BRINGING SCIENCE TO TREATMENT

Platelet therapy: a faster route to recovery?

In recent years, there’s been an increasing interest in platelet therapy as a treatment for speeding injury healing. But just how strong is the evidence for its use? Andrew Hamilton looks at the latest research.

Of all the injuries suffered by athletes participating in sport, those involving muscle tissue are among the commonest injuries – accounting for up to 50% of reported injuries1 2. Many muscle injuries result from excessive strain on muscle, during sprinting, jumping or other explosive contractions but they may also be the result of direct blows, or excessive eccentric contraction, when the muscle develops tension while lengthening. In this type of injury, the myotendinous junction of the superficial muscles involved is often affected –eg the rectus femoris , semitendinosus, and gastrocnemius muscles.

Despite the high frequency of muscle injury in athletes, there’s still considerable debate among clinicians as to what constitutes the ‘best’ method of its treatment. Much of course will depend on the diagnosis and grading of muscle injury – usually gained from a thorough clinical assessment. Imagining can provide additional guidance for the physiotherapist, although this often requires a referral involving additional cost and time.

Despite these caveats above, few clinicians would argue against the merits of some basic early treatment options to hasten the athlete’s return to sport practice. The most commonly used of these include rest, ice, compression and elevation (RICE) with a short period of immobilisation during the early postinjury phase. In addition, the short-term use of non-steroidal anti-inflammatory (NSAIDs), corticosteroid medications is often recommended3 4 5 6 7 8.

More than medication

While medications such as NSAIDs and corticosteroids have their place in the early stages of muscle injury treatment, there’s been an increasing interest in the use of autologous (cells and tissues derived from self) of biological products as an alternative or additional treatment for muscle injury. One such treatment is the use of blood platelets (blood cells whose function, along with the coagulation factors, is to stop bleeding) as used in platelet therapy.


Figure 1: Schematic representation of inflammation and repair/ remodelling processes following muscle injury9

 

 

 

 

Muscle inflammatory responses and macrophage cross-talk in response to acute muscle injury and/or, mechanical stress – eg exercise – activate the transcription factors NF-βB and/or c-Jun/AP-1, leading to expression and secretion of muscle factors (eg chemokines and non-protein mediators). These compounds in turn are responsible for the recruitment of immune cells from the circulation (neutrophils, monocytes) into the muscle. Once in the tissue, the infiltrating and resident immune cells produce additional factors that reciprocally affect the muscle. This leads to the acute inflammatory response necessary for pathogen clearance and tissue repair (green arrow).

Muscle inflammatory responses and macrophage cross-talk in response to acute muscle injury and/or, mechanical stress – eg exercise – activate the transcription factors NF-βB and/or c-Jun/AP-1, leading to expression and secretion of muscle factors (eg chemokines and non-protein mediators). These compounds in turn are responsible for the recruitment of immune cells from the circulation (neutrophils, monocytes) into the muscle. Once in the tissue, the infiltrating and resident immune cells produce additional factors that reciprocally affect the muscle. This leads to the acute inflammatory response necessary for pathogen clearance and tissue repair (green arrow).


Why platelets? When a muscle is injured and damaged, it undergoes a number of processes as part of the healing/repair process (see figure 1). During this process, there are two main phases:

  • The early phase of destruction (inflammatory phase), where affected cells including muscles, blood vessels, connective tissues and intramuscular nerve undergo death and breakdown.
  • The repair and remodelling phase, in which undifferentiated satellite cells (in response to various growth factors) proliferate and differentiate into mature myoblasts in an effort to replace the injured muscle fibre tissue.

In the inflammatory phase , the inflammation occurring after muscle injury usually leads to the accumulation of inflammatory cells, neutrophils and macrophages. In addition, blood platelet cells in the vicinity of the injured site become activated. These activated platelets undergo ‘degranulation’ releasing various substances, including growth factors (see box 1), which are stored in the alpha (􀁟) granules within platelets10. The accumulation of platelets in the vicinity of a muscle injury should therefore in theory provide more growth factors for the tissue, thereby aiding the repair and remodelling phase. In addition, platelets contain other important substances need for tissue repair and regeneration, such as adhesive proteins, clotting factors and their inhibitors, proteases, cytokines and membrane glycoproteins.

Theory and practice

Given the discovery that platelets play a vital role in muscle tissue repair, it wasn’t long before researchers wondered if platelet-rich plasma (PRP) injections into the site of an injured muscle could accelerate recovery time and thus hasten the return to sport of an injured athlete. These platelet-rich therapies are produced by centrifuging a quantity of the patient’s own blood and extracting the active, platelet-rich, fraction.

A 2009 study using an animal model showed that an autologous PRP injection significantly hastened tibialis anterior muscle recovery (from 21 days to 14 days11. Indeed, prior to this, Sanchez et al presented a similar finding at the 2005 World Congress on Regenerative Medicine. They noted that athletes receiving PRP injection under ultrasound guidance gained full recovery within half of the expected time12.

However, in 2010, the International Olympic Committee concluded that ‘currently there is very limited scientific evidence of clinical efficacy and safety profile of PRP use in athletic injuries’13. This stance was underlined by a systematic review article published the following year, reporting ‘there has been no randomised clinical trials of PRP effects on muscle healing’14. Fast forward to 2015 and what does the research about the efficacy or otherwise of PRP injections?

Box 1: Platelet-derived growth factors
There are a number of growth factors that have been identified as being released from platelets during the course of injury/healing(10). These include:

-Vascular endothelial growth factors
-Epidermal growth factor
-Basic fibroblast growth factors (bFGF)
-Insulin-like growth factor-1 (IGF-1)
-Transforming growth factor beta-1 (TGF-􀁠1)

In particular, research demonstrates that both IGF-1 and bFGF have the ability to accelerate healing following muscle and tendon injury(11).

Latest evidence

In the last 2-3 years, a flurry of papers has been published on the use of PRP therapy for muscle injury. A 2013 study on 30 professional athletes with acute local muscle injury seemed to provide positive evidence for PRP therapy15. Prior to the intervention, all the athletes underwent and ultrasound and sonoelastography (a form of ultrasound imaging that reveals mechanical propert ies of t issue) examination. Patients were then randomly assigned to 2 groups:

  • Group A received targeted PRP injection under ultrasound guidance plus and additional conservative treatment
  • Group B received conventional conservative treatment only

Pain was assessed according to visual analogue scale (0 to 10), while muscle function was assessed according to pain on resisted flexion or strength, and range of motion. Both groups were further evaluated in the days 1, 7, 14, 21, and 28 after commencing treatment.

Overall, the degree of pain relief was greater in group A compared to group B throughout the intervention. At the end of 28-day observation, 93 % of pain regression was declared by patients in group A vs. 80 % of regression of pain in group B. Also, at 7 and 14 days, significant improvements in strength and range of motion for PRP treatment group were observed. By the end of the study, subjective global function scores improved significantly in group A compared with group B – as evidenced by the average return-to-sport times – 10 days in group A and 22 days in group B.

A 2014 systematic review meanwhile produced less encouraging findings on the value of PRP16. The authors searched the literature for studies assessing the effects (benefits and harms) of platelet-rich therapies for treating musculoskeletal soft tissue injuries and where the primary outcomes were functional status, pain and adverse effects. The review included data from 19 trials totalling 1088 participants that compared platelet-rich therapy with placebo, autologous whole blood, dry needling or no platelet-rich therapy. These trials covered eight clinical conditions: rotator cuff tears (arthroscopic repair) (six trials); shoulder impingement syndrome surgery (one trial); elbow epicondylitis (three trials); anterior cruciate ligament (ACL) reconstruction (four trials), ACL reconstruction (donor graft site application) (two trials), patellar tendinopathy (one trial), Achilles tendinopathy (one trial) and acute Achilles rupture surgical repair (one trial). The results were as follows:

  • Medium-term function data at six months from five trials showed no difference between PRP and control groups;.
  • Long-term function data at one year pooled from 10 trials showed no difference between PRP and the control condition;
  • Data pooled from four trials that assessed PRP in three clinical conditions showed a small reduction in short-term pain in favour of PRT but the clinical significance of this result was marginal;
  • Seven trials reported an absence of adverse events following PRP therapy but four trials reported adverse events;
  • Pooled data for long-term function from six trials during rotator cuff tear surgery showed no statistically or clinically significant differences between PRP and control groups;
  • The evidence for all primary outcomes was judged as being of very low quality not least because the methods of preparing platelet-rich plasma varied and lacked standardisation and quantification of the plasma applied to the patient;

Fast forward a year and a 2014 study investigated the effect of a single PRP injection in the treatment of grade 2 hamstring muscle injuries17. Twentyeight patients diagnosed with an acute hamstring injury were randomly allocated to autologous PRP therapy combined with a rehabilitation program or a rehabilitation program only. The primary outcome of this study was time to return to play. In addition, changes in pain severity and pain interference scores over time were examined.

The results showed that patients in the PRP group achieved full recovery significantly earlier than controls. The mean time to return to play was 42.5 days in the control group and 26.7 days in the PRP group. Significantly lower pain severity scores were observed in the PRP group throughout the study. However, no significant difference in the pain interference score was found between the 2 groups. The authors concluded: ‘A single autologous PRP injection combined with a rehabilitation program is significantly more effective in treating hamstring injuries than a rehabilitation program alone’.

Figure 2: Timing of resumption of sports activity after acute hamstring injury18

The cumulative probability of a resumption of sports activity. Data for patients who had a non-hamstring injury before they resumed their sports activity were censored at the time of this injury.

The cumulative probability of a resumption of sports activity. Data for patients who had a non-hamstring injury before they resumed their sports activity were censored at the time of this injury.


Conflicting evidence

Later the same year however, a rigorous double-blind, placebo-controlled trial on the effectiveness of PRP injections for acute hamstring injury drew very different conclusions19. The researchers randomly assigned 80 competitive and recreational athletes with acute hamstring muscle injuries (as confirmed on magnetic resonance imaging) t o r e c e i v e intramuscular injections of PRP or isotonic saline as a placebo. Importantly, the patients, clinicians, and physiotherapists were a l l unaware of study-group assignments.

Each patient received two 3-ml injections with the use of a sterile ultrasound-guided technique; the first injection was administered within 5 days after the injury and was followed 5 to 7 days later by the second injection. Patients in the two study groups performed an identical, daily, progressively phased, criteria-based rehabilitation program, which was based on the best available evidence (detailed in the study). The rate of re-injury within 2 months after the resumption of sports activity was assessed as a secondary outcome measure.

The result showed that the median time until the resumption of sports activity was 42 days in the PRP group and 42 days also in the placebo group (see figure 2). The re-injury rate was 16% in the PRP group and 14% in the placebo group Although statistical analysis allowed for a small chance that there was a clinically relevant between-group difference, the authors concluded that in their study at least, intramuscular PRP injections provided no benefit over and above a placebo injection.

The rigorous design of this study and the relatively large number of subjects casts some serious doubts on the efficacy of PRP therapy. As if to underline these misgivings, the researchers carried out a 1-year follow-up study on the same group of athletes (published just last month) to see if there were any longer-term benefits of PRP therapy that might not have been picked up in the initial study20. In particular, they sought to establish the re-injury rates at one year following PRP, and any secondary outcomes such as alterations in clinical and MRI parameters, subjective patient satisfaction and the hamstring outcome score. Analysis of the data showed that just as at 2 months, one year later there were no significant between-group differences in the 1-year re-injury rate, or any other secondary outcome measure.

Another very recent study into the efficacy of PRP therapy was published just a few months ago. Researchers pooled the data from 19 previous randomised controlled trials, which had compared PRP therapy in patients with acute or chronic musculoskeletal soft tissue injuries with placebo, autologous whole blood, dry needling, or no PRP21. The authors concluded: ‘While several in -vitro studies have shown that platelet-derived growth factors can promote the regeneration of bone, cartilage, and tendons, there is currently insufficient evidence to support the use of platelet-rich therapy for treating musculoskeletal soft tissue injuries’. And as in the 2013 study highlighted earlier22, they also pointed out t h a t there i s a need f o r the standardisation of PRP preparation methods. The final conclusion was that the only circumstance where PRP therapy might offer tangible benefits is when conservative treatment has failed and the next treatment option is an invasive surgical procedure.

Conclusions and practical advice for the clinician

When a clinician has an athlete in their care, minimising the recovery time so that return to sport can take place as soon as possible is an important goal of any treatment. In theory, PRP therapy should speed healing and recovery and indeed, a few earlier studies seemed to suggest that PRP is a worthwhile adjunct alongside conventional treatment. However, larger and more rigorously constructed studies have failed to find solid evidence for the benefits of PRP, either in the short or longer term. One possible reason for the confusing picture is that the preparation of PRP is far from standardised, which means that the biologically active components in a PRP treatment might vary tremendously from study to study. As clinicians, our goal is to employ evidence-based practice and on this basis, we have to conclude that (as yet) there is simply insufficient evidence for the use of PRP therapy in the treatment of sports-related muscle injuries.

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