EDITORIAL Costs and benefits of PAS platelets: A mix of science, quality, and value
O
ver the past decade, platelet concentrates (PCs) have shown the greatest increases in blood product demand, being required both by changing population demographics, as well as by cancer therapy advances. At present these products are not routinely stored longer than 5 days, which increases logistic complexity and outdating. This abbreviated room temperature storage period followed early studies showing that these cells cannot be stored in the cold while maintaining posttransfusion survival.1 Room temperature storage was later shown to require gaspermeable containers to support the significant metabolic needs of higher energy turnover requirements associated with the higher temperature.2,3 Although subsequent studies provided more insight into the cause of the cold effect, this problem could not be easily ameliorated, and the next generational change in platelet (PLT) storage improvement focused on the approach of removing plasma and red blood cell (RBC)-focused nutrients, with replacement by PLT additive solutions (PASs).4-7 Three groups of investigators evaluated PLT storage options utilizing the application of electrolyte media to replace supernatant plasma, defining a physiologic electrolyte medium, and identifying the optimal nutrients to support cell energy production without incurring a pH penalty, since these manipulations had been associated with reduced PLT quality. The first commercial PAS was pioneered by Claes Hogman and launched in Sweden in 1991 followed over the next 20 years by several generational changes. With the recent approvals of PAS-C (PAS-3 or Intersol, Fresenius-Kabi, Lake Zurich, IL) and PAS-F (Isoplate, Terumo BCT, Denver, CO), PAS is now routinely available in the United States.8,9 Similar to RBC ASs (AS-1, -3, -5), PAS affords a number of operational advantages, including the potential for reduced transfusion reactions, enhanced plasma recovery, and improved cell quality. However, as the more than 5-year transition from CPDA-1 to AS demonstrated, the transition from one storage solution to another may take a surprisingly long time as the manufacturing process changes are learned, the improved clinical outcomes prove out, and the economic advantages become apparent. In this context, the article by Kacker and colleagues10 on the cost-effectiveness of PAS in preventing transfusion reactions in this edition of TRANSFUSION is an essential first step toward defining the product value to the hospital community, as the transfusion medicine community contemplates large-scale conversion of PC manufacture to PAS. TRANSFUSION 2013;53:2597-2602.
Early PAS development focused on plasma substitution, utilizing an electrolyte intravenous solution containing sodium chloride, gluconate, and acetate (Plasmalyte, Baxter International, Deerfield, IL).5 Subsequent scientific development included a systematic evaluation of various physiologic elements of plasma to ensure optimal PLT metabolic preservation,6 followed by the identification of acetate as an optimal energy substrate with the desirable attribute of supporting poststorage pH preservation.7 The various product generational changes were mostly dictated by the need for manufacturing simplicity, associated with a stepwise approach toward regulatory approval, since although the early studies had identified a 10-day storage potential, formulation refinement was essential for manufacturing.11,12 PAS-1 included only simple salt solutions associated with significant plasma carryover, and since glucose remained the primary PLT energy substrate, later studies showed that the reduced bicarbonate carryover was inadequate to maintain acceptable viability.13 The second-generation PAS-2 (T-Sol, Fenwal, Fresenius-Kabi) included acetate as a metabolic substrate, and although these improved both in vitro and in vivo variables, posttransfusion recoveries were modestly but significantly less than plasma PCs.14-17 However, the association of PAS-2 with significant reductions in posttransfusion reactions resulted in gradually increasing European uptake. Subsequently a number of extra additives were included to improve cell quality, including phosphate; K+ and Mg2+ salts; and in some cases, gluconate to improve energy metabolism, reduce metabolic stress, or enhance cell stability, which was anticipated to improve posttransfusion recoveries.16,17 It is the thirdgeneration PAS-C (PAS-3, Intersol, Fresenius-Kabi), which includes higher phosphate levels, that was first approved in the United States, a product previously mostly associated with pathogen reduction solutions.18,19 European studies had documented acceptable posttransfusion increments with PAS-C, and although the addition of K+ and Mg2+ salts improved in vitro values, this step did not result in commensurate in vivo improvements to alternative solutions.17 A fourth-generation PAS (PAS-F in ISBT nomenclature) has recently also been approved in the United States (Isoplate, Terumo BCT, Lakewood, CO).20 Both PAS-C and PAS-F have exhibited posttransfusion recoveries that meet the latest US FDA in vivo standards.18,20 PAS-C and PAS-F exhibited posttransfusion recoveries averaging 80.5 and 87% and survivals averaging 72 and 78% of the respective recovery and/or survival of contemporaneous fresh PLTs: the first new products to require contemporaneous poststorage comparison with Volume 53, November 2013 TRANSFUSION
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untreated fresh cells. These easily exceeded the 66% and more than 58% standards now demanded of new products. Since these solutions have either mostly been utilized clinically in association with pathogen reduction systems (INTERCEPT Cerus, Concord, CA) or alternatively represent variants of European earlier generation solutions, there are relatively few publications upon their clinical efficacy. As a result the Center for Biologics Evaluation and Research (CBER, FDA) has requested postmarketing studies, to affirm posttransfusion reaction noninferiority, the first of which has recently been reported at the transfusion-related acute lung injury (TRALI) mitigation workshop.21 These studies of 14,005 transfusions in three centers to 3646 recipients, where reactions were monitored according to the NSHN guidelines, showed a significant reduction in reactions from 1.37% to 0.55%. This 60% decrease may be related to the 55% modeled in the studies by Kacker and colleagues.10 Transfusion reactions after receiving PCs are more common than with other blood products and are largely an effect of (22°C) room temperature storage associated with the synthesis or release of many cell mediators known to cause recipient reactions.22-25 Reactions range from the more common mild allergic urticaria, through febrile nonhemolytic transfusion reactions (FNHTRs), to more severe manifestations with anaphylaxis or significant pulmonary symptoms, which have been classified by NSHN. After universal leukoreduction, which reduced white blood cell (WBC)-synthesized mediators, the recent incidence has been reported to range from 1% to 3%.21-24 Analysis of risk factors has led to the identification of a wide range of proinflammatory PLT cytokines, together with plasma complement fragments, bradykinins, and other biologic response modifiers or biogenic amines.25,26 Although PCs are antigenic, there was less relationship between transfusion-induced HLA or PLT antibody and reaction incidence than with the residual WBC load or storage duration.26 Recent reports have suggested that ABO incompatible plasma in PLTs is not similarly associated with FNHTRs.27 In addition to product characteristics there is evidence that recipient characteristics may interact with the product to induce reactions, with IgA deficiency being an especial concern. Analysis of TRALI reports has suggested that a combination of recipient conditioning events together with transfused mediators may be necessary to cause the pulmonary symptoms, which continues to be associated with approximately 17 reported transfusion-associated deaths per year.28,29 Since reactions are more frequent in a heavily transfused patient population, routine pretransfusion medication with antipyretics and antihistamines is common, although an increasing number of reviews have suggested that premedication is without systematic benefit.30-32 These reactions may be disruptive to both the patient and the physician in that the reaction may delay patient discharge 2598
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and may cause premature transfusion termination such that additional work-ups must be performed, with extra clinical and laboratory physician time being required.33,34 The recognition that significant numbers of PCs may have bacterial contamination has also increased the need for more intense and timely transfusion reaction analysis, which will increase the cost further.35 Since PAS is applied to the PC at the end of collection, it does not affect the separation process, but does reduce final product plasma load, and dilutes any preformed mediators. Early European studies mostly reported on PLT storage in PAS-2 (T-Sol) showed an overall approximately 50% reduction in reactions.15,36 The HOVON PAS-C study included analysis of posttransfusion increments and reactions over 7 days of PAS-3 22°C storage as the independent PAS-3 control within a pathogen reduction evaluation and showed a reduction in reactions from 11% to 9%.19 The recent US PAS-C studies on prestorage leukoreduced PCs showed a per-patient allergic reaction reduction from 3.13% to 0.83% and an FNHTR reduction from 1.91% to 0.48%, with some variability depending upon the institution.21,33,37 The overall odds ratio of reaction reduction of 0.403 was significant.21 In an alternative strategy where PAS was used to replace supernatant plasma shortly before transfusion to a small group of highly reactive recipients (akin to PLT washing), reactions in highly sensitized PLTs were reduced from 42% to 0.6%.38 As an alternative approach PC supernatant reduction to less than 100 mL or washing has been used to reduce transfusion reactions by 73 and 95%, respectively, and although the percentage of allergic transfusion reduction was greater with concentration and washing than with PAS, the differences were not significant in a recent comparison.22,23 Since the reactions in heavily transfused recipients are so common, and these may range from urticarial reactions to more rare anaphylactic reactions associated with pulmonary symptoms, it may be difficult to discourage the routine pretransfusion medication practice that has become commonplace.39 The studies reported by Kacker and coworkers in this issue of TRANSFUSION follow up on earlier studies that evaluated the benefit of plasma reduction to 100 mL, in comparison as an alternative to washing PLTs to achieve maximal plasma load reduction.22 Since PAS-SDP at a 35% residual plasma level may be expected to retain approximately 90 mL of residual plasma this might be expected to achieve comparable benefit. These studies evaluated the cost-effectiveness of inclusion of PAS as a corrective or a preemptive measure to reduce reactions. Assuming a hospital perspective that a PAS purchase decision would be based on an approach of direct achievable medical cost avoidance, the studies evaluated different methods of escalation of PC plasma reduction to respond to post–PC transfusion reactions.10 Transfusion scenarios were based on four outcomes: no reaction, a mild initial reaction,
EDITORIAL
repeat mild reactions, and severe reactions. Scenarios included plasma reduction by centrifugation in one arm later followed by PLT washing as the reaction level escalated: compared to the application of PAS either as a primary preemptive measure or as a secondary reactive measure upon initial reaction. A number of assumptions were made about reaction frequency and clinical response, which generally followed the direction of the earlier studies.22 The cost estimates of corrective action included the frequency of events associated with different approaches to unit processing, prophylactic medication, and implicated unit discard. Assumptions were made in connection with direct material and labor costs of plasma volume reduction or washing, as well as of the cost of pretransfusion medication, which was modeled based on reaction frequency and intensity. The analysis reviewed the effect of reactions upon operational transfusion costs, product loss, through reaction-associated product discontinuance, along with the estimated cost of reaction work-ups. These costs and frequency were then modeled using a Markov-based decision tree model to evaluate the financial outcomes relative to the cost of the health impact. Key assumptions included an assumption of a 1.57% isolated mild reaction rate, that 10% of these reactions resulted in a modified treatment with unit discontinuance, and that 0.13% of recipients had severe reactions. A 73% corrective response of plasma reduction was presumed along with a 95% correction based on washing based on the earlier studies, in comparison to a 56% reduction anticipated with PAS. The cost of routine pretransfusion medication with diphenhydramine at $4.11 was taken from an earlier study and assumed to occur in 67% of cases.33,34 A number of other assumptions related to the effect of severe reaction on increased hospitalization length of stay, and other hospital costs were taken from published data. These costs were then analyzed in multiple individual trials for each simulation and an average estimated along with a sensitivity analysis. The incremental effect of different PAS cost on apheresis PLT product transfusion costs were evaluated based on a PAS premium in the range of $5 to $50 per PC. Base case evaluation suggested that application of PAS would reduce transfusion cost by a median of approximately $1.65 to $2.03 if PAS was used only in response to a reaction, depending on the PAS cost range. Once PAS was applied prophylactically to avoid reactions, the incremental cost was $0.85 if PAS cost a premium of $10/unit and decreased the overall cost by $1.89 if pretransfusion medication was discontinued. One-way sensitivity analysis showed that prophylactic application of PAS-SDP reduced cost approximately $ 9.14 and that if changed prophylactic drug therapy was included the savings increased to $11.90. The probabilistic cost per reaction avoidance was $119/ reaction at $10 PAS increment and $678/reaction at a $15
PAS increment. These numbers should be related to the reported decrease in posttransfusion reactions of 60% in the recent US PAS-C study, suggesting that the final direct avoidable cost with drug pretransfusion medication elimination would be more than $12 per transfusion. In addition to the clinical advantages and cost benefit, there is the additional value of the extra plasma displaced by PAS utilization. Since both PAS-3 and PAS-F approvals include intended-use statements describing the application of the solutions in a 35%/65% split between plasma and PAS and the average actual plasma SDP supplied to the reviewer by the New York Blood Center has a volume of 252 mL, an average 35% of this volume will be displaced by the application of PAS in a single-unit collection. In practice, however, few SDPs are collected as single units, since most are now split in 1/2 or 1/3. Under these circumstances, each PAS-SDP unit requires plasma loads that are dictated by the manufacturer’s package inserts (operator’s manuals). These are developed based on the computer algorithms that are included in the current versions of the device software and are designed to ensure that the PC stays within predetermined limits that define the minimum and maximum PLT and plasma content that can sustain 5-day PLT storage at 22°C, while remaining within certain defined poststorage target pH levels. Since apheresis devices utilize a variable (approx. 1:9 to 1:10) ratio of ACD:whole blood as part of the collection process, it is possible to estimate how much plasma will be displaced by the application of PAS and which would now become available as source plasma for further manufacture. The PAS approvals have also included a recommendation that no more than 90% of the PAS-displaced plasma be harvested with an outside limit that no more than 5 mL of extra plasma may be collected than would have been required for a plasma PC.8,9,40 Greater plasma harvest results in the donor qualifying for the deferral obligations of the infrequent source plasma guideline, which include a 28-day deferral.41,42 The effect of these regulations and the 35/65 split of plasma:PAS in SDP products means that blood centers can ordinarily collect the displaced plasma which will vary based on the approved device collection algorithms that allows more plasma for triple products than for single products. Based on local per-SDP-product-volume experience this volume would average approximately 150 mL per product distributed or if a 40% single, 40% double, and 20% triple collection split rate is assumed, the extra available plasma per collection could increase by ∼250 mL per donation. This extra plasma could be expanded if the collection center opted to collect plasma according to the 1995 updated FDA requirement for infrequent plasma donors, which allows for collection of 500 mL of plasma for donors less than 175 lb and 600 mL of plasma for donors more than 175 lb.41 Since all devices are approved for the preparation of source plasma, and assuming a current Volume 53, November 2013 TRANSFUSION
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global price of $0.15/mL, PAS would allow the availability of an additional $24/product to $38/collection, which would likely cover the direct material PAS costs. Clearly, however, the blood center would incur additional labor costs and other expenses that may lessen the economic gains of the additional plasma recovery. If the blood center elected to convert such plateletpheresis donors to combined plasma and PLT donors (and accept the 28-day deferral), the plasma harvest could more than double depending on donor weight characteristics, with the Amicus device being cleared for an additional 100 mL of infrequent plasma harvest per month.41,42 A goal of PAS development included prolonged storage of greater than 7 days, and the PAS-C now used in conjunction with amotosalen pathogen reduction is increasingly used for 7-day storage in the EU.43,44 Manufacturing limitations, however, required a generational approach toward PAS implementation with the effect that PAS-2 exhibited reduced posttransfusion recoveries when compared to plasma controls.15,36 Few independent posttransfusion increment studies of PAS-C have been reported, since Intersol has mostly been combined with Intercept, the combination of which may affect posttransfusion increments.19,45 Isoplate is different enough from the most comparable European solutions and available radioisotope in vivo study reports are limited, such that posttransfusion increments are difficult to predict, and in this context the recent US studies are therefore important.17,33,37,46 The European study that independently reported PAS-C PLT transfusion increments included this as a control arm for a pathogen reduction trial. This study reported posttransfusion increments on 193 patients with 1-hour posttransfusion increments that were approximately 10% less with PAS and 24-hour increments that were 4% less, a difference that was not clinically significant.19 Subsequently two recent US studies have reported posttransfusion corrected count increments (CCIs) comparing plasma-SDP to PAS-SDP, one of which showed an approximately 24% CCI reduction at 1 hour, which was significant (p < 0.001), although the 18% to 19% 24-hour reduction in CCI was not, with no change in intertransfusion interval.33,37 Consequently clinical functionality appears acceptable and sets the stage for pathogen reduction systems that may require PAS as a posttreatment storage medium. In parallel with the clinical studies, development continues with fourth- and fifth-generation PAS, which include glucose for energy metabolism and bicarbonate as a pH stabilizer.47,48 These offer the opportunity for 90% to 95% plasma removal, and previous versions have been associated with comparable posttransfusion recoveries or prolonged storage capacity.11,43 The extent of plasma reduction becomes central when the avoidance of TRALI is considered since previous reports have suggested that even small quantities of residual plasma are capable 2600
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of initiating a TRALI event.49 A recent AABB workshop considered the application of PAS as a risk reduction strategy, and in conjunction with discontinuance of plasma product donation by females with HLA antibodies, this strategy may be effective. Certainly third-generation PAS application significantly reduces ABO titers to levels that may be sufficient to ameliorate the need for screening group O donors for high ABO titers.50 Although there may not be a direct relationship between anti-A or -B titers and febrile nonhemolytic reactions, the reduction in plasma antibody content is most effective in reducing hemolytic reaction rates, even if, as reported to the College of American Pathologists, few hospitals have routinely implemented ABO titering.51,52 A similar effective reduction in titer can be achieved through the use of PAS, although this may not directly relate to the reduction in FNHTRs.27,50 There also is the potential that the previously reported association between subsequent RBC antibody formation and febrile transfusion reactions may be benefited by broad adoption of PAS.53 Increased PC storage duration always raises the question of bacterial contamination risk, and studies have shown that although the doubling time is accelerated, the maximal bacterial load was unaffected.54 Since BacT/Alert detection is bacterial load based, it may be that the faster growth may support earlier detection and interdiction before unit release. In summary, the recent PAS approvals launch an opportunity for an improved patient experience and afford extra value in blood component utilization. This development offers a range of benefits to the many constituents involved in the production and transfusion of PCs. For the blood center the collection procedure is essentially identical and may avoid the need to return collected plasma, while PAS offers the opportunity to retain displaced plasma, which will support national supply sufficiency. For the hospital, it may reduce transfusion risk and simplify the logistics of ABO matching for PLT transfusions; for the doctor or patient it reduces transfusion reactions and should contribute to reduced TRALI risk. Since PAS-C and PAS-F already have latergeneration low-plasma products in scientific development, the fifth-generation versions may offer the opportunity for further transfusion reaction reduction; simplify donor logistics by eliminating the need for HLA screening of multiparous female donors; offer 10-day product storage opportunity, assuming that point-ofrelease bacterial screening supports adequate longstored product sepsis risk control.11,35
CONFLICT OF INTEREST The author has received lecture honoraria from Fenwal/ Fresenius and Terumo BCT and has served on the Medical Advisory Board of Verax, Inc.
EDITORIAL
Wm. Andrew Heaton, MD e-mail: [email protected] Transfusion Medicine Hofstra School of Medicine NSLIJ Health System Manhasset, NY
14. Gulliksson H, Eriksson L, Högman CF, et al. Buffy-coatderived platelet concentrates prepared from half-strength citrate CPD and CPD whole-blood units: comparison between three additive solutions: in vitro studies. Vox Sang 1995;68:152-9. 15. Wildt-Eggen D, Gulliksson H. In vivo and in vitro comparison of platelets stored in either synthetic media or plasma.
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Vox Sang 2003;84:256-64. 16. Hornsey VS, McColl K, Drummond O, et al. Extended storage of platelets in SSP+ platelet additive solution. Vox Sang 2006;91:41-6. 17. Diedrich B, Sandgren P, Jansson B, et al. In vitro and in vivo effects of potassium and magnesium on storage up to 7 days of apheresis platelet concentrates in platelet additive solution. Vox Sang 2008;94:96-102. 18. Vassallo RR, Adamson JW, Gottschall JL, et al. In vitro and in vivo evaluation of apheresis platelets stored for 5 days in 65% platlet additive solution/35% plasma. Transfusion 2010;50:2376-85. 19. Kerkhoffs JL, Van Putten WL, Novotny VM, et al. Clinical effectiveness of leucoreduced, pooled donor platelet concentrates, stored in plasma or additive solution with and without pathogen reduction. Br J Haematol 2010;150:20917.
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NewDrugApplicationsNDAs/UCM196957.pdf at www.FDA.gov. Dec 7, 2009. Simak J. Isoplate solution/platelet additive solution (PAS-F). BN 090067/0. Feb 19, 2013. [cited 2013 Sep 15]. Available from: URL: http://www.fda.gov/BiologicsBlood Vaccines/BloodBloodProducts/ApprovedProducts/ NewDrugApplicationsNDAs/ucm342639.htm FDA.gov.cber. Kacker S, Ness PM, Savage WJ, et al. The cost effectiveness of platelet additive solution to prevent allergic transfusion reactions. Transfusion 2013;53:2609-18. Holme S, Heaton WA, Whitley P. Platelet storage lesions in second-generation containers: correlation with in vivo behavior with storage up to 14 days. Vox Sang 1990;59: 12-8. Holme S, Heaton WA, Smith KT, et al. Evaluation of apheresis platelet concentrates collected with a reduced (30-mL) collection chamber with resuspension and storage in a synthetic medium. Vox Sang 1994;67:149-53. Murphy S, Kagen L, Holme S, et al. Platelet storage in synthetic media lacking glucose and bicarbonate. Transfusion 1991;31:16-20.
transfusion reactions to platelets and red blood cells through plasma reduction. Transfusion 2011;51: 1676-83. 23. Cardigan R, Sutherland J, Wadhwa M, et al. The influence of platelet additive solutions on cytokine levels and complement activation in platelet concentrates during storage. Vox Sang 2003;84:28-35. 24. Heddle NM, Klama L, Singer J, et al. The role of the plasma from platelet concentrates in transfusion reactions. N Engl J Med 1994;331:625-8. 25. Wadhwa M, Seghatchian MJ, Lubenko A, et al. Cytokine levels in platelet concentrates: quantitation by bioassays and immunoassays. Br J Haematol 1996;93:225-34. 26. Enright H, Davis K, Gernsheimer T, et al. Factors influencing moderate to severe reactions to PLT transfusions: experience of the TRAP multicenter clinical trial. Transfusion 2003;43:1545-52. 27. Yazer MH, Raval JS, Triulzi DJ, et al. ABO-mismatched transfusions are not over-represented in febrile nonhemolytic transfusion reactions to platelets. Vox Sang 2012; 102:175-7. 28. Silliman CC, Ambruso DR, Boshkov LK. Transfusionrelated acute lung injury. Blood 2005;105:2266-73.
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RegulatoryInformation/Guidances/Blood/ucm073382.htm 43. Heaton WA, Holme S, Keegan T. Development of a combined storage medium for 7-day storage of platelet concentrates and 42-day storage of red cell concentrates. Br J Haematol 1990;75:400-7. 44. Lozano M, Knutson F, Tardivel R, et al. A multi-centre study of therapeutic efficacy and safety of platelet components treated with amotosalen and ultraviolet A pathogen inactivation stored for 6 or 7 d prior to transfusion. Br J Haematol 2011;153:393-401. 45. McCullough J, Vesole DH, Benjamin RJ, et al. Therapeutic efficacy and safety of platelets treated with a photochemical process for pathogen inactivation: the SPRINT Trial.
34. Ezidiegwu CN, Lauenstein KJ, Rosales LG, et al. Febrile nonhemolytic transfusion reactions: management by pre-
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49. Win N, Chapman CE, Bowles KM, et al. How much residual plasma may cause TRALI? Transfus Med 2008;18: 276-80. 50. Becker JL, Mendez B, Striejewske J. Platelet additive solution is able to provide a product with predictably decreased titers of anti-A and B. Transfusion 2011;51:38A. 51. Fontaine MJ, Mills AM, Weiss S, et al. How we treat: risk mitigation for ABO-incompatible plasma in plateletpheresis products. Transfusion 2012;52:2081-5. 52. Quillen K, Sheldon SL, Daniel-Johnson JA, et al. A practical strategy to reduce the risk of passive hemolysis by screening plateletpheresis donors for high-titer ABO antibodies. Transfusion 2010;51:92-6. 53. Yazer MH, Triulzi DJ, Shaz B, et al. Does a febrile reaction to platelets predispose recipients to red blood cell alloimmunization? Transfusion 2009;49:1070-5. 54. Dumont LJ, Wood TA, Housman M, et al. Bacteria start growth earlier with slower doubling rates in PAS platelets compared to platelets in plasma. Transfusion 2009;49:44A.
O
ver the past decade, platelet concentrates (PCs) have shown the greatest increases in blood product demand, being required both by changing population demographics, as well as by cancer therapy advances. At present these products are not routinely stored longer than 5 days, which increases logistic complexity and outdating. This abbreviated room temperature storage period followed early studies showing that these cells cannot be stored in the cold while maintaining posttransfusion survival.1 Room temperature storage was later shown to require gaspermeable containers to support the significant metabolic needs of higher energy turnover requirements associated with the higher temperature.2,3 Although subsequent studies provided more insight into the cause of the cold effect, this problem could not be easily ameliorated, and the next generational change in platelet (PLT) storage improvement focused on the approach of removing plasma and red blood cell (RBC)-focused nutrients, with replacement by PLT additive solutions (PASs).4-7 Three groups of investigators evaluated PLT storage options utilizing the application of electrolyte media to replace supernatant plasma, defining a physiologic electrolyte medium, and identifying the optimal nutrients to support cell energy production without incurring a pH penalty, since these manipulations had been associated with reduced PLT quality. The first commercial PAS was pioneered by Claes Hogman and launched in Sweden in 1991 followed over the next 20 years by several generational changes. With the recent approvals of PAS-C (PAS-3 or Intersol, Fresenius-Kabi, Lake Zurich, IL) and PAS-F (Isoplate, Terumo BCT, Denver, CO), PAS is now routinely available in the United States.8,9 Similar to RBC ASs (AS-1, -3, -5), PAS affords a number of operational advantages, including the potential for reduced transfusion reactions, enhanced plasma recovery, and improved cell quality. However, as the more than 5-year transition from CPDA-1 to AS demonstrated, the transition from one storage solution to another may take a surprisingly long time as the manufacturing process changes are learned, the improved clinical outcomes prove out, and the economic advantages become apparent. In this context, the article by Kacker and colleagues10 on the cost-effectiveness of PAS in preventing transfusion reactions in this edition of TRANSFUSION is an essential first step toward defining the product value to the hospital community, as the transfusion medicine community contemplates large-scale conversion of PC manufacture to PAS. TRANSFUSION 2013;53:2597-2602.
Early PAS development focused on plasma substitution, utilizing an electrolyte intravenous solution containing sodium chloride, gluconate, and acetate (Plasmalyte, Baxter International, Deerfield, IL).5 Subsequent scientific development included a systematic evaluation of various physiologic elements of plasma to ensure optimal PLT metabolic preservation,6 followed by the identification of acetate as an optimal energy substrate with the desirable attribute of supporting poststorage pH preservation.7 The various product generational changes were mostly dictated by the need for manufacturing simplicity, associated with a stepwise approach toward regulatory approval, since although the early studies had identified a 10-day storage potential, formulation refinement was essential for manufacturing.11,12 PAS-1 included only simple salt solutions associated with significant plasma carryover, and since glucose remained the primary PLT energy substrate, later studies showed that the reduced bicarbonate carryover was inadequate to maintain acceptable viability.13 The second-generation PAS-2 (T-Sol, Fenwal, Fresenius-Kabi) included acetate as a metabolic substrate, and although these improved both in vitro and in vivo variables, posttransfusion recoveries were modestly but significantly less than plasma PCs.14-17 However, the association of PAS-2 with significant reductions in posttransfusion reactions resulted in gradually increasing European uptake. Subsequently a number of extra additives were included to improve cell quality, including phosphate; K+ and Mg2+ salts; and in some cases, gluconate to improve energy metabolism, reduce metabolic stress, or enhance cell stability, which was anticipated to improve posttransfusion recoveries.16,17 It is the thirdgeneration PAS-C (PAS-3, Intersol, Fresenius-Kabi), which includes higher phosphate levels, that was first approved in the United States, a product previously mostly associated with pathogen reduction solutions.18,19 European studies had documented acceptable posttransfusion increments with PAS-C, and although the addition of K+ and Mg2+ salts improved in vitro values, this step did not result in commensurate in vivo improvements to alternative solutions.17 A fourth-generation PAS (PAS-F in ISBT nomenclature) has recently also been approved in the United States (Isoplate, Terumo BCT, Lakewood, CO).20 Both PAS-C and PAS-F have exhibited posttransfusion recoveries that meet the latest US FDA in vivo standards.18,20 PAS-C and PAS-F exhibited posttransfusion recoveries averaging 80.5 and 87% and survivals averaging 72 and 78% of the respective recovery and/or survival of contemporaneous fresh PLTs: the first new products to require contemporaneous poststorage comparison with Volume 53, November 2013 TRANSFUSION
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untreated fresh cells. These easily exceeded the 66% and more than 58% standards now demanded of new products. Since these solutions have either mostly been utilized clinically in association with pathogen reduction systems (INTERCEPT Cerus, Concord, CA) or alternatively represent variants of European earlier generation solutions, there are relatively few publications upon their clinical efficacy. As a result the Center for Biologics Evaluation and Research (CBER, FDA) has requested postmarketing studies, to affirm posttransfusion reaction noninferiority, the first of which has recently been reported at the transfusion-related acute lung injury (TRALI) mitigation workshop.21 These studies of 14,005 transfusions in three centers to 3646 recipients, where reactions were monitored according to the NSHN guidelines, showed a significant reduction in reactions from 1.37% to 0.55%. This 60% decrease may be related to the 55% modeled in the studies by Kacker and colleagues.10 Transfusion reactions after receiving PCs are more common than with other blood products and are largely an effect of (22°C) room temperature storage associated with the synthesis or release of many cell mediators known to cause recipient reactions.22-25 Reactions range from the more common mild allergic urticaria, through febrile nonhemolytic transfusion reactions (FNHTRs), to more severe manifestations with anaphylaxis or significant pulmonary symptoms, which have been classified by NSHN. After universal leukoreduction, which reduced white blood cell (WBC)-synthesized mediators, the recent incidence has been reported to range from 1% to 3%.21-24 Analysis of risk factors has led to the identification of a wide range of proinflammatory PLT cytokines, together with plasma complement fragments, bradykinins, and other biologic response modifiers or biogenic amines.25,26 Although PCs are antigenic, there was less relationship between transfusion-induced HLA or PLT antibody and reaction incidence than with the residual WBC load or storage duration.26 Recent reports have suggested that ABO incompatible plasma in PLTs is not similarly associated with FNHTRs.27 In addition to product characteristics there is evidence that recipient characteristics may interact with the product to induce reactions, with IgA deficiency being an especial concern. Analysis of TRALI reports has suggested that a combination of recipient conditioning events together with transfused mediators may be necessary to cause the pulmonary symptoms, which continues to be associated with approximately 17 reported transfusion-associated deaths per year.28,29 Since reactions are more frequent in a heavily transfused patient population, routine pretransfusion medication with antipyretics and antihistamines is common, although an increasing number of reviews have suggested that premedication is without systematic benefit.30-32 These reactions may be disruptive to both the patient and the physician in that the reaction may delay patient discharge 2598
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and may cause premature transfusion termination such that additional work-ups must be performed, with extra clinical and laboratory physician time being required.33,34 The recognition that significant numbers of PCs may have bacterial contamination has also increased the need for more intense and timely transfusion reaction analysis, which will increase the cost further.35 Since PAS is applied to the PC at the end of collection, it does not affect the separation process, but does reduce final product plasma load, and dilutes any preformed mediators. Early European studies mostly reported on PLT storage in PAS-2 (T-Sol) showed an overall approximately 50% reduction in reactions.15,36 The HOVON PAS-C study included analysis of posttransfusion increments and reactions over 7 days of PAS-3 22°C storage as the independent PAS-3 control within a pathogen reduction evaluation and showed a reduction in reactions from 11% to 9%.19 The recent US PAS-C studies on prestorage leukoreduced PCs showed a per-patient allergic reaction reduction from 3.13% to 0.83% and an FNHTR reduction from 1.91% to 0.48%, with some variability depending upon the institution.21,33,37 The overall odds ratio of reaction reduction of 0.403 was significant.21 In an alternative strategy where PAS was used to replace supernatant plasma shortly before transfusion to a small group of highly reactive recipients (akin to PLT washing), reactions in highly sensitized PLTs were reduced from 42% to 0.6%.38 As an alternative approach PC supernatant reduction to less than 100 mL or washing has been used to reduce transfusion reactions by 73 and 95%, respectively, and although the percentage of allergic transfusion reduction was greater with concentration and washing than with PAS, the differences were not significant in a recent comparison.22,23 Since the reactions in heavily transfused recipients are so common, and these may range from urticarial reactions to more rare anaphylactic reactions associated with pulmonary symptoms, it may be difficult to discourage the routine pretransfusion medication practice that has become commonplace.39 The studies reported by Kacker and coworkers in this issue of TRANSFUSION follow up on earlier studies that evaluated the benefit of plasma reduction to 100 mL, in comparison as an alternative to washing PLTs to achieve maximal plasma load reduction.22 Since PAS-SDP at a 35% residual plasma level may be expected to retain approximately 90 mL of residual plasma this might be expected to achieve comparable benefit. These studies evaluated the cost-effectiveness of inclusion of PAS as a corrective or a preemptive measure to reduce reactions. Assuming a hospital perspective that a PAS purchase decision would be based on an approach of direct achievable medical cost avoidance, the studies evaluated different methods of escalation of PC plasma reduction to respond to post–PC transfusion reactions.10 Transfusion scenarios were based on four outcomes: no reaction, a mild initial reaction,
EDITORIAL
repeat mild reactions, and severe reactions. Scenarios included plasma reduction by centrifugation in one arm later followed by PLT washing as the reaction level escalated: compared to the application of PAS either as a primary preemptive measure or as a secondary reactive measure upon initial reaction. A number of assumptions were made about reaction frequency and clinical response, which generally followed the direction of the earlier studies.22 The cost estimates of corrective action included the frequency of events associated with different approaches to unit processing, prophylactic medication, and implicated unit discard. Assumptions were made in connection with direct material and labor costs of plasma volume reduction or washing, as well as of the cost of pretransfusion medication, which was modeled based on reaction frequency and intensity. The analysis reviewed the effect of reactions upon operational transfusion costs, product loss, through reaction-associated product discontinuance, along with the estimated cost of reaction work-ups. These costs and frequency were then modeled using a Markov-based decision tree model to evaluate the financial outcomes relative to the cost of the health impact. Key assumptions included an assumption of a 1.57% isolated mild reaction rate, that 10% of these reactions resulted in a modified treatment with unit discontinuance, and that 0.13% of recipients had severe reactions. A 73% corrective response of plasma reduction was presumed along with a 95% correction based on washing based on the earlier studies, in comparison to a 56% reduction anticipated with PAS. The cost of routine pretransfusion medication with diphenhydramine at $4.11 was taken from an earlier study and assumed to occur in 67% of cases.33,34 A number of other assumptions related to the effect of severe reaction on increased hospitalization length of stay, and other hospital costs were taken from published data. These costs were then analyzed in multiple individual trials for each simulation and an average estimated along with a sensitivity analysis. The incremental effect of different PAS cost on apheresis PLT product transfusion costs were evaluated based on a PAS premium in the range of $5 to $50 per PC. Base case evaluation suggested that application of PAS would reduce transfusion cost by a median of approximately $1.65 to $2.03 if PAS was used only in response to a reaction, depending on the PAS cost range. Once PAS was applied prophylactically to avoid reactions, the incremental cost was $0.85 if PAS cost a premium of $10/unit and decreased the overall cost by $1.89 if pretransfusion medication was discontinued. One-way sensitivity analysis showed that prophylactic application of PAS-SDP reduced cost approximately $ 9.14 and that if changed prophylactic drug therapy was included the savings increased to $11.90. The probabilistic cost per reaction avoidance was $119/ reaction at $10 PAS increment and $678/reaction at a $15
PAS increment. These numbers should be related to the reported decrease in posttransfusion reactions of 60% in the recent US PAS-C study, suggesting that the final direct avoidable cost with drug pretransfusion medication elimination would be more than $12 per transfusion. In addition to the clinical advantages and cost benefit, there is the additional value of the extra plasma displaced by PAS utilization. Since both PAS-3 and PAS-F approvals include intended-use statements describing the application of the solutions in a 35%/65% split between plasma and PAS and the average actual plasma SDP supplied to the reviewer by the New York Blood Center has a volume of 252 mL, an average 35% of this volume will be displaced by the application of PAS in a single-unit collection. In practice, however, few SDPs are collected as single units, since most are now split in 1/2 or 1/3. Under these circumstances, each PAS-SDP unit requires plasma loads that are dictated by the manufacturer’s package inserts (operator’s manuals). These are developed based on the computer algorithms that are included in the current versions of the device software and are designed to ensure that the PC stays within predetermined limits that define the minimum and maximum PLT and plasma content that can sustain 5-day PLT storage at 22°C, while remaining within certain defined poststorage target pH levels. Since apheresis devices utilize a variable (approx. 1:9 to 1:10) ratio of ACD:whole blood as part of the collection process, it is possible to estimate how much plasma will be displaced by the application of PAS and which would now become available as source plasma for further manufacture. The PAS approvals have also included a recommendation that no more than 90% of the PAS-displaced plasma be harvested with an outside limit that no more than 5 mL of extra plasma may be collected than would have been required for a plasma PC.8,9,40 Greater plasma harvest results in the donor qualifying for the deferral obligations of the infrequent source plasma guideline, which include a 28-day deferral.41,42 The effect of these regulations and the 35/65 split of plasma:PAS in SDP products means that blood centers can ordinarily collect the displaced plasma which will vary based on the approved device collection algorithms that allows more plasma for triple products than for single products. Based on local per-SDP-product-volume experience this volume would average approximately 150 mL per product distributed or if a 40% single, 40% double, and 20% triple collection split rate is assumed, the extra available plasma per collection could increase by ∼250 mL per donation. This extra plasma could be expanded if the collection center opted to collect plasma according to the 1995 updated FDA requirement for infrequent plasma donors, which allows for collection of 500 mL of plasma for donors less than 175 lb and 600 mL of plasma for donors more than 175 lb.41 Since all devices are approved for the preparation of source plasma, and assuming a current Volume 53, November 2013 TRANSFUSION
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global price of $0.15/mL, PAS would allow the availability of an additional $24/product to $38/collection, which would likely cover the direct material PAS costs. Clearly, however, the blood center would incur additional labor costs and other expenses that may lessen the economic gains of the additional plasma recovery. If the blood center elected to convert such plateletpheresis donors to combined plasma and PLT donors (and accept the 28-day deferral), the plasma harvest could more than double depending on donor weight characteristics, with the Amicus device being cleared for an additional 100 mL of infrequent plasma harvest per month.41,42 A goal of PAS development included prolonged storage of greater than 7 days, and the PAS-C now used in conjunction with amotosalen pathogen reduction is increasingly used for 7-day storage in the EU.43,44 Manufacturing limitations, however, required a generational approach toward PAS implementation with the effect that PAS-2 exhibited reduced posttransfusion recoveries when compared to plasma controls.15,36 Few independent posttransfusion increment studies of PAS-C have been reported, since Intersol has mostly been combined with Intercept, the combination of which may affect posttransfusion increments.19,45 Isoplate is different enough from the most comparable European solutions and available radioisotope in vivo study reports are limited, such that posttransfusion increments are difficult to predict, and in this context the recent US studies are therefore important.17,33,37,46 The European study that independently reported PAS-C PLT transfusion increments included this as a control arm for a pathogen reduction trial. This study reported posttransfusion increments on 193 patients with 1-hour posttransfusion increments that were approximately 10% less with PAS and 24-hour increments that were 4% less, a difference that was not clinically significant.19 Subsequently two recent US studies have reported posttransfusion corrected count increments (CCIs) comparing plasma-SDP to PAS-SDP, one of which showed an approximately 24% CCI reduction at 1 hour, which was significant (p < 0.001), although the 18% to 19% 24-hour reduction in CCI was not, with no change in intertransfusion interval.33,37 Consequently clinical functionality appears acceptable and sets the stage for pathogen reduction systems that may require PAS as a posttreatment storage medium. In parallel with the clinical studies, development continues with fourth- and fifth-generation PAS, which include glucose for energy metabolism and bicarbonate as a pH stabilizer.47,48 These offer the opportunity for 90% to 95% plasma removal, and previous versions have been associated with comparable posttransfusion recoveries or prolonged storage capacity.11,43 The extent of plasma reduction becomes central when the avoidance of TRALI is considered since previous reports have suggested that even small quantities of residual plasma are capable 2600
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of initiating a TRALI event.49 A recent AABB workshop considered the application of PAS as a risk reduction strategy, and in conjunction with discontinuance of plasma product donation by females with HLA antibodies, this strategy may be effective. Certainly third-generation PAS application significantly reduces ABO titers to levels that may be sufficient to ameliorate the need for screening group O donors for high ABO titers.50 Although there may not be a direct relationship between anti-A or -B titers and febrile nonhemolytic reactions, the reduction in plasma antibody content is most effective in reducing hemolytic reaction rates, even if, as reported to the College of American Pathologists, few hospitals have routinely implemented ABO titering.51,52 A similar effective reduction in titer can be achieved through the use of PAS, although this may not directly relate to the reduction in FNHTRs.27,50 There also is the potential that the previously reported association between subsequent RBC antibody formation and febrile transfusion reactions may be benefited by broad adoption of PAS.53 Increased PC storage duration always raises the question of bacterial contamination risk, and studies have shown that although the doubling time is accelerated, the maximal bacterial load was unaffected.54 Since BacT/Alert detection is bacterial load based, it may be that the faster growth may support earlier detection and interdiction before unit release. In summary, the recent PAS approvals launch an opportunity for an improved patient experience and afford extra value in blood component utilization. This development offers a range of benefits to the many constituents involved in the production and transfusion of PCs. For the blood center the collection procedure is essentially identical and may avoid the need to return collected plasma, while PAS offers the opportunity to retain displaced plasma, which will support national supply sufficiency. For the hospital, it may reduce transfusion risk and simplify the logistics of ABO matching for PLT transfusions; for the doctor or patient it reduces transfusion reactions and should contribute to reduced TRALI risk. Since PAS-C and PAS-F already have latergeneration low-plasma products in scientific development, the fifth-generation versions may offer the opportunity for further transfusion reaction reduction; simplify donor logistics by eliminating the need for HLA screening of multiparous female donors; offer 10-day product storage opportunity, assuming that point-ofrelease bacterial screening supports adequate longstored product sepsis risk control.11,35
CONFLICT OF INTEREST The author has received lecture honoraria from Fenwal/ Fresenius and Terumo BCT and has served on the Medical Advisory Board of Verax, Inc.
EDITORIAL
Wm. Andrew Heaton, MD e-mail: [email protected] Transfusion Medicine Hofstra School of Medicine NSLIJ Health System Manhasset, NY
14. Gulliksson H, Eriksson L, Högman CF, et al. Buffy-coatderived platelet concentrates prepared from half-strength citrate CPD and CPD whole-blood units: comparison between three additive solutions: in vitro studies. Vox Sang 1995;68:152-9. 15. Wildt-Eggen D, Gulliksson H. In vivo and in vitro comparison of platelets stored in either synthetic media or plasma.
REFERENCES 1. Murphy S, Gardner FH. Platelet preservation effect of storage temperature on maintenance of platelet viability— deleterious effect of refrigerated storage. N Engl J Med 1969;280:1094-98. 2. Murphy S, Kahn RA, Holme S, et al. Improved storage of platelets for transfusion in a new container. Blood 1982;60: 194-200. 3. Kilkson H, Holme S, Murphy S. Platelet metabolism during storage of platelet concentrates at 22 degrees C. Blood 1984;64:406-14. 4. Wandall HH, Hoffmeister KM, Sørensen AL, et al. Galactosylation does not prevent the rapid clearance of long-term, 4 C-stored platelets. Blood 2008;111: 3249-56. 5. Rock GA, Adams GA. Plasma-free medium for platelet
Vox Sang 2003;84:256-64. 16. Hornsey VS, McColl K, Drummond O, et al. Extended storage of platelets in SSP+ platelet additive solution. Vox Sang 2006;91:41-6. 17. Diedrich B, Sandgren P, Jansson B, et al. In vitro and in vivo effects of potassium and magnesium on storage up to 7 days of apheresis platelet concentrates in platelet additive solution. Vox Sang 2008;94:96-102. 18. Vassallo RR, Adamson JW, Gottschall JL, et al. In vitro and in vivo evaluation of apheresis platelets stored for 5 days in 65% platlet additive solution/35% plasma. Transfusion 2010;50:2376-85. 19. Kerkhoffs JL, Van Putten WL, Novotny VM, et al. Clinical effectiveness of leucoreduced, pooled donor platelet concentrates, stored in plasma or additive solution with and without pathogen reduction. Br J Haematol 2010;150:20917.
storage. US Patent No. 4,447,415. Issued May 8, 1984. 6. Holme S. Synthetic, plasma-free, transfusible platelet storage medium. US Patent No. 4,695,460. Issued Sep 22,
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8. Haddad S. Intersol solution/platelelet additive solution 3. BN 080041/0. [cited 2013 Sep 15]. Available from: URL:
units. Transfusion 2013;53:13A-278A. 22. Tobian AA, Savage WJ, Tisch DJ, et al. Prevention of allergic
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NewDrugApplicationsNDAs/UCM196957.pdf at www.FDA.gov. Dec 7, 2009. Simak J. Isoplate solution/platelet additive solution (PAS-F). BN 090067/0. Feb 19, 2013. [cited 2013 Sep 15]. Available from: URL: http://www.fda.gov/BiologicsBlood Vaccines/BloodBloodProducts/ApprovedProducts/ NewDrugApplicationsNDAs/ucm342639.htm FDA.gov.cber. Kacker S, Ness PM, Savage WJ, et al. The cost effectiveness of platelet additive solution to prevent allergic transfusion reactions. Transfusion 2013;53:2609-18. Holme S, Heaton WA, Whitley P. Platelet storage lesions in second-generation containers: correlation with in vivo behavior with storage up to 14 days. Vox Sang 1990;59: 12-8. Holme S, Heaton WA, Smith KT, et al. Evaluation of apheresis platelet concentrates collected with a reduced (30-mL) collection chamber with resuspension and storage in a synthetic medium. Vox Sang 1994;67:149-53. Murphy S, Kagen L, Holme S, et al. Platelet storage in synthetic media lacking glucose and bicarbonate. Transfusion 1991;31:16-20.
transfusion reactions to platelets and red blood cells through plasma reduction. Transfusion 2011;51: 1676-83. 23. Cardigan R, Sutherland J, Wadhwa M, et al. The influence of platelet additive solutions on cytokine levels and complement activation in platelet concentrates during storage. Vox Sang 2003;84:28-35. 24. Heddle NM, Klama L, Singer J, et al. The role of the plasma from platelet concentrates in transfusion reactions. N Engl J Med 1994;331:625-8. 25. Wadhwa M, Seghatchian MJ, Lubenko A, et al. Cytokine levels in platelet concentrates: quantitation by bioassays and immunoassays. Br J Haematol 1996;93:225-34. 26. Enright H, Davis K, Gernsheimer T, et al. Factors influencing moderate to severe reactions to PLT transfusions: experience of the TRAP multicenter clinical trial. Transfusion 2003;43:1545-52. 27. Yazer MH, Raval JS, Triulzi DJ, et al. ABO-mismatched transfusions are not over-represented in febrile nonhemolytic transfusion reactions to platelets. Vox Sang 2012; 102:175-7. 28. Silliman CC, Ambruso DR, Boshkov LK. Transfusionrelated acute lung injury. Blood 2005;105:2266-73.
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29. Food and Drug Administration. Annual summary for fiscal
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31. Kennedy LD, Case LD, Hurd DD, et al. A prospective, randomized, double-blind controlled trial of acetaminophen and diphenhydramine pretransfusion medication versus placebo for the prevention of transfusion reactions. Transfusion 2008;48:2285-91. 32. Sanders RP, Maddirala SD, Geiger TL, et al. Premedication with acetaminophen or diphenhydramine for transfusion with leucoreduced blood products in children. Br J Haematol 2005;130:781-7. 33. Tobian AA, Fuller AK, Uglik K, et al. The impact of platelet additive solution apheresis platelets on allergic transfusion reactions and corrected count increment. Transfusion 2013;53:13A-278A.
RegulatoryInformation/Guidances/Blood/ucm073382.htm 43. Heaton WA, Holme S, Keegan T. Development of a combined storage medium for 7-day storage of platelet concentrates and 42-day storage of red cell concentrates. Br J Haematol 1990;75:400-7. 44. Lozano M, Knutson F, Tardivel R, et al. A multi-centre study of therapeutic efficacy and safety of platelet components treated with amotosalen and ultraviolet A pathogen inactivation stored for 6 or 7 d prior to transfusion. Br J Haematol 2011;153:393-401. 45. McCullough J, Vesole DH, Benjamin RJ, et al. Therapeutic efficacy and safety of platelets treated with a photochemical process for pathogen inactivation: the SPRINT Trial.
34. Ezidiegwu CN, Lauenstein KJ, Rosales LG, et al. Febrile nonhemolytic transfusion reactions: management by pre-
Blood 2004;104:1534-41. 46. Cardigan R, Cooke L, Cookson P, et al. Recovery and sur-
medication and cost implications in adult patients. Arch Pathol Lab Med 2004;128:991-5. 35. Jacobs MR, Smith D, Heaton WA, et al. Detection of bacte-
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37. Galloway-Haskins R, Heaton WA, Nikolis N, et al. Post PAS 3 launch reaction rates (RR) and increments at North
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Shore University Hospital (NSUH). Transfusion 2013; 53(Suppl):190A. Azuma H, Hirayama J, Akino M, et al. Reduction in adverse reactions to platelets by the removal of plasma supernatant and resuspension in a new additive solution (M-sol). Transfusion 2009;49:214-8. Tobian AA, King KE, Ness PM. Transfusion premedications: a growing practice not based on evidence. Transfusion 2007;47:1089-96. Golding B. FDA 510k clearance memorandum BK 100044 Summary. Amicus separator system. [cited 2013 Sep 15]. Available from: URL: http://www.fda.gov/downloads/ BiologicsBloodVaccines/BloodBloodProducts/ ApprovedProducts/SubstantiallyEquivalent510kDevice Information/UCM236346.pdf FDA.gov.cber. July 29th, 2010. FDA Memorandum. Revision of FDA memorandum of August 27, 1982: requirements for infrequent plasmapher-
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49. Win N, Chapman CE, Bowles KM, et al. How much residual plasma may cause TRALI? Transfus Med 2008;18: 276-80. 50. Becker JL, Mendez B, Striejewske J. Platelet additive solution is able to provide a product with predictably decreased titers of anti-A and B. Transfusion 2011;51:38A. 51. Fontaine MJ, Mills AM, Weiss S, et al. How we treat: risk mitigation for ABO-incompatible plasma in plateletpheresis products. Transfusion 2012;52:2081-5. 52. Quillen K, Sheldon SL, Daniel-Johnson JA, et al. A practical strategy to reduce the risk of passive hemolysis by screening plateletpheresis donors for high-titer ABO antibodies. Transfusion 2010;51:92-6. 53. Yazer MH, Triulzi DJ, Shaz B, et al. Does a febrile reaction to platelets predispose recipients to red blood cell alloimmunization? Transfusion 2009;49:1070-5. 54. Dumont LJ, Wood TA, Housman M, et al. Bacteria start growth earlier with slower doubling rates in PAS platelets compared to platelets in plasma. Transfusion 2009;49:44A.
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