
fused platelets to maintain platelet counts higher than
20 3 109/L, believing that this level was required to
prevent spontaneous bleeding.154 However, serious
bleeding may not occur until platelet counts are
,5 3 109/L in the absence of other conditions that
impair hemostasis.155 The earliest efforts to determine
thresholds for prophylactic platelet transfusion were
complicated by the widespread use of aspirin as an
antipyretic agent, before its detrimental effects on pla-
telets were established.
There are three major difficulties encountered when
attempting to define an optimal prophylactic platelet
level: (1) serious hemorrhage is rare, even at very low
platelet numbers; (2) minor clinical bleeding is difficult
to quantify;156 and (3) platelet counts are less accu-
rately determined at the very low platelet numbers
found in severely thrombocytopenic patients.
Measurement of stool red cell loss by 51Cr red cell
 V. PLATELET TRANSFUSION THERAPY
labeling to estimate spontaneous bleeding in patients
with aplastic anemia revealed that stool blood loss was
not significantly elevated until platelet counts fell
below 5 3 109/L.157 A small clinical trial reported at
the same time suggested that major bleeding, mortal-
ity, and the use of red blood cell transfusions were not
different in patients who received prophylactic platelet
transfusions (,20 3 109/L) versus those who received
platelet transfusions only when bleeding (other than
from the skin or mucous membranes) developed.158
The most widely studied patients are those with acute
leukemias, although similar studies of patients with
solid tumors suggest that serious bleeding is uncom-
mon until platelet counts are ,10 3 109/L.159
One of the earlier larger trials designed to study the
safety of lowering platelet transfusion thresholds pro-
spectively followed 102 consecutive patients with acute
leukemia.160 Patients with platelet counts ,6 3 109/L
received prophylactic transfusions, whereas those with
counts .20 3 109/L were transfused only for major
bleeding or before significant invasive procedures.
Other thresholds were 6
11 3 109/L for patients with
fever or minor bleeding and 11
20 3 109/L for
patients with coagulation disorders and minor proce-
dures. Thirty-one major bleeding episodes occurred on
1.9% of the study days when platelet counts were
# 10 3 109/L and on only 0.07% of study days when
counts were between 10 and 20 3 109/L. The investiga-
tors concluded that a prophylactic level of 5 3 109/L
was safe in the absence of fever or bleeding. However,
several of the major bleeds occurred in the
6
10 3 109/L group of patients who were not receiv-
ing prophylactic platelet transfusions.
Prospective randomized platelet transfusion trials
have compared the bleeding risks and platelet transfu-
sion needs of groups of thrombocytopenic patients
who received platelets at either the 10 3 109/L or
20 3 109/L thresholds (Table 62-4).161
164 These studies
suggest that there are no differences in hemorrhagic
morbidity and mortality rates when the lower platelet
TABLE 62-4 Summary of Platelet Transfusion Trigger Trials
Study No. of Type
Patients
Gil-Fernandez 190 Bone marrow transplant
et al., 1996161
Heckman et al., 78 Acute leukemia
1997162
Rebulla et al., 255 Newly diagnosed acute
1997163 myeloid leukemia
Wandt et al., 105 Acute myeloid leukemia
1998164
VI. THERAPY TO INCREASE PLATELET NUMBERS AND/OR FUNCTION
1287
transfusion trigger values are used. When lower pro-
phylactic platelet transfusion thresholds are applied,
recipients are exposed to less donor blood, which in
turn will decrease the risk of transfusion-transmitted
disease and other complications associated with blood
transfusion.
Two more recent multicenter randomized controlled
trials have provided additional data regarding prophy-
lactic platelet transfusions. The PLAtelet DOse study
(PLADO) evaluated three prophylactic platelet doses
based on the recipient’s body surface area (low:
1.1 3 1011 platelets/m2; medium: 2.2 3 1011 platelets/
m2; and high: 4.4 3 10 11 platelets/m2).165 The study
compared the percentage of hospitalized oncology
patients who experienced at least grade 2 WHO bleed-
ing (i.e., mild but clinically significant blood loss).
Stable nonbleeding patients were transfused when the
morning platelet count was less than 10 3 109/L. No
significant difference in the percent of patients
experiencing at least grade 2 bleeding was found in
the three arms of the trial (71% low dose, 69% medium
dose, 70% high dose). The investigators concluded that
the prophylactic transfusion of lower doses of platelets
at a threshold of 10 3 109/L does not lead to increased
bleeding but may lead to more frequent albeit smaller-
dosed platelet transfusions. The risk of significant
bleeding did not appear to measurably increase until
the platelet counts fell below 5 3 109/L.
The Strategies for the Transfusion of Platelets study
(SToP) evaluated two prophylactic doses (low:
1.5
2.9 3 1011 platelets; and high: 3.0
6.0 3 1011 plate-
lets).166 Like the PLADO study, the SToP trial evalu-
ated prophylactic platelet dose with at least grade 2
WHO bleeding as the endpoint. This study was halted
prematurely due to a higher rate of serious grade 4
bleeds in the low-dose arm. However, there was no
significant difference in the number of $ grade 2
bleeds between the two groups. A third multicenter
trial that has recently closed, the Trial Of Prophylactic
Platelets Study (TOPPS), is comparing the efficacy of
Design Platelet Count Findings
Trigger ( 3 109/L)
Non-randomized 10 vs. 20 No difference in bleeding; fewer platelet
transfusions in 10k group
Randomized 10 vs. 20 No difference in bleeding
Randomized, 10 vs. 20 No difference in major bleeding; no
multi-institution difference in red cell transfusions
Prospective 10 vs. 20 No difference in bleeding; fewer platelet
comparison transfusions in 10 k group
1288 62. PLATELET TRANSFUSION MEDICINE
prophylactic and therapeutic platelet transfusions. The
prophylactic group will receive a platelet transfusion
at a 10 3 109/L threshold, whereas the therapeutic
group will only receive platelet transfusions when
actively bleeding.167 The endpoint for this study is
again $ grade 2 WHO bleeding.
There is no clear consensus on clinical indications
for prophylactic platelet transfusions, largely because
available objective data are insufficient to develop evi-
dence-based recommendations. Guidelines have been
developed over the years by a number of professional
groups, but there remains variability in the thresholds
selected for prophylactic platelet transfusions. If other
risk factors for bleeding exist, such as high fever, sep-
sis, hyperleukocytosis, or other hemostatic abnormali-
ties, higher thresholds for prophylactic transfusion are
indicated, although specific thresholds have not been
defined for these patients.168 Finally, profound anemia
can alter hemostasis and thus should be avoided in
patients with thrombocytopenia or platelet function
defects because red blood cells enhance the movement
of platelets across parallel streamlines in flowing
blood.169 The number of collisions between platelets
and a vessel wall is directly related to the number of
red cells (hematocrit), as demonstrated by a 50-fold
increase in platelet deposition when blood is compared
to PRP.170
Platelet counts are generally increased to at least
50 3 109/L before procedures such as lumbar puncture,
indwelling catheter insertion, liver biopsy, thoracentesis,
or transbronchial biopsy.171 Lower platelet counts are
considered acceptable for adults with acute leukemia
who undergo lumbar puncture.172 Children with acute
lymphoblastic leukemia and platelet counts .10 3 109/L
may tolerate lumbar puncture without serious complica-
tion.173 In general, platelet transfusions are not consid-
ered necessary prior to bone marrow aspiration or
biopsy if adequate surface pressure is applied to the site
after the procedure. Higher platelet levels (100 3 109/L)
are generally recommended for procedures involving the
central nervous system. However, the rationale for this
threshold remains unclear.
C. Efficacy of Platelet Transfusion
In clinical practice, it is difficult to evaluate the effi-
cacy of platelet transfusions for several reasons. First,
severe bleeding due to thrombocytopenia alone is rare.
Second, hemorrhagic death in thrombocytopenia is
even more uncommon in the absence of vascular dam-
age or a coagulopathic state. Finally, the methods used
to estimate the extent of bleeding remain challeng-
ing.174 Tests used to evaluate the effectiveness of plate-
let transfusions are classified into three general
VI. THERAPY TO INCREASE PLATELET NUMBERS AND/OR FUNCTION
categories: (1) in vitro platelet function and biochemis-
try; (2) in vivo platelet survival in the circulation; and
(3) clinical assessment of hemostatic efficacy, such as
monitoring of epistaxis, hematuria, and petechiae. The
latter measures are imprecise and difficult to
reproduce.
The bleeding time is not helpful in determining the
effectiveness of platelet transfusions. The bleeding
time becomes prolonged in a linear fashion as the
platelet count falls below 100 3 109/L,175 and it is pro-
longed beyond measure (.30 minutes) when platelet
counts fall below 10 3 109/L. In addition, the bleeding
time is difficult to reproduce, has a wide normal range,
is affected by a variety of drugs, and is prolonged in
anemia (see Chapter 26). Although stool blood loss has
been used to evaluate hemostasis in thrombocytopenic
patients, this technique is not widely available.34
Response to prophylactic platelet transfusions can
be estimated through the corrected-count increment
(CCI). This is performed by measuring a platelet count
10
60 minutes post-transfusion and then calculating
the CCI according to the following formula:
PostðµLÞ 2 PreðµLÞ
CCl 5 3 BSAðm2 Þ
# platelets 3 10211
where Post is the post-transfusion platelet count/μL
drawn 1 hour after completing the transfusion, Pre is
the pretransfusion platelet count/μL, # platelets is the
number of platelets transfused (1 WB-RDP 
0.5 3 1011; 1 apheresis platelet 3.0 3 1011 platelets),
and BSA is body surface area in square meters. In gen-
eral, patients with a low CCI (,5,000) have a less-
than-expected response to platelet transfusion. Patients
with a low 1-hour post-transfusion platelet increment
may have become alloimmunized to platelet
transfusions.176 These alloantibodies most commonly
develop from previous transfusions or pregnancies.
Autoantibodies encountered in ITP can also hasten
platelet removal. Nonimmune conditions, such as
fever, sepsis, and disseminated intravascular coagula-
tion (DIC), may also dramatically reduce the expected
increment. Overall, the CCI is considered a relatively
crude estimate of platelet survival.177
Animal models have been used on a limited basis to
study the efficacy of platelet components.178,179 These
models have been used to detect changes in the sur-
vival of platelets processed or stored under different
conditions in a much more controlled setting than in
human trials. They have also been applied to studies
of platelet substitutes and lyophilized platelets. Rabbit
models have been used to monitor the in vivo viability
of human platelet concentrates. Survival of human pla-
telets in rabbits has been studied by flow cytometry
using antibodies specific for GPIX.180 Ethyl palmitate
 V. PLATELET TRANSFUSION THERAPY
must be administered to animals before transfusion to
inhibit uptake of transfused human platelets by the
reticuloendothelial system. These models could prove
useful in comparing the viability of different platelet
preparations that cannot be easily tested in humans.
D. Platelet Dosing
Doses of transfused platelets are typically in the
range of 3 3 1011 platelets, which is approximately one
single-donor apheresis product or six pooled random-
donor PCs. This dose was not determined through
clinical trials, but through experience. Optimal adult
doses of platelets have not been clearly defined, and
doses are typically based on a number of factors unre-
lated to efficacy, such as cost and availability.181
Unlike children, an adult patient’s body weight or
body surface area is not usually considered when
determining the dose of platelets to administer.
Normal platelet survival is approximately 9 days.
However, patients undergoing induction chemother-
apy for leukemia often require platelet transfusions at
least every 3 days.182 Moreover, many patients require
daily platelet transfusions during periods of severe
bone marrow hypoplasia.
Some practitioners advocate providing larger doses
of platelets (e.g., 10
12 WB-RDP) every 2 or 3 days.183
Although this practice may not reduce the risk of
spontaneous bleeding, larger platelet doses may result
in a higher CCI and thus longer intervals between
each transfusion.184,185 Others have suggested that
smaller doses of platelets (e.g., 3 or 4 WB-RDP) can
reduce the total number of platelets required during a
patient’s thrombocytopenic period.186 Although
decreasing pool size provides a more economical dose,
this practice may result in an increased number of
individual transfusions, which can actually increase
overall costs.187 In summary, the number of platelets
provided per transfusion will remain largely based on
local preferences until optimal platelet doses are better
defined.
E. Platelet Transfusions in Other Settings
1. Immune Thrombocytopenia
Platelet transfusions are rarely indicated in patients
with autoimmune thrombocytopenias such as ITP.
Platelet transfusions are used only when these patients
develop major bleeding, not as a prophylactic measure
(see Chapter 40). If a patient with ITP develops life-
threatening bleeding, massive platelet transfusions
have appeared effective in a small group of patients.188
Similarly, platelet transfusions are often ineffective in
patients with post-transfusion purpura (Chapter 46),
VI. THERAPY TO INCREASE PLATELET NUMBERS AND/OR FUNCTION
1289
even when donor platelets are negative for the impli-
cated platelet antigen (e.g., anti-HPA-1a). Selected
donor platelets, however, play an important role in
treating some newborns with neonatal alloimmune
thrombocytopenia (NAT; Chapter 46).189 The majority
of these cases are attributed to fetomaternal incompati-
bility for the HPA-1a platelet-specific antigen. If
infants are severely affected, they can be transfused
with compatible HPA-1a-negative, washed platelets
collected from the mother or a phenotyped donor.
However, studies show that transfusing newborns
with NAT using platelets of unknown HPA type is an
acceptable alternative when HPA-compatible platelets
are not readily available.190
2. DIC and Massive Transfusion
PCs are often transfused in acute DIC when patients
are actively bleeding and severely thrombocytopenic
(, 50 3 109/L). Platelet transfusions do not, however,
appear useful in preventing bleeding in chronic DIC.
Massive blood transfusion, in which more than 1.5
times a patient’s blood volume is replaced with blood
products and crystalloid, can cause significant throm-
bocytopenia. In this situation, platelets are being con-
sumed, and there is a compounding dilution effect
caused by transfusing products such as red cells and
FFP that do not contain viable platelets. Fibrinogen
and coagulation factors are similarly diluted during
massive transfusions and, if not replaced with FFP,
will further diminish hemostatic capabilities. Platelet
transfusions were historically considered during mas-
sive transfusion when counts fell below 50 3 109/L.
However, more recent trauma and battlefield experi-
ence suggests that hemostasis is more quickly achieved
when a rapidly bleeding patient is transfused with red
cells, PC, and FFP in a ratio of 1:1:1.191 Maintaining
this ratio provides platelets and coagulation factors
that more closely approximate normal whole blood.
Platelet transfusions are frequently used during
and following liver transplantation. These patients,
like those with DIC, have complex hemostatic abnor-
malities, including coagulation factor defects and
hyperfibrinolysis that can further contribute to throm-
bocytopenic bleeding.
3. Bone Marrow Transplantation
Patients who undergo autologous and, especially,
allogeneic bone marrow transplantation have pro-
longed periods of thrombocytopenia that can require
substantial platelet transfusion support. Following
autologous peripheral blood stem cell transplants,
most patients recover platelet counts to levels above
20
50 3 109/L within 14 days of receiving stem cells.
However, platelet recovery time may be twice as long
when using allogeneic bone marrow, likely due to
1290 62. PLATELET TRANSFUSION MEDICINE
decreased collection of CD341 stem cells by this tech-
nique.192 There are several risk factors for prolonged
thrombocytopenia (,20 3 109/L) in this patient popu-
lation, but it is difficult to identify all patients at
risk.193 For example, autologous transplant patients
who receive numerous cycles of high-dose chemother-
apy are predisposed to poorer CD341 cell mobilization.
This leads to lower CD341 cell yields during harvesting
and subsequently delayed platelet recovery following
stem cell infusion.194 In contrast, patients who receive
higher numbers of stem cells (e.g., $ 5 3 106 CD341
cells/kg body weight) have shorter periods of severe
thrombocytopenia.195 Platelet engraftment and recovery
of platelet counts are preceded by an increase in reticu-
lated platelets (see Chapters 27 and 29); however, retic-
ulated platelets are rarely monitored following
transplant.196
A retrospective study conducted in France found
that patients undergoing reduced intensity condition-
ing for an allogeneic hematopoietic stem cell transplant
required fewer platelet transfusions while engrafting and
had shorter engraftment times than those patients receiv-
ing standard conditioning regimens.197 Alternatively,
umbilical blood transplants are often associated with a
prolonged engraftment period, and thus, higher plate-
let transfusion needs.
4. Cardiac Surgery
PCs are commonly provided during or soon after
cardiac surgery in patients undergoing cardiopulmo-
nary bypass (CPB) in an effort to limit postoperative
bleeding. The hemostatic defects associated with CPB
are complex but are generally related to anticoagulation,
hypothermic temperature changes, length of time on
bypass, and preoperative aspirin use (see Chapter 52).
Effects of CPB on platelets include platelet activation
due to exposure to foreign biomaterial surfaces, platelet
fragmentation, and impaired aggregation responses to
most agonists.198 There is usually some degree of plate-
let damage and thrombocytopenia during bypass sur-
gery, and platelet function defects may persist for days
after the procedure. However, the treatment of
post-CPB bleeding is not usually based on laboratory
monitoring and is largely empiric and institution
dependent.199 Although clinical trials are limited, none
have been able to demonstrate benefits of routine plate-
let administration during open-heart surgery, as deter-
mined by decreased red cell transfusions, chest tube
bleeding, or microvascular bleeding. Thus, many sur-
geons reserve platelet transfusions for patients who are
actually bleeding despite adequate surgical hemostasis.
Patients who have received aspirin or GPIIb-IIIa antago-
nists immediately before cardiac surgery are at addi-
tional risk for bleeding.200 In these cases, platelet
transfusions are commonly provided before surgery;
VI. THERAPY TO INCREASE PLATELET NUMBERS AND/OR FUNCTION
however, the dose of platelets required to minimize
bleeding has not been clearly defined. Some cardiac
programs utilized point-of-care testing technologies like
thromboelastography to help guide platelet transfusion
decisions (see Chapter 26). Like CPB, extracorporeal
membrane oxygenation and the use of ventricular assist
devices can result in severe hemostatic defects that
require frequent platelet transfusions.201
5. Inherited and Acquired Platelet
Function Defects
Patients with inherited (Chapter 50) or acquired
(Chapter 51) platelet function defects do not usually
require prophylactic platelet transfusions. However,
platelet transfusions are often used to treat bleeding epi-
sodes or are administered prior to surgery. Following
platelet transfusion, patients with Glanzmann throm-
basthenia may develop GPIIb-IIIa-specific antibodies
that can compromise survival and, thus, the efficacy of
further platelet transfusions.202 Similarly, patients with
Bernard
Soulier syndrome can develop GPIb-IX-V-spe-
cific antibodies. Desmopressin acetate203 (Chapter 60)
and recombinant activated factor VII (rFVIIa,
Chapter 61),204 which shorten the bleeding time of
many patients with congenital platelet function disor-
ders, are potential alternatives or adjuncts to platelet
transfusion therapy. The efficacy of rFVIIa in decreas-
ing bleeding has been demonstrated using a rabbit
model of severe thrombocytopenia.205 Patients with
acquired platelet defects caused by the myriad of
drugs with antiplatelet activity should have these med-
ications discontinued whenever possible prior to inva-
sive procedures. Finally, platelet transfusions can
increase platelet counts to safer levels without appar-
ent adverse effects in patients with abciximab-induced
thrombocytopenia (Chapter 41).206 Platelet transfusions
are not recommended in the setting of heparin-
induced thrombocytopenia (HIT, Chapter 42) because
of the (poorly quantified) risk that the transfusion may
precipitate acute thrombosis. However, many patients
with antibodies directed against the complex of plate-
let factor 4 and heparin implicated in HIT have been
transfused without developing thrombosis, and thus,
platelet transfusion can be considered when these
patients develop life-threatening bleeding.207
F. Autologous Platelet Donation and
Cryopreserved Platelets
Although autologous red cell donation is a standard
practice, autologous platelet donations are used only
rarely. Liquid stored platelets are not practical for
these purposes because of their limited 5-day shelf-life.
Thus, patients are unable to “bank” enough of their
 VI. ADVERSE REACTIONS TO PLATELET TRANSFUSION
own platelets prior to prolonged periods of thrombo-
cytopenia. However, platelets collected by apheresis
can be placed in a dimethyl sulfoxide (DMSO) cryo-
protectant and stored frozen at
80 C.208 They are
then thawed, washed to remove DMSO, and resus-
pended in autologous plasma or other solution before
transfusion. The techniques are not difficult to
perform, but most blood banks have not developed
procedures for preparing and storing such products.
In addition, frozen and thawed platelets undergo a
number of structural and metabolic changes that
adversely affect their in vivo survival.209 The U.S.
Department of Defense is interested in the further
development and clinical testing of frozen platelets for
battlefield supply. Preliminary results of a randomized
trial suggest that the recovery and survival of autolo-
gous platelets collected by apheresis and cryopre-
served are significantly less than autologous platelets
stored in plasma under normal conditions.210
Although the cryopreserved platelets do not meet FDA
criteria for liquid-stored platelets, it remains unclear if
the cryopreserved platelets prepared in this manner
would have clinical utility in preventing or slowing
thrombocytopenic bleeding. Autologous platelets have
been studied to aid wound healing and tissue regener-
ation.211 In one such approach, a platelet “gel” is pro-
duced by treating platelets with thrombin.212 Due to
claims for this processing being able to promote heal-
ing of various joint or musculoskeletal problems, this
procedure is also becoming popular in veterinary med-
icine and for treating some types of sports injuries.
VI. ADVERSE REACTIONS TO PLATELET
TRANSFUSION
Platelet transfusion therapy is not without risk
(Table 62-5). Common but non-life-threatening compli-
cations of platelet transfusions include febrile and
allergic transfusion reactions.213 Although PCs are
capable of transmitting viral disease, improved donor
testing has markedly decreased this risk. For example,
the estimated risks of HIV-1 or hepatitis C transmis-
sion from a platelet transfusion are far less than 1 in
1 million transfusions.214 Transfused PCs are more
likely to be contaminated by bacteria than by known
viruses. Patients who receive such bacterially contami-
nated products can develop serious septic reactions.
Because PCs contain viable lymphocytes, platelet
transfusion can also cause transfusion-associated graft-
versus-host disease in susceptible patients, a rare but
usually fatal reaction that is prevented by irradiating
PCs before transfusion.215 Transfusion-related acute
lung injury (TRALI), an often unrecognized cause of
noncardiogenic pulmonary edema, can follow platelet,
VI. THERAPY TO INCREASE PLATELET NUMBERS AND/OR FUNCTION
1291
plasma, or red cell transfusion.216 The infusion of bio-
active lipids found in stored platelets has been impli-
cated in the pathogenesis of TRALI.
A. Febrile Reactions to Platelet Transfusion
Febrile transfusion reactions (FTRs) are commonly
encountered with platelet transfusions. They usually
occur during the transfusion, but they may develop
minutes to several hours after the transfusion is com-
pleted. The frequency of FTR is estimated to be
between 4% and 30% of platelet transfusions.217 FTRs
typically present as fever ( . 1 C increase) and shak-
ing chills, and they may be accompanied by nausea,
vomiting, dyspnea, and hypotension. The severity of
symptoms appears related to the number of white
cells found in the product and/or the rate of transfu-
sion. Severe rigors promptly resolve when meperi-
dine is administered.218 Although patients are often
medicated with an antipyretic such as acetaminophen
before platelet transfusions to minimize FTRs, it is
unclear if this practice actually minimizes these reac-
tions.219 Premedication with intravenous corticoster-
oids in patients who have had repeated severe FTRs
may be useful; however, to be maximally effective,
these medications must be administered several
hours before transfusion. Antihistamines do not
appear useful in preventing or treating FTRs. If a
patient continues to have severe febrile reactions
despite leukoreduction, washed platelets that have
had most of the suspending plasma removed can be
considered.220
The mechanism of FTR was originally attributed to
interactions between cytotoxic antibodies in the plate-
let recipient and HLA and/or leukocyte-specific anti-
gens on donor white cells found in the product.221 The
formation of white cell antigen
antibody complexes
results in complement binding and subsequent release
of endogenous pyrogens such as tumor necrosis factor
(TNF)-α, interleukin (IL)-1, and IL-6. The direct activity
of various biological response modifiers including
cytokines plays a role in FTR.222 The incidence of FTR
may be directly related to the duration of platelet stor-
age.223 During PC storage, there is continued elabora-
tion of biologically active cytokines by residual white
cells, which include activated monocytes.224 The levels
of these cytokines, particularly of IL-1β and IL-6, corre-
late with the frequency of FTR.225 Other mediators are
primarily produced by platelets themselves. One such
example is soluble CD40 ligand, which is produced by
platelets and has been linked with febrile transfusion
reactions due to its upregulation of IL-6 and IL-8.226
Preparation technique may also influence the risk of
FTR. One prospective study designed to compare
1292 62. PLATELET TRANSFUSION MEDICINE
TABLE 62-5 Adverse Consequences of Platelet Transfusion
Therapy
Febrile transfusion reactions
Allergic reactions (urticarial and anaphylactic)
Septic reactions (bacterial)
Viral transmission (hepatitis B and C, human immunodeficiency
virus, cytomegalovirus)
Parasitic infection (Babesia microti, Trypanosoma cruzi, Plasmodium sp.)
Transfusion-associated graft-versus-host disease
Transfusion-related acute lung injury
Platelet refractory state due to HLA alloimmunization
Transfusion-associated immune modulation (TRIM)
Hypotensive reactions associated with angiotensin-converting
enzyme (ACE) inhibition
Post-transfusion purpura
single-donor apheresis platelets and PC prepared by
the BC and PRP techniques noted significantly more
FTRs in patients who received PRP-prepared PCs.227
However, there was no difference in platelet survival
between the different preparations based on CCI mea-
sured 1
6 and 18
24 hours post-transfusion.
It is generally accepted that leukoreducing PCs can
help minimize FTRs. The degree of leukoreduction is
limited by the available techniques. Third-generation fil-
ters eliminate .99.9% of white cells in a unit of red cells
obtained from a whole blood donation, leaving ,5 3 106
residual leukocytes. Prestorage leukoreduction, in which
white cells are removed soon after blood collection, may
even further reduce the likelihood of FTR.228
Leukoreduction filters not only remove white cells but
also have varying ability to directly remove biological
response modifiers, such as the chemokines IL-8 and
RANTES and the anaphylatoxins C3a and C5a.229,230
B. Bacterial Contamination of Platelet
Concentrates
The shelf-life of PCs was decreased from 7 to 5 days
in the mid-1980s, largely based on observations that
many cases of septic transfusion reactions occurred in
patients who received PCs stored for more than
5 days.231 Moreover, in vitro studies performed by
inoculating PCs with bacteria suggest that a significant
number of PCs experience the most rapid rate of bacte-
rial growth on days 6 and 7 of storage.232 The most
commonly implicated organisms in platelet septic
transfusion reactions are Gram-positive bacteria
(Staphylococcus sp.), although Gram-negative organisms
VI. THERAPY TO INCREASE PLATELET NUMBERS AND/OR FUNCTION
are also isolated (Table 62-6).233 Platelets, and other
blood products, can be contaminated by bacteria if a
donor is bacteremic during blood collection or if the
arm is improperly cleansed before venipuncture.
Blood donors must be in good health on the day of
donation. However, asymptomatic donors who may
have had gastroenteritis of short duration several days
before donation are potentially infectious. These
donors may have a prolonged period of asymptomatic
bacteremia that allows transmission of organisms like
Escherichia coli.234
Transfusing bacterially contaminated PCs can cause
septic reactions that may be fatal. Thus, standards have
been adopted in most countries that require blood col-
lection facilities and transfusion services to limit and
detect bacterial contamination in all platelet compo-
nents. No detection method has been universally
adopted and, regardless of the method, no bacterial
screening system is 100% sensitive to all bacterial patho-
gens. Different methods are used, depending on the
type of platelet donation (e.g., whole blood-derived vs.
apheresis). Most blood centers directly culture apheresis
PCs for bacteria and release the unit after the culture
has incubated between 12 and 36 hours.235 The most
commonly cultured bacteria are gram-positive organ-
isms such as Staphylococcus epidermidis, S. aureus, and
Streptococcus pneumoniae; these are often skin commen-
sals. Skin disinfection by povidone
iodine and isopro-
pyl alcohol helps to minimize venipuncture-related
contamination of platelet concentrates by skin flora.236
One method that can further reduce PC contamination
by skin flora bacteria utilizes a bypass inlet tube in
which the initial, and most likely contaminated, portion
of blood removed from the donor is diverted from the
remainder of the blood donation bag.237
Studies have been performed to determine if aphe-
resis platelet shelf-life could be safely extended from 5
to 7 days using bacterial monitoring systems.238 PCs
were cultured 24
36 hours after collection and then
released for transfusion if the screening culture was
negative for 24 hours after sampling. The results indi-
cated that screening cultures did prevent some
infected units from being transfused; however, the
strategy failed to successfully identify all contaminated
units. Hence, platelet shelf-life remains 5 days until
other methods can be developed to further reduce the
risk of bacterial contamination.
Given the limitations of current bacterial identifica-
tion systems, considerable research has been devoted to
improving these systems in order to limit PC contami-
nation. One difficulty is that the majority of PC cultures
that turn positive by automated bacterial culture screen-
ing systems do so well after 24 hours of sampling.
In these cases, the product often has already been trans-
fused.239 Delayed bacterial growth may be related to
 VI. ADVERSE REACTIONS TO PLATELET TRANSFUSION
TABLE 62-6 Organisms that may Contaminate Platelet
Concentrates
Bacillus species Propionibacterium acnes
B. cereus Pseudomonas aeruginosa
B. subtilis Salmonella species
Candida albicans Staphylococcus species
Clostridium perfringens S. aureus
Corynebacterium species S. epidermidis
Enterobacter cloacae Serratia marcescens
Escherichia coli Streptococcus species
Klebsiella oxytoca S. pyogenes
Leishmaniasis S. viridans
Morganella morganii
very low inoculum numbers and may also explain the
relatively low sensitivity (40%) of bacterial culture
screening techniques used to test PCs.240 Sensitivity of
culture systems can be improved by increasing sample
size. Doubling the sample size of apheresis platelet unit
culture specimens from 4 to 8 mL can relatively increase
the sensitivity of the culture by 54%.237
More sensitive bacterial screening systems are not
expected to eliminate the release of potentially contam-
inated PCs. Thus, a number of techniques have been
studied as alternatives to standard bacterial cultures.
One simple technique utilizes PC glucose concentra-
tions. A PC glucose level below 500 mg/dL, as mea-
sured by a glucometer on storage day 4 or 5, has been
proposed as a surrogate marker for positive cultures,
yielding false-negative rates similar to that of cul-
ture.241 PCR using bacterial 16s rRNA as a target can
detect bacteria in plasma and platelet-rich plasma in a
rapid and sensible manner, but molecular techniques
are not routinely used to monitor PCs.242 Bacteria can
be detected in platelets using flow cytometry by stain-
ing bacterial DNA with a fluorescent dye such as thia-
zole orange. This technique can detect bacteria in PCs
incubated for 24
48 hours; however, it may not be
sensitive enough to detect slower-growing bacteria.243
Finally, viable bacteria can be detected that are trapped
on PC filters using a fluorescent esterase detector cou-
pled to a bioimaging reader.244
C. Platelet Refractory State
Patients who receive long-term platelet support may
develop a refractory state in which transfused platelets
undergo accelerated destruction. Refractoriness to
platelet transfusion is often related to clinical condi-
tions that hasten platelet removal through either
VI. THERAPY TO INCREASE PLATELET NUMBERS AND/OR FUNCTION
1293
immune or nonimmune mechanisms (Table 62-7).245 In
the former situations, foreign donor HLA evokes an
immune response in the recipient that leads to the
rapid removal of transfused platelets.246 Presumably,
donor platelets become coated by HLA-specific, or in
some cases platelet-specific, antibodies. The antibody-
coated platelets are then removed from the circulation
in a manner akin to other immune thrombocytopenias.
Platelet alloimmunization rates are higher in patients
with prior pregnancies or transfusion. Overall, nonim-
mune platelet destruction caused by conditions such
as splenomegaly, infection, and antibiotic treatment
with amphotericin B is more frequent than that related
to immune mediated removal.247 The effects of ampho-
tericin B on platelet survival can be lessened by trans-
fusing platelets 2 hours after completing the
amphotericin infusion.248
Platelets express ABH, Lewis, P, and I blood system
antigens, as well as class I HLA-A, -B, and -C and
platelet-specific antigens (HPA). The ABH, class I
HLA, and HPA antigens are most relevant to alloge-
neic platelet survival.249 Platelet survival is impaired
when recipients with higher titer anti-A or anti-B IgG
antibodies are transfused with platelets carrying one of
these antigens.250 Although this problem is avoided by
using ABO-identical platelets (e.g, group O patients
receive group O PC), this option is not always avail-
able during blood shortages.251
Alloimmunization against HLA-A and HLA-B class I
antigens is the most common cause of an immune-
mediated platelet refractory state; mismatches of HLA-
C antigens are less important. Historically, patients at
particular risk for HLA alloantibody formation included
those who received multiple transfusions of non-leuko-
cyte-reduced blood components.252 It was then discov-
ered that primary HLA alloimmunization is reduced by
removing antigen-presenting cells (leukocytes) from PC
before transfusion and UVB irradiating transfused pla-
telets to inactivate antigen-presenting cells.105,253,254
Strategies used to reduce HLA alloimmunization are
especially effective in patients with hematologic malig-
nancies. Since the introduction of universal leukocyte
reduction by some blood collection facilities, there has
been a decrease in the rate of HLA alloimmunization in
multiply transfused patients.255
The management of platelet refractory patients varies
across institutions and is often related to the availability
of specialized testing and products.256 In nonbleeding
patients, prophylactic platelet transfusions are often
withheld. However, patients with significant bleeding,
other risk factors for bleeding, or those undergoing an
invasive procedure may require transfusion. Platelet
transfusion strategies in these cases include increasing
the dose of platelets or providing either HLA-selected
or cross-match-compatible platelets. Ideally, anti-HLA
1294 62. PLATELET TRANSFUSION MEDICINE

TABLE 62-7 Conditions Associated with a Platelet Refractory
State
Nonimmune Mechanisms
Splenomegaly
Disseminated intravascular
coagulation
Drugs (antibiotics,
amphotericin B)
Sepsis, fever, viremia
Graft-versus-host disease
Immune Mechanisms
Alloantibodies to class I HLA
antigens
Alloantibodies to platelet-specific
antigens
Autoantibodies to platelet-specific
antigens
Circulating immune complexes
transiently improve the response to transfused plate-
lets. Patients with ITP who are bleeding and respond-
ing poorly to standard platelet transfusions may
benefit from continuous 24-hour infusions of both
intravenous immunoglobulin and platelets.263
Continuous platelet infusions, or “platelet drips,” are
typically performed by infusing three pooled WB-
RDPs or a WB-RDP pooled product or one-half of an
apheresis-derived PC every 4 hours. They can be
infused through electromechanical pumps because
these devices do not appear to harm platelets.264

D. Hypotensive Reactions during Platelet

antibodies should be identified in the patient before
HLA-specific products are obtained.257 Products are col-
lected by apheresis and are selected based on the HLA-
A and HLA-B types of the donor and intended recipi-
ent. Because the HLA system is extremely polymorphic,
a large number of HLA-typed donors is needed to sup-
port refractory patients.258 The use of HLA-selected or
“matched” platelets in patients who are not alloimmu-
nized with the goal of preventing such immunization is
not warranted.259
Platelet crossmatching is performed by reacting
recipient serum with potential donor platelets that are
fixed to a solid support. The compatibility is deter-
mined based on the presence or absence of reactiv-
ity.260 An incompatible platelet cross-match predicts a
poor response in more than 90% of transfusions,
whereas a compatible cross-match is 50% predictive of
a successful transfusion.261 Large collection facilities
often combine the two approaches: PCs are selected
for cross-matching based on the class I HLA types of
the donor and recipient. Patients who have developed
both HLA and platelet-specific antibodies are particu-
larly difficult to manage. Other approaches that have
been explored to support HLA-alloimmunized patients
are based on reducing the expression of class I HLA
antigens on platelets.262 Treatments that are effective
for many autoimmune thrombocytopenias including
corticosteroids, chemotherapy, and splenectomy are
not useful in most patients who have become alloim-
munized to platelet transfusions.
Patients with ITP (see Chapter 40) usually respond
very poorly to platelet transfusions because donor
platelets are rapidly coated with platelet autoantibo-
dies and are removed from the circulation.
Interestingly, patients with ITP and extremely low
platelet counts infrequently experience serious bleed-
ing and hence do not usually require prophylactic
platelet transfusions despite extremely low platelet
counts. Intravenous immunoglobulin, which is often
used as a treatment for ITP (see Chapter 40), may
Transfusions
Serious hypotensive episodes have been described
in patients on angiotensin-converting enzyme (ACE)
inhibitors who were transfused with PCs through
negatively charged bedside leukocyte reduction fil-
ters.265 These reactions began soon after the infusion
was initiated and subsided rapidly after the transfu-
sion was terminated. The mechanisms responsible for
the hypotension appear to involve bradykinin (BK)-
related peptides with vasodilatory activity, which are
generated when blood contacts a negatively charged
artificial surface. BK and its active metabolites are
rapidly degraded to inactive compounds through
reactions that require ACE. Therefore, patients on
ACE inhibitor medications are less able to degrade
these vasodilatory substances and, presumably, are at
risk for hypotension caused by decreased systemic
vascular resistance. In vitro studies have shown that
supernatant bradykinin levels markedly increase
when PCs are passed through certain negatively
charged filters.266 Furthermore, patients who receive
PCs through a negatively charged filter experience
significant increases in BK levels during the first 5
minutes of transfusion.267 A metabolic abnormality
has been identified in several blood recipients who
have developed such reactions.268 This defect affects
the degradation of des-Arg9-bradykinin, a metaboli-
cally active metabolite of BK that is primarily inacti-
vated by ACE and aminopeptidase P. Accordingly,
the half-life of des-Arg9-bradykinin was significantly
longer in patients on ACE inhibitors who experienced
severe hypotensive reactions than in control patients.
Based on these studies, it appears that both patient
and product-related factors contribute to the patho-
genesis of severe hypotensive reactions to platelet
transfusion. The incidence of these reactions has
decreased now that the vast majority of PCs are leu-
kocyte reduced before storage; bedside filtration is
rarely performed today.269

VI. THERAPY TO INCREASE PLATELET NUMBERS AND/OR FUNCTION

 REFERENCES
VII. THROMBOPOIETIC GROWTH
FACTORS IN PLATELET TRANSFUSION
THERAPY
The use of hematopoietic growth factors helps to
limit patient exposure to allogeneic blood components.
For example, recombinant erythropoietin therapy has
dramatically decreased the need for red cell transfu-
sions in many patients. Efforts continue to produce sim-
ilar agents that would reduce the need for platelet
transfusion therapy in treating thrombocytopenic
patients (see Chapter 59). Other potential applications
of thrombopoietic growth factors include stimulating
platelet apheresis donors, which would increase platelet
yields during a single collection.270 During the 1990s a
recombinant human, truncated form of the thrombo-
poietin (TPO) receptor, pegylated megakaryocyte
growth and development factor (PEG-MGDF), was
evaluated for these purposes.271 This agent stimulates
the production of platelets that are not activated, as
determined by surface P-selectin expression and surface
binding of annexin V. In addition, direct exposure of
stored PC to PEG-MGDF did not appear to hasten
development of the platelet storage defect, as assessed
by a battery of in vitro tests of platelet structure and
function.272 The platelets produced in response to this
growth factor demonstrated normal responses to plate-
let agonists and exhibited normal ATP release in vivo.273
PEG-MGDF has also been administered to normal
donors, in which case a single 2 μg/kg dose produced a
doubling of the platelet count within 9
14 days, and a
single 3 μg/kg dose produced platelet counts of approx-
imately 600 3 109/L.273
These studies showed that MGDF could be used to
increase the yield of platelets from volunteer platelet
apheresis donors and that platelets collected from these
“stimulated” donors are viable and would improve
platelet counts when transfused to thrombocytopenic
recipients. However, several platelet donors developed
neutralizing antibodies directed against endogenous
TPO.270 These antibodies produced severe thrombocyto-
penia ( , 10 3 109/L), and subsequently, trials in normal
volunteer donors were suspended. Alternatives to PEG-
MGDF that are in various stages of development (as
discussed in detail in Chapter 59) could significantly
impact platelet transfusion therapy by reducing platelet
transfusion needs of thrombocytopenic patients and by
increasing platelet yields in volunteer donors. These
newer thrombopoietic growth factors include two FDA-
approved drugs: romiplostim, a recombinant TPO
receptor agonist that is used to treat ITP;274 and eltrom-
bopag, an orally active small molecule TPO agonist that
has been used to treat ITP and thrombocytopenia asso-
ciated with hepatitis C-induced cirrhosis.275
VI. THERAPY TO INCREASE PLATELET NUMBERS AND/OR FUNCTION
1295
VIII. CONCLUSIONS
Platelet transfusion therapy has benefited large
numbers of patients who are thrombocytopenic or
have platelet function defects. In most cases, these
transfusions occur without serious complications
because of efforts to improve the safety of the blood
supply. Platelet transfusions will become even safer
with further advances in donor testing and the devel-
opment of techniques that detect or eliminate bacteria
and other pathogens that may contaminate PCs. The
efficacy of platelet transfusion therapy has also
improved during the past 40 years by optimizing the
processes used to prepare and store PCs. Storage con-
ditions have been selected to minimize the changes in
platelet structure and function that occur during room
temperature storage. A large number of in vitro labora-
tory tests have been used to compare different meth-
ods for PC preparation and storage. These tests
correlate with tests of in vivo hemostatic function to
varying degrees, but no single test provides a complete
measure of platelet quality. Innovative yet practical
in vitro methods are needed that more accurately pre-
dict and assess platelet function and viability in vivo.
Although alternatives to liquid-stored PCs are under
active development (e.g., making platelets ex vivo; see
Chapter 63), it appears that whole blood-derived and
apheresis PCs will remain in widespread clinical use
for the foreseeable future.
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