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During whole-blood donation, large numbers of red blood cells (RBCs) are removed from the donor, and the frequency of whole-blood donations is limited to prevent anemia and iron deficiency. Incidentally, this limitation prevents significant losses of donor platelets (PLTs) and lymphocytes (LYMPHs). Assuming a donor blood PLT count of 200 × 109 per L and LYMPH count of 2 × 109 per L, the collection or loss per each 500-mL whole-blood donation would be 1.0 × 1011 PLTs and 1.0 × 109 LYMPHs. If 4 whole-blood units were donated annually, the total collection or loss would be only 4.0 × 1011 PLTs and 4.0 × 109 LYMPHS per year, quantities easily replaced in the bloodstream by production and/or redistribution of new cells. Thus, whole-blood donations have not raised concerns about either short-term thrombocytopenia and/or lymphocytopenia or about long-term “exhaustion” of thrombopoiesis or the induction of immunodeficiency. In contrast, apheresis technology using automated blood separators has made it possible to collect vast quantities of individual blood cell types, including PLTs and LYMPHs, at each donation. Moreover, because nearly all RBCs can be returned to the donor to minimize the possibility of significant iron deficiency anemia, apheresis donations can be repeated frequently at close intervals, raising concerns that massive collections or losses of PLTs and LYMPHs could lead to clinically significant long-term problems in donors. These concerns were particularly worrisome in the 1970s and 1980s when apheresis PLT units were heavily contaminated with LYMPHs. Blood separator technology, however, has been refined over the years, and it is currently possible to collect highly purified PLTs with minimal contamination by other cells (e.g., leukoreduced PLT units that contain <106 white cells [WBCs] and are nearly devoid of RBCs). Thus, repeated plateletpheresis donations, using modern-generation blood separators, result in substantial PLT collections or losses, but relatively small LYMPH losses from donors. Several lessons can be learned, pertaining to the quantity of donor PLTs and LYMPHs collected or lost and the potential for donor harm, by reviewing information about older-generation apheresis technology. In a review article published in 1983,1 the number of PLTs collected per donation varied with the type of blood separator used and plateletpheresis methods, but ranged from about 3 × 1011 to 7 × 1011 per procedure. The decrease in donor blood PLT count immediately after each plateletpheresis procedure was 20 to 30 percent below the prepheresis value, with return to normal within 6 days. Because FDA guidelines in effect at the time2 required donor prepheresis blood PLT counts to be at least 150 × 109 per L, with the minimum interval between each plateletpheresis to be 48 hours and the frequency of donation not to exceed 2 per week, 6 per month, and 12 per year, donor blood PLT counts only occasionally decreased below 100 × 109 per L after plateletpheresis.1 If a donor experienced the maximum of 12 plateletpheresis procedures permitted per year, the total number of PLTs collected or lost annually would range from 36 × 1011 to 84 × 1011, a quantity generally accepted at that time as having little to no clinically significant long-term effects.1 The number of aphereis collections from one donor in 1 year was increased by the FDA to 24 on October 7, 1988. To support this feeling of safety, even donors with low-normal blood PLT counts (150 × 109-180 × 109/L) were reported to donate multiple PLT units safely at 28-day return intervals.3 Donors (n = 33) with a history of predonation PLT counts of 150 × 109 to 180 × 109 per L donated 99 PLT units using a continuous-flow blood separator that was programmed, using historic donor blood PLT counts, to collect 3 × 1011 PLTs each donation. When the actual prepheresis donor PLT count results were known later, only 35 of the 99 collections were performed with the day of donation PLT count truly less than 180 × 109 per L. For these 35 plateletpheresis procedures, the donor predonation PLT count was 168 × 109 per L, postdonation PLT count was 111 × 109 per L, and PLT yield was 5.4 × 1011 per unit (mean values) with 99% of units containing at least 3 × 1011 PLTs. Donor blood PLT counts decreased a mean of 34 percent during plateletpheresis, with the lowest postdonation count being 69 × 109 per L. This decrease was transient, and 96 percent of subsequent plateletpheresis donations were performed as scheduled at 28-days intervals, with predonation PLT counts always greater than 150 × 109 per L (often >180 × 109/L).3 Thus, in the early years of plateletpheresis, donor PLT losses were not of great concern. In contrast to the acceptance that donor PLT losses could be readily restored, repeated plateletpheresis procedures with early-generation blood separators led to concerns that removal of vast quantities of LYMPHs and plasma immunoglobulins—to the extent that their concentrations in donor blood often decreased below the normal range—might be harmful. It was feared that LYMPH loss might lead to significant immunodeficiency, a condition sometimes associated with increased rates of infections, malignancy, and autoimmune disease. Using primary immunodeficiency diseases and acquired immunodeficiency states (e.g., therapeutic lymphocytapheresis, chronic thoracic duct drainage, and intestinal lymphangiectasia) as models to judge competency of the immune system, it was concluded that clinically significant immunodeficiency became apparent in some patients when serum IgG levels were less than 200 mg per dL and/or blood LYMPHs less than 1 × 109 per L.4 Review of these three models of chronic LYMPH loss offers perspective about the possible clinical importance of apheresis donor LYMPH collection or loss.4 Several investigators used repeated lymphocytapheresis, at times combined with plasmapheresis, to treat patients with rheumatoid arthritis. After removal of 1 × 1011 to 4 × 1011 LYMPHs (two to three apheresis procedures weekly for 5 to 10 weeks), patient blood LYMPH counts fell by approximately 80 percent and remained at less than 50 percent of preprocedure values for several months. Mitogenic response of patient LYMPHs to phytohemagglutinin diminished, but positive skin tests remained reactive, and antibodies were formed in response to immunization. Despite the LYMPH losses, increased infections were not reported. Chronic thoracic duct drainage, a technique for immunosuppression in organ allograft recipients, led predominately to T-LYMPH losses and cellular immunodeficiency. After losses of 1 × 1011 to 5 × 1011 LYMPHs (usually after a few weeks of cannulation and drainage), patient blood LYMPHs decreased nearly to undetectable levels, skin reactivity to primary and recall sensitization became negative, LYMPH mitogenic response decreased, and plasma immunoglobulins decreased by approximately 50 percent. The time needed for patient blood LYMPHs and immunoglobulin levels to return to normal ranged from weeks to months. Intestinal lymphangiectasia is an acquired or congenital disorder characterized by dilated lymphatic channels, protein-losing gastroenteropathy, and abnormalities of both humoral and cell-mediated immunity. LYMPHs (primarily recirculating, long-lived T-LYMPHs) and immunoglobulins are lost into the lumen of the gastrointestinal tract, with blood LYMPHs decreasing to approximately 30 percent of normal values (well below 1 × 109/L). Anergy to recall antigens, failure of primary sensitization to dinitrochlorobenzene, and impaired graft rejection have been demonstrated. Blood LYMPHs exhibit markedly impaired proliferation to mitogens, specific antigens, and allogeneic cells, all of which correlate to the degree of lymphocytopenia. Immunoglobulins in serum decrease by approximately 50 percent, primarily due to gastrointestinal loss, and antibody production to some types of antigens is diminished. Despite these findings, excessive infections were not reported. Thus, based on these models of LYMPH collection or loss, the quantity of LYMPHs that must be removed from a patient to produce clinically significant lymphocytopenia and/or abnormal results of immune function tests could not be predicted precisely but, generally, was at least 1 × 1011 LYMPHs collected or lost over a fairly brief period of weeks. The extent and clinical manifestations of long-term immunodeficiency, or even at what point significant immune dysfunction might occur during continuing LYMPH collections or losses, was not well defined. Moreover, it was not possible to clearly correlate the clinical consequences of immune dysfunction (e.g., increased infections, malignancy, or autoimmunity) with blood LYMPH counts or results of immune function tests. Applying this information to plateletpheresis,4 donor LYMPHs collected or lost during each plateletpheresis procedure using older-generation blood separators ranged from approximately 1 × 109 to 10 × 109, depending on methods, although some techniques resulted in smaller collection or loss of only 107 to 108 LYMPHs per procedure. The short-term changes in blood LYMPH counts that occurred during or immediately after a single plateletpheresis procedure were without known adverse effects, with pre- and postplateletpheresis donor LYMPH counts generally differing by not more than 20 percent. These decreases were transient and, apparently, caused no immunologic dysfunction. The effects of repeated plateletpheresis donations over longer periods of time, using older-generation blood separators, however, were not clearly defined (reviewed in Strauss4). The annual loss of LYMPHs for a donor undergoing monthly plateletpheresis (i.e., 12 procedures) would be 12 × 109 to 120 × 109 (i.e., ranging from 1.2 × 1010 to 1.2 × 1011 LYMPHs per year). In one study, 10 donors experienced plateletpheresis weekly for 10 weeks. Total LYMPH collection or loss was estimated to be 3.5 × 1010 LYMPHs per donor. T-LYMPHs were unchanged. B-LYMPHs were decreased in 5 of 10 donors, but they returned to normal values within 1 month after completing the 10 procedures. Concentrations of serum IgG, IgA, and IgM remained normal. In another study, 21 donors experienced a mean of 17 plateletpheresis procedures. Results were compared to a control group of 21 subjects who donated 1 to 4 whole-blood units. In apheresis donors, values were significantly decreased (p <0.05) for blood LYMPHs (decreased 23%), T-LYMPHs (decreased 27%), and serum IgG (decreased 14%). Most apheresis donors were retested 8 months after discontinuing plateletpheresis and, although no significant improvements in test results were found, the donors appeared healthy. When restudied 2 years later, values had returned to normal. In another retrospective study, 11 donors experienced 50 to 142 cytapheresis procedures during a 5- to 9-year period and, in addition, previously had given 12 to 255 units of whole blood. The total LYMPH loss per donor was estimated to be 24.5 × 1010 (range, 14.2 × 1010 to 41.2 × 1010). Thus, cumulative LYMPH losses over several years of donation ranged from about 1.5 × 1011 to 4.0 × 1011. When compared to normal controls, values were not significantly different for blood hematocrit, neutrophil, monocyte, and PLT counts or for serum total proteins, albumin, and immunoglobulins. Absolute blood counts, however, were significantly decreased for total LYMPHs (mean value, 1.415 × 109/L), OKT4 helper LYMPHs (0.641 × 109/L), and OKT8 suppressor LYMPHs (0.471 × 109/L) with the OKT4 : OKT8 ratio of 1.36 for donors versus 1.50 for controls. The total LYMPH count in donors, although significantly lower than in control subjects, was still within the normal range, and the percentages (rather than absolute number values) of LYMPH subpopulations were not decreased when compared to controls. The donors were healthy, and the authors concluded that no clinically important detrimental effects of LYMPH collection or loss could be found for multiple cytapheresis plus whole-blood donations occurring over a period of several years. Thus, as reviewed in 1984,4 the risks, if any, of clinically significant donor lymphocytopenia and immunodeficiency were unknown. Based on knowledge of congenital and acquired immunodeficiency disorders and on experience with plateletpheresis donors experiencing relatively large LYMPH losses due to older-generation blood separators, it seemed likely that immune dysfunction would not occur unless more than 1 × 1011 LYMPHs were collected or lost over relatively brief periods of time. Thus, it was quite appropriate to adhere to FDA guidelines.2 Often, donors were temporarily deferred when their blood LYMPH counts decreased below 1 × 109 per L or serum gammaglobulin levels decreased below normal values and, then, resumed donating when laboratory results returned to normal. Many refinements of automated blood separators have been made since 1985, and it is quite routine to collect between 3.5 × 1011 and 9.5 × 1011 PLTs during a single plateletpheresis donation with donor LYMPH losses being consistently 106 or less. The PLTs collected during each single plateletpheresis donation are divided into 1, 2, or 3 leukoreduced PLT units containing 3.0 × 1011 to 3.5 × 1011 PLTs each (i.e., single, double, or triple collections). It is possible to combine PLT donation with donation of plasma and/or RBCs in a multiunit apheresis procedure. Because large volumes or numbers of blood components can be collected frequently, concerns about donor safety continue. Accordingly, FDA recently revised guidelines for plateletpheresis.5 Among the many guidelines stated, those of particular interest for this discussion are as follows. PLT donors must fulfill the usual requirements for blood donation, must not be taking PLT-inhibitory drugs, and should have a blood sample taken before donation for a PLT count (although the PLT count can be performed after the donation). Donors with a blood PLT count known to be less than 150 × 109 per L must be deferred. If the predonation PLT count is not performed until after the donation, triple PLT units cannot be collected from first-time donors. A donor should undergo no more than 24 plateletpheresis procedures during a 12-month period, without regard to whether they are single-, double-, or triple-PLT-unit collections. The interval between single-unit collections must be at least 2 days, with no more than two procedures per 7 days. The interval between double- or triple-PLT-unit collections should be at least 7 days. The blood separator should be set for a postdonation donor PLT count target of no less than 100 × 109 per L. Donor blood PLT counts must be periodically reviewed and, if known to decrease below 100 × 109 per L, the donor must be deferred until it returns to at least 150 × 109 per L. Notably, neither donor blood LYMPH counts nor cumulative LYMPH losses are addressed by the current FDA guidance, although total WBC collection for single, double, and triple leukoreduced PLT units cannot exceed 5 × 106, 8 × 106, and 12 × 106, respectively.5 Thus, donor LYMPH losses are no longer a concern because, even with the worst-case scenario that 100 percent of WBCs collected along with PLTs are LYMPHs (an incorrect assumption), the maximum number of donor LYMPHs collected or lost in 24 plateletpheresis donations permitted in 1 year of single PLT units would be 1.2 × 108 and the corresponding number for 24 triple PLT unit donations is 2.8 × 108, values considerably lower than the LYMPHs collected or lost by a single whole blood donation! In contrast to no longer having concerns about clinically significant lymphocytopenia and immunodeficiency in repeat plateletpheresis donors, the situation with the long-term effects of repeated PLT collections remains controversial and difficult to manage, in terms of accurately informing donors of the risks of repeated plateletpheresis and providing measures to guarantee donor safety. In this issue of TRANSFUSION,6 investigators at the Mayo Clinic address this problem. [Note: The article was written and reviewed before the final FDA guidance was published.] Donors were studied who successfully completed plateletpheresis one or more times using a modern blood separator, with at least one donation being a double or triple PLT unit. A total of 471 donors donated 1 to 34 times (median, 4) during 0.3 to 131 weeks (median, 72), with a yield of 2 to 65 PLT units (median, 7). Individual donors donated up to 15 single PLT units and up to 27 doubles and 7 triples, respectively. Median donor blood PLT counts before the first plateletpheresis were 250 × 109 per L and before the last plateletpheresis procedure were 272 × 109 per L, an increase of 5.5 percent (p = 0.0001). Median donor blood LYMPH counts were 1.630 × 109 per L before the first plateletpheresis procedure and 1.580 × 109 per L before the last, a decrease of 3.7 percent (p = 0.0001). Although the increase in donor blood PLTs and the decrease in LYMPHs was significant, they were quite modest and have no apparent clinical significance. A number of other statistical analyses were performed investigating several aspects of donors and donations, finding either nothing of significance or detecting relationships of minor, if any, clinical importance. The authors concluded that limitations on the number of apheresis PLT units donated within 12 months are not warranted when based on donor blood PLT and LYMPH counts.6 Although their data were derived from a large number of donors and were extensively analyzed, the report has several shortcomings and is of questionable sufficiency to support their primary conclusion. Remembering that the FDA limit is 24 plateletpheresis donations during a 12-month period (without regard for single, double, or triple PLT units), their donors experienced a median of only 4 plateletpheresis procedures with a median of 7 PLT units donated over a median time of 72 weeks (i.e., 18 months). The majority of their donors donated 1 to 5 times, with only a rare individual donating more than 20 times. Thus, the overall extent of their donation experience was modest. Individual donors rarely met FDA limitations, let alone exceeded the limits to test the effects on donors who go beyond. The duration of their study was relatively brief (i.e., longest interval between the first and last plateletpheresis procedure was 131 weeks), so that their experience does not address another concern underlying the purpose of limiting apheresis PLT donations, namely, the possibility that the cumulative effects of multiple PLT donations year after year might lead to “exhaustion of thrombopoiesis” with impaired ability of the marrow to sustain normal blood PLT counts or to recover promptly as compensation for the stress of PLT donation. Thus, to conclude that “limitations on the number of apheresis PLT products donated within 12 months do not seem warranted. . . .” seems, in my opinion, to overextend their data. In support of the Mayo Clinic report,6 Katz and colleagues7 studied 953 donors who experienced plateletpheresis during one calendar year, 101 of whom donated 24 times (mean of 1.8 PLT products per donation). Predonation blood PLT counts for 60 of these donors experiencing 24 plateletpheresis procedures in 1 year were plotted for donations 1 through 24, and there were no significant statistical or clinical differences detected over time. Predonation donor PLT counts were lower when the interdonation interval was 1 week versus 2 or 3 weeks, suggesting that a period of time was needed for increased thrombopoiesis and “recovery” of blood PLTs. None of the 60 donors, however, was deferred for a blood PLT count of less than 150 × 109 per L during the year of their 24 donations.7 In contrast and in support of limiting apheresis PLT donations, investigators at the National Institutes of Health8 suggested that “. . . apheresis facilities sho
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