5From all selected papers the maximum possible amount of available data were

retrieved. Data reported in ways that did not allow pooling (e.g. medians and ranges or interquartile ranges), were recalculated into means and standard deviations, which do allow pooling. Data were extracted from graphs when necessary. Therefore, we were able to pool the results and perform the meta-analyses on data from as many papers as possible.

Another important strength of this study is the quality of included data. Risk of bias was assessed in two different ways and we found perfect agreement between the two assessment tools. Out of 135 studies reporting at least one platelets measurement 16 were excluded based on the risk of bias assessment. Of the remaining studies data that allowed for pooling of results in the meta-analyses could be extracted from 46.

A possible limitation is that not enough randomized trials were included to perform a meta-analysis restricted to randomized trials. However, to have full transparency of our reporting, we showed results stratified between randomized trials and non- randomized trials in the supplemental material. All results in these analyses were in the same direction and in the same magnitude as those presented in the main text. Another remark to be made is about the high heterogeneity between the studies measured as I2_{. As recommended by The Cochrane, besides verifying the data and}

exploring the heterogeneity, a random-effects meta-analysis was performed.25

We found indications of the presence of publication bias. The funnel plot shows a slight preference for smaller studies favoring fresher platelets and Egger's bias coefficient also indicates the presence of publication bias. However, the funnel plot is centered around zero by subtracting the standardized mean effect. Therefore, the largest observed ‘negative effect’, is in reality still an effect in favor of fresher platelets. Thus, although publication bias may have had a minor effect on the size of our effect estimates, it seems unlikely that this could have materially influenced our conclusions.

These potential consequences of transfusing older platelets, however, have to be put in perspective relative to the consequences of supplying exclusively fresher platelets. The Dutch blood supply organization (Sanquin) switched to extended storage of platelets (i.e. maximum storage of seven days instead of five) in 2002. This prolongation of storage time reduced outdating from 20% to about 10%, reducing cost and increasing platelet availability.26

In conclusion, our results indicate that fresh platelets are more likely to result in a successful transfusion than old platelets. With successful transfusion defined as a count increment based measurement being above a specific threshold. However, as currently judged by means of a corrected count increment, the success of a transfusion results from a mixing of effects of patient and product related factors. To be clinically relevant the judgment of success of a transfusion should depend on patient related factors only and be separated from product related factors as much as possible. So besides body surface area and platelet dose of the product, storage time should also be taken into account, to arrive at an even better corrected count increment to judge the success of transfusions. We therefore recommend more research into a storage time independent measure for the success of a platelet transfusion.

Supplemental material

Available at http://onlinelibrary.wiley.com/doi/10.1111/vox.12443/full#footer- support-info

Appendix S1. Protocol

Appendix S2. Search strategy: queries

Appendix S3. Reference list and qualitative overview – Included papers

Appendix S4. Funnel plot per outcome; forest plots of weighted mean differences per outcome, product group and population (patients/volunteers); and Summary mean differences according to study design (RCT/Non-RCT)

Appendix S5. Underlying distributions (absolute numbers) of the weighted mean differences

Acknowledgements

We wish to thank Jan Schoones (senior medical librarian at the Walaeus library; LUMC) for his help with developing the search queries, Pieter van der Meer for his input about platelets product, Ruifang Li for the Chinese papers translation, Saurabh Zalpuri for the translation of a Russian paper, Oliver Zilch for the translation of a German paper, and Dirk de Korte, Leo van de Watering and Marian van Kraaij for their useful comments on our manuscript.

Chapter 5

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