Platelet efficacy revisited?

A lthough a prevalent consensus supports the view that platelet (PLT) transfusion plays a key role in preventing bleeding in severely thrombocytopenic patients, a unique definition and commonly accepted level of “adequate clinical efficacy” of PLT support are still lacking. This is not surprising if one considers the complex laboratory and clinical settings surrounding the simple therapeutic procedure of PLT transfusion. In fact, a large number of variables belonging to the product and/or to the patient can affect PLT transfusion outcome. PLTs for transfusion can be prepared from whole blood by the PLTrich plasma or the buffy coat methods or by apheresis (three basic procurement procedures). Storage can take place in 100% plasma or in 1/3 plasma and 2/3 PLT additive solution (two basic storage media); PLTs are mostly stored for 5 days but in some cases for 7 days (two maximum expiration times). Further processing may include white blood cell removal—which is optional in some countries and universal in others—and/or gamma irradiation, pathogen inactivation, and/or cryopreservation, although the latter does not currently have a wide clinical use. Therefore, in total we can currently offer clinicians PLT products differing at least for 3 ¥ 2 ¥ 2 = 192 known variables. On top of this we should add the individual donor biomedical variables, but I propose to ignore them within the context of this discussion simply because they are poorly defined and appreciated. Finally, our PLT products enter the bloodstream of surgical or medical recipients—who can be “otherwise healthy” or affected by mild to severe comorbidities—with the task of repairing vascular damage and preventing or stopping blood loss. In the extreme scenario, we would theoretically need 192 (product variables) ¥ 4 (main recipient categories) or 768 randomized clinical trials to accurately test the efficacy of each product that could be used for PLT transfusion versus a “reference” product in each recipient category. All the above considerations relate to the PLT product(s) and the recipient(s), but what about the quantity of clinical and laboratory evidence needed before a specific product can be (confidently! ) deemed “effective”? When I was younger and much more intimidated by the intricacies of sophisticated statistics, I learned from a wise statistician that one should aim at a minimum of 20 replicates (i.e., n = 20 would generally “suffice”) in an investigation where the outcome variable is quantitative, whereas an n of 60 would be needed for qualitative (categorical) evaluations, such as “effective” versus “ineffective” PLT transfusion. From this information I concluded that being able to use a quantitative outcome measure would save a lot of work and resources. The above numbers and related reasoning came to my mind when I had the opportunity to read the interesting study by Apelseth and colleagues, which is published in this issue of TRANSFUSION. Being an old “platelet aficionado” I was attracted by the methodologic evaluation specified in the title, which refers to the therapeutic efficacy of PLT transfusion. As elegantly discussed by Giangregorio and Cook in another recent TRANSFUSION article, “a research study should be based on a clear and relevant research question. ” In this regard, Apelseth and colleagues wisely removed from their study design some of the basic recipient variables mentioned above and concentrated their attention on the condition of acute leukemia. This decision was appropriate as patients with acute leukemia represent the most frequent and frail category of PLT users. However, the authors did appropriately analyze a number of clinical, immunologic, and pharmacologic factors known to be detrimental to PLT support such as fever, infection, HLA alloimmunization, and treatment with antibiotics. As I was progressing through the article, I perceived an instinctive feeling of concern when I noted that the whole study had been done with (only) 40 transfusions (28 conventional gamma-irradiated products and 12 pathogen-inactivated photochemical-treated PLT concentrates) given to (only) 10 patients in a total of (only) 188 patient-days with chemotherapy-induced cytopenia. How could I reconcile the results based on the small numbers from this study with the “impressive” retrospective analysis by Friedmann and coworkers, involving 2942 patients receiving PLT transfusion over a 10-year period at a single institution, with a total of 79,546 patient days of thrombocytopenia, which showed that the only predictors of severe bleeding (i.e., lack of clinical efficacy) of 17 clinical and laboratory parameters investigated were uremia, hypoalbuminemia, medication with aminocaproic acid, and (surprisingly? ) a “bleed within the previous 5 days”? Apparently, low PLT counts were not predictive of severe bleeding in the study by Freidmann and colleagues. So, how could such a small study by Apelseth and colleagues provide clear and conclusive evidence on such a complicated issue? The question is further complicated by the fact that two potentially important product TRANSFUSION 2010;50:745-747.