In the treatment of cancer patients, wider use of aggressive chemotherapy, bone marrow transplants, and peripheral stem cell transplants has led to significant increases in platelet use. At M. D. Anderson Cancer Center, platelet transfusions have increased by approximately 40% per year during the past decade. Currently, 3000-4000 units of random-donor platelets (RDP) and 500-600 units of single-donor platelets (SDP) collected by apheresis are used by our patients every month. To maintain an inventory sufficient to meet such large demands, it is necessary for transfusion services to store platelet concentrates (PC) for several days or more.
Unfortunately, platelet transfusions are frequently accompanied by adverse reactions, most commonly nonhemolytic transfusion reactions (NHTR). Until recently, it was generally assumed that febrile NHTR were caused by the interaction between anti-leukocyte antibodies in the patient's plasma and leukocytes in the platelet product (1-3). To prevent such reactions, leukocyte reduction filters became widely used and are now recommended for patients who are likely to receive long-term platelet support (4). Some studies have shown that filtration significantly reduces the rate of febrile NHTR by reducing leukocyte levels, but reactions to leukocyte-reduced PC still occur (5-7). Furthermore, some reactions have been observed to occur on the first platelet transfusion in male patients not previously tranfused (8). Together, these observations suggest that NHTR are not always caused by immunologically mediated antigen-antibody reaction and that there may be more than one mechanism of NHTR associated with platelet transfusion.
In fact, there is a growing body of literature demonstrating that some NHTR are caused by inflammatory cytokines that are released from leukocytes in PC during storage (9-14). Thus, we will review here the role of cytokines in the pathogenesis of NHTR and the effect of storage time on the frequency of such reactions.
Frequency and Nature of Adverse Reactions to Platelet
Transfusion
Transfusion reactions are more frequent with platelet
transfusions than with red cell transfusions. The reported incidence of adverse
reactions to platelet transfusion ranges from 5% to 31% (8,11). In a recent
prospective study, Heddle et al. reported adverse reactions in 30.8% of
platelet transfusions versus 6.8% of red cell transfusions (11). Mangano et al.
reported that 14% of patients who received filtered transfusions also
experienced febrile reactions (7).
The clinical characteristics of platelet transfusion reactions vary from febrile NHTR and allergic reactions to chills, discomfort, tachycardia, and respiratory difficulties. A febrile NHTR is conventionally defined as a rise in temperature of 1 degree Celsisus or more in association with a transfusion. Interestingly, we and others have found that transfused patients having an NHTR will still often complain of chills and discomfort even after the fever has been subdued with prophylactic antipyretics (11). Allergic reactions include hives, urticaria, pruritus, erythema, bronchospasm, and hypotension. Anaphylactic reactions may occur in IgA-deficient patients. Transfusion-related acute lung injury, a rare but acute respiratory distress syndrome, can also occur.
As previously reported, the overall incidence of transfusion reaction at our institution (1.1%) is much lower than the incidence among the general population reported in the literature (15). It is unclear, however, whether this lower incidence of transfusion reaction represents underreporting or a unique phenomenon among cancer patients. Recently, we have noticed that relatively more of our patients are experiencing allergic or urticarial reactions than febrile reactions following platelet transfusion (Table 1). The relatively lower rate of febrile reactions may be due to the increased use of leukodepletion filters, which effectively prevents most febrile reactions. The allergic or urticarial reactions may likely be due to sensitization to plasma constituents that cannot be filtered out.
| Product type* | No. febrile reactions | No. allergic/ urticarial reactions |
|---|---|---|
| PRBC | 105 | 81 |
| SDP | 16 | 87 |
| RDP | 54 | 98 |
| * | PRBC, packed red blood cells; SDP, single-donor platelets; RDP, random-donor platelets. |
Effect of PC Storage Time on Febrile Reaction Rate
Whereas red cells
in additive solutions are stored at 4 degrees Celsius for up to 42 days,
platelets are only stored at 22 degrees Celsius for up to 5 days. Yet, several
studies have reported an association between longer storage times of platelets
and greater numbers of NHTR. For instance, Muylle et al. noted an increased
incidence and severity of reactions to platelets stored longer than 5 days (9).
Heddle et al. reported that age of the PC and absolute white blood cell (WBC)
count were the best predictors of a reaction and speculated that biologic
mediators within PC are released during storage (11). On our part, we conducted
a review of all NHTR involving RDP at M. D. Anderson from June 1989 through
June 1993 (n=186). Of all NHTR, 75% were caused by RDP stored for more than 3
days. No correlation was noted between NHTR and other clinical factors,
including patient's age, sex, and diagnosis.
Cytokines in PC
It is possible that cytokines play a role in NHTR to
PC. Cytokines are hormonelike substances that are secreted by macrophages,
lymphocytes, and endothelial cells and that regulate a variety of cell
functions including inflammatory responses. Some cytokines, such as
interleukin-1-beta (IL-1-beta), tumor necrosis factor-alpha (TNF-alpha), and
interleukin-6 (IL-6)--all of which mediate inflammatory responses--also may act
as pyrogens. Since PC contain significant numbers of leukocytes, including
monocytes and lymphocytes, it is not surprising that cytokines can accumulate
during storage.
Muylle et al. tested the hypothesis that increased cytokine levels in PC are responsible for febrile NHTR by measuring several cytokine levels in PC at various times of storage up to 7 days (10). Increased IL-6 levels were found in 8 of 12 PC after 3 days of storage and in 10 of 12 PC after 5 and 7 days of storage. Most PC with an increased IL-6 level also showed increased TNF-alpha and IL-1-beta levels. Increased levels of these cytokines were found when the WBC count in PC exceeded 3 billion per liter. In the second part of Muylle's study, 45 patients receiving WBC-reduced PC were evaluated for transfusion reaction. Six of 45 platelet transfusions were complicated by a febrile reaction. All six reaction-causing PC showed significantly higher levels of TNF-alpha and IL-6 than PC not causing reactions. Taken together, Muylle's data strongly support the hypothesis that transfusion reactions are not always the result of an antigen-antibody reaction but could be caused by large amounts of cytokines contained in PC.
In another study, Heddle et al. separated standard PC into plasma and cellular components and transfused them separately. Reactions occurred more frequently with plasma (20/64) than with cellular components (6/64)(P=0.009), and reactions to the plasma components were more likely to be severe; a strong positive correlation was also observed between the reactions and the concentration of IL-1-beta and IL-6 in the plasma supernatant.
In a recent study, Aye et al. tested the feasibility of preventing cytokine accumulation by filtration to reduce WBC in PC prior to storage (13). Compared with unfiltered PC, filtered PC showed no rise by day 3 in the levels of IL-1-beta (27.7 pg/mL unfiltered vs 0.6 pg/mL filtered), IL-6 (114.2 pg/mL vs 0.4 pg/mL), and IL-8 (4.2 ng/mL vs 0.02 ng/mL). By day 5, further increases in the levels of all cytokines were noted in unfiltered PC but not in filtered PC: IL- , 105.4 pg/mL vs 0.4 pg/mL; TNF-alpha, 42.2 pg/mL vs 7.5 pg/mL; IL-6, 268.8 pg/mL vs 0.4 pg/mL; IL-8, 7.6 ng/mL vs 0.02 ng/mL. The exponential increase in cytokine accumulation in this and other studies strongly suggests that these cytokines are being actively produced by WBC during storage of PC at 22 degrees Celsisus (10,13).
The question then is when and how to further reduce the number of contaminating WBC in PC.
Implications for Delivery of Services to M. D. Anderson Patients
In
the late 1980s, we in M. D. Anderson's Section of Transfusion Medicine began
noticing that RDP stored for up to 5 days were more often implicated in
reported NHTR than PC stored for fewer days. The same held true for SDP.
Together, these observations led to a change (still in effect) in our internal
policy relating to the production and storage of PC: now, whenever possible,
SDP are to be transfused within 1 day and RDP within 1-2 days after collection.
However, during periods of shortages (i.e., during long weekends, holidays, and
summertime), we are forced to import RDP from local and national sources that
insist on a "first in, first out" policy. Thus, we often end up buying 4- to
5-day-old PC owing to a sales strategy beyond our control. It is interesting to
note that the number of NHTR (whether febrile or allergic) increases notably
when such outside RDP are used, despite intense leukodepletion by filters prior
to transfusion.
We have also noticed that, despite being stored for less than 20 hours and despite being leukodepleted, significant numbers of SDP are being implicated in NHTR. In these cases, the number of WBC harvested during platelet pheresis is so high that even the short-term storage at room temperatures (22 degrees Celsisus) may actually promote the production of soluble cytokines, which in turn may be responsible for the clinical manifestations of NHTR.
In light of the untoward effects induced by less-than-desirable RDP stored for long periods, we may have to consider resorting to manually washing PC with normal saline to remove as much of the supernatant plasma as possible. However, this extra handling of bags of platelets would not only be conducive to the loss of transfusable elements but also increase the chances of bacterial contamination and its possible deleterious effects. In addition, the process of manually washing platelets would delay tranfusion of the PC another 2-2.5 hours.
Considerations for the Future
Several manufacturers are seriously
engaged in the design and evaluation of in-line filtration devices that would
allow the removal of contaminating WBC as soon as the unit of blood is
collected and brought to the processing laboratory. In all likelihood, such a
device will be available in the next 2-3 years. However, the cost of using this
technology will obviously drive up the cost of the final tranfusion product.
Compared with the general patient population, our patient population at M. D.
Anderson seems to undergo therapies that are more aggressive and
myelosuppressive and that require prolonged support with platelet transfusion.
Thus, the higher cost of providing effective hemotherapeutic support to and
lessening the chance of febrile NHTR in these patients will have to be factored
into the already expensive global cost/charge for treating the particular
disease processes.
References