The growing practice of “splitting” double-dose apheresis platelet products

The growing practice of “splitting” double-dose apheresis platelet products

Transfus. Sci. 1993; 14:364-368 Printed in Great Britain. All rights reserved 0955-3886/93 $6.00+0.00 Copyright 9 1993 Pergamon Press Ltd Hemapheres...

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Transfus. Sci. 1993; 14:364-368 Printed in Great Britain. All rights reserved

0955-3886/93 $6.00+0.00 Copyright 9 1993 Pergamon Press Ltd

Hemapheresis Listening Post The Growing Practice of "Splitting" Double-dose Apheresis Platelet Products

A review of blood collection and transfusion statistics compiled during the past five years reveals that the collection and transfusion of platelets using apheresis techniques has significantly grown. ~Heightened awareness of the risk of disease transmission via blood transfusion coupled with the ability to decrease this risk by using apheresis products on the part of both physicians and patients have directly contributed to this growth. While the demand for these products has increased, blood collection facilities have witnessed a significant erosion of the donor base. Increased viral marker testing and more aggressive donor history assessments have caused an increased portion of the population to be designated as ineligible as blood donors. The dichotomy of increasing demand and dwindling supply have caused blood collection facilities to review their apheresis policies and procedures in an effort to expand the number of patients that can be transfused from a single apheresis platelet, in essence, doing more with less. Current technology allows an operator of apheresis equipment to manipulate the "routine" procedure and obtain a product with extremely high platelet yields, often more than twice the minimum yield required by the U.S. Food and Drug Administration IFDAI and the American Association of Blood Banks IAABB}. As a result, many collection facilities have implemented programs designed to almost routinely collect "double-dose" platelet products. These products are then divided into two therapeutic doses thereby enabling two patients to benefit from a single apheresis platelet collection. Splitting double-dose apheresis platelet products has become common practice in many facilities yet regulations assuring consistent quality for the final product have yet to be formulated. Without such regulations, many issues warranting extensive discussion have surfaced. This paper presents some of these concerns. QUALITY As mentioned earlier, split apheresis platelet products are a relatively new phenomenon. As with the introduction of any new product, quality is of prime importance. With this product one must be concerned with both the quality of the final product as well as quality of the production process, especially since there are no established procedures for its production. Platelet viability during storage is directly related to various factors that affect platelet metabolism. These factors include platelet concentration, storage temperature, pH, plasma volume, storage container permeability and container agitation. Before receiving FDA approval, the manufacturers have demonstrated to the FDA that the viability of the platelets is assured most of the time ff the procedure is followed 364

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by the operator. In order to obtain a quantity of platelets sufficient to generate a split product, procedural modifications must often be made. It is imperative that the facility choosing to prepare split products evaluate fully the effects of these modifications on the final product quality. Some of the parameters of concern include the following: Ratio of Container Surface Area to Platelet Concentration

The viability of stored platelets is directly related to the concentration of platelets contained in the plastic storage bag. If the storage temperature is constant, the platelet has a constant oxygen requirement. 2 Therefore, the number of platelets that can be stored is dependent upon the permeability of the storage container. There is a linear relationship between the upper limit of platelets that may be stored and the permeability of the platelet storage container, a A large number of platelets can exceed the available oxygen within the plastic container resulting in an increased production of lactic acid and a subsequent decrease in platelet quality. Caution must be taken to the quantity of platelets stored in a given bag. Ratio of Container Surface Area to Total Plasma Volume

If, by modifying the collection procedure, the plasma volume routinely collected is increased, the ratio of container surface area to total plasma volume is altered. The final pH of the product is maintained by the permeability of the container. There is a direct relationship between volume of the plasma exposed to the inner surface of the container and the material which comprises the container. Increasing the volume of plasma to be stored in a container of a given size alters this ratio and may adversely affect the final pH. Quality assurance programs need to be adjusted to test for the average plasma volume obtained from the modified procedure, not for the average plasma volume using the non-modified procedure. In fact, questions arise as to whether or not those products tested for quality assurance should represent the average volume of those at the upper end of the expected volume range. Ratio of Plasma Volume to Platelet Concentration

In order to produce two split products which meet the m i n i m u m criteria for transfusion established by the FDA and the AABB, the procedure must be modified so that more than the average number of expected platelets is collected. Unless the volume of plasma is proportionately altered, the ratio of plasma volume to platelet concentration is altered. This could have a detrimental effect on the final pH of the product as by-products of platelet metabolism increase. Quality assurance programs need to be adjusted to test for the average platelet concentration obtained from the modified procedure, not for the average platelet yield using the non-modified procedure. In fact, questions arise as to whether or not those products tested for quality assurance should represent the average yield of those at the upper end of the expected yield range. Manufacturer's Instructions and Recommendations

A search of the literature indicates that there is an insufficient amount of published studies indicating the m a x i m u m platelet concentration which will still maintain a quality product. The Haemonetics apheresis CLX storage container was studied by Kenney et al. demonstrating platelet viability for yields up to 5.2 x 10 u for a dual bag system or 2.6 x 1011 per bag.* Fenwal notes an upper platelet yield of 3.3 x 10 n per single PL732 storage container in their literature s while the COBE literature recommends storage volumes of 150--400 mL per bag with an upper limit u 14t4~

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of 8.4 x 10 x~platelets. 6 It is clear that more study regarding the upper limits of platelet concentration and volume collected needs to be done before a standardized procedure can be developed. In the absence of such a standardized procedure, however, the facility which chooses to modify the approved collection procedure is responsible for demonstrating the acceptable quality of a product which exceeds the average expected platelet yield or volume of plasma. Preparation Anomalies

It cannot be assumed that splitting a product into two equal volumes will result in two equal components. In fact, unless the splitting procedure is strictly controlled, the final result may be two products with radically different platelet concentrations. A splitting procedure must be developed which has been demonstrated to produce t w o final platelet products which meet all of the facility's quality assurance parameters, including the targeted average collection goal. Quality assurance testing must be performed on both final products, in addition to a sample from the whole. Once developed, strict adherence to this procedure must be maintained. Finally, it must be recognized that the splitting process will cause some loss of platelets. Our own data suggests that the median platelet loss is 0.3 x 1011 Irange = 0-0.7 x 10 H) when apheresis platelets are split. The platelet loss must be considered when developing eligibility criteria for splitting of apheresis products. THERAPEUTIC EFFECTIVENESS OF SPLIT APHERESIS PLATELETS

Regardless of the definition of an acceptable platelet dose created by the FDA or the AABB7, the average concentration of apheresis platelets prepared by a collection facility is in reality the standard by which clinicians judge the efficacy of a product. Over the course of time, a clinician will empirically expect a certain percentage rise in the patient's platelet count for every apheresis platelet transfused. In most instances, the expectation has been developed through use of the product, not the application of formulas. Usage patterns are created from fulfilment of the clinician's expectation. Splitting apheresis platelet products may have the effect of lowering the overall average platelet concentration of apheresis platelet products produced by a facility if the split product is not equal to the facility's present standard. The lower average means that these products will no longer be able to meet the clinician's expectations. Unless a successful education program has been implemented, demand for products may increase, not because of any real need, but because of unmet expectations. This increase in demand may eliminate any potential supply gains realized from product splitting. It is imperative that the users and the suppliers have a clear understanding of the expected results. The collection facility must develop standards which incorporate the agreed upon expectations. Clinicians must be a part of the decision. If, for example, the clinician's expectation is a product that contains 4.0 x 101' platelets in order to be therapeutically effective, either through historical use or through facility education, the facility must ensure that this standard is met, not merely the minimum standards established by the FDA and the AABB. This does not suggest that changes cannot be made, but rather that changes cannot be made in a vacuum. Doing so will only serve to undermine the entire process resulting in the realization of gains in one area at the expense of other areas. CUSTOMER NOTIFICATION Once it has been demonstrated that the split product meets all quality assurance standards of the facility, the medical director of each transfusing institution must be

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notified, in writing, of the new product, its overall effect on current practice and expectations, content and instructions for use, etc. Available literature uses data from non-split products. It is the responsibility of the collecting facility to ensure that the literature distributed to its transfusing facilities concerning the products produced reflect the products produced, especially if the product differs siL'nificantly from those described in the literature. Failing to do so perpetuates unmet expectations on the part of the clinician. D O N O R NOTIFICATION

The collection procedure used to obtain products eligible for splitting differs from routine procedures especially in terms of time required from the donor. It is the responsibility of the collection facility to fully explain the process to the donor so that the donor's expectations are met. Failing to inform the donor of the process may erode the donor's confidence thereby indirectly further eroding the donor base. PRICING

In this economic climate of cost containment, the issue of price must be addressed, particularly if a product has the potential of affecting usage patterns. Pricing decisions should actively involve the consumer. For example, if a lower average platelet yield is expected to result in a 10% increase in product demand, the consumer has a vested interest in a pricing strategy which does not increase the overall cost of the consumer, since the increased demand was caused by the actions of the supplier, not the consumer. On the other hand, if the average platelet yield is maintained and more products are produced from the same number of disposables, the supplier may decide to reduce the price of apheresis platelets and pass along the resulting savings to the consumer. As a result, the supplier may find that the new pricing structure is especially attractive to the user, resulting in an increased demand for apheresis platelets and a reduction of requests for platelet concentrates. A decision to leave the price stable, thereby increasing revenue to the center, without the participation of the consumer may eventually result in bad publicity and resultant consumer distrust. DISCUSSION

While the ability to expand the number of patients that can be transfused from a single apheresis platelet is quite attractive, without proper quality control and communication from the collection center, this program can result in a product that is inferior in therapeutic benefit and an erosion in donor and hospital confidence in the collection center. Establishing guidelines for split products is difficult when presently, storage guidelines for single apheresis products are in question. While the current FDA guidelines and AABB standards for pH of platelet preparations is a pH greater than 6.0, studies have correlated decreased in v~vo survival with decreasing levels of pH. s This has led some investigators to recommend pH levels between 6.8 and 7.4. 9 In my investigation of the "splitting" process to identify upper platelet yield boundaries for available storage containers it became apparent that published parameters were limited. Most of the work submitted to the FDA by the manufacturers did not attempt to identify the viability of platelets collected in large quantities. This finding has relevance to single donor apheresis products with high platelet yields that are n o t intended to be split. Many physicians believe that the collection center should try to collect as many platelets from a single donor for transfusion to a single patient. Some collection centers have responded to this demand by collecting apheresis products with yields regularly over 7.0 x 1011. As mentioned earlier, the available literature

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establishes an upper platelet yield limit of 5.2 x 10 H for the Haemonetics CLX dual bag system (2.6 x 10 H per bag), 6.6 x I0 n for the Baxter PL732 dual bag system (3.3 x 10 n per bag) and 8.4 x 10 n for each COBE single platelet bag (or a concentration of 1.0-2.1 x 106 per microliter for final volumes of 150-400 mL). The question of quality of the platelets arises w h e n yields exceed the established boundaries. While the FDA 1988 Revised Guideline for the Collection of Platelets, Pheresis establishes a quality control procedure for product quality, collection centers can pass m o n t h l y quality control even though m a n y products can be issued that are not reflective of those chosen from quality control testing. It is stated in the guideline that of the four (4} products required for testing, all m u s t be tested for pH at the time of issue or the m a x i m u m storage time allowable for the bag system used. Products tested in the quality control program should mirror the products issued and all collection procedures used. It is clear that more studies are necessary to identify the upper and lower boundaries of platelet storage containers. Collection centers must remain aware that they are one m e m b e r of a partnership which involves the donors, transfusion services, hospital administrators, clinicians and patients. Operating in a vacuum can disturb the normal balance established by the partnership. Any proposed changes by one of the partners m u s t be communicated to all other members so that expectations remain consistent.

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REFERENCES Council of Community Blood Centers. Donor Resources Committee: Pilot Blood Collection Survey 1993. Kilkson H, Holme S, Murphy S: Platelet metabolism during storage of platelet concentrates at 22~ Blood 1984; 64:406-414. Holme S, Heaton A, Momoda G: Evaluation of a new, more oxygen-permeable, polyvinyl chloride container. Transfusion 1989; 29:159-164. Kenney DM, Peterson [L Smith DV: Extended storage of single-donor apheresis platelets in CLX blood bags: effect of storage on platelet morphology, viability and in vitro function. Vox Sang 1988; 54:24-33. Baxter Biotech, Fenwal Division. Protocol for split products. Hemasphere (COBE Newsletter} 1992; 5{No.1):6. American Association of Blood Banks, Standards for Blood Banks and Transfusion Services, 15th edit. 1993, Vol. 11. Holme S, Heaton WAL, Whitley P: Platelet storage lesions in second generation containers: correlation with/n v~vo behavior with storage up to 14 days. Vox Sang 1990; 59:12-18. Moroff G, Holme S: Concepts about current conditions for the preparation and storage of platelets. Transfus Meal Rev 1991; 5:48-59. Frederick B. Axelrod, MD* Central Indiana Regional Blood Center Inc.

*Address for correspondence: Medical Director, Central Indiana Regional Blood Center Inc., 3450 N. Meridian St., Indianapolis, IN 46208, U.S.A.