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Int J Sports Med 2019; 40(07): 427-433
DOI: 10.1055/a-0884-0734
Review
© Georg Thieme Verlag KG Stuttgart · New York

Current Insights into the Potential Misuse of Platelet-based Applications for Doping in Sports

David Scully
1   Hull York Medical School, Centre for Atherothrombotic and Metabolic Disease, Hull, United Kingdom of Great Britain and Northern Ireland
,
Antonios Matsakas
1   Hull York Medical School, Centre for Atherothrombotic and Metabolic Disease, Hull, United Kingdom of Great Britain and Northern Ireland
› Author Affiliations
Further Information

Publication History



accepted 25 March 2019

Publication Date:
23 April 2019 (online)

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Abstract

Platelet-based applications are currently used for the delivery of growth factors and other biomolecules as autologous biomaterials in regenerative medicine and cosmetic therapies. Many studies have revealed that platelet-based applications such as platelet-rich plasma and platelet releasate exhibit beneficial biological effects after a sports injury or trauma when administered locally by intramuscular injections. At present, treatment of the public, patients and athletes with platelet-based applications is permitted and regulated by the Food and Drug Administration and the World Anti-Doping Agency. Since 2011 the use of autologous platelet-rich plasma is permitted in competitive sports by the World Anti-Doping Agency, due to the lack of evidence in performance enhancement and anabolic effects. However, accumulating research has recently shed light on the role of platelet-derived growth factors in wound healing, skeletal myogenesis, muscle stem cell function and tissue regeneration. Although any ergogenic potential of platelet-rich plasma and platelet releasate on intact skeletal muscle and human sports performance remain to be established, novel evidence suggests that platelet-derived growth factors can modulate muscle, tendon, ligament, protein synthesis/degradation, vascularization, energy utilization and regenerative capacity in various experimental settings. Since platelet-based applications are currently not prohibited, they constitute a tool for potential abuse and doping in sports. The aim of this review is to critically discuss and assimilate current insights and biological evidence that set the ground for exploitation and misuse in competitive sports, and develop strategies to combat these activities.

Key words

platelet-rich plasma - world anti-doping agency - prohibition list - growth factors - sports injury
 

  • References

  • 1 Andia I, Abate M. Platelet-rich plasma: Combinational treatment modalities for musculoskeletal conditions. Front Med 2018; 12: 139-152
    CrossrefPubMedGoogle Scholar
  • 2 Brossi PM, Moreira JJ, Machado TS, Baccarin RY. Platelet-rich plasma in orthopedic therapy: A comparative systematic review of clinical and experimental data in equine and human musculoskeletal lesions. BMC Vet Res 2015; 11: 98
    CrossrefPubMedGoogle Scholar
  • 3 Lee KS, Wilson JJ, Rabago DP, Baer GS, Jacobson JA, Borrero CG. Musculoskeletal applications of platelet-rich plasma: fad or future?. AJR Am J Roentgenol 2011; 196: 628-636
    CrossrefPubMedGoogle Scholar
  • 4 McClure MJ, Garg K, Simpson DG, Ryan JJ, Sell SA, Bowlin GL, Ericksen JJ. The influence of platelet-rich plasma on myogenic differentiation. J Tissue Eng Regen Med 2016; 10: E239-E249
    CrossrefPubMedGoogle Scholar
  • 5 Mosca MJ, Rodeo SA. Platelet-rich plasma for muscle injuries: Game over or time out?. Curr Rev Musculoskelet Med 2015; 8: 145-153
    CrossrefPubMedGoogle Scholar
  • 6 Navani A, Li G, Chrystal J. Platelet rich plasma in musculoskeletal pathology: a necessary rescue or a lost cause?. Pain Physician 2017; 20: E345-E356
    PubMedGoogle Scholar
  • 7 Nguyen RT, Borg-Stein J, McInnis K. Applications of platelet-rich plasma in musculoskeletal and sports medicine: an evidence-based approach. PM R 2011; 3: 226-250
    CrossrefPubMedGoogle Scholar
  • 8 Sánchez M, Anitua E, Delgado D, Sánchez P, Orive G, Padilla S. Muscle repair: Platelet-rich plasma derivates as a bridge from spontaneity to intervention. Injury 2014; 45: S7-S14
    PubMedGoogle Scholar
  • 9 Scully D, Naseem KM, Matsakas A. Platelet biology in regenerative medicine of skeletal muscle. Acta Physiol (Oxf) 2018; 223: e13071
    CrossrefPubMedGoogle Scholar
  • 10 Dimauro I, Grasso L, Fittipaldi S, Fantini C, Mercatelli N, Racca S, Geuna S, Di Gianfrancesco A, Caporossi D, Pigozzi F, Borrione P. Platelet-rich plasma and skeletal muscle healing: A molecular analysis of the early phases of the regeneration process in an experimental animal model. PLoS One 2014; 9: e102993
    CrossrefPubMedGoogle Scholar
  • 11 Li H, Hicks JJ, Wang L, Oyster N, Philippon MJ, Hurwitz S, Hogan MV, Huard J. Customized platelet-rich plasma with transforming growth factor beta1 neutralization antibody to reduce fibrosis in skeletal muscle. Biomaterials 2016; 87: 147-156
    CrossrefPubMedGoogle Scholar
  • 12 Li H, Usas A, Poddar M, Chen CW, Thompson S, Ahani B, Cummins J, Lavasani M, Huard J. Platelet-rich plasma promotes the proliferation of human muscle derived progenitor cells and maintains their stemness. PLoS One 2013; 8: e64923
    CrossrefPubMedGoogle Scholar
  • 13 Saury C, Lardenois A, Schleder C, Leroux I, Lieubeau B, David L, Charrier M, Guevel L, Viau S, Delorme B, Rouger K. Human serum and platelet lysate are appropriate xeno-free alternatives for clinical-grade production of human MuStem cell batches. Stem Cell Res Ther 2018; 9: 128
    CrossrefPubMedGoogle Scholar
  • 14 Scully D, Sfyri P, Verpoorten S, Papadopoulos P, Munoz-Turrillas MC, Mitchell R, Aburima A, Patel K, Gutierez L, Naseem KM, Matsakas A. Platelet releasate promotes skeletal myogenesis by increasing muscle stem cell commitment to differentiation and accelerates muscle regeneration following acute injury. Acta Physiol (Oxf) 2019; 225: e13207
    CrossrefPubMedGoogle Scholar
  • 15 Bernuzzi G, Petraglia F, Pedrini MF, De Filippo M, Pogliacomi F, Verdano MA, Costantino C. Use of platelet-rich plasma in the care of sports injuries: Our experience with ultrasound-guided injection. Blood Transfus 2014; 12 (Suppl. 01) s229-s234
    PubMedGoogle Scholar
  • 16 Rettig AC, Meyer S, Bhadra AK. Platelet-rich plasma in addition to rehabilitation for acute hamstring injuries in NFL players: Clinical effects and time to return to play. Orthop J Sports Med 2013; 1: 2325967113494354
    CrossrefPubMedGoogle Scholar
  • 17 Wetzel RJ, Patel RM, Terry MA. Platelet-rich plasma as an effective treatment for proximal hamstring injuries. Orthopedics 2013; 36: e64-e70
    CrossrefPubMedGoogle Scholar
  • 18 Wasterlain AS, Braun HJ, Harris AH, Kim HJ, Dragoo JL. The systemic effects of platelet-rich plasma injection. Am J Sports Med 2013; 41: 186-193
    CrossrefPubMedGoogle Scholar
  • 19 WADA. World Anti-Doping Code.In Available from https://www.wada-ama.org/sites/default/files/resources/files/WADA_Prohibited_List_2010_EN.pdf World Anti-Doping Agency, Montreal; World Anti-Doping Agency 2010 accessed on 23/11/2018
    PubMed
  • 20 WADA. World Anti-Doping Code.In Available from https://www.wada-ama.org/sites/default/files/resources/files/WADA_Prohibited_List_2011_EN.pdf World Anti-Doping Agency, Montreal; World Anti-Doping Agency 2011 accessed on 23/11/2018
    PubMed
  • 21 Wijten P, van Holten T, Woo LL, Bleijerveld OB, Roest M, Heck AJ, Scholten A. High precision platelet releasate definition by quantitative reversed protein profiling—brief report. Arterioscler Thromb Vasc Biol 2013; 33: 1635-1638
    CrossrefPubMedGoogle Scholar
  • 22 Burkhart JM, Vaudel M, Gambaryan S, Radau S, Walter U, Martens L, Geiger J, Sickmann A, Zahedi RP. The first comprehensive and quantitative analysis of human platelet protein composition allows the comparative analysis of structural and functional pathways. Blood 2012; 120: e73-e82
    CrossrefPubMedGoogle Scholar
  • 23 Borrione P, Gianfrancesco AD, Pereira MT, Pigozzi F. Platelet-rich plasma in muscle healing. Am J Phys Med Rehabil 2010; 89: 854-861
    CrossrefPubMedGoogle Scholar
  • 24 Denapoli PM, Stilhano RS, Ingham SJ, Han SW, Abdalla RJ. Platelet-Rich Plasma in a Murine Model: Leukocytes, Growth Factors, Flt-1, and Muscle Healing. Am J Sports Med 2016; 44: 1962-1971
    CrossrefPubMedGoogle Scholar
  • 25 Hammond JW, Hinton RY, Curl LA, Muriel JM, Lovering RM. Use of autologous platelet-rich plasma to treat muscle strain injuries. Am J Sports Med 2009; 37: 1135-1142
    CrossrefPubMedGoogle Scholar
  • 26 Huang S, Wang Z. Platelet-rich plasma-derived growth factors promote osteogenic differentiation of rat muscle satellite cells: In vitro and in vivo studies. Cell Biol Int 2012; 36: 1195-1205
    CrossrefPubMedGoogle Scholar
  • 27 Im W, Ban JJ, Lim J, Lee M, Chung JY, Bhattacharya R, Kim SH. Adipose-derived stem cells extract has a proliferative effect on myogenic progenitors. In Vitro Cell Dev Biol Anim 2014; 50: 740-746
    CrossrefPubMedGoogle Scholar
  • 28 Martins RP, Hartmann DD, de Moraes JP, Soares FA, Puntel GO. Platelet-rich plasma reduces the oxidative damage determined by a skeletal muscle contusion in rats. Platelets 2016; 27: 784-790
    CrossrefPubMedGoogle Scholar
  • 29 Notodihardjo PV, Morimoto N, Kakudo N, Matsui M, Sakamoto M, Liem PH, Suzuki K, Tabata Y, Kusumoto K. Gelatin hydrogel impregnated with platelet-rich plasma releasate promotes angiogenesis and wound healing in murine model. J Artif Organs 2015; 18: 64-71
    CrossrefPubMedGoogle Scholar
  • 30 Pinheiro CL, Peixinho CC, Esposito CC, Manso JE, Machado JC. Ultrasound biomicroscopy and claudication test for in vivo follow-up of muscle repair enhancement based on platelet-rich plasma therapy in a rat model of gastrocnemius laceration. Acta Cir Bras 2016; 31: 103-110
    CrossrefPubMedGoogle Scholar
  • 31 Takase F, Inui A, Mifune Y, Sakata R, Muto T, Harada Y, Ueda Y, Kokubu T, Kurosaka M. Effect of platelet-rich plasma on degeneration change of rotator cuff muscles: In vitro and in vivo evaluations. J Orthop Res 2017; 35: 1806-1815
    CrossrefPubMedGoogle Scholar
  • 32 Tsai WC, Yu TY, Chang GJ, Lin LP, Lin MS, Pang JS. Platelet-Rich Plasma Releasate Promotes Regeneration and Decreases Inflammation and Apoptosis of Injured Skeletal Muscle. Am J Sports Med 2018; 46: 1980-1986
    CrossrefPubMedGoogle Scholar
  • 33 Harriss DJ, Macsween A, Atkinson G. Standards for ethics in sport and exercise science research: 2018 Update. Int J Sports Med 2017; 38: 1126-1131
    Article in Thieme ConnectPubMedGoogle Scholar
  • 34 Schippinger G, Fankhauser F, Oettl K, Spirk S, Hofmann P. Does single intramuscular application of autologous conditioned plasma influence systemic circulating growth factors?. J Sports Sci Med 2012; 11: 551-556
    PubMedGoogle Scholar
  • 35 Mishra A, Harmon K, Woodall J, Vieira A. Sports medicine applications of platelet rich plasma. Curr Pharm Biotechnol 2012; 13: 1185-1195
    CrossrefPubMedGoogle Scholar
  • 36 Creaney L, Hamilton B. Growth factor delivery methods in the management of sports injuries: the state of play. Br J Sports Med 2008; 42: 314-320
    CrossrefPubMedGoogle Scholar
  • 37 Engebretsen L, Steffen K, Alsousou J, Anitua E, Bachl N, Devilee R, Everts P, Hamilton B, Huard J, Jenoure P, Kelberine F, Kon E, Maffulli N, Matheson G, Mei-Dan O, Menetrey J, Philippon M, Randelli P, Schamasch P, Schwellnus M, Vernec A, Verrall G. IOC consensus paper on the use of platelet-rich plasma in sports medicine. Br J Sports Med 2010; 44: 1072-1081
    CrossrefPubMedGoogle Scholar
  • 38 Miroshnychenko O, Chang WT, Dragoo JL. The use of platelet-rich and platelet-poor plasma to enhance differentiation of skeletal myoblasts: Implications for the use of autologous blood products for muscle regeneration. Am J Sports Med 2017; 45: 945-953
    CrossrefPubMedGoogle Scholar
  • 39 Borrione P, Fossati C, Pereira MT, Giannini S, Davico M, Minganti C, Pigozzi F. The use of platelet-rich plasma (PRP) in the treatment of gastrocnemius strains: A retrospective observational study. Platelets 2018; 29: 596-601
    CrossrefPubMedGoogle Scholar
  • 40 Borrione P, Grasso L, Chierto E, Geuna S, Racca S, Abbadessa G, Ronchi G, Faiola F, Di Gianfrancesco A, Pigozzi F. Experimental model for the study of the effects of platelet-rich plasma on the early phases of muscle healing. Blood Transfus 2014; 12 (Suppl. 01) s221-s228
    PubMedGoogle Scholar
  • 41 Bubnov R. Ultrasound guided injections of Platelets Rich Plasma for muscle injury in professional athletes. Comparative study. Med Ultrason 2013; 15: 101-105
    CrossrefPubMedGoogle Scholar
  • 42 Sassoli C, Frati A, Tani A, Anderloni G, Pierucci F, Matteini F, Chellini F, Zecchi Orlandini S, Formigli L, Meacci E. Mesenchymal stromal cell secreted sphingosine 1-phosphate (S1P) exerts a stimulatory effect on skeletal myoblast proliferation. PLoS One 2014; 9: e108662
    CrossrefPubMedGoogle Scholar
  • 43 Sassoli C, Pini A, Chellini F, Mazzanti B, Nistri S, Nosi D, Saccardi R, Quercioli F, Zecchi-Orlandini S, Formigli L. Bone marrow mesenchymal stromal cells stimulate skeletal myoblast proliferation through the paracrine release of VEGF. PLoS One 2012; 7: e37512
    CrossrefPubMedGoogle Scholar
  • 44 Sassoli C, Vallone L, Tani A, Chellini F, Nosi D, Zecchi-Orlandini S. Combined use of bone marrow-derived mesenchymal stromal cells (BM-MSCs) and platelet rich plasma (PRP) stimulates proliferation and differentiation of myoblasts in vitro: New therapeutic perspectives for skeletal muscle repair/regeneration. Cell Tissue Res 2018; 372: 549-570
    CrossrefPubMedGoogle Scholar
  • 45 Tsai WC, Yu TY, Lin LP, Lin MS, Wu YC, Liao CH, Pang JS. Platelet rich plasma releasate promotes proliferation of skeletal muscle cells in association with upregulation of PCNA, cyclins and cyclin dependent kinases. Platelets 2017; 28: 491-497
    CrossrefPubMedGoogle Scholar
  • 46 Laver L, Carmont MR, McConkey MO, Palmanovich E, Yaacobi E, Mann G, Nyska M, Kots E, Mei-Dan O. Plasma rich in growth factors (PRGF) as a treatment for high ankle sprain in elite athletes: a randomized control trial. Knee Surg Sports Traumatol Arthrosc 2015; 23: 3383-3392
    CrossrefPubMedGoogle Scholar
  • 47 Saturveithan C, Premganesh G, Fakhrizzaki S, Mahathir M, Karuna K, Rauf K, William H, Akmal H, Sivapathasundaram N, Jaspreet K. Intra-articular hyaluronic acid (HA) and platelet rich plasma (PRP) injection versus hyaluronic acid (HA) injection alone in patients with grade III and IV knee osteoarthritis (OA): a retrospective study on functional outcome. Malays Orthop J 2016; 10: 35-40
    CrossrefPubMedGoogle Scholar
  • 48 Schnabel LV, Mohammed HO, Miller BJ, McDermott WG, Jacobson MS, Santangelo KS, Fortier LA. Platelet rich plasma (PRP) enhances anabolic gene expression patterns in flexor digitorum superficialis tendons. J Orthop Res 2007; 25: 230-240
    CrossrefPubMedGoogle Scholar
  • 49 Wu YT, Ho TY, Chou YC, Ke MJ, Li TY, Huang GS, Chen LC. Six-month efficacy of platelet-rich plasma for carpal tunnel syndrome: A prospective randomized, single-blind controlled trial. Sci Rep 2017; 7: 94
    CrossrefPubMedGoogle Scholar
  • 50 Zanon G, Combi F, Combi A, Perticarini L, Sammarchi L, Benazzo F. Platelet-rich plasma in the treatment of acute hamstring injuries in professional football players. Joints 2016; 4: 17-23
    Article in Thieme ConnectPubMedGoogle Scholar
  • 51 Arslan E, Nellesen T, Bayer A, Prescher A, Lippross S, Nebelung S, Jahr H, Jaeger C, Huebner WD, Fischer H, Stoffel M, Shakibaei M, Pufe T, Tohidnezhad M. Effect of platelet mediator concentrate (PMC) on Achilles tenocytes: an in vitro study. BMC Musculoskelet Disord 2016; 17: 307
    CrossrefPubMedGoogle Scholar
  • 52 Virchenko O, Grenegard M, Aspenberg P. Independent and additive stimulation of tendon repair by thrombin and platelets. Acta Orthop 2006; 77: 960-966
    CrossrefPubMedGoogle Scholar
  • 53 Davidson J, Jayaraman S. Guided interventions in musculoskeletal ultrasound: what's the evidence?. Clin Radiol 2011; 66: 140-152
    CrossrefPubMedGoogle Scholar
  • 54 Sengodan VC, Kurian S, Ramasamy R. Treatment of partial rotator cuff tear with ultrasound-guided platelet-rich plasma. J Clin Imaging Sci 2017; 7: 32
    CrossrefPubMedGoogle Scholar
  • 55 Thokala RP, Radhakrishnan K, Anandan A, Panicker VK. Recovery of platelet count among apheresis platelet donors. J Clin Diagn Res 2016; 10: EC01-EC04
    PubMedGoogle Scholar
  • 56 Fukuda K, Miyata H, Kuwano A, Kuroda T, Tamura N, Kotoyori Y, Kasashima Y. Does the injection of platelet-rich plasma induce changes in the gene expression and morphology of intact Thoroughbred skeletal muscle?. J Equine Sci 2017; 28: 31-39
    CrossrefPubMedGoogle Scholar
  • 57 Zammit PS, Golding JP, Nagata Y, Hudon V, Partridge TA, Beauchamp JR. Muscle satellite cells adopt divergent fates: a mechanism for self-renewal?. J Cell Biol 2004; 166: 347-357
    CrossrefPubMedGoogle Scholar
  • 58 Kadi F, Charifi N, Denis C, Lexell J, Andersen JL, Schjerling P, Olsen S, Kjaer M. The behaviour of satellite cells in response to exercise: What have we learned from human studies?. Pflugers Arch 2005; 451: 319-327
    CrossrefPubMedGoogle Scholar
  • 59 WADA. World Anti-Doping Code. In, World Anti-Doping Agency, Montreal.Available from https://www.wada-ama.org/sites/default/files/prohibited_list_2018_en.pdf World Anti-Doping Agency 2018 accessed on 23/11/2018
    PubMed
  • 60 Beitzel K, Allen D, Apostolakos J, Russell RP, McCarthy MB, Gallo GJ, Cote MP, Mazzocca AD. US definitions, current use, and FDA stance on use of platelet-rich plasma in sports medicine. J Knee Surg 2015; 28: 29-34
    PubMedGoogle Scholar
  • 61 Bachl N, Derman W, Engebretsen L, Goldspink G, Kinzlbauer M, Tschan H, Volpi P, Venter D, Wessner B. Therapeutic use of growth factors in the musculoskeletal system in sports-related injuries. J Sports Med Phys Fitness 2009; 49: 346-357
    PubMedGoogle Scholar
  • 62 Jiang L, Luan Y, Miao X, Sun C, Li K, Huang Z, Xu D, Zhang M, Kong F, Li N. Platelet releasate promotes breast cancer growth and angiogenesis via VEGF-integrin cooperative signalling. Br J Cancer 2017; 117: 695-703
    CrossrefPubMedGoogle Scholar
  • 63 Franco AT, Corken A, Ware J. Platelets at the interface of thrombosis, inflammation, and cancer. Blood 2015; 126: 582-588
    PubMedGoogle Scholar
  • 64 Salamanna F, Veronesi F, Maglio M, Della Bella E, Sartori M, Fini M. New and emerging strategies in platelet-rich plasma application in musculoskeletal regenerative procedures: General overview on still open questions and outlook. Biomed Res Int 2015; 2015: 846045
    PubMedGoogle Scholar
  • 65 Le ADK, Enweze L, DeBaun MR, Dragoo JL. Current Clinical Recommendations for Use of Platelet-Rich Plasma. Curr Rev Musculoskelet Med 2018; 11: 624-634
    CrossrefPubMedGoogle Scholar
  • 66 Bottegoni C, Dei Giudici L, Salvemini S, Chiurazzi E, Bencivenga R, Gigante A. Homologous platelet-rich plasma for the treatment of knee osteoarthritis in selected elderly patients: An open-label, uncontrolled, pilot study. Ther Adv Musculoskelet Dis 2016; 8: 35-41
    CrossrefPubMedGoogle Scholar
  • 67 Anitua E, Prado R, Orive G. Allogeneic platelet-rich plasma: At the dawn of an off-the-shelf therapy?. Trends Biotechnol 2017; 35: 91-93
    CrossrefPubMedGoogle Scholar
  • 68 Xiong G, Lingampalli N, Koltsov JCB, Leung LL, Bhutani N, Robinson WH, Chu CR. Men and women differ in the biochemical composition of platelet-rich plasma. Am J Sports Med 2018; 46: 409-419
    CrossrefPubMedGoogle Scholar