Blood, 1 March 2002, Vol. 99, No. 5, pp. 1878-1878
CORRESPONDENCE
To the editor:
Management of anticoagulation-associated toxicity during
large-volume leukapheresis of peripheral blood stem cell donors
We write to direct attention to the management of
anticoagulation-associated toxicity during large-volume leukapheresis
(LVL), a potential source of donor morbidity as described in a recent comprehensive report comparing experiences during marrow and peripheral blood stem cell (PBSC) donation.1
PBSCs are collected from donors during LVL by the process of
apheresis.2 During apheresis, anticoagulation is necessary to prevent coagulation and clumping of the collected component. The
most frequently utilized apheresis anticoagulant is citrate, which is
returned to the donor at a rate that depends on the whole blood
processing rate and the ratio of citrate anticoagulant to whole
blood.3 The use of citrate-mediated anticoagulation in the apheresis device does not result in systemic anticoagulation due to
metabolism and redistribution of citrate in the donor
circulation.3,4 Modest but significant elevations in serum
citrate levels, however, frequently occur in apheresis donors, who may
experience symptoms associated with decreased ionized calcium levels
resulting from formation of calcium-citrate complexes.3
The establishment of standard citrate administration rates for
plateletpheresis has resulted in procedures that are generally well
tolerated.3,5 But during much longer LVL procedures, blood
citrate accumulation may eventually outpace metabolism when citrate is
administered at rates used during plateletpheresis, resulting in
markedly decreased ionized calcium levels and severe donor
symptoms.6
There is no single standard method to reduce citrate toxicity during
LVL. One approach to this problem is to combine heparin administration
with a reduced citrate infusion rate, thus limiting the amount of
citrate returned to the donor while providing anticoagulation during
apheresis. But heparin administration may also be associated with
toxicity,4 and the single serious adverse event that
occurred in a donor during PBSC collection in the study by Rowley et al was the development of a large painful hematoma associated with use of
a femoral catheter for central venous access and heparin administration.1 Whether this adverse event was caused
solely by the use of heparin cannot be established, but administration of 1000 to 2000 units of heparin per hour over several hours of LVL
could produce systemic anticoagulation of a degree that might warrant
delay in removal of a central venous catheter or require additional
monitoring.4,7
An alternative method to reduce the toxicity associated with
administration of large quantities of citrate during LVL is to balance
the citrate required for anticoagulation in the apheresis device with a
controlled infusion of calcium to the donor.6,8,9 When
dosed according to the citrate administration rate and infused with
citrated blood immediately prior to entering the donor circulation, calcium infusions safely and reliably attenuate the decline that normally occurs in donor ionized calcium levels, since the fraction of
total calcium present in ionized form exhibits a tight, linear relationship with blood citrate concentration.5,6 The
marked elevations in parathyroid hormone and decreases in potassium and phosphate that normally occur due to unopposed citrate administration during LVL are also ameliorated by calcium
supplementation.6 When citrate and calcium administration
are linked in this fashion, we have noted no significant
adverse effects related to calcium prophylaxis in more than 400 leukapheresis procedures of 12 to 25 liters processed, lasting 3 to 5 hours and performed at citrate infusion rates of 2.5 mg/kg/min and
higher in children and adults. When utilizing calcium prophylaxis as an
antidote to citrate toxicity during LVL, heparin anticoagulation is not
required and LVL may be comfortably performed, with9 or
without concomitant laboratory testing.6,8
Charles D. Bolan and Susan F. Leitman
Correspondence: Charles D. Bolan, National Institutes of Health,
Department of Transfusion Medicine, Buildling 10, Room 1C711, 10 Center
Drive, MSC 1184, Bethesda, MD 20892-1184
References
1.
Rowley SD, Donaldson G, Lilleby K, Bensinger WI, Applebaum FR.
Experiences of donors enrolled in a randomized study of allogeneic bone marrow or peripheral blood stem cell transplantation.
Blood.
2001;97:2541-2548[Abstract/Free Full Text].
2.
Corbin F, Cullis HM, Freireich EJ, et al.
Development of apheresis instrumentation. In:
McLeod BC,Price TH,Drew MJ, eds.
Apheresis: Principles and Practice. Bethesda, MD: AABB Press; 1997:1-26.
3.
Hester JP, McCullough J, Mishler JM, Szymanski IO.
Dosage regimens for citrate anticoagulants.
J Clin Apheresis.
1983;1:149-157[Medline]
[Order article via Infotrieve].
4.
Simon TL, McLeod BC.
Physiology of apheresis. In:
McLeod BC,Price TH,Drew MJ, eds.
Apheresis: Principles and Practice. Bethesda, MD: AABB Press; 1997:67-84.
5.
Bolan CD, Greer SE, Cecco SA, Oblitas JM, Rehak NN, Leitman SF.
Comprehensive analysis of citrate effects during plateletpheresis in normal donors.
Transfusion.
2001;41:1165-1171[Medline]
[Order article via Infotrieve].
6.
Bolan CD, Cecco S, Wesley RA, et al.
Citrate effects and intravenous calcium administration: a controlled study in allogeneic blood stem cell donors undergoing large volume leukapheresis [abstract].
Transfusion.
1999;39:122S.
7.
Hirsh J.
Heparin.
N Engl J Med.
1991;324:1565-1574[Medline]
[Order article via Infotrieve].
8.
Korbling M, Huh YO, Durett A, et al.
Allogeneic blood stem cell transplantation: peripheralization and yield of donor-derived primitive hematopoietic progenitor cells (CD34+ Thy-1dim) and lymphoid subsets, and possible predictors of engraftment and graft-versus-host disease.
Blood.
1995;86:2842-2848[Abstract/Free Full Text].
9.
Passos-Coelho JL, Braine HG, Wright SK, et al.
Large-volume leukapheresis using regional citrate anticoagulation to collect peripheral blood progenitor cells.
J Hematother.
1995;4:11-19[Medline]
[Order article via Infotrieve].
