Ness, Paul M. MD*†; Campbell-Lee, Sally A. MD†
Abbreviations:HIV human immunodeficiency virus, HLA human leukocyte antigen, PC platelet concentrates, SDP single donor platelets, SPTR septic platelet transfusion reactions
The development of plastic bags and techniques to separate platelets from other blood elements have made platelet transfusion therapy available since the 1950s . Platelet concentrates (PC) derived from whole blood collections became the initial standard of care. However, many patients became alloimmunized and required platelets from donors with specific human leukocyte antigen (HLA) types. This medical necessity drove the development of apheresis procedures that allow collection of an adult dose of compatible platelets from a single donor, referred to as single donor platelets (SDP).
From 1997 to 1999, the number of PCs and SDPs transfused increased from 11,777,000 equivalent units to 11,913,000 equivalent units per year. In 1999, 7,220,000 of the above equivalent units of platelets were SDP and 4,693,000 were PC. This 6.4% increase in SDP usage from 1997 to 1999 suggests an increasing trend to SDP usage . Overall platelet usage is likely to increase further, particularly because of advances in hematopoietic progenitor cell transplantation and continued use in coronary artery bypass graft patients, solid organ transplants, and trauma.
Although platelets are used in many clinical settings, their principal therapeutic role is to treat acute hemorrhage caused by thrombocytopenia and to provide prophylaxis from hemorrhage during periods of bone marrow aplasia for patients with oncologic diseases. Both PC and SDP are generally very effective for most patients, but current platelet transfusion therapy is limited by two major concerns: (1) many patients subjected to chronic platelet transfusion support still become alloimmunized, leading to concerns about preventing alloimmunization or handling alloimmunization when it occurs; and (2) many patients have adverse reactions to transfused platelets including the serious consequences of bacterial contamination of platelets stored at 22 to 24°C .
Currently, there is debate about which platelet product should be used. Largely because of the lower cost, many transfusion services favor PC, with SDP reserved for patients who require HLA-matched platelets. This review will discuss five areas that should be considered when considering the use of SDP or PC: (1) the impact on infectious complications, (2) transfusion reaction rate, (3) the evolving trend toward universal leukodepletion, (4) the reduction of transfusion frequency in patients with bone marrow suppression, and (5) the treatment and prevention of alloimmunization. We believe that when the issues of patient care are given highest priority, substantial arguments can be made to support the extensive use of SDP rather than PC, and that these arguments are particularly relevant to the care of patients with hematologic diseases.
The risks for transmission of the human immunodeficiency virus (HIV), hepatitis B and C viruses, and human T-cell lymphotrophic virus have markedly decreased during the past several years. The risk of transfusion-transmitted HIV, reported as 1 in 493,000 units in 1996 , is now estimated as 1 in 677,000 units . In addition, the risk of transmission of HIV and hepatitis C has decreased further because of the advent of nucleic acid testing.
Therefore, the role of SDP in decreasing donor exposure to transfusion-transmitted viruses is not as important as it once was. However there are no recent changes in donor testing that have decreased the risk of a septic transfusion reaction, and many hematologists still are unaware of the frequency of these events. Septic platelet transfusion reactions (SPTR) are the most common serious infectious risk of transfusion today in the United States. SPTR can be attributed to contamination of the platelet product from donor skin flora or inadvertent selection of donors with asymptomatic bacteremia.
We recently reported our 12-year experience, which examined the efficacy of the increasing use of SDP to reduce SPTR [6••]. We developed a prospective monitoring system in 1986 whereby all febrile transfusion reactions to platelets were evaluated by culture of the platelet bag. Confirmed cases of SPTR were identified by isolation of the same bacteria from the bag and from the patient’s blood, or by a positive Gram stain of the bag confirming a positive platelet culture. During 12 years of observation, we increased the use of SDP from 51.7 to 99.4% of all platelet transfusions with approximately 15,000 annual platelet transfusions. The incidence of SPTR decreased from 1 in 4818 transfusions to 1 in 15,098 transfusions. Because our observations began at a time when 50% of our transfusions were SDP, the incidence of SPTR with the exclusive use of PC would be expected to have been about 1 in 2000 transfusions. We observed that the rate of SPTR is five times higher among recipients of PC pools than recipients of SDP and noted a threefold reduction in SPTR by switching to SDP. Our results also demonstrate that these events can be severe: four of 23 cases (17.4%) were fatal, which is similar to other published data .
Several methods of bacterial detection in blood components have been investigated, including automated culture of bacteria , detection of bacterial metabolic byproducts by platelet swirling , indirect measurements of bacterial metabolism , and direct detection of bacteria by Gram stain . None of these methods has been incorporated into laboratory practice, either because of poor sensitivity, length of time required to perform testing, or cost. The most promising technique, automated bacterial detection, would still require sampling times of 24 hours or more . The short shelf life of platelet concentrates would prohibit this practice in most transfusion services, although the storage period could be increased if an effective bacterial screening method could be implemented.
A number of methods to eradicate bacteria from platelet components have also been investigated, including treatment with psoralens and ultraviolet light . The advantage of these methods is that in addition to bacteria, viruses and white blood cells are also eliminated from the blood product. Although phase III studies of psoralen are currently underway, concerns about platelet damage and potential toxicities must be considered before implementation. A randomized, double-blind trial compared the efficacy and safety of psoralen-treated PC to untreated PC in 103 thrombocytopenic oncology patients . Hemostasis, corrected count increment, transfusion intervals, transfusion reactions, and refractoriness were similar in both groups. If psoralen treatment of PC is approved for use, the number of SPTR should be drastically reduced.
Single donor platelets are an important mechanism to reduce SPTR. However, SPTR are not eradicated by the use of SDP; other means to reduce and eliminate this transfusion hazard will be necessary. Until more specific means to eliminate SPTR are developed, we believe that SDP are a useful means of limiting their occurrence in transfused patients.
Reduction in transfusion reactions
Along with the risk of infectious disease transmission, transfusions also carry the hazard of adverse reactions. These reactions include hemolytic, febrile nonhemolytic, and allergic reactions, and transfusion-related acute lung injury (TRALI). When platelet products are considered, there is little concern with hemolytic transfusion reactions because only a small number of red blood cells are contained in this component.
On the other hand, febrile nonhemolytic reactions are the most common type of reaction associated with platelet products. Febrile nonhemolytic reactions can be caused by contaminating white blood cells or by cytokines in the plasma that are produced by the white blood cells during storage [14•]. A prospective study analyzing the incidence of platelet transfusion reactions in relation to the length of storage found 4% of the 4926 platelet transfusions given were associated with transfusion reactions. Sixty-one percent of these transfusion reactions were febrile nonhemolytic . The same study also found that SDP accounted for 17% of all platelet transfusions and had a reaction rate of 1.78%, whereas PC were associated with a reaction rate of 4.51%. After 3 days of storage, the number of platelet products causing febrile nonhemolytic transfusion reactions increased, from 2% at 3 days to 3.5% at 4 and 5 days. No reactions occurred with the transfusion of leukoreduced platelets on the first day of storage. Reactions peaked at 0.9% at 5 days.
Transfusion reactions to platelets can be limited by a number of methods. Some physicians administer premedications such as acetaminophen or diphenhydramine to prevent febrile or allergic responses, although the efficacy of premedication has not been clearly shown in carefully conducted trials . Prestorage removal of white cells reduced febrile transfusion reactions to platelets in several studies , and platelet washing can reduce allergic reactions from plasma components . The reduction of febrile nonhemolytic transfusion reactions is a real benefit in considering the use of SDP over PC, but the level of benefit may be decreased by the use of leukodepleted platelets or platelets with a shorter duration of storage.
As leukoreduction becomes more common, allergic reactions are replacing febrile reactions as the most common adverse events in platelet transfusion practice. Because cells or plasma constituents can provoke allergic reactions, limiting donor exposure to such allergens with SDP can be advocated to prevent these events. TRALI reactions, also attributed to donor plasma, are also likely to be reduced by SDP but data are not yet available to prove this supposition.
Leukoreduced blood components have proven benefit for three indications: (1) the prevention of febrile nonhemolytic transfusion reactions, (2) the reduction of infectious risks from cell-associated viruses such as cytomegalovirus, and (3) the reduction of alloimmunization in transfusion recipients. Much has been made of the additional immunomodulatory effects of transfusion, such as a potential increase in postoperative infections and cancer recurrence [19•]. The effect of leukoreduced blood components on these complications is highly controversial.
Regardless of whether leukoreduction is applied universally or on a case-by-case basis, many patients will require leukodepleted platelet components. Current apheresis equipment can provide leukoreduced products at the time of collection. The advantage of this process leukodepletion is a decrease in the amount of cytokines, which cause febrile nonhemolytic transfusion reactions, released during storage. A comparison of three blood cell separators using elutriation, periodically alternating interface position (PAIP), or in-line filtration as methods of white blood cell reduction was reported . In-line filtered SDPs had a lower white blood cell content (mean, 0.088 × 10 6 ) than SDPs prepared using elutriation or PAIP (means, 0.31 and 0.89 × 10 6 , respectively). However, platelet yield was higher in SDPs collected on the elutriation device (mean, 5.0 × 10 11 ) than with in-line filtration (mean, 3.28 × 10 11 ). PCs can also be filtered, but simple methods to leukodeplete PCs at the blood center are less available. SDPs therefore have the current advantage over PCs in providing leukodepleted platelet support, regardless of white blood cell removal technique.
Transfusion frequency and dosage
The kinetics of transfused platelets have been carefully studied by Hanson and Slichter , who demonstrated a direct relation between platelet dose and its effect on post-transfusion platelet count. From these data, it seems logical that higher post-transfusion platelet counts would result in a longer period of time for the platelet count to return to baseline and that larger doses of platelets would reduce the required transfusion frequency. A randomized trial was performed to evaluate the use of lower-dose SDP (containing a mean of 3.1 × 10 11 platelets) for prophylactic transfusion in nonrefractory nonbleeding thrombocytopenic patients [22•]. Higher-dose SDP contained a mean of 5.0 × 10 11 platelets. Thirty-seven percent of lower-dose SDPs had platelet count increments of more than 20,000 per uL, with 81% of higher-dose SDP having an increment above 20,000 per uL. In addition, the use of lower-dose SDP had a 39 to 82% increase in the relative risk per day of needing supplementary platelet transfusions. A study by Norol et al.[23•] demonstrated that higher platelet doses produced larger platelet increments and resulted in the increase of transfusion intervals to as long as 2 days compared with lower doses. This practice has important implications fo patient care; as many patients with hematologic or oncologic diseases move to outpatient therapies, prolonged transfusion-free intervals can substantially improve the quality of their lives, reducing the need for clinic visits to receive additional platelet support.
This practice may also have a significant economic impact. An economic analysis of the study by Klumpp et al.[22•] revealed that with the lower-dose SDP, the average patient in the study would have required 60% more transfusions. This practice would result in a cost to the hospital of $4486 per patient, compared with a cost of $2804 per patient for patients receiving larger SDP doses .
These data argue against splitting large SDP collections and suggest a medical benefit to giving patients larger doses of platelets from apheresis donors. Although larger doses of PCs could also provide the same benefit, the problems of increased donor exposure with infectious risks and transfusion reactions would suggest SDP as the better therapy for stable outpatients.
Treatment and prevention of alloimmunization
Platelet alloimmunization remains the most important long-term complication of platelet transfusion therapy. Refractoriness is most commonly associated with antibodies against alloantigens on platelets. These antibodies are produced as an immune response to HLA class I antigens on leukocytes and platelets. The incidence of this problem depends on the patients under study, their previous transfusions or pregnancies, and the intensity of therapy. One third of patients with acute leukemia may become refractory to platelets during their therapy. Once a patient becomes alloimmunized, platelet transfusions with SDP that are either HLA-matched or crossmatched are the standard of care. Some attempts have been made to use PC for refractory patients, but the heterogeneity of the HLA system makes success unlikely. When HLA-matched or crossmatched platelets are unsuccessful, which is not uncommon, experimental approaches employing intravenous immunoglobulin infusions may be attempted .
Because the consequences of alloimmunization and refractoriness can be severe, efforts have focused on their prevention. A multicenter randomized blinded study, the Trial to Reduce Alloimmunization to Platelets (TRAP), included adolescent and adult patients with acute leukemia [26••]. The participants were randomized to four transfusion groups: PC, leukodepleted PC, ultraviolet B–irradiated PC, and filtered SDP. The data demonstrated that any of the three treatment arms was successful in reducing alloimmunization to HLA antigens from a rate of 13% in the control group (PC) to 3 to 5% in the experimental transfusion groups. Ultraviolet B irradiation is not a licensed procedure and is therefore unavailable currently. The TRAP results suggest that leukodepletion is a practical method to reduce alloimmunization. There was no significant advantage of SDP over PC in this study for the prevention of alloimmunization, so SDP cannot be supported over PC for oncology patients on that basis alone.
Single-donor platelets have major advantages over PC when considering the risk of SPTR, platelet transfusion management of the alloimmunized or refractory patient, ease of leukoreduction, and the ability to reduce transfusion frequency and donor exposure. However, the current economic climate in medicine demands that the cost effectiveness of various medical interventions be examined. Major tensions exist between the quest for a zero-risk blood supply and what is cost effective compared with other medical therapies.
Lopez-Plaza and co-workers  have investigated the cost effectiveness of reducing donor exposures by SDP. Although their analysis does not suggest that the exclusive use of SDP meets current target levels, they readily acknowledge that cost issues are not the only consideration when eliminating all transfusion risk remains a national goal. In addition, their model shows that SDP are more costly for patients with hematologic malignancies than for cardiac bypass surgery, because oncology patients have shorter life expectancies; most oncologists assume their patients will enter remission and would want their patients to avoid a preventable life-threatening complication despite the cost.
In closing, we have considered five areas where SDP have been proposed to have advantages over PC. SDP outperform PC in ease of leukoreduction, decreasing the risk of SPTR, treating alloimmunization, and increasing the transfusion interval. SDP should be the platelet therapy of choice for hematologic patients. This recommendation would be tempered if a mechanism to avoid SPTR can be developed and implemented. Even if SPTR can be prevented by other means, however, the significant advantages to patients of fewer transfusion reactions, the potential to receive higher doses, and the ability to handle the vexing problems of alloimmunization will make SDP our preferred choice for hematology–oncology platelet recipients.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• Of special interest
•• Of outstanding interest
1. Baldini M, Costae N, Dameshek W: The viability of stored human platelets. Blood 1960, 16: 1669–1672.
2. Comprehensive Report on Blood Collection and Transfusion in the United States in 1999: Bethesda, MD: National Blood Data Resource Center; 2001:10–11.
3. Klein HG, Dodd RY, Ness PM, et al.: Current status of microbial contamination of blood components: summary of a conference. Transfusion 1997, 37: 95–101.
4. Schreiber GB, Busch MP, Kleinman SH, et al.: The risk of transfusion-transmitted viral infections. The Retrovirus Epidemiology Donor Study. NEJM 1996, 334: 1685–1690.
5. Kleinman S, Busch MP, Korelitz JJ, et al.: The incidence/window period model and its use to assess the risk of transfusion-transmitted human immunodeficiency virus and hepatitis C virus infection. Transfus Med Rev 1997, 11: 155–172.
6.•• Ness PM, Braine HG, King KE, et al.: Single donor platelets reduce the risk of septic transfusion reactions. Transfusion 2001, in press. This study provides data on the ability of SDP to reduce SPTR.
7. Goldman M, Blajchman Ma: Blood product-associated bacterial sepsis. Trans Med Rev 1991, 5: 73–83.
8. Wagner SJ, Robinette D: Evaluation of an automated microbiologic blood culture device for detection of bacteria in platelet components. Transfusion 1998, 38: 674–679.
9. Wagner SJ, Robinette D: Evaluation of swirling, pH and glucose tests for the detection of bacterial contamination in platelet concentrates. Transfusion 1996, 36: 989–993.
10. Burstain JM, Brecher ME, Workman K, et al.: Rapid identification of bacterially contaminated platelets using reagent strips: glucose and pH analysis as markers of bacterial metabolism. Transfusion 1997, 37: 255–258.
11. Yomtovian R, Lazarus HM, Goodnough LT, et al.: A prospective microbiologic surveillance program to detect and prevent the transfusion of bacterially contaminated platelets. Transfusion 1993, 33: 902–909.
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platelet function. Vox Sang 2000, 78: 209–216.
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) photochemically treated platelets are safe and effective for support of thrombocytopenia: results of the EUROSPRITE phase 3 trial [abstract]. Blood 96:819.
14.• Heddle NM, Klama L, Singer J, et al.: The role of the plasma from platelet concentrates in transfusion reactions. NEJM 1994, 331: 670–671. This important study highlights the causes and mechanisms of febrile platelet transfusion reactions.
15. Sarkodee-Adoo CB, Kendall JM, Sridhara R, et al.: The relation between the duration of platelet storage and the development of transfusion reactions. Transfusion 1998, 38: 229–235.
16. Kennedy LD, Cruz JM, Restino MS, et al.: Comparison of acetaminophen and diphenhydramine versus placebo for the prevention of febrile or allergic transfusion-associated reactions [abstract]. Blood 1999, 94: 375.
17. 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 transfusion. Transfusion 1993, 33: 794–797.
18. Buck SA, Kickler TS, et al.: The utility of platelet washing using an automated procedure for severe platelet allergic reactions. Transfusion 1987, 27: 391–393.
19.• Blajchman MA: Transfusion-associated immunomodulation and universal white cell reduction: are we putting the cart before the horse? Transfusion 1999, 39: 665–670. This is an important commentary on a pertinent issue in transfusion medicine.
20. Moog R, Muller N: White cell reduction during platelet pheresis: a comparison of three blood cell separators. Transfusion 1999, 39: 572–577.
21. Hanson SR, Slichter SJ: Platelet kinetics in patients with bone marrow hypoplasia: evidence for a fixed platelet requirement. Blood 1985, 66: 1105–1109.
22.• Klumpp TR, Herman JH, Gaughan JP, et al.: Clinical consequences of alterations in platelet transfusion dose: a prospective, randomized, double-blind study. Transfusion 1999, 39: 674–681. This study evaluates the use of lower dose SDP versus higher dose SDP.
23.• Norol F, Bierling P, Roudot-Thoraval F, et al.: Platelet transfusion: a dose-response study. Blood 1998, 92: 1448–1453. Such studies in transfusion medicine are uncommon, and these provide important information regarding the response to variations in platelet dosage.
24. Ackerman SJ, Klumpp T, Guzman G, et al.: Economic consequences of alterations in platelet transfusion dose: analysis of a prospective, randomized, double-blind trial. Transfusion 2000, 40: 1457–1462.
25. Kickler TS, Braine HG, Ness PM, et al.: A randomized, placebo-controlled trial of high dose intravenous gammaglobulin in ameliorating alloantibody mediated platelet destruction. Blood 1990, 75: 313–316.
26.•• The Trial to Reduce Alloimmunization to Platelets: Leukocyte reduction and ultraviolet B irradiation of platelets to prevent alloimmunization to platelet transfusions. NEJM 1997, 33:1861–1869.This is a landmark study comparing alloimmunization outcomes in leukemia patients receiving PC or SDP with various modifications.
27. Lopez-Plaza I, Weissfeld J, Triulzi DJ: The cost-effectiveness of reducing donor exposures with single-donor versus pooled random-donor platelets. Transfusion 1999, 39: 925–932.
Edited by S Gerald Sandler
© 2001 Lippincott Williams & Wilkins, Inc.