Review of the Evidence Behind Platelet-Rich Plasma Therapy

Musculoskeletal injuries are a common cause of severe long-term pain and physical disability. Increasing in popularity in sports medicine is the use of autologous platelet-rich plasma (PRP) therapy to biologically enhance healing. The prominence provided by professional athletes in a variety of fields including football, baseball, basketball, figure skating, and golf,^1-3 who credit PRP therapy with faster return to competition after a joint injury, has brought exposure to PRP therapy as a desirable treatment for a range of sports-related injuries, compared to the more traditional treatment approach that may involve medications, physical therapy, or surgery. 

While basic science and preclinical data support some benefit of PRP for a variety of sports-related injuries, robust randomized trials are limited. Despite lack of approval by the US Food and Drug Administration (FDA), PRP therapy is gaining unproven acceptance as treatment for sports-related injuries.⁴

Platelet rich plasma therapy is not a new concept. Over the past 2 decades, PRP therapy has been used to improve wound healing and bone grafting procedures in several clinical areas including neurosurgery; oral, periodontal, cosmetic, and maxillofacial surgery; otolaryngology; head and neck surgery; urology; orthopedic/spinal surgery; and cardiothoracic and general surgery.^{5, 6} In recent years PRP therapy has gained prominence among sports medicine specialists, professional athletes, and increasingly among individuals engaged in recreational sports. 

According to Michael Hall, MD, senior orthopedic surgery resident at the NYU Hospital for Joint Diseases in New York, “Use of PRP has increased, in large part due to new devices that enable fast preparation in the outpatient setting. A patient gives a blood sample and 30 minutes later can receive their injection….. There is always a risk of infection with any injection, and some have reported increased pain or inflammation at the injection site, but otherwise the risks with PRP appear minimal.” ⁷

It is important to clarify what PRP therapy is, the current understanding of its mechanism of action, and evidence for its effectiveness in treating common sports injuries.

Platelet-rich plasma, also referred to as platelet-enriched plasma, platelet-rich concentrate, autologous platelet gel, and platelet releasate, is defined as a plasma fraction of autologous blood having platelet concentration above baseline, and prepared from blood drawn from the patient. 

Platelets are separated from other blood cells and then concentrated by centrifugation. The concentrated platelets are recombined with the remaining blood, and the platelet-rich blood is injected directly into the patient’s injured area. Despite its pervasive use, the clinical efficacy of PRP therapy and its precise mechanisms of action have yet to be clearly defined.

In addition to platelets, PRP contains a variety of growth factors, including transforming growth factor-β, platelet-derived growth factor, insulin-like growth factor-I, vascular endothelial growth factor, epidermal growth factor, and hepatocyte growth factor.^4,8  Many of these growth factors have been shown to enhance one or more phases of bone and soft tissue healing. 

Basic research suggests that PRP exerts its effects through many downstream events secondary to the degranulation of platelets releasing growth factors and other bioactive agents into the local environment, resulting in chemotaxis of inflammatory cells and activation and proliferation of local progenitor cells. It is believed that PRP can augment or stimulate healing by turning on the same biological processes that normally occur to initiate healing after musculoskeletal injury. ^8,9

In vitro studies have demonstrated that PRP can enhance the proliferation of stem cells and fibroblasts.¹⁰ The initial vascular response to injury includes the release of subendothelial factors that attract circulating platelets and activate coagulation proteins. Platelets aggregate and adhere to the site of injury, where they release granules containing serotonin, thromboxane, and adenosine, and initiate coagulation and the formation of fibrin. Local production of thrombin enhances activation of platelets and the subsequent formation of a hemostatic plug that minimizes further bleeding.

Production of thrombin and activation of platelets also initiate the process of wound healing via thrombin-dependent cell activation and platelet-dependent angiogenesis. Degranulation of the alpha granules in platelets containing growth factors is believed to be important in early wound healing. When the platelets in PRP are activated by thrombin, they release growth factors and other substances that serve to accelerate the wound-healing process by increasing cellular proliferation, matrix formation, osteoid production, connective tissue healing, angiogenesis, and collagen synthesis. ^{9, 5}

Platelets in PRP are also believed to play a role in host defense mechanism at the wound site by producing signaling proteins that attract macrophages. Studies have demonstrated antimicrobial activity against Escherichia coli; Staphylococcus aureus, including methicillin-resistant S aureus; Candida albicans, and Cryptococcus neoformans, potentially improving wound healing. ⁵

Although the literature provides evidence from preclinical and small-scale clinical studies on the benefits of PRP therapy for sports-related injuries, currently robust evidence from randomized studies is limited.¹¹ It is also thought that its effects may vary depending on the location of injury and the concentration of important growth factors involved in various soft tissue healing responses. ⁸ Consequently, several prospective randomized controlled trials are in progress to better understand PRP’s mechanism of action and formally demonstrate efficacy in placebo-controlled trials.¹²

Evidence from studies that show a positive benefit of PRP is largely circumstantial.^13-17 One study involved 75 patients diagnosed with acute muscle injuries who were randomly allocated to autologous PRP therapy combined with a rehabilitation program or a rehabilitation program only. The study reported that patients in the PRP group achieved full recovery significantly earlier than controls (P=.001).¹⁴ 

Furthermore, significantly lower pain severity scores were observed in the PRP group throughout the study, although recurrence rate after 2-year follow-up was not statistically significant between the groups. Similar results were reported in a study involving 28 patients diagnosed with acute hamstring injury. The researchers found that patients in the PRP group achieved full recovery significantly earlier than controls (P=.02). ¹⁵

Larger-scale studies, including a Cochrane review, have reported no additional benefit of PRP therapy compared to intensive rehabilitation for treating sports injuries.^18-22 A recent example is a study involving 90 professional athletes with hamstring injuries as identified on magnetic resonance imaging who were randomly assigned to injection with PRP intervention, platelet-poor plasma (PPP-control), or no injection. ¹⁸ The study found no benefit of a single PRP injection over intensive rehabilitation.

Summary and Clinical Applicability

Platelet-rich plasma therapy is now commonly used to treat chronic tendinopathies, including lateral epicondylosis, plantar fasciitis, Achilles and patellar tendinopathies, and acute ligamentous injuries. Sports medicine clinics are also offering PRP treatments for acute injuries such as acute muscle tears, medial collateral ligament tears, and ankle sprains.^11,23  

Some of the advantages of PRP therapy that have been reported include its natural healing process, the ease of preparation and administration, relative safety compared to allogeneic or homologous plasma, and its favorable cost. 

PRP has also been reported to reduce pain through the effects of bioactive molecules and growth factors present in alpha granules.^5,24  Dr Hall cautions that each patient and injury is unique; therefore, it is important to discuss any treatment with an orthopedic surgeon. According to Dr Hall, “Some believe that PRP may catalyze the body’s repair mechanisms at areas of injury, improve healing, and shorten recovery time; however, there currently is minimal evidence of this clinically and more research must be performed.” ⁷

Overall, a clear evidence for the benefit PRP therapy and recommendations for it use must await more robust evidence from clinical trials.

References

1. PRP Treatments. Athletes using PRP. Available at: http://www.prptreatments.org/sports-medicine/athletes-using-prp/. Accessed April 23, 2016.
2. Luks HJ. Is PRP therapy approved for athletes in the 2014 Winter Olympics? Available at: http://www.howardluksmd.com/sports-medicine/prp-therapy-approved-athletes-olympics/. Accessed April 23, 2016.
3. Niesen J. Platelet-rich plasma therapy big with athletes. July 3, 2012. Available at: http://www.foxsports.com/north/story/platelet-rich-plasma-therapy-big-with-athletes-070312. Accessed April 23, 2016.
4. Dhillon RS, Schwarz EM, Maloney MD. Platelet-rich plasma therapy – future or trend? Arthritis Res Ther. 2012;14(4):219.
5. Lacci KM, Dardik A. Platelet-rich plasma: support for its use in wound healing. Yale J Biol Med. 2010;83(1):1-9.
6. Smith RG, Glassmann CJ, Campbell MS. Platelet-rich plasma: properties and clinical applications. Summer 2007 – Vol.2, No.2. Available at: http://www.jlgh.org/Past-Issues/Volume-2—Issue-2/Platelet-rich-Plasma.aspx. Accessed April 23, 2016.
7. American Association for the Advancement of Science (AAAS). Platelet-rich plasma: does it work? Public release: 1-Oct-2009. http://www.eurekalert.org/pub_releases/2009-10/aaoo-ppd092909.php. Accessed April 23, 2016.
8. Middleton KK, Barro V, Muller B, Terada S, Fu FH. Evaluation of the effects of platelet-rich plasma (PRP) therapy involved in the healing of sports-related soft tissue injuries. Iowa Orthop J. 2012;32:150-163.
9. Mehta V. Platelet-rich plasma: a review of the science and possible clinical applications. Orthopedics. 2010;33(2):111.
10. Kakudo N, Minakata T, Mitsui T, Kushida S, Notodihardjo FZ, Kusumoto K. Proliferation-promoting effect of platelet-rich plasma on human adipose-derived stem cells and human dermal fibroblasts. Plast Reconstr Surg. 2008;122(5):1352-1360.
11. Kon E, Filardo G, Di Martino A, Marcacci M. Platelet-rich plasma (PRP) to treat sports injuries: evidence to support its use. Knee Surg Sports Traumatol Arthrosc. 2011;19(4):516-527.
12. US National Institutes of Health. Platelet-rich plasma therapy for shoulder pain in persons with spinal cord injury. Available at: https://clinicaltrials.gov/ct2/results?term=platelet+rich+plasma+therapy&Search=Search. Accessed April 23, 2016.
13. Podesta L, Crow SA, Volkmer D, Bert T, Yocum LA. Treatment of partial ulnar collateral ligament tears in the elbow with platelet-rich plasma. Am J Sports Med. 2013;41(7):1689-1694.
14. Rossi LA, Molina Rómoli AR, Bertona Altieri BA, Burgos Flor JA, Scordo WE, Elizondo CM. Does platelet-rich plasma decrease time to return to sports in acute muscle tear? A randomized controlled trial. Knee Surg Sports Traumatol Arthrosc. 2016. [Epub ahead of print].
15. Hamid A, Mohamed Ali MR, Yusof A, George J, Lee LP. Platelet-rich plasma injections for the treatment of hamstring injuries: a randomized controlled trial. Am J Sports Med. 2014;42(10):2410-2418.
16. Kon E, Filardo G, Delcogliano M, et al. Platelet-rich plasma: new clinical application: a pilot study for treatment of jumper’s knee. Injury. 2009;40(6):598-603.
17. Ragab EM, Othman AM. Platelet rich plasma for treatment of chronic plantar fasciitis. Arch Orthop Trauma Surg. 2012;132(8):1065-1070.
18. Hamilton B, Tol JL, Almusa E, et al. Platelet-rich plasma does not enhance return to play in hamstring injuries: a randomised controlled trial. Br J Sports Med. 2015;49(14):943-950.
19. Reurink G, Goudswaard GJ, Moen MH, et al. Rationale, secondary outcome scores and 1-year follow-up of a randomised trial of platelet-rich plasma injections in acute hamstring muscle injury: the Dutch Hamstring Injection Therapy study. Br J Sports Med. 2015;49(18):1206-1212.
20. Moraes VY, Lenza M, Tamaoki MJ, Faloppa F, Belloti JC. Platelet-rich therapies for musculoskeletal soft tissue injuries. Cochrane Database Syst Rev. 2014;4:CD010071.
21. Kearney RS, Parsons N, Metcalfe D, Costa ML. Injection therapies for Achilles tendinopathy. Cochrane Database Syst Rev. 2015;5:CD010960.
22. Grambart ST. Sports medicine and platelet-rich plasma: nonsurgical therapy. Clin Podiatr Med Surg. 2015;32(1):99-107.
23. 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(3):628-636.
24. Knezevic NN, Candido KD, Desai R, Kaye AD. Is platelet-rich plasma a future therapy in pain management? Med Clin North Am. 2016;100(1):199-217.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

This article originally appeared on Clinical Pain Advisor