Reply: Double-blind clinical trial to compare autologous fat grafts versus autologous fat grafts with PDGF: no effect of PDGF.

Abstract

Sir: We thank Dr. Gigliofiorito for his comments regarding our article entitled “Double-Blind Clinical Trial to Compare Autologous Fat Grafts versus Autologous Fat Grafts with PDGF: No Effect of PDGF.”1 Regarding his interesting observation of potential thrombocytopenia in human immunodeficiency virus patients and its possible influence on the platelet count, we should note that none of the patients in this study had thrombocytopenia (defined as a total platelet count <150 × 103 cells/μl). Thrombocytopenia was a general contraindication for elective surgery, so no patients with thrombocytopenia were included in it. Every patient had virologic and immunologic stability and was under highly active antiretroviral therapy. There is a strict association between active human immunodeficiency virus replication and human immunodeficiency virus–related thrombocytopenia. The introduction of highly active antiretroviral therapy was followed by a substantial reduction in the incidence of thrombocytopenia because of its ability to limit platelet and bone marrow damage induced by uncontrolled human immunodeficiency virus replication and opportunistic infections.2 The reference about hematologic manifestations of human immunodeficiency virus presented by Dr. Gigliofiorito was published in 1987.3 In more recent studies, thrombocytopenia affects only 4 to 5 percent of human immunodeficiency virus patients.4 The evolution of the disease, the control of complications, and the survival rates have improved in recent decades. Human immunodeficiency virus patients have become chronic, stable, well-controlled patients (including hematologic control). Indeed, the use of platelet-derived growth factor (PDGF) leads to controversial results because of the lack of systematization of preparation techniques. In our work, the preparation technique of platelet-rich plasma was manual. Currently, there are numerous devices that provide platelet-rich plasma with higher concentrations of PDGF than those obtained by classic technique of centrifugation and manual pipetting. It could be that these devices obtain the best results. There are also numerous commercial interests involved. There are even differences in the production of PDGF depending on the device used, as the work by Everts et al. shows.5 Everts et al. compared three devices in vitro: the Gravitational Platelet Sequestration System (Biomet Biologics, Warsaw, Ind.), the Electa Cell-Separator (Sorin Group, Mirandola, Italy), and the Autologous Growth Factor Filter (Interpore Cross International, Irvine, Calif.). The comparison showed variation among the three devices in the quality of platelet-rich plasma preparation method and in the amount of PDGF released after activation. Kakudo et al. evaluated the effect of different concentrations of activated platelet-rich plasma on adipose-derived stem cells and human fibroblasts, and observed that the addition of certain concentrations of activated platelet-rich plasma (5 percent) to these cells increased cell proliferation but that major concentrations of PDGF could reduce cell proliferation compared with controls.6 Further studies on these ideal concentrations are required. Our results agree with experimental work in mice where Por et al. compared two groups of mice to evaluate the effect of platelet-rich plasma on fat graft survival.7 They injected platelet-rich plasma and fat into mice in one group and only fat into mice in another group. The platelet-rich plasma was obtained by the Medtronic Magellan system device (Medtronic, Minneapolis, Minn.). After 16 weeks, biopsy specimens were taken from fat grafts to evaluate certain parameters, and they observed that there were no differences between groups. Perhaps the levels of PDGF themselves are actually involved in the process of adipose regeneration and neovascularization but are not sufficient or do not last long enough to improve fat survival. We know that platelet-rich plasma exerts its effect for 5 to 10 days as observed Pietrzak and Eppley,8 or for 2 weeks as shown by the work on bone regeneration by Wiltfang et al.9 This period may be too short to enhance the survival of fat grafts. Yuksel et al. improved fat graft survival with the addition of insulin and insulin-like growth factor-1 through a polylactic-co-glycolic-acid/polyethylene glycol microspheres delivery system, allowing sustained release for at least 28 days.10 The PDGF sequence of action in the fat survival has been little studied and is poorly understood. Although vascular endothelial growth factor is involved in the survival of fat grafts, it is expressed only on day 7 after injection.11 Perhaps by then the concentration of growth factors released by the platelet-rich plasma has been reduced and is not sufficient to improve fat graft survival. In addition, angiogenesis in the adipose tissue has special characteristics that could not be provided by the added platelet-rich plasma.12 Specifically, the creation of a neovascular network requires a sequence of events, including the release of proteases from the activated endothelial cells, with consequent degradation of vascular basement membrane, migration of endothelial cells into the interstitial space, endothelial cell proliferation, and differentiation into mature vessels. Platelet-rich plasma injection may not be sufficient to initiate this cascade of events and therefore may not improve fat graft integration. Therefore, we fully agree with Gigliofiorito et al. that more studies are needed to determine the actual effectiveness of platelet-rich plasma. DISCLOSURE The authors have no financial interest to declare in relation to the content of this communication. Eva Guisantes, M.D., Ph.D. Plastic Surgery Department Hospital of Terrassa Joan Fontdevila, M.D., Ph.D. Plastic Surgery Department Hospital Clinic of Barcelona, and University of Barcelona Barcelona, Spain