Comparison of Conventional Dose Versus Superdose Platelet-Rich Plasma for Knee Osteoarthritis: Response

Authors’ Response:

We would like to thank the readers for their insightful comments on our recently published article titled “Comparison of Conventional Dose Versus Superdose Platelet-Rich Plasma for Knee Osteoarthritis: A Prospective, Triple-Blind, Randomized Clinical Trial.” ¹³ The questions raised through this letter to the editor are genuine, and we will try to give appropriate explanations for all the queries in a comprehensive and detailed manner.

It is crucial to understand that whenever we talk about superdose platelet-rich plasma (PRP),^2,13 its therapeutic properties are governed by 2 factors. Firstly, a higher volume, and secondly, a higher absolute number of platelets, which ultimately lead to a higher content of growth factors responsible for its enhanced anabolic potential and tissue regenerative behavior.

It has rightly been pointed out by the readers that the effect of PRP cannot be attributed to platelets alone, but we would also like to state that the majority of growth factors in plasma are concentrated inside these platelets, which are released upon their degranulation.^1,4 Platelets serve as the primary reservoir of these growth factors in plasma, with their alpha granules housing a high concentration of key factors such as platelet-derived growth factor (PDGF), transforming growth factor–beta (TGF-β), vascular endothelial growth factor (VEGF), and insulin-like growth factor (IGF).^5,11 Magalon et al ⁷ did a comparative study of different PRP preparation devices using a single donor and concluded that there was a positive correlation between the platelet dose and the concentration of growth factors at the injection site. This makes PRP an abundant source of these growth factors, hence widely used for various therapeutic purposes.^4,11,12 Having said that, we also agree that there are multiple other variables related to PRP and its therapeutic effects. Recent evidence highlights that we should look at finer aspects of PRP preparation such as the presence or absence of an activator, leukocyte-rich or leukocyte-poor PRP, and granulocyte-rich or granulocyte-poor PRP.^6,9,14 The DEPA classification was also introduced in an attempt to create uniformity in PRP preparation and reporting. ⁸ It states that there should be uniformity in reporting the dose of platelets, the efficiency of platelet capture, the purity of the obtained product, and the presence or absence of activators used in PRP. The previous classification by Mishra et al ¹⁰ and the PAW classification ³ used 2 or 3 variables, but the DEPA classification used 4 variables in an attempt to standardize PRP usage. The “D” in DEPA stands for the dose of platelets administered, which is further subdivided from A to D in decreasing order of absolute platelet numbers injected. “A” refers to an absolute platelet count >5 billion. In our study, group B exhibited a mean platelet count of 5.65 billion.

As far as Table 3 is concerned, group A had a mean platelet concentration of 732.04 ± 304.38 × 10³/µL, and group B had a mean platelet concentration of 681.44 ± 276.05 × 10³/µL, leading to a mean platelet count of 2.82 billion in group A (4 mL) and 5.65 billion in group B (8 mL). We would like to thank the readers for pointing out the typographical error of the P value in the comparison between absolute platelet counts of groups A and B. We would like to clarify that there was indeed a statistically significant difference in the absolute platelet count between the 2 groups, since the absolute number of platelets in group B was nearly 2 times that of group A (P < .001), which leads to the result of the superdose group being better at sequential follow-up visits.

Another interesting comment raised by the readers is that we should've used the same volume of PRP in both groups and kept different platelet concentrations across the 2 groups (twice that of one group) to effectively isolate the true influence of the absolute platelet number on PRP properties. To clarify this point, we would like to state that our primary objective was to compare 2 different volumes of injectable PRP for knee osteoarthritis. Since the platelet concentrations didn't differ by a significant amount in the 2 groups, doubling the volume of PRP in one group meant that it would also double the absolute number of platelets in that group. Our study was based on the understanding that most of the growth factors in PRP are derived from platelets, whereas other cytokines and molecules such as alpha-2 macroglobulin contribute a far lesser amount of growth factors compared to platelets. ¹⁵ As suggested by the readers, if we had to conduct an ideal study to isolate the effect of an absolute platelet count of 5 billion versus a count of 2 to 3 billion, the volume of PRP should have been fixed at 4 mL. However, creating 2 statistically and significantly different platelet concentrations is itself tedious and would need altogether different PRP production techniques, making it technically infeasible. We would still like to take this suggestion in a positive way and try to do a study on this topic in the near future to evaluate the isolated effect of absolute platelet count on the clinical efficacy of PRP.