The Evaluation and Management of Platelet Refractoriness
and Alloimmunization
Eduardo Delafior-Weissand Paul D. Mintz
T HE ARREST of hemorrhage associated with
an increase in the patient's platelet count after
blood transfusion was first reported by Duke in
1910.' It was not until the 1960s that clinical
studies showed that therapeutic platelet transfu-
sions decreasedfatal hemorrhagic complications in
thrombocytopenic patients2 and that prophylactic
platelet transfusions reduced episodes of bleeding.3
More recent reports have suggestedthat a threshold
of I O,OOO/~for prophylactic platelet transfusion is
equivalent to 20,OOO/~ in the absence of addi-
tional complicating clinical factors such as platelet
dysfunction, associated coagulopathy, or primary
defects of vascular integrity.4.5 The hemostatic
benefit of platelet transfusion is presumably medi-
ated through an increase in the posttransfusion
platelet count above a target level, and clai"!s that
platelet transfusion may be beneficial even in the
absence of such an increase are not commonly
accepted.
DEFINITION OF REFRACTORINESS
Plateletrefractorinessis empirically definedas a
lack of responsein posttransfusionplatelet incre-
ments after 2 or more consecutivetransfusionsof
an adequatedoseof allogeneicplatelets.Refractori-
nessis due to the shortenedsurvival of the trans-
fusedplateletsin therecipient'scirculation.Histori-
cally, it has been describedin 20% to 60% of
patientswho havereceivedmultiple platelettrans-
fusions.6The causesof platelet refractorinesscan
be groupedinto immuneand nonimmunecauses.
The percentplateletrecovery(PPR)afterplatelet
transfusionsis the percentageof transfusedplate-
lets circulating at the time the count is determined
From the Departments of Pathology and Internal Medicine.
University of Virginia Health System, Charlottesville. VA.
Address reprint requests to Paul D. Mintz. MD. Directol;
Clinical Laboratories and Blood Bank. University of Virginia
Health System. Box 800286. Charlottesville. VA 22908.
Copyright c 2000 by WB. Saunders Company
0887- 7963/0011402-0007$3.00/0
180
Transfusion Medicine Reviews, Vol 14, No 2 (April), 2000: pp 180-196
r
QV'
and is calculatedby the following fonnul.
(platelet increment per JJL)
X (weight in kg)
X (blood volume as 75 mUkg)
PPR; X 100 (for percent)
-
(plateletcount of transfused
productper ~)
X (volume of product in mL:
The posttransfusionplatelet count is dependenton
the pretransfusionplateletcount, the doseof plate-
lets transfused,and other factors that affect the
recovery,both technicaland clinical. In individuals
without splenomegaly,one third of radiolabeled
autologousplatelets are reversibly pooled in the
spleenat anygiven time, whereastwo thirdsremain
in the circulation,Sso adjustmentsto the recovery
needto be made.Recoveryof autologousplatelets
is on theorderof66 ~ 8% and approaches100%in
asplenic individuals.9 Recovery is modestly re-
duced in thrombocytopenicpatients with counts
below 50,000/~ to approximately50% :!: 22%.10
Another measurementof platelet transfusion
recovery in the clinical setting is the posttransfu-
sion correctedcount increment(CCI). The CCI is
calculat~dasfollows7:
(Platelet increment per ilL)
X (body surfaceareain squaremeters)
CCI=
Numberof plateletstransfused(X 1011)
From the CCI, the formula for the calculationof
an effective dose(ED) of plateletsis derived from
the following formula:
(desiredPLT count incrementper~)
X (body surfaceareain squaremeters)
ED(XIOJI) =
ex{x:Cted
correctedcountincrement
The actualunits of the CCI are (squaremeters)/
(~ X 1011),although as an index it is typically
written without units. The CCI between 10 min-
utesll and I hourposttransfusion12is usedtypically
to determinethe adequacyof responseto platelet
transfusions.The expected posttransfusionCCI
between 10 minutes and I hour is greater than
PLATELET REFRACTORINESS AND ALLOIMMUNIZATION
7.500, representing recovery of at least 20% to
30%. Values below these have been associated with
accelerated platelet destruction.13 Although occa-
sionally low CCI or percent recoveries occur for a
variety of reasons other than refractoriness, poor
responsesto at least 2 sequential transfusions of an
adequatedose of platelets is considered evidence of
platelet refractoriness. Repeatedly low CCls be-
tween 10 minutes and I hour posttransfusion are
generally attributed to an immune cause,12although
in some alloimmunized patients good increments
can still be achieved with incompatible platelets.14
In some patients with other reasons for accelerated
destruction, the CCI at these times may be low. A
CCI measured 18 to 24 hours after the transfusion
of platelets is usually approximately 60% of the
I-hour CCI and should be greater than 4,500,13
equivalent to a recovery greater than 15%. A
reduced CCI at 18 to 24 hours after a nonnal CCI at
I hour has been interpreted as representing evi-
dence of increased consumption owing to nonim-
mune clinical causes,I5 although in s~me patients
this can represent immune destruction.
The maximal lifespan of rein fused autologous
radiolabeled platelets is approximately 9.5 := 0.6
days, with 85% removed by senescence.1oA fixed
number of platelets are lost at random, presumably
maintaining the vascular integrity. Overall survival
of platelets is decreased proportionally to the
degree of thrombocytopenia. When the platelet
count is greater than I OO,OOO/~L, platelet life span
is independent of the count, but life span is
modestly reduced in patients with counts between
50,000 and lOO,OOO/~Lto 7.0 + 1.5 days, and
markedly reduced when platelet counts fall below
50.000/~ to 5.1 + 1.9 days.lo A fixed number of
approximately 7,100 platelets/lJlid is consumed.
Because this represents only 18% of the nonnal
rate of platelet turnover (41,200 platelet/lJlid), the
fixed platelet consumption does not have a signifi-
cant effect on overall platelet survival when counts
are over lOO,OOO/~.However, as the platelet count
decreasesbelow 1OO,OOO/~,a larger proportion of
platelets are devoted to daily endothelial support
and overall platelet lifespan decreases.to
The importance of precise timing of samples for
correct estimation of the CCI has been shown by
del Rosario and Kao,I6 in a study in which the
investigators used the average reduction rate of 800
platelets/1JL/h to make approximations to the pre-
181
transfusion or posttransfusion counts when these
were not available. Iii This study underscores the
importance of obtaining platelet counts immedi-
ately before transfusion and I{) minutes to I hour
posttransfusion.
Although platelet retractoriness in individual
patients can be attributed to single identifiable
clinical factors, including fever, neutropenia, dis-
seminated intravascular coagulation (DIC), and
sepsis/infection, in many cases it is multifactorial,
and no single clinical factor is an accurate predictor
of posttransfusion platelet increments across pa-
tients.17
NONIMMUNE CAUSES OF REFRACTORINESS
Platelet Quality
When the posttransfusion platelet count does not
increase as expected, one possibility is that an
inadequate dose of platelets was administered as a
result of platelet loss due to washing or filtration.
Although most studies have found that leukoreduc-
tion filters result in the loss of less than 10% of
platelets during filtration, some studies have re-
ported loss of as much as 24 ::!: 15% of apheresis
platelets and 20 ::!: 9% of pooled platelets.18Such
losses may be independently associated with de-
creased posttransfusion CCI.19 The platelet dose
should be adjusted to the patient's blood volume,
and some patients require proportionally more
platelets to achieve adequate increments. Other
factors that may detrimentally atTect the quality of
the platelets during storage include pH lower than
6.2, incorrect storage temperature, and mode of
agitation. Gamma-irradiation of platelets with 25
Gy does not affect platelet function or posttransfu-
sion survival.2o However, in the Trial to Reduce
Alloimmunization to Platelets (TRAP) study, ultra-
violet B (UVB) irradiation at dosages used to
prevent alloirnmunization (1.5 J/cm2) was indepen-
dently associatedwith lower posttransfusion CCIS.19
Platelet Age
There are conflicting reports regarding the ben-
efit of fresh platelets.21.22
In one study, patients with
infection, DIC. or splenomegaly were refractory to
older platelets but not to fresh platelets}3 The
possible advantage of fresher platelets in improv-
ing the response to platelet transfusions in patients
with nonimmune refractoriness has been attributed
to activation of platelets during storage.24In one

study, the proportion of activated platelets in S-day-
old platelet concentrates was 15% to 20%. and
these were cleared more rapidly from the circula-
tion after transfusion than were fresher platelets.25
After an initial phase of splenic sequestration and
later release to the circulation, some transfused
platelets may recover their normal function and
lose evidence of activation within 24 hours after
transfusion.26 In several studies, recoveries were
10% to 59% higher with fresher platelet products.
usually in those patients with fever. O[C, or spleno-
megaly.22.27In the TRAP study,19 transfusion of
platelets stored for less than 48 hours resulted in
greater posttransfusion increments. The criteria for
diagnosing platelet refractoriness in this study
included failure to respond to fresh or ABO-
matched platelets as an initial therapeutic maneu-
ver in refractory patients. Slichter et aJ2Khave
reported the preliminary results of a small prospec-
tive randomized trial comparing fresh and stored
apheresis and pooled platelet concentrates. A de-
crease in the viability of stored platelets became
statistically significant only after 5 days of storage
for both products. As a practical matter. the freshest
platelets available for transfusion at most institu-
tions may be I to 2 days old because of transmis-
sible disease testing and shipment.
Clinical Condition.\'
Platelet refractoriness most commonly results
from clinical conditions associated with acceler-
ated platelet consumption. These may coexist with
alloantibody-mediated refractoriness.1S.17Spleno-
megaly, DIC, amphotericin B therapy, bone mar-
row transplantation, veno-occlusive disease of the
liver, and graft-versus-host disease have been re-
ported to reduce platelet recovery.6.IS.29-32 In pa-
tients undergoing hematopoietic stem cell transplan-
tation, poor posttransfusion CCls at 16 hours were
significantly correlated with high total bilirubin.
total body irradiation. high serum tacrolimus. and
high serum cyclosporin by multivariate analysis.32
A multivariate analysis of clinical factors associ-
ated with decreased posttransfusion increments in
the TRAP study showed fever, infection, bleeding,
splenomegaly, gamma-irradiation. concurrent am-
photericin B therapy, as well as a history of
previous pregnancy in women, to be independently
associated with decreased CCls.19 Those transfu-
sions associated with moderate to severe transfu-
DELAFLOR-WEISS AND MINTZ
sion reactions were also associated with lower
I-hour CCIs}3
When alloantibodies cannot be demonstrated by
the laboratory and fewer than 3 weeks have elapsed
since starting chronic transfusion therapy in pa-
tients without a history of previous exposure to
HLA antigens by transfusion. solid organ trans-
plant. or previous gestations. nonimmune clinical
refractoriness is the likely cause. Although platelet
refractoriness in individual patients can be attrib-
uted to single identifiable clinical factors, in many
cases it is multifactorial. and no single clinical
factor is a predictor of posttransfusion platelet
increments across patients. L7
Although fever has been implicated in decreased
platelet recoveries. it is unclear whether the sepsis.
DIC. or the antibiotic treatment associated with
fever rather than the fever per se are the
cause}.6.15.34.35
There is no evidence that decreasing
fever with antipyretics will improve recoveries.
Treating the underlying cause of fever and control
of DIC may be of value at improving the platelet
counts.
IMMUNE CAUSES OF REFRACTORINESS
ABO Incompatibility
There is a highly variable ABH expression.
greater than 20-fold. on the surfaces of platelets of
different persons.36and only 7% of non-group a
platelets express high levels of A or B antigens as
determined by enzyme-linked immunosorbent as-
say and immunoblotting studies. Expression corre-
lates with the levels of glycosyltransferase in the
serum of the donor. In contrast to red cells, which
express type 2 ABH chains. platelets express equal
amounts of type 2 and type I chains.37
Severnl studies have addressed the significance
of ABa group compatibility in the response to
platelet tmnsfusion.3841 In recipients with high
titers of anti-A or anti-B isoagglutinins (eg. >64).
ABa-incompatible platelet transfusions may con-
sistently fail to produce adequate responses,42but
incompatible transfusions have been reported to be
as effective as ABa-identical platelets in patients
with lower titer isoagglutinins.43 In one report.
CCIs were higher in patients who received ABa
identical pooled platelets, intermediate in those
who received ABa plasma incompatible platelets.
and lowest in recipients of ABa major incompat-
ible concentrates.41Aster38 reported that the mean
recovery of radiolabeled AI platelets transfused
PLATEl IRINESS AI JIMMUNIZA"
into 0 recipients was only 19% and that of AI B
platelets transfused to 0 recipients only 8%, as
compared with recovery of 63% observed when
ABO-compatible platelets were transfused. In the
same study, transfusion of incompatible group B
platelets resulted in recoveries similar to those of
compatible transfusions. ABO antigen density on
the platelet ~urt.ace may influence the result of
tran~fusions, because group Az platelets express
approximately 40-fold less A antigen than Al
platelets and may provide good recoveries in group
a patients even in recipients with high titers of
anti-A isoagglutinins.44 Transfusion of ABO-
incompatible donor plasma also may result in
reduced platelet recoveries. ABO incompatible
donor pla~ma in platelet products result in poor
responsespresumably from the fonnation of circu-
lating immune complexes (CIC) with the soluble A
and B substance in the recipient's plasma with
resultant increased platelet clearance.40Based on
the available clinical evidence. a trial of platelet
concentratesABa compatible with recipient plasma
to refractory patients with isoagglutinin titers above
64 is reasonable and may result in adequate
CCIS.J9.41 This practice defines the role of ABO
incompatibility in particular patients and may be all
that is necessary.
HLA Incompatibility
HLA antibodies are usually detected by lympho-
cytotoxicity testing. The percentage of panel cells
to which the patient has developed HLA antibodies
is called the panel reactive antibody (PRA) level.4s
PRA may be used to screen patients receiving
chronic transfusion therapy, and increases in PRA
levels occurring over time may be used to predict
alloimmune refractoriness.4s.46 Reactivity with over
70% of the panel lymphocytes is the usual cutoff
used in the clinical setting to diagnose alloimmuni-
zation.
Fewer than 50% of refractory patients have
evidence of platelet or lymphocytotoxic (LCT)
HLA antibodies.47.48Most studies have shown a
clear relationship between the presence of HLA
LCT antibodies and concomitant platelet refractori-
ness!.12.3S.-I9
although in I series only 30% of all
alloimmunized patients were refractory to platelet
transfusion.so
Platelets express 73% of the whole blood load of
class I HLA-A and HLA-B antigen,SI but they do
not express class II HLA antigens. Platelets alone
are a very weak stimulus for the fonnation of
antibodies to HLA class I antigens. becausealloan-
tigen recognition usually requires expression of
both class I and class II HLA antigens, found on the
surface of donor leukocytes. Residual donor leuko-
cytes in red blood cells or platelet concentrates
provide a source of antigen-presentingcells (APC).52
Leukoreduction to less than I to 5 X I Q6 per
transfusion minimizes the APCs in the transfused
product and decreasesthe total antigen load, shown
in various studies to be effective in preventing
alloimmunization and refractoriness to platelet trans-
fusion.50.53.54Ultraviolet B irradiation abolishes
APC stimulation in mixed lymphocyte cultures and
may cause specific unresponsiveness to HLA anti-
gens.55Leukoreduction and UV-B irradiation were
equivalent in preventing alloimmunization, as
shown in the TRAP study.50The rate of alloimmu-
nization was not statistically different between
recipients of leukoreduced platelets, 18%, and
recipients of UV-B irradiated platelets, 21%, as
opposed to 45% in patients receiving untreated
blood products. Refractoriness was lower in the
intervention arms: 3% and 5% in recipients of
leukoreduced and UV-B irradiated products, respec-
tively, compared with the controls (13%). In a
separate prospective randomized study of patients
selected for low-risk histories for alloiminunization
(not previously exposed to HLA antigens), a reduc-
tion in alloimmunization from 42% to 7% was
observed with leukoreduced blood components.54
Primary alloimmunization to HLA antigens oc-
curs at a median of 3 to 4 weeks (range, 2 to 56
weeks) after the first transfusion in those who
receive multiple transfusions. 55Patients with previ-
ous exposure to HLA antigens are at high risk to
develop alloimmunization and platelet refractori-
ness and may do so earlier than patients without
such history.46.56In the absenceof previous transfu-
sion, alloimmunization develops in 4% of women
after one pregnancy and 26% after four pregnan-
cies.51In the TRAP study, leukoreduction or UVB
irradiation reduced the risk of HLA-aIloimmuniza-
tion even in patients with previous exposure to
HLA alloantigens.50In contrast, Sintnicolaas et a}46
found that leukoreduction did not prevent second-
ary HLA-alloimmunization (43% v 44%) or plate-
let refractoriness (41 % v 29%, P = .52) in patients
with a history of pregnancy in a randomized
prospective study. When prefonned alloantibodies
are present before the current course of transfusion.
 184
they tend to persist, whereas de novo antibodies are
more likely to be transient,58 Patients receiving
high-dose steroids may have their HLA-alloimmu-
nization delayed to a mean of 7 to 8 weeks (range.
2-15 weeks),4'1.5'1
Selection of HLA-matched platelets. Selection
of platelets for transfusion basedon HLA matching
improves posttransfusion platelet recovery in pa-
tients with platelet refractoriness due to alloimmu-
nization to HLA antigens.47.60 Daly et al12reported
significantly improved CCIs by transfusing HLA-
matched products to patients who had LCT antibod-
ies and poor I-hour CCIs to pooled platelets. Peters
et al61 studied the kinetics of HLA-matched 1111n-
labeled allogeneic platelets in 5 patients with
alloimmune refractoriness and found that recovery
at 1 hour postinjection and median platelet lite span
improved with HLA matching.
HLA antibodies may be classified in 2 groups:
those that recognize only an epitope in a particular
HLA allele (private epitopes), such as HLA A2 !}r
HLA B 12. and those that recognize more than I
gene product. In the latter group, there are antibod-
ies that may recognize structurally similar epitopes
in different gene products or identical epitopes
present in different alleles (public epitopes). Differ-
ent epitopes that are sufficiently similar to be
recognized by a specific HLA alloantibody are said
to belong to a cross-reactive group.
Most patients who develop alloimmunization are
broadly immunized to class I HLA antigens. and
only a minority of refractory patients have clear-cut
specificities to private class I antigens.62This broad
reactivity is not caused by multiple alloantibodies
but instead is usually attributable to 1 or 2 antibod-
ies directed against public specificities present in a
relatively large percentage of the population. For
example, Bw4 and Bw6 are public antigens en-
coded by a diallelic system. These antigens are
associated with 2 different sets of HLA-B antigens.
Special techniques such as binding assays using
labeled antiglobulin reagents may be required to
detect these antibodies.
HLA matching requires knowledge of the patient
and prospective platelet donor HLA phenotypes.
The principles of selecting compatible platelet
products are basedon (I) Selecting a donor with an
HLA phenotype identical to the recipient (or not
expressing any antigens other than those present in
the recipient), or selecting crossmatch-compatible
platelets; (2) Selecting a donor with partial identity
DELAFLOR-WEISS AND MINTZ
to the recipient but possessing nonidentical anti-
gens that are considered to be cross-reactive and
not immunogenic to the recipient; (3) identification
of antibody specificities and selection of donors
who lack the corresponding antigen; (4) finding
selectively mismatched donors for those antigens
that are known not to be strongly expressed in
donor platelets or for which expression is variable.
For HLA-alloimmunized patients matched to
private antigens. prospective donors are classified ..
based on the number of antigens identical to the
recipient (Table I). Platelet count increments with
A and BU matches are equivalent and superior to C
and 0 matches in alloimmunized refractory pa-
tients.60.63One study63 found that CCIs with BX
matches were lower than with A and BU matches
but higher than those with C and 0 matches.
Overall. only 80% of alloimmunized clinically
stable patients benefit from fully HLA-matched
products.6.64Failure rates with platelet transfusions
selected using CREGs has been reported to be as
high as 41 %.63 Some transfusions within CREGs
are more successful than others. Bidirectional trans-
fusion within donor-recipient cross-reactive pairs
AI/All. A2/A28. B5/18. and B7/B22 resulted in
good platelet increments. whereas Al/A3. A3/AII.
85/BI5. B5/B17. 88/B14. BI2/B21. and B7/B27
did poorly.65
Reasons for the failure of HLA-matched transfu-
sions include undiagnosed clinical factors. alloim-
munization to platelet-specific or minor histocom-
Table 1. Grades of HLA Matching Between
Recipient and Donor
Grade
All 4 antigens in the donor are identical to the
recipient
B1U Only 3 donor antigens are identified. All are
present in the recipient.
82U Only 2 donor antigens identified. Both are pre-
sent in the recipient.
B1X Three donor antigens are identical to the
recipient, fourth is a member of a cross-reac-
tive group.
B2UX Two of the 3 detectable donor antigens are pre.
sent in the recipient. The third is a member
of a cross-reactive group.
B2X Two donor antigens are identical to the
recipient, 2 are cross-reactive.
Three donor antigens are identical to the
recipient, 1 antigen is mismatched.
D Two donor antigens are identical to the
recipient. 2 mismatched.
Adapted from McFarland.'45
PLATELET REFRACTORINESS AND ALLOIMMUNIZATION
patibility antigens. ABO group mismatch. and use
of older products. In addition to the clinical factors
mentioned. development of intragroup antibodies
to cross-reactive HLA antigens may contribute to
failure of the BX matches.
Platelet .\"electionbased on specific HLA antigen
mismatch. Characterization of the patient's anti-
body may be useful in certain circumstances to
choose donors by selective mismatch in patients
who are less broadly immunized. For example.
patients who develop antibodies against a single
HLA class I antigen (eg, HLA A2) may receive
effective platelet transfusions specifically selected
to be negative for the HLA A2 antigen.66.67 Pooled
platelets. some of which would be expected not to
express the antigen. also may be effective. In
practice. this may be tried if it is difficult to find
good HLA matches for a particular recipient and
partially matched transfusions are unsuccessful.
Trans.fusin,~HLA antigen-positive platelets in
the presence of HLA antibody. There are.50,000
to 120.000 HLA molecules per platelet.51Expres-
sion of some of the class I HLA antigens on the
platelet surface may vary by a factor of 35-fold for
HLA-B 12.68 8-fold for HLA-B8.69 32-fold for
Bw4. and 20-fold for Bw6!0 In many patients with
antibody to HLA B 12. transfusion of HLA-B 12
antigen-positive platelets may result in adequate
responses. Expression of B 12 is enhanced when
A 11 is also present. but decreasedwhen A2. A3. or
Aw28 are present.68Expression of Bw4 is stronger
when associated with B5 or B27. and weaker with
B13. Expression of Bw6 is stronger with B7. Bl5
or B35, but weaker with B8 or B 14.70Platelets with
low antigen expression may not be efficiently
destroyed by the antibody. In one study, 69% of
immunized patients respondedto HLA-B 12 antigen-
positive platelets.48In selected refractory patients,
it may be possible to use this information to select
among incompatible platelets for transfusion, if
compatible products are not available.
Return to unselected platelets. LCT HLA anti-
bodies may be transient. They have been reported
to disappear in 40% of patients after I week to
several months. despite continued platelet transfu-
sions,6.49.58.59and previously refractory patients
have regained good responses to unmatched plate-
lets for periods from 2 weeks to 36 months.49Other
studies have described similar findings.58.59Devel-
opment of anti-idiotypic antibodies reactive with
the variable regions of HLA antibodies has been
185
demonstrated in two thirds of patients who lose
their HLA alloantibodies and may explain this
phenomenon.71Patients who demonstrate alloim-
mune refractoriness deserve a trial of unmatched
platelets at intervals after the diagnosis of refracto-
riness. Serial determination of LCT or platelet
antibody may guide this therapy.
Selection of platelet.\" ba.\"edon platelet cross-
match. Ordering HLA-matched platelets does not
guarantee an adequate match. In one study, 43% of
such products were BX or C matches}2 The
rationale for platelet cross-matching is to select a
compatible platelet concentrate irrespective of the
nature of alloimmunization (ie, to HLA or platelet-
specific antigens). Platelets compatible with the
recipient's serum in vitro are selected from single
donor platelet units available at the time of testing
the inventory. Because ABC major incompatibility
often leads to an incompatible cross-match, only
ABC-compatible platelet units should be cross-
matched.
Platelet cross-matching has the advantage of
allowing selection of platelets from a larger pool of
donors who otherwise would have not been se-
lected becauseeither they are poor matches (BX, C,
or D) or their HLA type is unknown.73Some blood
centers include the HLA type of the donor, if
known, on all single-donor platelets. This can guide
the hospital transfusion service in selecting prod-
ucts to cross-match. Even in highly alloimmunized
patients, 5% of unselected screened donors may be
compatible by cross-match.
In most studies, cross-matching has been found
to be equivalent to HLA matching in terms of
predicting adequate responses to platelets transfu-
sion. The sensitivity and specificity of cross-
matching to predict good responsesin patients have
been reported to be greater than 80% in clinically
stable patients}4.7S Although selection of cross-
matched platelets usually results in adequaterecov-
eries, in one study this strategy was inferior to HLA
grades A and BU matching}3-7S Friedberg et al76
observed equivalent results with cross-match and
HLA match, although HLA matching benefited
only the subgroup of patients with good HLA
matches (grades A or BU). None of 31 cross-match
incompatible platelets provided an adequate incre-
ment. An incompatible cross-match result predicts
poor responses, but a compatible cross-match does
not exclude a poor response.6 As with red cell
antibodies, the sensitivity of the cross-match is
 186
insufficient to detect all alloantibodies. The ability
of the cross-match to predict posttransfusion re-
sponses may be lower (60% to 80%) in unselected
refractory thrombocytopenic patients than in those
who are clinically "stable" (80% to 100%), that is,
without associated clinical factors./) A theoretical
limitation of using cross-matched rather than HLA-
matched platelets may be the exposure of the
patient to a greater number of mismatched HLA
antigens to which alloimmunization is possible.
Several methods of cross-matching have been
described and found similarly useful to predict the
CCI, including solid-phase red cell adherence
(SPRCA),77 flow cytometry,78 immunofluores-
cence, LCT cross-matches, radiolabeled antiglobu-
lin test, complement fixation, platelet serotonin
release, platelet factor 3 release, and platelet aggre-
gation.79Rachel et al8ofound an overall correlation
of 97% between SPRCA cross-matching and trans-
fusion outcome. The commercially available
SPRCA assay (Capture-P@,IMMUCOR, Norcross,
GA) was described by Bock et al.s! SPRCA tests
cannot differentiate between alloimmunization to
HLA or platelet-specific antigens. Chloroquine or
acid stripping of the platelets before SPRCA or
platelet cross-match, differential platelet/lympho-
cyte reactivity, monoclonal antibody-specific immo-
bilization of platelet antigens assay,82or differential
coating of HLA and human platelet antigen (HPA)
antigen by enzyme immunoassay83may be of value
in differentiating HLA from HPA antibodies.
We believe that either platelet cross-matching or
ordering HLA-matched platelets is an equally ap-
propriate strategy to treat the alloimmunized, refrac-
tory patient. The decision regarding which to use
should be made initially by each hospital in consul-
tation with its blood supplier and should be deter-
mined largely by local factors (eg, Does the hospi-
tal perform platelet cross-matching? Does the blood
center have a large HLA-ty~d donor base?) Pa-
tients not responding to cross-match-<:ompatible
platelets should be given HLA-matched products in
case the cross-match is not sufficiently sensitive to
detect alloantibodies present. Patients for whom
good HLA matches are not available may benefit
from the determination of cross-match compatibil-
ity with the best HLA-matched products that can be
found.
Selection of platelets based on platelet-specific
antigen matching. The understanding of the role
of platelet-specific antigens in alloimmunization
DELAFLOR-WEISS AND MINTZ
and platelet refractoriness is evolving. Thirteen
human platelet antigen (HPA) systems have been
described (Table 2). Cases in which poor platelet
recoveries are seen after transfusion of HLA-
matched and ABO-identical platelets prompt con-
sideration of the presence of platelet-specific allo-
immunization.58.84 In multitransfused patients,
alloimmunization to platelet-specific antigens is
most commonly directed to antigens with pheno-
typic frequencies below 30%,85.86 whereas alloanti-
bodies directed to the high-i.nciqence antigens are
rare.56.87
Although Murphy and Waters88 estimated the
frequency of platelet-specific antibodies to be 20%
to 25% in multi transfused patients, in the recent
TRAP study,5Oonly 8% of the patients developed
antibodies to platelet-specific antigens. Simulta-
neous alloimmunization to HLA and platelet-
specific antigens is not rare. KickIer et al89 identi-
fied antibodies to GPllb/IIIa in 9 of 293
multi transfused thrombocytopenic patients, and all
9 were also alloimmunized to HLA antigens. In one
report, 90% of patients alloimmunized to platelet
antigens also had HLA antibodies.90Between 20%
and 25% of patients broadly alloimmunized to
HLA antigens also may be alloimmunized to plate-
let-specific antigens. The contribution of platelet-
specific alloimmunization to platelet refractoriness
has not been entirely defined. Some studies have
found no clear correlation between platelet-specific
antibodies and poor responses to platelet transfu-
sion.91.92Leukoreduction does not appear to affect
the rate of alloimmunization to platelet-specific
antigens.so
For a patient with a documented platelet-specific
alloantibody who is refractory to HLA-matched
platelets, the transfusion of platelets lacking the
corresponding antigen may be beneficial. Keko-
mill et al93reported 67 successful transfusions to 6
patients who were simultaneously alloimrnunized
to HLA and platelet-specific antigens, with plate-
lets matched to both antigen groups. Donor selec-
tion based on platelet-specific antigen genotyping
by polymerase chain reaction using allele-specific
primers to HPA sequences has been reported.94
Empiric transfusion of platelets of known HLA and
platelet-specific antigen types may detennine which
alloantibodies are causing refractoriness in an indi-
vidual patient.
PLATELET REFRACTORINESSAND ALLOIMMUNIZATION 187

Table 2. Human Platelet Alloantigens

HPA-2a (KOb) Ib Thr145

HPA-2b (Ko., Sibs) Met145

HPA-3 HPA-3a IBak., Lek.) lib lIe843

HPA-3b tBakb) Ser843

HPA-4 HPA-4a (Pen', Yuk"' ilia Arg143

HPA-4b (Pen", Yuk') Gln143

HPA-5a (B,o, Zav.) la Lys505

HPA-5b (Br., Zav., Hc.) Glu505

HPA-6 HPA-6a (Cab) ilia Arg489

HPA-6bW (Cae,rue) Gln489

HPA-7a (MOb) Ilia Pro407

HPA-7bW (Mo.) Ala407

HPA-8 HPA-8a Ilia Arg636

HPA-8bW (Sf') Cys636

HPA-9 HPA-9a lib Val837

HPA-9bW(Maxo) Met837
HPA-l0a Ilia Arg62
HPA-10bW (LaO) Gln62
HPA.11 HPA-l1a ilia Arg633
HPA-11bW(GroO) His633
HPA-12 HPA-12a Ib Gly15
HPA-12bW (IVO) Glu15
HPA-13 HPA.13a la Thr799
HPA.13bW(SitO) Met799
HPA-t HPA. (CeO' ilia Not known
HPA-t HPA. (Vao) ilia Not known
HPA-t HPA. (PeO) Ib Not known

NOTE, These also are known as "platelet-specific antigens," 145.'46

Abbreviations: HPA, human platelet alloantigen; NA, not available.
'Phenotypic frequencies for the Caucasian population only.
tNumber not yet assigned,

Autoantibodies, Drug-Induced Antibodies and without endogenousplateletsavailablefor testing,

Passively Acquired Antibodies
The presence of platelet autoantibodies may
impair the responseto transfused allogeneic plate-
lets; however. decreasedplatelet survival occurs in
only a minority of patients in whom they are
detected. Platelet autoantibodies have been re-
ported in acute leukemia. lymphoproliferative dis-
orders. solid tumors. sepsis. cytomegalovirus infec-
tions. and hematopoietic stem cell transplantation
and its complications.9I,92.9s-98
In patients with severe thrombocytopenia and
it may be difficult to prove the existence of
autoantibodies,especially at a time when most
circulating plateletsare previouslytransfusedallo-
geneic platelets. When strongly suspectedclini-
cally, or a previous diagnosis of autoimmune
thrombocytopeniaalreadyhasbeenmade,a trial of
high-dose steroids, splenectomy,or intravenous
immunoglobulin(IVIG) may bejustified.99
Many drugshavebeenimplicatedin thedevelop-
mentof immuneor nonimmunethrombocytopenia.
Someof theseare likely to be usedin patientswith

hypoproliferative thrombocytopenia requiring mul-
tiple transfusions (eg, cephalosporins, penicillin,
methycillin, TMP-SMX, pentamidine, vancomy-
cin, and amphotericin 8).6 Diagnosis dcpends on
cliciting a temporal relationship of thrombocytope-
nia and platelet refractoriness with the use of the
drug and demonstration of drug-related antibod-
ies.1lXJ Evaluation for drug-induced antibodies may
be warranted in the subset of patients with temporal
ass()Ciation to the exposure of an offending drug
and the onset of refractorine~s. 8ecau~e of the
complexity of the clinical situation, it may not be
easy to identify which factors are responsible for
refractoriness, and the offending agent should be
withdrawn when the diagnosis is strongly sus-
pected, if possible.
The presence of circulating immune complexes
and clearance of platelets by the reticuloendothelial
system may induce thrombocytopenia. 101As noted,
ABO-incompatible plasma in transfused platelets
may contribute to formation of immune com-
plexes.40The presenceof IgG antibodies to. plasma
proteins was found to increase progressively with
platelet transfusions and to correlate with platelet-
bound IgG and refractoriness.,o2 The degree to
which this phenomenon poses a problem in most
patients is unknown.
MANAGEMENT WHEN COMPATIBLE
PLATELETS ARE UNAVAILABLE
OR INEFFECTIVE
Alternative strategies for managing thrombocyto-
penic refractory patients have been reported mainly
in small uncontrolled studies or case reports, and
interpretation of the benefits of these modalities is
difficult. Positive results may be more likely to be
reported and published than negative results. No
clear-cut recommendations can be made regarding
these therapies (Table 3).
Cryopreservation of AutoLogous PLateLets
Platelets collected during recovery of chemother-
apy may be frozen in the cryoprotectant dimethyl
sulfoxide until needed. Approximately 50% of the
platelets are recovered after processing and transfu-
sion. The platelets have normal function and sur-
vival. Funke et allO3 reported 78 transfusions of
autologous cryopreserved platelets to 8 alloimmu-
nized patients. The in vitro platelet recovery was
85 :t 4%, with a posttransfusion CCI of 11,000.
More recently, Torretta et al104 used single-
DELAFLOR.WEISS AND MINTZ
collection autologousplatelets cryopreservedfor
25 patientsreceiving high-dosechemotherapyfor
breast cancer. Mean platelet recovery was 63%
(range.44% to 81%) after freezing and thawing.
Twenty-threepatients did not require allogeneic
platelet transfusions.and 21 patients had I-hour
CCls greater than 7.500. Platelet size was larger
than fresh controls. and there was reducedadeno-
sine diphosphate-inducedaggregation.but other
agonistresponseswere adequate.For patientswho
will go throughprolongedperiodsof thrombocyto-
penia.severalcollectionsmay be necessary.Cryo-
preservationmay be usedfor thosealloimmunized
patientswith few or no compatibledonors.but its
implementationis difficult. and this practiceis not
widespread.
Antifibrinolytics
Bleeding was controlled with epsilon-aminoca-
proic acid (EACA) in 90% (36 of 40) of patients
with autoimmune thrombocytopenia or bone mar-
row failure and alloimmune refractoriness to plate-
let transfusions.'os-1o1In one randomized study
comparing platelet transfusions with and without
EACA in 18 thrombocytopenic leukemic patients,
there was no significant difference between groups
in "major bleeding" or number of platelet transfu-
sions required. However, the authors reported "over-
all less bleeding" in the treated group.IOSTranex-
amic acid was found to reduce hemorrhage in a
double-blind trial in thrombocytopenic patients,
without an increase in thromboembolic complica-
tions.l09 Antifibrinolytic therapy is worth trying for
bleeding thrombocytopenic patients without com-
patible platelets available, or for those who fail to
respond to compatible products.
Intravenous Immunoglobulin
Although IVIG therapy may be efficacious for
some cases of autoimmune thrombocytopenia,llo
there are conflicting data on the treatment of
platelet transfusion refractoriness with IVIG. Most
published studies have shown some benefit,lll-119
but in 3 studies no advantage was noted. 120-122
Of a
total of 66 patients reported, 37 (56%) had improve-
ment in platelet counts posttransfusion, reduction
in bleeding, or decreased platelet transfusion re-
quirements. It is possible that successful studies are
more likely to be reported. KickIer et all18 reported
a randomized placebo-controlled clinical trial of
alloirnrnunized refractory patients treated with IVIG
PLATELET REFRACTORINESS AND ALLOIMMUNtZATION 189

Table 3. Treatment of Platelet Refractoriness

8 8 85% Recovery
25 23 63% Recovery

17 EACA 17 5 9 loading, 6 g/d thereafter

9EACA 9 16-24 g/d
14 EACA 13 8-24 g/d
9 Platelets + EACA No difference in "major bleed- 100 mg/kg loading dose
9 Platelets ing"; "overall less bleeding" 12-24 g/d thereafter
109* 6 Tranexamic acid (6 Place- 5 6 g/d
bo-no response)
IVIG
111 3 2 0.4 g/kg/d x5 d
112 3 2 0.4 g/kg/d x5 d
113 3 3 0.9 gikg
114 19 13 0.4 g/kg/d x5 d followed by 0.8
g/kg/d x 5 d
3 3 2 g/kg/d x2-5 d
116 2 2 0.4 g/kg/d x5 d
117 10 6 0.4-08 g/kg/d x5 d
118* 7 (5 Placebo-no response) 5 0.4 g/kg/d x5 d
119 2 2 Pt. 1: 0.4 gikg/d x5 d
Pt. 2: 1 gikg/d x2 d
120 5 0 0.4 gikg/d x5 d
121 7 0 0.4 g/kg/d x5 d
122 11 0 0.4-0.6 gikg/d x5 d
Total 75 38 (51%)
Plasma exchange
124 18 11 (61%) 10 LId x2-3 d
Staphylococcal A protein
126 6 0.5-2 L plasma processed. 1-4
treatments
127 3 0 2 L plasma processed. 4 treat-
ments
Total 13 6(46%)
Massiveplatelet transfusion
130 2 20 Units to adsorb the anti-
body. Improved increments
observed thereafter.
Cyclosporin A
131 2 1 12.5 mg/kg/d
132 1 1 300 mg/d
133 1 1 3.3 mg/kg twice daily
Antithymocyte globulin
135 4 3 Disappearance of alloantibody
HLA stripped platelets
136 1 Patient 1 73% Recovery in normal sub-
2 Normal subjects jects; results in patient com-
parable to HLA-matched
137 2 1 GI bleeding stopped
138 1 1 GI bleeding stopped
Vinblastine-loaded platelets
139 1 (11 courses) Effect lasted a few days;
bleeding stopped
-Prospective controlled study.
190
at 4(X) mg/kg/d for 5 days. Five of 7 patients
receiving IVIG had significant increases in CCI at I
to 6 hours compared with pretreatmcnt values, but
only one had improved platelet survival at 24
hours. Improvement in I-hour CCI was seen in 4
patients receiving HLA-mismatched platelets. Re-
sponse~~een with IVIG are usually rapid, ranging
from I to 9 days, and last for 6 to 8 weeks. One
report documented a responselasting over I year in
a patient receiving chronic platelet support.117Pro-
posed mechanisms include macrophage Fc receptor
blockade, platelet coating, and displacement of
previously bound antibodies from the platelet sur-
face.123All studies on the treatment of refractori-
ness are confounded by the spontaneous loss of
antibody. Physicians must be mindful that a course
of high-dose therapy costs several thousand dollars.
Other Options
Plasma exchange. Therapeutic plasmapheresis
was reported in only 1 case series of 18 ~lloimmu-
nized patients.124A response was seen in 8 of 13
patients with detectable LCT antibodies at the time
of pheresis. The authors concluded that the best
responses are seen with 10-liter plasma exchanges
perfonned daily for 3 days. Plasmapheresis also
may be considered in patients with autoantibodies
or drug-induced thrombocytopenia as a means of
removing IgG or immune complexes. This therapy
is employed only rarely owing to its limited
reported success.
Anti-D immune globulin. Heddle et al125re-
ported a randomized trial of weekly intravenous
anti-D (20 ~g/kg) or placebo given to 43 Rh-
positive acute leukemia patients at diagnosis, to
prevent the development of refractoriness and to
improve posttransfusion platelet increments. No
differences were observed between groups, except
for an increase in red cell transfusions in the
treatment group.
Immunoadsorption: Staphylococcal Protein A
Columns. There are 2 small case series on the use
of extracorporeal immunoadsorption in the treat-
ment of platelet refractoriness. In a study by
Christie et al,126 6 of 10 patients refractory to
platelet transfusions responded to treatment with
staphylococcal protein A columns (PROSORBA,
IMRE Corp., Seattle, WA) after failing other immu-
nosuppressive therapy. Responding patients had
posttransfusion CCIs at 10 minutes to 2 hours of
48,000 compared with 16,000 pretreatment. Eight
DELAFLOR.WEISS AND MINTZ
of these patients had demonstrable platelet antibod-
ies. Patients recei ved from I to 14 treatments, and
the total volume of treated plasma ranged from 500
to 2,0<)0 mL per treatment at a rate of 10 to 20
mUmin with apheresis equipment (CS-3000, Bax-
ter, Deerfield, IL) or by an off-line procedure. In
another clinical study, Lopez-Plaza et al127found
no effect in 3 patients. It has been hypothesized that
although staphylococcal protein A binds IgG (ex-
cept IgG3), the key effect is not immunoadsorption
but immunomodulation by induction of anti-
idiotypic antibodies.128.129 The usefulness of this
expensive approach needs to be confirmed.
Massive platelet transfusion. Transfusion of
large doses of platelets to immunoadsorb alloanti-
body or block the phagocytic system has been
described in 2 patients. 130After 20 pooled platelet
units were transfused, the subsequent doses re-
sulted in improved responses and produced a
clinically evident effect on hemostasis. Alterna-
tively, continuous platelet transfusion (eg, I dose
every 4 to 6 hours) has been tried with low success
in patients refractory to compatible platelets or for
whom such products are unavailable.
Immunosuppressive therapy. After 2 to 3 weeks
of treatment with 20 mg/kg/d cyclosporin A, refrac-
tory dogs had improvements in recovery and sur-
vival. Response correlated wi~h drug levels.13!
Improvement has been reported in 4 patients.131-133
Yamamoto et al132 reported reduction in LCT
antibodies in a 26-year-old patient with aplastic
anemia treated with 300 mg cyclosporin A daily for
77 days. PRA decreased from 12 to 3 of 20 cells.
Slichter et al134observed reversal of alloimmuniza-
tion with antithymocyte globulin (ATG) and procar-
bazine in an animal model.134Transient improve-
ment was shown in one clinical report.135
HIA Stripped Platelets. Shanwell et al136treated
one HLA-aIloimmunized refractory patient with
platelets stripped of HLA antigens with citric acid
treatment at pH 2.8. Good posttransfusion incre-
ments were documented on 2 occasions. Two
additional patients have been treated success-
fuIly.m.138
Vinblastine Loaded Platelets. Wong et al139
described the use of vinblastine-loaded platelets
(VLP) in a patient with aplastic anemia, thrombocy-
topenia, and bleeding who developed refractoriness
associatedwith LCT antibody. The infusion ofVLP
24 hours before an infusion of pooled platelets
resulted in good increments. The effect was main-
PLATELET REFRAC AND Al IIMMUNIZATION
tained only for a few days. t\ total of II courses of
VLP were infused, until the bleeding symptoms
improved. The authors based their study on the
successful results obtained by Ahn et all-lO in
patients with idiopathic thrombocytopenia, and
hypothesized that VLP produce reticuloendothelial
system blockade.
Thrombopoietin and platelet growth .factors.
Hematopoietic growth factors, particularly throm-
bopoietin (TPO) and interleukin-li (IL-ll), may
accelerate endogenous platelet recovery, decreas-
ing dependency on platelet transfusions. 141TPO
increases the size and number of megakaryocytes,
stimulates expression of platelet-specific markers
(eg, CD4l and CD6l), and sensitizes platelets to
the aggregating effects of agonists.'41-'44Platelets
remove TPO from the circulation, and it has been
suggested that platelet transfusions may blunt the
recovery of megakaryocytes.TPO generatesimpres-
sive thrombocytosis in mice and humans and
modifies thrombocytopenia after chemorac}iother-
apy in animals.141.142 TPO has been available for
clinical trials as recombinant human TPO (rHuTPO)
or polyethyleneglycol-conjugated recombinant hu-
man megakaryocyte growth and development fac-
tor (PEG-rHuMGDF) and has been shown to return
platelet counts to normal significantly faster, with
higher nadir counts.143.144 In patients receiving
nonmyeloablative chemotherapy (eg, carboplatin
for gynecologic malignancies), platelet counts start
to increase after 3 to 4 days of TPO, with a peak
effect at 12 to 14 days, with up to a 50% decreasein
the need for platelet transfusion.141.144 However,
neither minimal to no effect in platelet nadirs or
time to recovery nor a reduction in the need for
transfusion of platelets has been observed after
hematopoietic stem cell transplants or myeloabla-
tive chemotherapy for acute leukemia.141 PEG-
rHuMDGF has been shown to increase plateletpher-
esis yield 3-fold in stimulated donors.141However,
all clinical trials with PEG-rHuMGDF were stopped
in 1998 because of development of antibodies to
the recombinant molecule that cross-react with
endogenous TPO. These antibodies caused throm-
bocytopenia in almost 10% of normal treated
volunteer plateletpheresis donors. This problem has
not been associatedwith rHuTPO.141.142
IL-ll works in concert with IL-3 to increase the
size, number, and ploidy of megakaryocyte colo-
nies and to increase platelet counts.142It has been
reported to prevent severe cumulative thrombocyto-
penia in breast cancer patients after high-dose
chemotherapy and may decrease the need for
platelet transfusions.\42rHuIL-11 (Neumega, Genet-
ics Institute, Cambridge, MA) has been approved
for the prevention of severe thrombocytopenia and
reduction in the need for platelet transfusions after
chemotherapy in patients with solid tumors receiv-
ing nonmyeloablative chemotherapy.14\IL-II is of
limited value in patients receiving myeloablative
chemotherapy.141.142 Combinations of IL-6 and
granulocyte-colony-stimulating factor have been
observed to enhance platelet recovery minimally
after intensive chemotherapy, although they are not
currently used for this indication. 142
APPROACH TO THE REFRACTORY PATIENT
When refractoriness to platelet transfusion is
diagnosed, a systematic approach to elucidating its
origin may help direct clinical management. Blood
product variables, clinical factors, and the possibil-
ity of alloimmunization must all be considered.
Physicians should be mindful that clinical factors
are more common causes of refractoriness than
alloimmunization and that in some patients the
nature of the platelet concentrates themselves can
be significant as well. Furthermore, many clinical
and product variables (eg, fever, bone marrow
transplantation, ABO compatibility, days of stor-
age) affect platelet recovery in some patients but
not in others.
If a patient develops refractoriness to platelet
transfusions, a subsequent transfusion of an ad-
equate dose of ABO-identical platelets that are as
fresh as possible (preferably less than 2 days old)
should be tried. In addition, verification of the
timing of the pretransfusion and posttransfusion
platelet counts is important. If a long time has
elapsed between either count and the transfusion,
the diagnosis of refractoriness may not be accurate.
Treatment of clinical factors such as infection,
DIC, veno-occlusive disease, and adjustment of
drugs may be necessary to improve platelet counts
and responsivenessto platelet transfusion. If refrac-
toriness has occurred within 3 weeks of the first
transfusion in a patient not previously exposed to
foreign HLA antigens, an alloimmune cause is less
likely.
Patients should be typed for class I HLA antigens
at the time of diagnosis. If a transfusion of an
adequatedose of ABO-identical platelets stored for
2 days or less does not result in an acceptable
192
increasein the plateletcount. then testing for LCT
antibodies is indicated. If LCT antibodies are
detected. then HLA-matched or cross-match-
compatibleplateletsshouldbe transfused.Someof
these patients also may need ABO-identical or
freshplatelets.Somepatientsmay haverising titers
of anti-A or anti-B. if they received ABO-
incompatible platelet transfusionsearlier in their
treatment. and may thereafter require ABO-
identical platelets. When only low-grade HLA
matchesare available (eg. BX. C. or D). cross-
match-<:ompatible platelets.if available.may pro-
vide better responses.If only platelets that are
partially HLA-matched can be collected. it may
also prove helpful to cross-matchtheseproducts.
Physicians should remember that HLA class I
antigenscauserefractorinessin only a minority of
patientswho arealloimmunizedto them.
If there is difficulty finding well-matchedplate-
lets for a particular patient. the use of platelets
expressing HLA CREGs may benefit some pa-
tients. Also. mismatching for antigens net well
expressedby platelets(eg. HLA-B 12) may prove
useful.Patientsnot responsiveto partially matched
plateletsmay be evaluatedfor alloimmunizationto
public epitopes (eg. Bw4 or Bw6). If tound.
patientsshouldbe treatedwith plateletsselectedfor
compatibility for the alloantibodydetected.
Whenit is difficult to find well-matchedplatelets
and patientsare not respondingto transfusionsof
plateletsexpressingHLA CREGs.determinationof
the specificity of the HLA alloantibodiesmay help
guide the selectionof productsfor transfusionin
somepatients.This strategyhasprovedparticularly
usefulfor patientsalloimmunizedto HLA-A2.
In patients who continue to be refractory to
HLA-matchedor cross-match-compatibleplatelet
transfusions.other causesshould be suspected.If
platelet transfusionswell matched for HLA anti-
gens do not result in expectedin posttransfusion
platelet count increments. testing for platelet-
specific antibodiesshould be considered.If such
antibodies are present.antigen-negativeplatelets
REFERENCES
I. Duke WW: The relationof blood plateletsto hemolThagic
disease:Descriptionof a methodfor detemlining the bleeding
time and coagulationtime and report of three casesof hemor-
rhagic diseaserelieved by transfusion.lAMA 55:1185-1192,
1910
2. Han T, StutzmanL. Cohen E. et a1: Effect of platelet
DELAFlOR-WEISS AND MINTZ
should be provided. if possible. For individual
patients alloimmunized to both HLA and platelet-
~pecific antigens. responsivenessto individual trans-
fusions of known HLA and platelet antigen types
may help determine which alloantibody or alloanti-
bodies are principally responsible for refractori-
ness.
Patients should be monitored every few weeks
for the persistence of alloantibody. because many
patients lose detectable alloimmunization even with
continuing transfusions. Such patients may no
longer require HLA-matched or cross-match-
compatible platelets. although failure to detect
antibodies in vitro does not necessarily mean that
there will be no alloantibody-mediated refractori-
ness in vivo, owing to imperfect test sensitivity.
Patients who are refractory despite the use of the
available strategies described above may require
additional treatment or preventive strategies. al-
though the efficacy of these modalities is unproven.
A course of anti fibrinolytic therapy to arrest hemor-
rhage is relatively safe and inexpensive and may be
highly efficacious. IVIG (0.4 g/kg/d X 5 days).
although expensive and of unproven efficacy. may
result in good platelet recovery in some patients.
Other options described above are rarely used
owing to their very limited reported success.
The transfusion of leukocyte-reduced cellular
components to prevent alloimmunization has
emerged as a cornerstone of addressing the prob-
lem of platelet transfusion refractoriness. Although
this strategy is of proven value. some patients will
continue to develop alloimrnune-mediated refracto-
riness to platelet transfusion.5OThe evaluation and
management of these patients poses a complicated
clinical challenge. The conditions that can contrib-
ute to refractoriness have variable significance in
different patients, and the available therapeutic
options have variable success in different patients.
Each refractory patient has a unique constellation
of factors that contribute to her or his own insuffi-
cient responseto platelet transfusions.
transfusionon hemolThage in patientswith acuteleukemia:An
autopsystudy.Cancer19:1937-1942.1966
3. Higby DI. CohenE, Holland IF. et al: The prophylactic
treatmentof thrombocytopenicleukemicpatientswith platelets:
A doubleblind study.Transfusion14:440-446.1974
4. HeckmanKD, Weiner aI, Davis CS. et a1:Randomized
PLATELET REFRACTORINESSAND AllOIMMUNIZATION
stu~y of prophylactic platelet transfusion threshol~ ~uring
in~u(;tion thcrapy for a~ult acute leukemia: 1(),OOO/~1versus
20.(xx)/~I.JClinOncoI15:1143-1149,1997
5. Rebulla P, Finazzi G, Marangoni F. et al: A multicenter
ran~omize~ trial of the threshold fur prophylactic platelet
transfusions in adults with acute myeloid leukemia. N Engl J
Me~337:1870-1875,1997
n. Slichter SJ: Mechanisms and Management of Platelet
Refractoriness, in Nan(;e SJ (ed): Transfusion Medicine in the
1990's. Arlington, VA, American Association of Blood Banks,
199(),pp95-179
7. Herman J: Platelet transfusion therapy, in Mintz PD (ed):
Transfusion Therapy: Clinical Principles and Practice. Bethesda.
MD, AABB Press, 1999, pp 65- 79
8. Aster RH, Jand! JH: Platelet sequestration in man. I.
Methods. J Clin Invest 43:843-845, 1964
9. Harker LA: The role of the spleen in thrombokinetics. J
Clin Lab Med 77:247-253,1971
10. Hanson SR, Slichter SJ: Platelet kinetics in patients with
bone marrow hypoplasia: Evidence for a fixed platelet require-
ment. Blood 66: 1105-1109,1985
II. O'Connell B, Lee EJ, Schiffer CA: The value of 10-
minute posttransfusion platelet counts. Transfusion 28:66-67,
1988
12. Daly PA, Schiffer CA, Aisner J, et al: Platelet transfusion
therapy: One-hour posttransfusion increments are v:rtuable in
predicting the need for HLA-matched preparations. JAMA
243:435-438,1980
13. Bishop JF, Matthews JP, Yuen K, et ..1:The definition of
rcfractoriness to platelet transfusions. Transfus Med 2:35-41,
1992
14. S(;hiffer CA, O'Connell, Lee EJ: Platelet transfusion
therapy for alloimmunized patients: Selective mismatching for
HLA B 12, an antigen with variable expression on platelets.
Blood74:1172-1176,1989
15. Bishop JF, Matthews JP. McGrath K, et al: Factors
innuencing 20-hour increments after platelet transfusion. Trans-
fusion 31:392-396,1991
16. del Rosario MLU, Kao KJ: Determination of the rate of
reduction in platelet counts in recipients of hematopoietic stem
and progenitor cell transplant: Clinical implications for platelet
transfusion therapy. Transfusion 37: 1163-1168, 1997
17. Friedberg RC, Mintz PD: Causes of refractoriness to
platelet transfusion. CUff Opin Hematol 2:493-498, 1995
18. Kao KJ, Mickel M, Braine HG, et al: White cell reduction
in platelet concentrates and packed red cells by filtration: A
multicenter clinical trial. Transfusion 35:13-19,1995
19. Enright H, Gemsheimer T, Woodson R, et al: Factors
inftuencing the response to platelet transfusion. Blood 90:
lI75A,I997(abstr)
20. Moroff G, George VM, Siegl AM, et al: The inftuence of
irradiation on stored platelets. Transfusion 26:453-456, 1986
21. Shanwell A, Larsson S, Aschan J, et al: A randomized
trial comparing the use of fresh and stored platelets in the
treatment of bone marrow transplant recipients. Eur J Haematol
49:77-81, 1992
22. Peter-Salonen K, Bucher U, Nydegger UE: Comparison
of posttransfusion recoveries achieved with either fresh or
stored platelet concentrates. Blut 54:207-212, 1987
23. Norol F, Kuentz M, Cordonnier C, et al: Inftuence of
93
clinical status on the efficiency of stored platelet transfu!;ion. Br
1 HaematoI86:125-129. 1994
24. Funheer R. Moddennan PW, Veldman H. et al: Detection
of platelet activation with monoclonal antibodies and flow
I:ytometry: Changes during platelet storage. Transfusion 30:20-
25,1990
25. Rinder HM, Murphy M. Mitchell lG. et al: Progressive
platelet activation with !;torage: Evidence for shortened survival
of activated platelets after trdnsfusion. Transfusion 31 :409-414,
1991
26. Michelson AD. Barnard MR. Hechtman HB. et al: In vivo
tracking of platelets: Circulating degranulated platelets rapidly
loose surface P-selectin but continue to circulate and function.
Blood 84:320A. 1994 (abstr)
27. Murphy S, Gardner PH: Platelet preservation: Effect of
storage temperature on maintenance of platelet viability-
Deleterious effect of refrigerated storage. N Engl 1 Med
280:1094-1098,1969
28. Slichter SJ, Grabowski M. Townsend-McCall. et al:
Prospective randomized transfusion trial to directly compare
fresh and stored apheresis platelets (AP) and pooled random
donor platelet concentrates (PC) in thrombocytopenic patients.
Blood 92:2771 A. 1998 (abstr)
29. McFarland lG, Anderson AF, Slichter Sl: Factors influ-
encing the transfusion re!;ponse to HLA-.~clected apheresis
donor platelets in patient!; refractory to random platelet concen-
trates. Br 1 HaematoI73:380-386. 1989
30. Bishop lF, McGrath K. Wolf MM. et al: Clinical factors
influencing the efficacy of pooled platelet transfusions. Blood
71:383-387.1988
31. KJingemann HG, Self S, Banaji M, el al: Refractorine!;s
to random-donor platelet transfusions in patients with aplastic
anemia: A multivariate analysis of data from 264 cases. Br 1
HaematoI66:115-12I,1987
32. Ishida A, Handa M, Wakui M. et al: Clinical factors
influencing posttransfusion platelet increment in patients under-
going hematopoietic progenitor cell transplantation: A prospec-
tive analysis. Transfusion 38:839-847, 1998
33. Enright H. GernsheimerT. McCullough J, et al: Moderate
to severe reactions to platelet transfusion: Experience of the
TRAP multicenter trial. Blood 90: 1172A. 1997 (abstr)
34. Doughty HA, Murphy MF, Metcalfe P. et al: Relative
importance of immune and nonimmune causes of platelet
refractoriness. Vox Sang 66:200-205. 1994
35. Alcorta I, Pereira A. Ordinas A: Clinical and laboratory
factors associated with platelet transfusion refractoriness: A
case-control study. Br 1 HaematoI93:220-224, 1996
36. Ogasawara K, Ueki J, Takenaka M. et al: Study on the
expression of ABH antigens on platelets. Blood 82:993-999,
1993
37. Dunstan RA, Simpson MB, Knowles RW. et al: Origin of
ABH antigens on human platelets. Blood 65:615-619, 1985
38. Aster RH: Effect of anticoagulant and ABO incompatibil-
ity on recovery of transfused human platelets. Blood 26:732-
743,1965
39. Lee EJ, Schiffer CA: ABO compatibility can influence
the results of platelet transfusion: Results of a randomized trial.
Transfusion 29:384-389, 1989
40. Heal 1, Masel D, Rowe 1. et al: Circulating immune
 194
complexes involving the ABO system after platelet transfusion.
Br J HaematoI85:566-572. 1993
41. Heal JM. Blumberg N. Masel D. et al: An evaluation of
crossmatching. HLA. and ABO matching for platelet transfu-
,ions to refractory patients. Blood 70:23-30. 19R7
42. Brand r\. Sintnicolaas K. Claas FHJ. et al: ABH antibod-
ies cau~ing platelet tran~fusion refractoriness. Tran~fu~ion 26:
463-466. 1986
43. Carr R. Hutton J. Jenkins J. et al: Tran~fu.,ion of
ABO-mismatched platelets Icads to early platelet refractoriness.
Br J HaematoI75:40R-413. 1990
44. SkogenB. RosseboHansenB. HusebekkA. et al:
Minimal expression of blood group A antigen on thrombocytes
from A2 individuals. Transfusion 28:456-459. 1988
45. Hogge DE. McConnell M. Jacobson C. et al: Platelet
refractoriness and alloimmunization in pediatric oncology and
bone marrow transplant patients. Transfusion 35:645-652. 1995
46. Sintnicolaas K. vaan Marwijk M. van Kooij HC. et al:
Leukocyte depiction of random single-donor platelet transfu-
sions does not prcvent secondary human Icukocyte antigen-
alloimmunization and refractoriness: A randomized prospective
study. Blood 85:824-828.1995
47. Yankee RA. Graff KS. Dowling R. et al: Selection of
unrelated compatible platelet donors by lymphocyte HLA
matching. N Engl J Med 288:760-764. 1973
48. Schiffer CA. O'Connell B. Lee EJ: Platelet tra."sfusion
therapy for alloimmunized patients: Selective mismatching for
HLA B 12. an antigen with variable expression on platelets.
Blood 74: 1172-1176. 1989
49. Lee EJ. Schiffer CA: Serial measurement of Iymphocyto-
toxic antibody and response to non matched platelet transfusions
in alloimmunized patients. Blood 70: 1727-1729. 19R7
50. The Trial to Reduce Alloimmunization to Platelets Study
Group: Leukocyte reduction and ultraviolet B irradiation of
platelets to prevent alloimmunization and refractoriness to
platelet transfusions. N Engl J Med 337: 1861-1869. 1997
51. Kao KJ. Cook DJ. Scomik JC: Quantitative analysis of
platelet surf.ace HLA by W6/32n anti-HLA monoclonal anti-
body. Blood 68:627-632.1986
52. Tew JG. Thorbecke GH. Steinman RM: Dendritic cells in
the immune-response: Characteristics and recommendcd nomen-
clature. J Reticuloendothelial Soc 31 :371-380. 1982
53. Oksanen K. Kekomaki R. Ruutu T. et at: Prevention of
alloimmunization in patients with acute leukemia by use of
white cell-reduced blood components: A randomized trial.
Transfusion 31:588-594.1991
54. van Marwijk Kooy M. van Prooijen HC. Moes M. et al:
Use of leukocyte-depleted platelet concentrates for the preven-
tion of refractoriness and primary HLA alloimmunization: A
prospective. randomized trial. Blood 77:201-205.1991
55. Kripke ML: Immunologic unresponsiveness induced by
ultraviolet radiation. Immunol Rev 80:87-102. 1984
56. Novotny VMJ. van Doom R. Witvliet MD. et al:
Occurrence of allogeneic HLA and non-HLA antibodies after
transfusion of prestorage filtered platelets and red blood cells: A
prospective study. Blood 85:1736-1741.1995
57. Taanig E. Skibsted L: The frequency of platelet alloanti-
bodies in pregnant women and the occurrence and management
of neonatal alloimmune thrombocytopenic purpura. Obstet
Gynecol Surv 45:525-525. 1990
58. Murphy MF. Metcalfe P. Ord J. et al: Disappearance of
DELAFLOA-WEISS AND MINTZ
HLA and platelet-specific antibodies in acute leukemia patients
alloimmunized by multiple transfusions. Br 1 Haematol 67:255-
260, 1987
59. Pamphilon DH, Farrell DH, Donaldson C, et al: Develop-
ment of Iymphocytotoxic and platelet-reactive antibodies: A
prospective randomized study in patients with acute leukemia.
VoxSang57:177-181,1989
60 Duquesnoy RJ: Donor selection in platelet transfusion
therapy of alloimmunized thrombocytopenic patients, in Green-
walt Tl, lamieson GA (eds): The Blood Platelet in Transfusion
Therapy. New York, NY, Alan R. Liss, 1978, pp 229-2~3
61. Peters AM, Porter IB, Saverymuttu SH, et al: The
kinetics of unmatched and HLA-matched I I I In-labelled homolo-
gous platelets in recipients with chronic marrow hypoplasia and
anti platelet immunity. Br 1 Haematol60: 117-127, 1985
62. MacPherson BR, Hammond PB, Maniscalco CA: Alloim-
munization to public HLA antigens in multi-transfused platelet
recipients. Ann Clin Lab Sci 16:38-44, 1986
63. KickJerTS, Braine HG, Ness PM: The predictive value of
platelet crossmatching for alloimmunized patients. Transfusion
25:385-389, 1985
64. Duquesnoy Rl. Filip 01, Rodey GE, et al: Successful
transfusion of platelets "mismatched" for HLA antigens to
alloimmunized thrombocytopenic patients. Am 1 Hematol 2:219-
226, 1977
65. Dahlke MB, Weiss KL: Platelet transfusion from donors
mismatched for cross-reactive HLA antigens. Transfusion 24:
299-302, 1984
66. Hussein MA, Lee EJ, Fletcher R, Schiffer CA: The effect
of Iymphocytotoxic antibody reactivity on the results of single
antigen mismatched platelet transfusions to alloimmunized
patients. Blood 87:3959-3962,1996
67. Duquesnoy Rl. Filip 01, Aster RH: Influence of HLA-A2
on the effectiveness of platelet transfusions in alloimmunized
thrombocytopenic patients. Blood 50:407-412, 1977
68. Liebert M, Aster RH: Expression of HLA-B 12 on
platelets, on lymphocytes and in serum: A quantitative study.
Tissue Antigens 9: 199-208, 1977
69. Aster RH, Szatkowski N, Liebert M, et al: Expression of
HLA-BI2, HLA-B8, Bw4, and w6 on platelets. Transplant Proc
9:1695-1696,1977
70. Szatkowski NS, Aster RH: HLA antigens of platelets, IV:
Influence of "private" HLA-B locus specificities on the expres-
sion of Bw4 and Bw6 on human platelets. Tissue Antigens
15:361-368,1980
71. Atlas E, Freedman 1, Blanchette V, et al: Down regulation
of the anti-HLA alloimmune response by variable region
reactive (anti-idiotypic) antibodies in leukemic patients trans-
fused with platelet concentrates. Blood 81 :538-542, 1993
72. Friedberg RC, Donnelly SF, Boyd lC, et al: Clinical and
blood bank factors in the management of platelet refractoriness
and alloimmunization. Blood 81:3428-3434,1993
73. O'Connell BA, Lee El, Rothko K, et al: Selection of
histocompatible apheresis platelet donors by cross-matching
random donor platelet concentrates. Blood 79:527-531,1992
74. MoroffG, Garratty G, Hal 1M, et al: Selection of platelets
for refractory patients by HLA matching and prospective
crossmatching. Transfusion 32:633-640, 1992
75. Gelb AB, Leavitt AD: Crossmatch-compatible platelets
improve corrected count increments in patients who are refrac-
PLATELET REFRAC )RINESS AND ALLOIMMUNIZATION
tory to randomly o;clccted platclets. Transfu.o;ion 37:624-630,
1997
7(;. Friedherg RC, Donnelly SF, Mintz PO: Independent roles
for platclct crossmatching and HLA in the selection of platelets
for alloimmuni7.ed patients. Transfusion 34:215-220,1994
77. Rachel JM, Sinor LT, Tawfik OW, et al: A solid phase red
ccll adherence test for platelet cross-matching. Med Sci Lab
42:194-195. 19li5
78. Sintnicolaas K. Lowenberg B: A flow cytometric platelet
immunofluorescence crossmatch for predicting successful HLA-
matched platelet transfusions. Br J Haematol 92:1005-1010,
1996
79. Wu KK, Hoak JC, Koepke JA, et al: Selection of
compatible platelet donors: A prospective evaluation of three
cross-matching techniques. Transfusion 17:638-643, 1977
80. Rachel JM, Summers TC, Sinor LT, et al: Use of a solid
phase red blood cell adherence method for pretransfusion
platelet compatibility testing. Am J Clin Pathol 9():63-68, 1988
Ii I. Bock M, Heim MU, Schleich I, et al: Platelet crossmatch-
ing with Capture-P: Clinical relevance. Infusiontherapie 4:183-
185,1989
82. Kiefel V. Santoso S, Weisheit M, et al: Monoclonal
antibody-specific immobilization of platelet antigens (MAIPA):
A new tool for the identification of platelet-reactive antibodies.
Blood70:1722-1726,1987 . induced immune thrombocytopenias. Transfus Med Rev 7:275-
li3. Moore SB, DeGoey SR: Serum platelet antibody testing:
Evaluation of ~olid phase enzyme immunoassay and compari-
son with indirect immunofluorescence. Coagulation Transfus
Med 109:190-195, 1998
84. Brubaker DB, Romine M: Relationship of HLA and
platelet-reactive antibodies in alloimmunized patients refractory
to platelet therapy. Am J Hematol 26:341-352, 1987
85. Schnaidt M, Northoff H, Wernet D: Frequency and
specificity of platelet-specific alloantibodies in HLA immunized
haematologic oncologic patients. Transfus Med 6: 111-114, 1996
86. Wernet D. SchnaiJt M, Mayer G, et al: Serological
screening, using three different test systems of platelet trans-
fused patients with hematologic oncologic disorders. Vox Sang
65:108-113.1993
87. Freedman J, Hornstein A: Simple method fordifferentiat-
ing between HLA and platelet-specific antibodies by flow
cytometry. Am J HematoI38:314-320, 1991
88. Murphy MF, Waters AH: Immunologicat aspects of
platelet transfusions. Br J Haematol60:409-414, 1985
89. Kickier TS. Kennedy SD, Braine HG: Alloimmunization
to platelet-specific antigens in glycoproteins IIb-lIIa and Ib/IX
in multiply transfused thrombocytopenic patients. Transfusion
30:622-625,1990
90. Kurz M, Grinix H, Hocker p, et al: Specificities of
anti-platelets antibodies in multitransfused patients with hemato-
oncological disorders. Br J HaematoI95:564-569, 1996
91. Godeau B, Fromont P, SerorT, et al: Platelet alloimmuni-
zation after multiple transfusions: A prospective study of 50
patients. Br J Haematol 31 :395-400, 1992
92. Meenaghan M, Judson p, Yousaf K, et al: Antibodies to
platelet glycoprotein V in poly transfused patients with hemato-
logical disease. Vox Sang 64: 167-170, 1993
93. Kekomaki S, Volin L, Koistinen p, et al: Successful
treatment of platelet transfusion refractoriness: The use of
platelet transfusions matched for both human leukocyte antigens
(HLA) and human platelet alloantigens (HPA) in alloimmunized
patients with leukemia. Eur 1 Haematol 60: 112-118. 1998
94. Skogen B. Bellissimo DB, Hessner Ml, et al: Rapid
detennination of platelet alloantigen genotypes by polymerase
chain reaction using allele-specific primers. Transfusion 34:955-
960. 1994
95. Van tier Lelie 1, van der Plas-Van Dallen CM, von dem
Borne AEGKr: Platelet autoantibodies in septicaemia. Br 1
HematoI58:755-758, 1984
96. Hebart H, Einsele H, Klein R, et al: CMV infection after
allogeneic bone marrow transplantation is associated with the
occurrence of various autoantibodies and monoclonal gammapa-
thies. Br 1 HematoI95:138-144, 1996
97. Sivakumaran M, Hutchinson RM, Pringle H. et al:
Thrombocytopenia following autologous bone marrow transplan-
tation: Evidence for autoimmune aetiology and B-cell clonal
involvement. Bone Marrow Transplant 15:531-536, 1995
98. Bierling P. Cordennier C, Fremont P. et al: Acquired
autoimmune thrombocytopenia after allogeneic bone marrow
transplantation. Br 1 Haematol 59:643-646, 1985
99. Bussel IB, Pham LC, Aledort L, et al: Maintenance
treatment of adults with chronic refractoty immune thrombocy-
topenic purpura using repeated intravenous infusions of gamma-
globulin.Blood72:121-127,1988
100. McFarland IG: Laboratory investigation of drug-
287,1997
101. Kutti 1, Zaroulis CG, Safai-Kutti S, et al: Evidence that
circulating immune complexes remove transfused platelets from
the circulation. Am 1 Hematolll:255-259, 1981
102. Heal 1M. Cowles 1, Masel D, et al: Antibodies to plasma
proteins: An association with platelet transfusion refractoriness.
Br 1 Haematol 80:83-90. 1992
103. Funke I. Wiesneth M. Koerner K. et al: Autologous
platelet transfusion in alloimmunized patients with acute leuke-
mia. Ann Hematol71: 169-173,1995
104. Torretta L. Perotti C. Pedrazzoli P. et al: Autologous
platelet collection and storage to support thrombocytopenia in
patients undergoing high-dose chemotherapy and circulating
progenitor cell transplantation for high risk breast cancer. Vox
Sang 75:224-229. 1998
105. BartholomewlR. Salgia R, Bell WR: Control of bleed-
ing in patients with immune and non immune thrombocytopenia
with aminocaproic acid. Arch Intern Med 149:1959-1961.1989
106. Garewa!HS, Durie BGM: Anti-fibrinolytic therapy with
aminocaproic acid for the control of bleeding in thrombocytope-
nic patients. Scand 1 Haematol 35:497-500. 1985
107. Gardner FH. Helmer RE: Aminocaproic acid: Use in
control of hemolThage in patients with amegakaryocytic throm-
bocytopenia. lAMA 243:35-37, 1980
108. Gallardo RL, GardnerFH: Antifibrinolytic therapy for
bleeding control during remission induction for acute leukemia.
Blood 62:202A. 1983 (abstr)
109. Avvisati G, ten Cate lW, Buller HR, et al: Traxenamic
acid control of haemorrhage in acute promyelocytic leukaemia.
Lancet2:122-124,1989
110. Fehr 1. Hoffman V, Kappeler U: Transient reversal of
thrombocytopenia in idiopathic thrombocytopenic purpura by
high-dose intravenous gammaglobulin. N Engl 1 Med 306:1254-
1258.1982
III. Kekomaki R. Elfenbein G. Gardner R. et al: Improved
196
rc~ponse of patients refractory to random-donor platelet tran~fu-
,ions by intravenous gamma globulin. Am J Med 76: 199-203
1984
112. Bierling P. Cordonnier C, Rodet M. et al: High do~e
intravenous gammaglobulin and platelettr;lnsfusions in leukae-
mic HLA-immuni7.ed patients. Scand J Haematol 33:215-220.
19114
113. Junghans RP. Ahn YS: High-do~e intravenous gamma
globulin to suppres~ alloimmune de~truction of Jonor platelets.
Am J Med 76:204-208. 1984
t 14. Zeigler ZR. ShaJduck RK. Ro~enfeld CS. et al: Intrave-
nous gamma globulin decreases platelet associated IgG and
improves transfusion responses in platelet refractory _tales. Am
J Hematol38 15-23. 1991
115. Atrah HI. Sheehan T. Gribben J. et al: Improvement of
post platelet transfusion increments following intravenous immu-
noglobulin therapy for leukaemic HLA-immunized patients.
Scand J Haematol 36: 160-164, 1986
116 Becton OL. Kinney TR. Schaffee S. et al: High-Jose
intravenous immunoglobulin for severe platelet alloimmuniza-
lion. Pediatrics 74:1 120-1123. 1984
117. Zeigler ZR. Shadduck RK. Rosenfeld CS. ct al: High-
Jose intravenous gamma globulin improves responses to single-
donor platelets in patients refractory to platelet transfusion.
Blood 70:1433-1436. 1987
118. KicklerT. Braine HG. Piantadosi S. etal: A raodomized~
placebo-controlled trial of intravenous gammaglobulin in alloim-
munized thrombocytopenic patients. Blood 75:313-316. 1990
119. Kurtzberg J. Friedman HS. Kinney TR. et al: Treatment
of platelet alloimmunization with intravenous immunoglobulin:
Two case reports and review of the literature. Am J Med
83:30-33. 1987
120. Knupp C. Chamberlain JK. Raab SO: High-Jose intrave-
nous gamma globulin in alloimmunized platelet transfusion
recipients. Blood 65:776. 1985
121. Lee EJ. Norris O. Schiffer CA: Intravenous immune
globu~i!, for patients alloimmunized to random donor platelet
transfusion. Transfusion 27:245-247. 1987
122. Schiffer CA. Hogge DE. Aisner J. et al: High-dose
intravenous gammaglobulin in alloimmunized platelet transfu-
sion recipients. Blood 64:937-940,1984
123. Kekomaki R. Myllyla G: Effect of nonnal serum on the
binding of specific antibodies and platelet-unrelated immune
complexes to human platelets. Scand J Immunol 9:527-535.
1979
124. Bensinger WI. Buckner CD. Clift RA. et ;)1: Plasma
exchange for platelet alloimmunization. Transplantation 41 :602-
605.1986
125. Heddle NM. KJama L. Kelton JG. et al: The use of
anti-D to improve post-transfusion platelet response: A random-
ized trial. Br 1 Haematol 89: 163-168. 1995
126. Christie 01. Howe RB. Lennon SS. et al: Treatment of
refractoriness to platelet transfusion by protein A column
therapy. Transfusion 33:234-242. 1993
127. Lopez-Plaza I. Miller K. Leitman SF: Ineffectiveness of
protein A adsorption in the treatment of platelet refractoriness. 1
Clin Apheresis 7:33. 1992 (abstr)
128. Rock G: The application of protein A immunoadsorp-
DELAFLOR-WEISS AND MINTZ
tion to remove platelet alloantibodies. Transfusion 33: 192-194.
1993
129. Franchini E: Treatment of refractoriness to platelet
transfusion by protein A column therapy: The role of the IgG
subclasses. Transfusion 33:961-962.1993
130. Nagasawa T. Kim BK. Baldini MG: Temporary suppres-
sion of circulating antiplatelet alloantibc)dies by the massive
infusion of fresh. stored. or lyophilized platelets. Transfusion
18:429-435. 1978
131. Slichter SJ. Deeg HJ. Storb R: Prevention and reversal
of platelet alloimmunization with cyclo.sporin A. Blood 58:
186A. 1981 (abstr)
132. Yamamoto M. Ideguchi H. Nishimura J. et al: Treatment
of platelet-alloimmunization with cyclosporin A in a patient
with aplastic anemia. Am J Hematol 33:220-221. 1990
133. Tilly H. Azagury M. Bastit D. et al: Cyclosporin for
treatment of life-threatening alloimmunization. Am J Hematol
34:75-76.1990
134. Slichter SJ. Weiden PL. Kane Pl. et al: Approaches to
preventing or reversing platelet alloimmunization using animal
models. Transfusion 28: 103-108. 1988
13.1. Sabbe UM. ClassFHJ. Haak HL. et al: Anti-thymocyte
globulin (ATG) can eliminate platelet refractoriness. Blut 42:331-
335. 1981
136. Shanwell A. Sallander S. Olson I. et al: An alloimmu-
nized. thrombocytopenic patient successfully transfused with
acid-treated. random-donor platelets. Br J Haematol 79:462-
465.1991
137. Novotny VM. Huizinga TW. van Doom R. et al: HLA
class I-eluted platelets as an alternative to HLA-matched
platelets. Transfusion 36:438-444. 1996
138. Castro E. Mancunill J. Barea L. et al: Acid elution of
plateletsHLA-ciass I antigensin the treatmentof a refractory
patient.Br J HaematoIIOO:245-246. 1998
139. WongP. Hiruma K. Endoh N. et al: Vinblastine-loaded
platelet transfusion in an alloimmunized patient. Br J Haematol
65:380-381.1987
140. Ahn YS. Byrnes JJ. Harrington WJ. et al: The treatment
of idiopathic thrombocytopenia with vinblastine-loaded plate-
lets. N EngIJMed298:1101-1107. 1978
141. Kuter DJ. Cebon J. Harker LA. et al: Platelet growth
factors: Potential impact on transfusion medicine. Transfusion
39:321-332.1999
142. WhitsettCF: The role of hematopoietic growth factors
in transfusion medicine. in Mintz PD (ed): Transfusion Therapy:
Clinical Principles and Practice. Bethesda.MD. AABB Press.
1999. pp 399-427
143. Kaushansky K: Thrombopoietin. N Engl J Med 339:746-
754.1998
144. Price TH. Adamson JW: Hematopoietic growth factors
in transfusion medicine. in Ganser A. Hoelzer D (eds): Cyto-
kines in the Treatment of HematopoieticFailure.New York. NY.
Marcel Dekker. 1999. pp 327-357
145. McFarland J: Platelet immunology and alloimmuniza-
tion. in Rossi EC. Simon TL. Moss GS. et aI (eds): Baltimore.
MD. Williams & Wilkins. 1996. pp 231-244
146. SantosoS. Kiefel V: Human platelet-specificalloanti-
gens: Update. Vox San!! 74:249-253. 1998 (SUDDI2)