The platelet prophylactic transfusion trigger: when expectations meet reality

In this issue of TRANSFUSION, two hospitals, the University of Ottawa and the University of Minnesota, report their experience in regard to a prophylactic platelet (PLT) transfusion threshold of 10 × 109 per L.1,2 In both cases, the authors express disappointment in the observed compliance with such a threshold; in the case of the University of Minnesota, the minimal impact of lowering the threshold on PLT utilization was also noted. To understand the rationale for prophylactic PLT transfusions, one must first be familiar with PLT kinetics. The mean PLT life span in circulation after release from a megakaryocyte is 8 to 10 days (as measured in a normal study subject). The mean residual life span of circulating PLT population at a given time (the residual mean life span [RML], again as measured in a normal subject) is 4 to 5 days. The RML corresponds to the maximal expected life span of donated PLT product after infusion into a patient. Interestingly, the life span of a PLT is dependent on a patient's count. Although a PLT survives approximately 9 days in a normal individual, PLTs have a reduced survival in a thrombocytopenic patient. The explanation offered for these observed differences is that PLTs are removed from the circulation by at least two different mechanisms.3 The first is simply PLT senescence, which accounts for the majority of PLT loss in a normal individual, and the second is a constant loss due to the routine maintenance of vascular integrity (an endothelial supportive role). The number of PLTs required for this endothelial supportive roll has been estimated to be 7.1 × 103 per µL per day. It is thought that in thrombocytopenic patients the constant loss for homeostatic maintenance represents a more significant fraction of the circulating PLTs, thus reducing PLT survival. The clinical evidence supporting the use of prophylactic PLT transfusions has been recently extensively reviewed.3,4 In brief, before 1960 (before PLT transfusions were widely available), death from bleeding complications was common in leukemic patients receiving intensive chemotherapy. In a 1962 article by Gaydos and coworkers,5 92 consecutive patients with acute myelogenous leukemia (n = 34) or acute lymphoblastic leukemia (n = 57) from the National Cancer Institute were reviewed.5 A relationship between hemorrhage and PLT count was demonstrated in these patients (none received PLT transfusions). The authors were unable to determine a distinct threshold that was associated with hemorrhage. Serious bleeding was rare, however, at PLT counts exceeding 20 × 109 per L. Based largely on this study, it became common practice to transfuse prophylactically at PLT counts less than or equal to 20 × 109 per L.3,4 In 1992, Beutler6 questioned the use of the 20 × 109 per L threshold and called for the use of lower thresholds.6 In 1997 two randomized controlled studies compared the safety of using a 20 × 109 per L versus a 10 × 109 per L threshold. In the first study by Heckman and colleagues7 from the University of Iowa, 78 patients undergoing induction therapy for acute leukemia were randomly assigned to receive prophylactic apheresis PLT concentrates when the PLT count was not more than 10 × 109 per L or not more than 20 × 109 per L.7 There was no significant difference in the total number of bleeding episodes per arm. This study concluded that the choice of threshold can decrease the total utilization of PLTs with only a small adverse effect on bleeding and no statistically significant effect on morbidity. A second study by Rebulla and associates8 randomly assigned 255 patients with acute myeloid leukemia treated in 21 centers in Italy. The risk of major bleeding (defined as any bleeding more than petechiae, mucosal, or retinal bleeding) in the two arms did not differ (p = 0.41). A subsequent third trial published in 2002 by Zumberg and colleagues9 from the University of Florida studied 159 hematopoietic stem cell transplant recipients who were randomly assigned to two arms to receive a prophylactic PLT transfusion when the morning PLT count fell below 10 × 109 or 20 × 109 per L. There were no significant differences in bleeding or severity of bleeding. No deaths were attributed to bleeding.9 Interestingly, although the conclusions of these studies have been widely accepted and broadly implemented, it has been pointed out that none of these studies was explicitly designed and powered to test noninferiority or equivalence concerning outcomes such as frequency of bleeding events.10 It has been suggested that even if combined, these studies probably do not have sufficient power to demonstrate equivalence of the two transfusion triggers. A fourth trial published in 2005 (after the above analysis) by Diedrich and coworkers11 from the Karolinska University randomly assigned 166 allogeneic hematopoietic progenitor cell transplant recipients to a prophylactic PLT transfusion trigger less than 10 × 109 or 30 × 109 per L.11 They found no significant differences in survival, death, or hospital stay. The incidence and type of bleeding were comparable. No deaths were attributed to hemorrhage. In 2004, approximately 1.4 million apheresis PLTs and 1.5 million whole blood–derived PLT concentrates were transfused in the United States alone.12 It has been estimated that the cost of PLTs exceeds $1 billion per year.13 Prophylactic PLT transfusions often make up the majority of PLT transfusions at a given institution. For example, in this issue, the University of Ottawa reported that 67 percent of all PLT transfusions were transfused to hematology oncology or marrow transplant patients. Of these, 78 percent were given prophylactically.1 Thus, 52 percent of all PLT transfusions transfused at the University of Ottawa were given prophylactically. Similarly, the University of Minnesota reported that overall, 74 percent of all PLT transfusions were given for prophylaxis against bleeding.2 It is likely that such estimates generally reflect the current high percentage of prophylactic PLT utilization in large tertiary hospitals (where most PLTs are transfused). This observation is supported by a 1991 survey of United States hospitals that found that greater than 70 percent of hospitals reported that prophylaxis was the primary indication for PLT transfusions.14 Thus, any initiative to safely modify the use of prophylactic PLT transfusions has the potential to greatly impact the overall practice of PLT transfusion, reduce health-care costs, and increase PLT availability. Both studies published in this issue of TRANSFUSION lament the lack of compliance with the 10 × 109 per L trigger in their respective institutions. It is important to realize, however, that even in the optimized setting of a research study, compliance with a 10 × 109 per L (or even a 20 × 109/L) trigger remains problematic. In the study by Heckman and coworkers,7 14 of 37 patients (37.8%) in the 10 × 109 per L and 6 of 41 patients (14.6%) in the 20 × 109 per L arm received PLTs that were protocol violations.7 In the study by Rebulla and coworkers7 22.6 percent of the patients in the 10 × 109 per L arm experienced transfusions at a higher trigger owing to the presence of concomitant risk factors and an additional 5.4 percent were due to protocol violations (total, 28%).8 Similarly, in the study by Zumberg and colleagues,9 a mean of 4.27 of the 10.4 (41%) and 1.89 of 10.2 (18.5%) transfusions per patient were given above the indicated 10 × 109 and 20 × 109 per L transfusion trigger, respectively. Finally, in the study by Diedrich and colleagues,11 transfusions to patients at a higher PLT count than that allowed for a bleeding patient (WHO Grades II-IV) in the protocol occurred in 4 of 15 patients in the lower trigger arm and in 3 of 13 in the higher trigger arm. Thus, in the reality of routine practice, difficulties with compliance with the trigger recommendations should not come as a surprise. One of the goals of lowering the PLT transfusion trigger is to decrease the utilization of PLT transfusions. One must have reasonable expectations, however, regarding the amount of decrease. Mathematical modeling predicted a 14.5 percent decrease in PLT utilization from a decrease in the PLT prophylactic transfusion threshold from 20 × 109 to 10 × 109 PLTs per L.15 In the study by Rebulla and associates8 the lower PLT threshold was associated with a 21.5 percent reduction in PLT usage. Similarly, the study by Heckman and colleagues,7 although not quite reaching significance, found that patients in the not more than 10 × 109 per L arm received a lower number of PLT transfusions (seven) compared to the not more than 20 × 109 per L (11, a 35% difference; p = 0.07).7 The study by Zumberg and coworkers9 found no significant differences in PLT usage between the two thresholds. The authors, however, felt that a decrease in PLT use was not achieved because of safety measures incorporated into their study design. Finally in the study by Diedrich and coworkers,10 the number of PLT units transfused was significantly lower in the 10 × 109 per L trigger arm compared to the 30 × 109 per L arm (median, 4 vs. 10, respectively, a 60% difference).10 In the current article by Greeno and coworkers2 from the University of Minnesota, the authors found that new transfusion guidelines which changed the recommended prophylactic PLT transfusion threshold from 20 × 109 to 10 × 109 per L resulted in only a minor change in overall PLT usage. It is important to note, however, that before this change in guidelines, 20 percent of all transfusions designated prophylactic were given for pretransfusion counts of less than 10 × 109 PLTs per L. This percentage only increased to 28 percent after the implementation of the new guidelines. This suggests that many of their clinicians may have already been aware of the published literature supporting the use of a prophylactic threshold of 10 × 109 per L and had already been using this threshold in those patients deemed a safe candidate for such a lower threshold. Thus the observed small increase in use of the lower trigger may simply reflect that the institutional guidelines lagged the clinical practice. Given that 74 percent of all transfusions were prophylactic in this study, even if all of the prophylactic transfusions had been reduced from a threshold of 20 × 109 to 10 × 109 PLTs per L and there had been a 21.5 percent decrease in utilization (similar to the decrease observed by Rebulla), there would have only been an expected 15.9 percent (21.5% of 74%) overall decrease in PLT utilization.8 Clearly, this is an unrealistic expectation because many patients have additional risk factors for bleeding (e.g., uremic PLT dysfunction, liver failure, or a history of prior bleeds) that would necessitate a higher transfusion trigger. Nevertheless, despite the small observed increase in prophylactic transfusions at the lower transfusion trigger, there was still a 10 percent decrease overall (3,890 vs. 3,511) in the total number of transfusions and a 7 percent decrease in the number of units transfused (15,810 vs. 14,771). Although neither of these changes reached significance, the fact that PLT transfusions decreased at all, given that there is an ever increasing trend in the total number of PLT transfusions nationwide, is impressive. Greeno and colleagues2 suggest that other options such as decreased PLT dosing may be required to reduce PLT utilization. Mathematical modeling has suggested that smaller more frequent transfusions can reduce the number of PLTs required to maintain a patient above a specific transfusion trigger, whereas higher doses can prolong the interval between transfusions but would require the transfusion of increased numbers of PLTs.15 One randomized controlled study of low-dose versus standard PLT transfusions (3 PLT units vs. 5 PLT units) in recipients of autologous peripheral blood progenitor cell (PBPC) transplantation or acute leukemia (n = 111) concluded that low-dose PLT transfusions were safe (with a median absolute increase in major bleeding events of 3.2%) and effective and reduced PLT utilization (the median total of whole blood–derived PLT units transfused per patient was 3 in the low dose group vs. 5 in the standard dose group—a 25 percent decrease in total utilization).16 A much larger study of PLT dosing is currently ongoing in the United States by the National Heart Lung and Blood Institute's (NHLBI) Transfusion Medicine Hemostasis Clinical Trials Network (TMH CTN).17 The prospective, multicenter trial will enroll 1350 hospitalized patients with thrombocytopenia secondary to chemotherapy or hematopoietic stem cell transplantation. In this study patients are randomly assigned to one of three PLT treatment dosage arms: high dose (4.4 × 1011/m2), medium dose (2.2 × 1011/m2), and low dose (1.1 × 1011/m2) based on body surface area. It is anticipated that this study will close in Fall 2007. Although low-dose therapy may ultimately be proven safe and effective, it has been pointed out that other considerations, such as patient convenience (e.g., outpatient transfusions) and staffing, may favor a higher-dose strategy in certain settings because of the prolonged transfusion-free interval.18 Despite the widely held practice of prophylactic PLT transfusions, it has never been proven that a prophylactic PLT transfusion strategy is actually necessary. A recent prospective study of 106 clinically stable patients receiving 140 autologous PBPC transplants for which a PLT transfusion was only used when relevant bleeding occurred (more than petechial) found only minor or moderately severe bleeding was observed (19%).19 No severe or life-threatening bleeding was observed. Compared with a historical control group, the number of PLTs transfused was reduced by one-half. A prospective multicenter randomized trial comparing a therapeutic transfusion strategy with the standard prophylactic PLT transfusion strategy with a trigger of 10 × 109 per L after autologous PBPC transplantation is currently under way in Germany.20 Although the study plans to enroll 200 patients, an interim analysis of the first 92 patients found no major clinically relevant bleeds and the number of PLT transfusions was reduced by approximately 50 percent. The two studies in this issue of TRANSFUSION underscore the difficulties inherent in changing prophylactic PLT transfusion practice. Expectations of a substantial decrease in PLT utilization must be tempered by the realization that 1) only moderate decreases in usage are to be expected based on the literature; 2) some clinicians may already be utilizing the lower trigger and thus a change in an institution's guidelines may have less effect on utilization than expected; 3) not all patients would qualify for a lower PLT threshold; 4) compliance with the transfusion guidelines will, in all likelihood, never be 100 percent in clinical practice; and 5) not all PLT transfusions are given for prophylaxis. It is also important to realize that the current practice of utilizing prophylactic PLT transfusions (including the choice of PLT dose) is not based on rigorous randomized controlled studies and may be suboptimal or even unnecessary. We are fortunate that there are several studies currently in progress that will address many of the unanswered questions that affect our daily use of PLTs. Inevitably, our current practice will be affected by the outcomes of these studies. We will likely have much to learn and unlearn. In preparing this editorial, I am reminded of my first day of medical school, where I, like countless others before me, was told “about 50 percent of what you are about to learn is false; unfortunately, we don't know which 50 percent.”

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