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Comparison of the Acute Inflammatory Response of 2 Commercial PRP Systems: Letter to the Editor

Dear Editor: We read the article by Dragoo and colleagues titled ‘‘Comparison of the Acute Inflammatory Response of Two Commercial Platelet-Rich Plasma Systems in Healthy Rabbit Tendons’’ with great interest. The authors conducted the work, which was supported by the manufacturer of the leukocyte-poor platelet-rich plasma (LP-PRP) device, under the premise that leukocyte-rich PRP (LRPRP) would incite a greater acute inflammatory response to the detriment of the treated tissue than LP-PRP, based on the results of in vitro studies. However there is an everexpanding body of primary clinical literature that does not support these findings, and to the contrary, indicates an anti-inflammatory and pain relieving therapeutic effect of LR-PRP in tendinopathy (reviewed in Fitzpatrick et al) and in osteoarthritic patients (reviewed in Chang et al, Khoshbin et al, and Laudy et al). Much of the primary literature comprising these systematic reviews was available at the time that this article was published, however those findings were not considered by Dragoo et al when conceiving their study, nor was this body of evidence adequately addressed in their discussion. In fact, the results of more recent studies and systematic reviews clearly indicate that LR-PRP gives a greater patient benefit in tendinopathy as well as in osteoarthritis than does LP-PRP. The objective of the rabbit study by Dragoo and colleagues was to evaluate the inflammatory effect of LRPRP versus LP-PRP after intratendinous patellar tendon injection. The outcome measures employed were based on standard tissue histopathological analysis using only hematoxylin and eosin (H&E) staining at 5 and 14 days after injection. Therefore, the entire study relied on the assumption that leukocyte detection in extravascular tissues 5 days after injection is indicative of an acute inflammatory reaction leading to the recruitment of leukocytes from the circulation into the injected tissue. The 5-day time point was chosen based on a typical rabbit leukocyte lifespan of less than 5 days, supposing that at this time point only recruited leukocytes would be present in the injected tissue. Literature from in vitro studies does indeed support a short lifespan of isolated granulocytes, however it has also been well established that a multitude of plateletand leukocyte-derived growth factors, chemokines, and inflammatory mediators increase the granulocyte lifespan several fold (reviewed in Kolaczkowska and Kubes as well as Mantovani et al), leading to a neutrophil halflife of over 5 days. In addition, the major leukocytes in rabbit blood are mononuclear cells, not granulocytes, representing approximately 70% of the total cells. These mononuclear leukocytes have a lifespan of at least 2 weeks. Therefore, there is an inherent and obvious problem with the assumption that leukocyte detection in extravascular tissues 5 days after injection is indicative of an acute inflammatory reaction. Standard H&E staining cannot distinguish between activated leukocytes that may have been recruited to the injection site from the circulation (properly interpreted as an inflammatory reaction) and the naı̈ve resting leukocytes that were concentrated into the LR-PRP (Table 3 of Dragoo et al) and introduced to the tissue via injection. Because the authors did not validate the disappearance of injected leukocytes 5 days after injection or differentially label cells to distinguish between recruited and injected populations, it was not established that any of the leukocytes observed in the LR-PRP– injected tissue were actually recruited from the circulation to the injection site. This deficiency leaves any conclusions with respect to inflammatory reactions due to LR-PRP factually baseless and invalid. Thus, the only conclusion that can be made from the standard histopathology in this case is that LR-PRP containing concentrated leukocytes was indeed injected into the tissue. To the contrary, because LP-PRP showed a lack of leukocytes in the tissue at 5 days after injection, the finding of a large leukocyte infiltration at day 14 does indeed signify that a robust, albeit not acute, inflammatory reaction occurred. However, since the sterile saline control showed a similar robust inflammatory reaction on day 14, no specific conclusions regarding inflammatory effects of LP-PRP could be valid either. As other authors have not reported similar effects of saline injections into rabbit tendon tissue, it is possible that the particular model and/or injection paradigm used in the Dragoo et al study is inappropriate for studying inflammatory reactions. The lack of leukocytes in the LP-PRP–injected tissue at 5 days after injection is also of great interest because it is well established that acute leukocyte infiltration into damaged tissue is driven primarily by chemokine and cytokine release from activated platelets. This observation would indicate either that platelets in LP-PRP are completely deficient in activation and subsequent degranulation in vivo, as has been shown on in vitro studies, and are therefore incapable of initiating an acute inflammatory reaction required for activating a healing response, or that the tissue samples analyzed for histology were biased against demonstrating leukocyte infiltration that may be perceived as detrimental to the tissue. The authors also biased their statistical analyses by counting white blood cells twice in the tendon scores presented in Tables 4 and 5 of their article; once as individual parameters, and again as the total white blood cell count. It would be of interest to see the statistical analyses once this error is corrected. There is also no specific staining included in the study to determine vascularity, fiber structure, or the degree of fibrosis. Given the apparent pathological state of the tissue as presented in the The American Journal of Sports Medicine, Vol. 44, No. 12 2016 The Author(s)