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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 92 No. 4 (August 15), 1998:
pp. 1448-1453
Platelet Transfusion: A Dose-Response Study
By
Françoise Norol,
Philippe Bierling,
Françoise Roudot-Thoraval,
Françoise Ferrer Le Coeur,
Claire Rieux,
Anne Lavaux,
Mathieu Kuentz, and
Najib Duedari
From ETS Sud-Est Francilien, Hôpital Henri Mondor, Creteil;
Unité Evaluation Etude, Hôpital Henri Mondor, Creteil;
Service d'Hématologie, Hôpital Henri Mondor, Creteil; and
Unité de Médecine Transfusionnelle et
d'Hémovigilance, Hôpital Henri Mondor, Creteil, France.
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ABSTRACT |
Early recommendations on prophylactic transfusion of
thrombocytopenic patients involved a standard platelet dose of about 0.5 × 1011/10 kg body weight. Given the lack of data
supporting this dose, we prospectively studied the dose response to
platelet transfusions in adults and children with hematologic
malignancies. Each patient received, in similar clinical conditions, a
medium, high, and very high dose of fresh (< 24 hours old)
ABO-compatible platelets, in the form of apheresis platelet
concentrates (APC). For the adults, the medium dose was defined as APC
containing between 4 and 6 × 1011 platelets, the high
dose between 6 and 8 × 1011, and the very high dose > 8 × 1011; for the children, the three doses corresponded to
2 to 4, 4 to 6, and > 6 × 1011 platelets. The end
points were the platelet increment, platelet recovery, and the
transfusion interval, and the results were compared with a paired
t-test. Sixty-nine adults and 13 children could be assessed. Recoveries
in the adults were similar with the three doses (from 28% to 30%),
but the high and very high doses led to a significantly better platelet
increment (52 and 61 × 109/L, respectively) than the
medium dose (33 × 109/L, P < .01). The main
difference was in the transfusion interval, which increased with the
dose of platelets transfused, from 2.6 days with the medium dose to 3.3 and 4.1 days with the high and very high doses, respectively (P < .01). The positive effect of the high dose was observed regardless
of pretransfusional clinical status, but was more marked in patients
with no clinical factors known to impair platelet recovery. In these
patients, a platelet dose of 0.07 × 1011 per kg of body
weight led to a transfusion interval of more than 2 days in 95% of
cases. In patients with clinical factors favoring platelet consumption,
the proportion of transfusions yielding an optimal platelet increment
and transfusion interval increased with the dose of platelets.
The platelet dose-effect was also significant in the children, in
whom the high and very high doses led to 1.5-fold to twofold higher
posttransfusion platelet counts and transfusion intervals. We conclude
that transfusion of high platelet doses can reduce the number of
platelet concentrates required by thrombocytopenic patients and
significantly reduce donor exposure.
© 1998 by The American Society of Hematology.
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INTRODUCTION |
PLATELET SUPPORT ENABLES aggressive
myelosuppressive radiation therapy and chemotherapy to be administered
safely.1 Despite the recent cloning of the gene encoding
thrombopoietin, the major growth factor for the megakaryocytopoietic
lineage, and trials of its use in vivo,2 platelet
transfusions will remain vital for many years to support
thrombocytopenic patients. Platelet transfusion practices have been the
subject of numerous editorials, guidelines, and consensus
conferences.3-7 Many reports have either supported or
argued against the use of therapeutic versus prophylactic platelet
transfusion8,9 and discussed the advantages of apheresis platelet concentrates (APC) relative to platelet concentrates prepared
from whole blood, as well as the threshold platelet count for
prophylactic transfusion10 and the influence of
compatibility.11 Most of these reports also discussed the
cost/efficacy and risk/benefit ratios of various transfusion
strategies. In contrast, very few investigators have analyzed platelet
dose requirements in thrombocytopenic patients. Based on the expected
posttransfusion recovery and life span of transfused platelets, a dose
of around 0.5 × 1011 platelets/10 kg body weight has
long been recommended12 and has been the rule in many
institutions. Many years ago we adopted a policy based on the
collection of APC containing high doses of apheresis platelets and
their transfusion undivided. This resulted in the transfusion of
platelet doses higher than those usually given. As expected, we
obtained higher posttransfusion platelet counts, but also a longer
transfusion interval. To validate this high-dose strategy, we conducted
a prospective study comparing three platelet doses in thrombocytopenic
patients treated for hematologic malignancies and then attempted to
define the required platelet dose in these patients.
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MATERIALS AND METHODS |
Patients
Consecutive patients managed in our institution from December 1992 to
October 1995 and likely to require several platelet transfusions after
induction chemotherapy for acute myeloid leukemia (AML) or conditioning
for allogenic bone marrow transplantation (BMT) were included in the
study. Adult and children (defined as patients under 15 years of age
and weighing less than 50 kg) were analyzed separately.
Pretransfusion Evaluation
Age, sex, and diagnosis were recorded before transfusion.
Pretransfusion factors likely to affect platelet recovery were also documented and included temperature, spleen size, intravenous administration of amphotericin B on the day of the transfusion, and
graft-versus-host disease (GVHD) or veno-occlusive disease (VOD) in
patients undergoing allogenic BMT. Patients were deemed infected in
case of microbiologically documented infection or persistent
temperature above 38°C during the transfusion protocol. VOD was
diagnosed according to Jones et al.13 Acute GVHD was diagnosed and graded on the basis of the usual criteria.14
Anti-HLA antibodies were detected using the standard NIH
microlymphocytotoxicity test (LCT) with a panel of samples from 30 selected donors carrying the most frequent HLA antigens. Patients were
screened at the time of induction and then once a week while receiving
platelet transfusions. In case of platelet refractoriness and negative
LCT, anti-HLA antibodies were tested for by using an
antiglobulin-augmented lymphocytotoxicity assay15 and a
platelet immunofluorescence test (PIFT) was performed.
Platelet Transfusion Protocol
Patients received single-donor APC obtained on one of three cell
separators [Spectra (Cobe), AS104
(Fresenius), and Vivacell (Dideco)]. All
platelets transfused were fresh (less than 24 hours old) and
ABO-compatible. APC were leukocyte-depleted to reach a target residual
leukocyte count below 1 × 106. Leukocytes were
automatically depleted during the collection procedure on the Spectra
(Cobe) and AS 104 (Fresenius) cell separators; APC collected on the
Vivacell (Dideco) cell separator were leukocyte-depleted by
centrifugation and filtration as previously described.16 The number of platelets collected was measured in each APC (Model JT,
Coulter Electronic), after leukocyte depletion.
Patients were transfused prophylactically whenever their platelet
counts fell to between 10 and 20 × 109/L. All fresh
APC were received in the afternoon, after testing; thus, taking into
account the fall in platelet count during the day and the rate of
platelet consumption in the previous days, the platelet count required
in the morning to plan a transfusion was approximately between 15 and
25 × 109/L. Three different platelet doses were
transfused to each patient; in adults, the medium dose was defined as
transfusion of APC containing between 4 and 6 × 1011
platelets, the high dose between 6 and 8 × 1011, and
the very high dose above 8 × 1011. In children, the
medium, high, and very high doses corresponded to transfusion of
respectively 2 to 4, 4 to 6, and > 6 × 1011 platelets. The doses were defined relative to the
number of platelets contained in the APC rather than the patient's
body weight, as we usually transfuse the highest available dose,
without adapting it precisely to the patient's weight; however, the
doses received per kg of body weight were retrospectively calculated
for each transfusion. The sequence of administration of the different
doses depended solely on APC availability, as the other contraints of the transfusion protocol did not permit randomization and as each patient serves as their own control.
Patients were classified as having or not having clinical factors known
to impair platelet recovery; in patients with such factors, clinical
status had to remain unchanged during the transfusion protocol.
Patients previously alloimmunized or who developed anti-HLA
and/or antiplatelet antibodies during the study, patients
submitted to particular platelet transfusion policies (eg, patients who received heparin or antithrombotic drugs), patients with a change in
clinical status during the transfusion protocol, and patients who did
not receive the three doses as planned were excluded from the analysis.
In Vivo Evaluation
The following parameters were evaluated: (1) the platelet increment,
ie, the difference between the pretransfusion platelet count and that
measured 12 hours after transfusion (both measured in the morning); (2)
platelet recovery, calculated according to the following formula:
Posttransfusion  Pretransfusion Platelet Count (× 109/L) × Patient Total Blood Volume (L) × 100 Number of Platelets Transfused (× 1011); (3) the
transfusion interval, defined as the time between the transfusion
analyzed and the next required transfusion, ie, when the platelet count
fell to 15 to 25 × 109/L. The transfusion interval
was measured in whole days; and (4) the daily platelet requirement,
calculated as the fall in the number of platelets between 2 consecutive
days.
Furthermore, in view of these results, we attempted to determine the
optimal platelet dose per kg of body weight in adult patients. This
dose was arbitrarily defined as the dose leading to a platelet
increment of at least 50 × 109/L and to a transfusion
interval of more than 2 days in patients without factors favoring
platelet consumption. In patients with such factors, the required
platelet increment and transfusion interval were at least 20 × 109/L and 2 days, respectively.
Statistical Analysis
Results are expressed as means ± standard deviation (SD). As each
patient received all three doses of platelets, we compared the platelet
increment, platelet recovery, and the transfusion interval by using a
paired t-test (the results of the transfusion with the medium
dose was compared with those of the high dose, and results of the high
dose with those of the very high dose). The difference was considered
significant if P < .05.
The relationship between the doses received per kg of body weight and
the platelet increment and the transfusion interval were studied
separately in patients with and without clinical factors favoring
platelet consumption. For cut-off of platelet doses ranging from 0.06 to 0.14/kg, we calculated the proportion of transfusions responsible
for the platelet increment and the transfusion interval as defined
above. Statistical analysis was performed using BMDP
statistical software.
| |
RESULTS |
Evaluation of the Dose-Effect of Platelet Transfusions
Adults.
A total of 196 adults were enrolled in the study, but only 69 could be
evaluated: 41 patients with anti-HLA and/or antiplatelet antibodies and 21 patients who required special transfusion policies were excluded, as were 32 patients who failed to receive the correct dose of platelets at the time planned, and 33 patients whose clinical status changed during the protocol. The 69 assessable patients had a
mean age of 38 (range, 17 to 58) and comprised 37 men and 32 women; 27 were treated for AML and 42 had undergone allogeneic BMT. Their mean
weight was 64 kg (range, 49 to 110 kg). In the medium, high, and very
high dose groups, the mean numbers of transfused platelets were 4.6, 6.5, and 8.9 × 1011, respectively, corresponding to a
mean number of platelets per kg body weight of 0.08, 0.10, and 0.14 × 1011. As shown in Table 1, mean
platelet recoveries were similar in the three doses groups at between
28% and 30%. The posttransfusion platelet increment increased
significantly with the number of platelets transfused (P < .01): the mean pretransfusion platelet counts were 19, 22, and
21 × 109/L in the three dose groups, and
the mean posttransfusion counts were 52, 73, and 83 × 109/L, respectively. In parallel, we observed a
significantly longer interval between transfusions after the high dose
(3.3 days) and very high dose (4.1 days) compared with the medium dose
(2.6 days) (P < .01).
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Table 1.
Prospective Comparison of the Platelet Increment,
Platelet Recovery, and Transfusion Interval After Medium, High, and
Very High Doses of Platelets in 69 Adults
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To determine if factors known to affect platelet recovery could mask
the dose-response, patients were distinguished according to their
clinical status. As shown in Fig 1, the
dose-response effect was more evident in the 29 patients without
clinical factors likely to affect platelet recovery: the interval
between transfusions reached an average of 2.9 and 3.9 days after
transfusion of the medium and high doses (P < .01) and
increased to 4.5 days after transfusion of the very high dose
(P < .05). In the remaining 40 patients with clinical factors
potentially influencing platelet consumption, the difference remained
significant between the medium and high doses, with a mean platelet
increment of 22 and 31 109/L and a mean interval between
transfusion of 1.4 and 2.1 days, respectively (P < .05), but there was no further significant improvement with the very
high dose.
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| Fig 1.
Comparison of the platelet increment and transfusion
interval after medium, high, and very high doses of platelets according to pretransfusion clinical status. * Significant difference between medium and high dose and high dose and very high dose. Comparisons were
made using a paired t-test. ( ) Clinical factors of platelet consumption. ( ) No clinical factors of platelet consumption.
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In the group of patients without clinical factors likely to affect
platelet recovery, we calculated the fall in the platelet count from
day to day after the three doses of platelets
(Fig 2). We observed that the rate of fall
was similar after transfusion of the medium, high, and very high doses,
with a mean daily requirement of respectively 18, 19, and 20 x
109/L (range, 11 to 44 × 109/L); it was
not significantly different when platelet counts were from 50 to 100 × 109/L (mean, 23 × 109/L) in
comparison with counts <50 × 109/L (mean, 17 × 109/L).
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| Fig 2.
Evaluation of the mean daily fall of the platelet count
after medium, high, and very high doses of platelets in patients
without clinical factors favoring platelet consumption. * In seven
patients, the platelet counts on days 3, 4, and 5 after medium, high,
and very high doses were not relevant because the patients were
retransfused on the day before; so in these patients, the counts on
these days were estimated and extrapolated from the fall in the
platelet count in the previous days.
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Children.
Thirty-three children undergoing allogeneic BMT were enrolled. Eleven
were excluded because they failed to receive the correct dose at the
planned time, and nine because of a change in clinical status during
the protocol. Thirteen children were thus assessable. Their mean age
was 11 years (range, 7 to 14) and their mean weight 34 kg (range, 24 to
44).
The mean absolute numbers of platelets transfused were 3.3, 4.9, and 7 × 1011, respectively, in the medium, high, and very
high dose groups, corresponding to a mean number of platelets per kg of
body weight of 0.10, 0.15, and 0.22 × 1011,
respectively. Mean recovery was similar to that obtained in the adults
(28% to 32%), but some low-weight, clinically stable children showed
recovery of the majority of platelets transfused (up to 75%). As shown
in Table 2, the dose effect was very
pronounced in the children. The posttransfusion platelet increment
increased with the dose of platelets transfused, from 37 × 109/L with the medium dose to 64 × 109/L
with the high dose (P < .05) and 98 × 109/L with the very high dose (P < .01), and the
interval before the next transfusion also increased significantly from
2.5 days to 3.4 and 4.4 days.
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Table 2.
Prospective Comparison of the Platelet Increment,
Platelet Recovery and Transfusion Interval After Medium, High, and
Very High Doses of Platelets in 13 Children
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Definition of the Optimal Platelet Dose per kg of Body Weight in
Adult Patients
For each transfusion, the dose transfused per kg of body weight was
calculated. We determine for doses ranging from 0.06 to 0.14 × 1011 per kg, the percent of transfusions leading to the
required platelet increment and transfusion interval
(Fig 3). In patients without clinical
factors favoring platelet consumption, a threshold seemed to be
achieved with a dose of 0.07 × 1011 per kg of body
weight, for which more than 95% of transfusions yielded a transfusion
interval of more than 2 days. At this dose, 62% of the patients
achieved the required increment of at least 50 × 109/L platelets. In contrast, in patients with clinical
factors known to affect platelet recovery, the more platelets we
transfused, the higher the proportion of transfusions leading to a
platelet increment  20 × 109/L (from 72% to 100%
for doses from 0.06 to 0.14/kg body weight). In parallel, the percent
of transfusions leading to the required transfusion interval increased
from 49% to 89%. With a platelet dose of 0.10 × 1011/kg, the required interval was obtained in 70% of
cases.
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| Fig 3.
Definition of an optimal dose of platelets per kg body
weight according to pretransfusion clinical status. For cut-off of doses ranging from 0.06 to 0.14 × 1011 per kg body weight
in adult patients, the percent of transfusions leading to a required
platelet increment and transfusion interval was determined. (A)
Required platelet increment and transfusion interval were arbitrarily
defined as increment 50 × 109/L and interval > 2 days in patients without clinical factors known to affect platelet
consumption. (B) In patients with factors favoring platelet
consumption, required platelet increment and interval were at 20 × 109/L and 2 days, respectively.
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DISCUSSION |
Platelet recovery is usually about 60% of the number of autologous
platelets transfused, but may be as low as 20% to 40% after homologous transfusion in patients with factors affecting platelet recovery.17 Given the mean number of platelets in 1 U of
blood (around 0.5 × 1011), the calculated platelet
increment per platelet unit transfused is of the order of 12 to
25 × 109. Morrison12 suggested
that 5 U of platelets were needed for an adult. This empiric figure has
rarely been challenged. The NIH consensus conference suggested 1 U/10
kg body weight or an APC per transfusion3 and the British
Committee for Standards in Hematology7 proposed a formula
taking into account the desired platelet increment, the patient's
blood volume, and a recovery factor, resulting in recommended platelet
doses of approximately 3 × 1011 for adults.
Very few teams have investigated the platelet dose-response. In 1983, Roy et al18 compared two platelet doses in children who
received a mean of 2.6 and 3.4 U per transfusion. The average 1-hour
increments were very small with both doses (18 and 25 × 109/L) and the incidence of bleeding was similar; the lower
dose was thus recommended. More recently, Andreu19 reviewed
results obtained with four doses of platelets in patients with AML and reported a significantly better response to the higher doses.
We report the first prospective comparison of three different doses of
platelets. We attempted to eliminate all factors other than the number
of platelets transfused that could affect efficiency: platelets were
fresh, ABO-compatible, and administered in similar clinical conditions
to the same patient. APC were routinely leukocyte-depleted before
storage, as the quality of stored platelets can be improved by reducing
the number of contaminating leukocytes. Platelets were irradiated, if
needed, just before transfusion. In these conditions, we observed
beneficial effects of high platelet doses not only in terms of higher
posttransfusion platelet counts, but also longer intervals between
transfusions. The larger platelet increments obtained with higher
platelet doses increased the transfusion interval from 2 to 4 days.
The longer platelet life span after high doses could be explained by
previously reported platelet kinetics in patients with bone marrow
hypoplasia. Hanson and Slichter20 forwarded the concept of
a given platelet requirement to support vascular integrity, random
platelet utilization averaging 18% of overall platelet turnover in
normal individuals; however, this proportion increased rapidly as the
platelet count fell below 100 × 109/L.Using
51Cr-labeled platelets, they found that autologous and
homologous platelet survival correlated directly with the platelet
count, with a reduction in the platelet life span to 3 to 4 days when the count fell below 50 × 109/L. This agrees with our
observation, in patients without clinical factors favoring platelet
consumption, of a mean regular daily platelet requirement of 19 × 109/L (corresponding to a mean of 31% of circulating
platelets). Our study thus supports the concept that after the number
of platelets needed for maintenance has been reached, the remaining
platelets will continue to circulate, and that the higher the count,
the longer the platelets will circulate. This could also account for the weaker dose-effect relationship in patients with clinical factors
potentially inducing platelet destruction, independantly of platelet
numbers and random utilization.
The inclusion criteria were very restrictive as regards the
characteristics of the APC transfused and allowed for no change in
clinical status; this led to the exclusion of a large number of
patients. We therefore confirmed our results by a retrospective analysis of all the transfusions received by the cohort of adult patients included in this prospective study; we found a posttransfusion platelet increment of 31, 52, and 64 × 109/L,
respectively after transfusion of the medium, high, and very high
platelets doses; in addition, transfusion intervals increased with the
dose of platelets transfused, from 2.4 to 3.1 and 4 days, respectively, showing that the beneficial effects of high doses are
also observed in routine use whatever the characteristics of APC
trasfused (data not shown). Interestingly, our results are very close
to those obtained by Andreu19 in a retrospective study of
AML patients.
The dose-effect relationship was much more marked in children, for whom
lower doses are usually recommended.21 If we compare the
same dose of 4 to 6 × 1011 in adults and children,
there was a 1.5-fold to twofold higher platelet increment and
transfusion interval in the latter. As in adults, the results of the
prospective study were confirmed by the retrospective analysis of our
transfusion practice. These excellent results explain why, in our
experience, some children underwent BMT with platelets from only five
donors.
Having demonstrated the dose-effect of platelet transfusions, it may be
helpful to determine an "optimal dose" of platelets. Our study
suggests that the optimal dose may be 0.07 × 1011
platelets/kg for patients without clinical factors favoring platelet consumption (1.5 U/10 kg body weight in patients receiving random platelet concentrates). In patients with clinical factors known to
affect platelet comsumption, the more platelets we give, the larger the
proportion of patients achieving an optimal platelet increment and
transfusion interval.
We conclude that high doses of APC can significantly reduce the need
for transfusion support in thrombocytopenic patients, and thereby
reduce donor exposure. This transfusion policy is practical, as
concentrates containing more than 5 to 6 × 1011
platelets can routinely be obtained with new apheresis devices. In our
experience and that of others,22 such doses can be obtained in more than 60% of apheresis procedures. Furthermore, initial studies suggest that very high platelet yields (>10 × 1011) can be obtained after administration of
thrombopoietin to platelet donors.23 We therefore recommend
that APC should not be split, but transfused entirely to increase the
transfusion interval and reduce donor exposure.
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FOOTNOTES |
Submitted September 9, 1997;
accepted April 10, 1998.
Address reprint requests to Françoise Norol, MD,
Etablissement de Transfusion Sanguine, Hôpital Henri Mondor, 51, Av du Maréchal de Lattre de Tassigny, 94000 Creteil, France.
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" is accordance with 18 U.S.C. section 1734 solely to indicate this fact.
| |
ACKNOWLEDGMENT |
We are grateful to G. Van Waeg for editing of the manuscript and B. Raisonnier for data collection.
| |
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M. A. Blajchman, S. J. Slichter, N. M. Heddle, and M. F. Murphy
New Strategies for the Optimal Use of Platelet Transfusions
Hematology,
January 1, 2008;
2008(1):
198 - 204.
[Abstract]
[Full Text]
[PDF]
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R. M. Kaufman
Platelets: Testing, Dosing and the Storage Lesion--Recent Advances
Hematology,
January 1, 2006;
2006(1):
492 - 496.
[Abstract]
[Full Text]
[PDF]
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A. Greinacher
The more the better?
Blood,
January 15, 2005;
105(2):
442 - 442.
[Full Text]
[PDF]
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L. Sensebe, B. Giraudeau, L. Bardiaux, E. Deconinck, A. Schmidt, M.-L. Bidet, C. LeNiger, E. Hardy, C. Babault, and D. Senecal
The efficiency of transfusing high doses of platelets in hematologic patients with thrombocytopenia: results of a prospective, randomized, open, blinded end point (PROBE) study
Blood,
January 15, 2005;
105(2):
862 - 864.
[Abstract]
[Full Text]
[PDF]
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D. van Rhenen, H. Gulliksson, J.-P. Cazenave, D. Pamphilon, P. Ljungman, H. Kluter, H. Vermeij, M. Kappers-Klunne, G. de Greef, M. Laforet, et al.
Transfusion of pooled buffy coat platelet components prepared with photochemical pathogen inactivation treatment: the euroSPRITE trial
Blood,
March 15, 2003;
101(6):
2426 - 2433.
[Abstract]
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H. Wandt, G. Ehninger, and W. M. Gallmeier
New Strategies for Prophylactic Platelet Transfusion in Patients with Hematologic Diseases
Oncologist,
October 1, 2001;
6(5):
446 - 450.
[Abstract]
[Full Text]
[PDF]
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L. T. Goodnough, D. J. Kuter, J. McCullough, S. J. Slichter, J. DiPersio, J. Romo, R. Peterson, K. J. Smith, T. Raife, D. Tomita, et al.
Prophylactic platelet transfusions from healthy apheresis platelet donors undergoing treatment with thrombopoietin
Blood,
September 1, 2001;
98(5):
1346 - 1351.
[Abstract]
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Abstract
Introduction
Abstract