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January-April 1995
Nonhemolytic Transfusion Reaction to Platelet Concentrates: Induction by Cytokines Released During Storage

By Yang O. Huh, M.D., and Benjamin Lichtiger, M.D., Ph.D.

Copyright 1993-2010 The University of Texas MD Anderson Cancer Center, Houston, Texas. All rights reserved.

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 MD 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.

Table 1. Number of Febrile and Allergic Reactions to Blood Products at MD Anderson Cancer Center, 1990-1994 Product type*

Product type*No. febrile reactionsNo. allergic/
urticarial reactions
PRBC10581
SDP1687
RDP5498

*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 MD 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 MD Anderson Patients

In the late 1980s, we in MD 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 MD 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

  1. Payne R. The association of febrile transfusion reaction with leukoagglutinins. Vox Sang 2:233-241, 1957.
  2. Payne R, Rolfs MR. Further observations on leukoagglutinin transfusion reactions in women. Am J Med 29:449-458, 1960.
  3. Perkins HA, Payne R, Ferguson J, Wood M. Nonhemolytic transfusion reaction: Quantitative effects of blood components with emphasis on isoantigenic incompatibility of leukocytes. Vox Sang 11:578-600, 1966.
  4. Lane TA, Anderson KC, Goodnough LT, et al. Leukocyte reduction in blood component therapy. Ann Intern Med 117:151-162, 1992.
  5. Kalmin ND, Orrell JE, Villarreal IG. An effective method for the preparation of leukocyte-poor platelets. Transfusion 27:281-283, 1987.
  6. Sniecinski I, O'Donnell MR, Nowicki B, Hill LR. Prevention of refractoriness and HLA-alloimmunization using filtered blood products. Blood 71:1402-1407, 1988.
  7. Mangano MM, Chambers LA, Kruskall MS. Limited efficacy of leukopoor platelets for prevention of febrile transfusion reaction. Am J Clin Pathol 95:733-738,1991.
  8. Chambers LA, Kruskall MS, Pacini DG, Donovan LM. Febrile reaction after platelet transfusion: The effect of single versus multiple donors. Transfusion 30:219-221, 1990.
  9. Muylle L, Wouters E, De Bock R, Peetermans ME. Reactions to platelet transfusion: The effect of the storage time of the concentrate. Transfus Med 2:289-293, 1992.
  10. Muylle L, Joos M, Wooters E, et al. Increased tumor necrosis factor alpha (TNF-alpha), interleukin 1, and interleukin 6 (IL-6) levels in the plasma of stored platelet concentrates: Relationship between TNF-alpha and IL-6 levels and febrile transfusion reactions. Transfusion 33:195-199, 1993.
  11. Heddle NM, Klama LN, Griffith L, et al. A prospective study to identify the risk factors associated with acute reactions to platelet and red cell transfusions. Transfusion 33:794-797, 1993.
  12. Heddle NM, Klama L, Singer J, et al. The role of plasma from platelet concentrates in transfusion reactions. N Engl J Med 331:625-628, 1994.
  13. Aye MT, Palmer DS, Giulivi A, Hashemi S. Effect of filtration of platelet concentrates on the accumulation of cytokines and platelet release factors during storage. Transfusion 35:117-124, 1995.
  14. Stack G, Snyder EL. Cytokine generation in stored platelet concentrates. Transfusion 34:20-25, 1994.
  15. Huh YO, Lichtiger B. Transfusion reactions in patients with cancer. Am J Clin Pathol 87:253-257, 1987.

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