Blood, 15 May 2002, Vol. 99, No. 10, pp. 3867-3868
CORRESPONDENCE
To the editor:
Thrombopoietin in healthy donors
With concern we would like to react to the two Amgen-supported
studies, presented in the September 1, 2001, issue of this journal, in
which platelets harvested from thrombopoietin (TPO)-treated volunteer donors are used for prophylactic platelet support of chemotherapy-induced thrombocytopenia.1,2 We would have
welcomed an accompanying editorial comment considering the ethics of
TPO prescription in unrelated volunteer donors. Kuter et
al1 mention the perception that single donor (SD)
platelets are a better product compared to pooled random-donor
concentrates as a rationale for the use of TPO for volunteer donors.
There are, however, no data supporting the presumptions mentioned: the
reduced exposure to different donors is a theoretical risk and not
based on an increased incidence of transmitted infections; the risk of
bacterial contamination is indeed increased in pooled platelets but
influenced by production center and prevented by bacterial monitoring;
the lower occurrence of febrile reactions to SD platelets is based on
studies performed prior to leukoreduction and not confirmed by studies
using leukoreduced platelets3; and the reduction in
HLA-alloimmunization is based on a small and outdated study using
non-leukocyte-depleted transfusions in which HLA-immunization was
postponed (instead of reduced).4 It is curious that
the authors do not quote a more recent extensive United States trial
not confirming the advantage of SD platelets to prevent
HLA-immunization and platelet refractoriness.5
In the article by Goodnough et al2 it is concluded that the
costs of apheresis may be reduced by splitting apheresis products with
a high yield into 2 to 6 transfusion products. In the context of costs
we would like to stress that in most parts of the world random
pooled-platelet concentrates are still standard issue because of cost
and existing infrastructures. Thrombapheresis is a bigger burden for
the donor when compared to whole-blood donation because it is related
to an increased risk for adverse events combined with longer duration
of the procedure. Moreover, insufficient systematic follow-up studies
have been performed to demonstrate that repeated exposure to
extracorporeal circuit is inert.6,7 The fact that
platelets are a perishable commodity will not be changed by
administering TPO to healthy donors to increase the platelet yields of
apheresis platelets, and thus we cannot follow this argument put
forward by Kuter et al. The comparison with the use of other
hematopoietic growth factors in healthy donors does not stand. Only
recently granulocyte colony-stimulating factor (G-CSF) was accepted for
use in healthy volunteer donors in Europe because of long-term
experience in both patients and related healthy donors. We do not see
any need for erythropoietin (Epo) administration to healthy volunteer
donors outside the setting of autologous transfusions. In the case of
both G-CSF and Epo, autoantibody induction has been proven to be
extremely rare. The goal of blood transfusion service is to provide
optimal safe blood products but not at the cost of increased risk to
the donor. The proposition of administration of an unwarranted drug
with unknown long-term side effects and potential "auto"-antibody
inducing capacity upon multiple administrations to healthy unrelated
volunteer donors should be withheld. Even if nonimmunogenic TPO will be
developed, the blood transfusion services should refrain from
administering this drug to volunteer donors until long-term experience
in patients and possibly (as suggested by Kuter et al) in
HLA-compatible related donors, in the case of HLA sensitization in
patients with an extremely rare HLA phenotype, is accumulated as was
the case with G-CSF.
Robert M. Verdijk
Correspondence: Robert M. Verdijk, Dept of Immunohematology and
Blood Transfusion, E3-Q, Leiden University Medical Center, PO Box 9600, 2300 RC, Leiden, The Netherlands; e-mail: rmverdijk{at}lumc.nl
References
1.
Kuter DJ, Goodnough LT, Romo J, et al.
Thrombopoietin therapy increases platelet yields in healthy platelet donors.
Blood.
2001;98:1339-1345[Abstract/Free Full Text].
2.
Goodnough LT, Kuter DJ, McCullough J, et al.
Prophylactic platelet transfusions from healthy apheresis platelet donors undergoing treatment with thrombopoietin.
Blood.
2001;98:1346-1351[Abstract/Free Full Text].
3.
Anderson NA, Gray S, Copplestone JA, et al.
A prospective randomized study of three types of platelet concentrates in patients with haematological malignancy: corrected platelet count increments and frequency of nonhaemolytic febrile transfusion reactions.
Transfus Med.
1997;7:33-39[CrossRef][Medline]
[Order article via Infotrieve].
4.
Gmur J, Von Felten A, Osterwalder B, et al.
Delayed alloimmunization using random single donor platelet transfusions: a prospective study in thrombocytopenic patients with acute leukemia.
Blood.
1983;62:473-479[Abstract/Free Full Text].
5.
Leukocyte reduction and ultraviolet B irradiation of platelets to prevent alloimmunization and refractoriness to platelet transfusions: the Trial to Reduce Alloimmunization to Platelets Study Group.
N Engl J Med.
1997;337:1861-1869[Abstract/Free Full Text].
6.
Karadogan I, Ozdogan M, Undar L.
Single automated donor plateletpheresis increases the plasma level of proinflammatory cytokine tumor necrosis factor-alpha which does not associate with endothelial release markers von Willebrand factor and fibronectin.
Transfus Sci.
2000;23:171-175[CrossRef][Medline]
[Order article via Infotrieve].
7.
Stohlawetz P, Stiegler G, Jilma B, Dettke M, Hocker P, Panzer S.
Measurement of the levels of reticulated platelets after plateletpheresis to monitor activity of thrombopoiesis.
Transfusion.
1998;38:454-458[CrossRef][Medline]
[Order article via Infotrieve].
Response:
Thrombopoietin therapy increases platelet yields in healthy
platelet donors
We agree with Verdijk that apheresis platelets have not been
definitively shown to be superior to pooled random-donor platelets and
are therefore not the standard of care in parts of the world. However,
apheresis platelets do represent about two thirds of the product that
is transfused in the United States,1 and this may increase
if viral inactivation procedures become widely accepted. Whether or not
this practice is appropriate was not the subject of our studies nor one
we sought to defend. Extensive efforts have been undertaken to increase
the yield of apheresis platelet product,2 and our studies
have demonstrated that a recombinant thrombopoietin might also be of
benefit.3,4
Exposing healthy donors to hematopoietic growth factors has long
been controversial, as has the concept of exposing donors to apheresis
devices themselves. Donors have recently been asked to increase their
donation of a variety of apheresis products (platelets, granulocytes,
red cells, plasma) and peripheral blood stem cells. Shortages of
apheresis platelets are not uncommon. To ask whether thrombopoietin
(TPO) might join granulocyte colony-stimulating factor (G-CSF) and
erythropoietin (EPO) as mobilizing agents was a valid clinical research
issue that was approved by the appropriate institutional review boards
and regulatory agencies, along with meticulous monitoring by the
investigators to insure the safety of the donors. There were no adverse
consequences to any of the donors.
In questioning the "ethics of TPO prescription in unrelated
volunteer donors," Verdijk should distinguish between a preliminary phase 1/2 clinical trial that we performed and its widespread use in
the blood supply industry. Upon completion of our trial and before
embarking on further platelet donor studies, a very large safety study
of paid healthy volunteers was conducted, and it was here that some
were found to develop autoantibodies to TPO after multiple
injections.5 This finding resulted in the discontinuation of our studies of platelet donors with this recombinant thrombopoietin.
We believe that we have established the simple principle that
thrombopoietin therapy can increase platelet apheresis yields. If
apheresis platelet collection continues to be an important source of
platelets and if a "nonimmunogenic" thrombopoietin is developed,
further studies would be warranted to determine whether this approach
would be of widespread use to increase the supply of platelets. A
program involving HLA-compatible related donors would be an ideal area
for investigation.
David J. Kuter and Lawrence T. Goodnough
Correspondence: David J. Kuter, Hematology/Oncology Unit,
Massachusetts General Hospital, 100 Blossom St, Cox 640, Boston, MA
02114; e-mail: kuter.david{at}mgh.harvard.edu
References
1.
National Blood Resource Center.
Comprehensive report on blood collection and transfusion in the United States in 1999. Bethesda, MD: American Association of Blood Banks; 2001.
2.
Goodnough LT.
Platelet transfusion therapy.
J Clin Apheresis.
2001;16:43-48[CrossRef][Medline]
[Order article via Infotrieve].
3.
Kuter DJ, Goodnough LT, Romo J, et al.
Thrombopoietin therapy increases platelet yields in healthy platelet donors.
Blood.
2001;98:1339-1345.
4.
Goodnough LT, Kuter DJ, McCullough J, et al.
Prophylactic platelet transfusions from healthy apheresis platelet donors undergoing treatment with thrombopoietin.
Blood.
2001;98:1346-1351.
5.
Li J, Yang C, Xia Y, et al.
Thrombocytopenia caused by the development of antibodies to thrombopoietin.
Blood.
2001;98:3241-3248[Abstract/Free Full Text].
