Research Review By Dr. Shawn Thistle©

Date Posted:

June 2010

Study Title:

Platelet-Rich Plasma: From basic science to clinical application

Authors:

Foster TE, Puskas BL, Mandelbaum BR et al.

Author's Affiliations:

Boston University School of Medicine, Boston University, Massachusetts; Santa Monica Orthopaedic and Sports Medicine Group, Santa Monica, California, USA.

Publication Information:

American Journal of Sports Medicine 2009; 37(11): 2259-2272.

Background Information:

Research into bone, ligament and tendon healing has led to the development of many products and methods designed to stimulate biological factors and promote healing. In particular, the use of autologous and recombinant products is rapidly expanding in sports and orthopedic medicine. One such product is Platelet-Rich Plasma (PRP), which has recently received abundant media attention due to its association with some controversial professional athletes (does Tiger Woods ring a bell?). Although most RRS readers would not actually administer PRP treatments, your patients have likely asked you about it. In fact, as you’ll see below, it may represent a viable treatment option for some of your patients. As evidence-informed clinicians, we should have a working knowledge of a variety of treatment options, including those that may lie outside our immediate scope of practice. Therefore, the purpose of this review is to provide pertinent clinical and basic science information about PRP, and summarize the current state of the literature pertaining to its potential and current uses within musculoskeletal medicine.

Background Information on PRP:

  • PRP has been used in surgery for over 20 years, and has been studied since the 1970s in the fields of general and maxillofacial surgery.
  • In the literature PRP is also referred to as: platelet-rich concentrate, platelet gel, preparation rich in growth factors, platelet releasate.
  • Recently, the role of PRP in muscle/tendon/bone healing has been studied in the orthopedic literature.
  • There are numerous animal and basic science studies as well as small case reports/series on PRP, but there are only a few controlled, clinical studies published to date (more are coming).
  • The clinical trials that have been published typically have small numbers of subjects and are therefore underpowered statistically, making generalization of results difficult at this time.
Basic Principles of PRP:
  • The overall goal of PRP it to deliver a high concentration of platelet growth factors to an area of injured tissue to enhance tissue healing.
  • Platelets are small, mononucleated bodies in peripheral blood, known for their role in hemostasis and blood clot formation.
  • Platelets contain high levels of cytokines, growth factors and other biologically active compounds that initiate and regulate the basic components of wound healing.
  • Remember, plasma is the fluid component of blood, which itself contains clotting factors, proteins and ions.
  • In normal blood, the concentration of platelets is 150 000/μL to 300 000/μL
  • Concentration of platelets in PRP: normally PRP preparations contain 1 000 000/μL resulting in a 3-5-fold increase in growth factor concentrations.
  • Bioactive factors in PRP: PRP can potentially enhance healing by delivering a high concentration of various cytokines (contained in the α-granules in platelets) including: transforming-growth-factor-β (TGF-β), platelet-derived growth factor (PDGF), epidermal growth factor, vascular endothelial growth factor (VEGF) and endothelial cell growth factor. PRP also contains: serotonin, histamine, dopamine, calcium and adenosine (all non-growth factors that have an effect on the biological aspects of wound healing - inflammation, proliferation, healing,
  • The platelets in PRP are delivered in a clot, which contains numerous cell adhesion molecules including fibrin, vitronectin and fibronectin – these molecules play a role in cell migration and “scaffold” formation, both of which can enhance healing.
Formulation and Administration of PRP:
  • PRP can only be made from anti-coagulated blood (if the platelets are already part of a clot, they cannot be separated).
  • PRP can also NOT be made from serum (the clear fluid portion of blood that remains when clotting factors are removed).
  • PRP preparation involves adding citrate to whole blood (to bind ionized calcium to inhibit the clotting cascade – anyone having histology/immunology flashbacks yet?)
  • The blood is then centrifuged, resulting in PRP, which then must be clotted in order to be administered to the treatment site (bovine thrombin is often used to activate this mechanism).
  • Once injected, the platelets release ~70% of their stored growth factors within 10 minutes, and nearly 100% within 1 hour (small amounts continue to be released for up to 8-10 days).
  • The use of bovine thrombin creates the potential for antibody formation – this is rare but potentially serious complication of PRP treatment.
Effects of PRP on Soft Tissue:
  • Tendons: it is important to distinguish between acute tendon injury and chronic tendinosis – the stages of healing and remodeling may be quite different in these two conditions. In general, the literature to date (conducted mostly on animals) has demonstrated that PRP positively shifts gene expression and matrix synthesis in tendon and tendon cells (including increasing total collagen types I and III fiber synthesis with no apparent concomitant increase in catabolic molecules such as matrix metalloproteinases [MMP-1 and MMP-3]).
  • Muscle: several cytokines in PRP have known benefits for muscle healing, again demonstrated primarily in animal studies.

Current Clinical Application of PRP:

General Points:
  • It is important to note that high quality studies on PRP are essentially absent at this time, despite some promising results from case reports, small case series, and basic science/animal studies.
  • It is also noteworthy that there is some controversy in the human literature (including case reports etc.) regarding the efficacy of PRP.
  • Historically, the literature has been focused on intra-operative applications of PRP – such as repairing surgical wounds – below 3 additional areas of recent research will be briefly discussed.
PRP for Chronic Tendinopathy:
  • There is low level evidence that those with chronic, recalcitrant lateral epichondylalgia who have not improved with conventional treatment (physical therapy, counter-force bracing, corticosteroid injection) may benefit from PRP – post-injection rehabilitation must include strengthening and functional training progressions over 6-8 weeks. Immobilization does not appear to be necessary after PRP injection. The biggest study on this condition to date involved 140 patients (1).
  • A more recent RCT (n=54) on lateral epichondylagia patients suggests that PRP may be more beneficial for relieving pain and restoring function that corticosteroid injections (2).
  • It has also been proposed that PRP may benefit those with chronic Achilles tendinopathy due to the pathological mechanism involved with this condition – repetitive microtrauma leading to localized degeneration and weakness with or without concomitant swelling of the paratenon.
  • Those who advocate PRP use for Achilles cases suggest that ultrasonographic guidance should be used during injection to ensure accuracy. Further, contrary to the lateral elbow, experts recommend bracing Achilles patients and removing them completely from athletic activity – active and passive ROM plus standard rehabilitation soon follows.
  • A recent trial on Achilles tendon cases (n=54 – 27 treated with PRP) indicated that the addition of PRP to standard eccentric exercise protocol did NOT enhance clinical outcomes (3).
  • For those with recalcitrant plantar fasciitis, PRP injection should be followed with immediate weight-bearing and a standard rehabilitation program over 6-8 weeks.
  • There are animal studies suggesting that PRP may be of use in chronic patellar tendinosis (“Jumper’s knee”), but human evidence is lacking.
  • The authors of this review summarized their recommendations for PRP use in chronic tendinopathy (in general) as follows: 1) patients should have severe symptoms for at least 3 months that have not responded to conservative therapy 2) clinical findings are confirmed on MRI or ultrasound 3) the patient has a “washout” period from NSAID medications (and should avoid their use 3-4 weeks after PRP injection to avoid potential interference with muscle healing).
PRP & Bone Healing/Osteoarthritis:
  • It is hypothesized that PRP could provide growth factors that could positively influence bone healing.
  • The bulk of the existing literature on this topic has been conducted intra-operatively and overall the results are inconclusive at this time.
  • Regarding osteoarthritis – the interaction of PRP with chondrocytes may enable improved treatment of articular cartilage lesions. Some case studies are promising, but no high quality trials have been published on this topic. Further research is clearly needed.
PRP for Acute Ligament Injuries:
  • This application of PRP has recently gained popularity due to successful use in some professional athletes (Tiger Woods comes to mind), despite the limited published evidence on this topic.
Potential Concerns Regarding PRP:
  • For acute muscle injuries, come experts have suggested that PRP could promote a fibrotic healing response due to the elevation of TGF-β levels after injection (which has been shown to stimulate fibrosis in in vitro muscle studies) – this could potentially be countered via the administration of anti-TGF-β agents.

Future Research Directions:

  • In general, a number of questions about PRP’s biological mechanisms remain unanswered.
  • As mentioned above, higher quality human studies are required.
  • Further research is particularly required in the differential effects of PRP on acute versus chronic muscle/tendon problems, as well as the ideal timing for PRP injection (or the necessity of serial injections?)
  • The kinetics of cytokine release from various PRP preparations must be investigated – this information could assist in dictating ideal injection scheduling.
  • The effect of local tissue pH requires investigation as well since cytokine release from PRP seems to be pH dependent (4).
  • The methods of creating and administering PRP should also be standardized – there is currently a lot of variability in these factors, making generalizing difficult.

Clinical Application & Conclusions:

As newer research emerges on PRP, the clinical picture for this new intervention will hopefully become clear. For now, prudent clinicians should have a working knowledge of the existing literature so we can discuss this option with our patients, and perhaps refer to the appropriate provider if PRP treatment is appropriate (or available).

In the sports world, PRP is currently very controversial in terms of regulation and legality. In September of 2009, the World Anti-Doping Agency declared that platelet-derived preparations were prohibited when administered intra-muscularly (and that other routes of administration require a declaration of use that is in compliance with the International Standard for Therapeutic Use Exemptions) – murky water to say the least! From a performance enhancement perspective, it appears unlikely that PRP would provide an acute benefit, but further research is required to clarify this issue.

PRP has a logical proposed mechanism of action, and has a low risk of rejection (as the patient’s own blood is used). However, optimal preparation, administration and other factors must be determined before PRP moves to the forefront in orthopedic and sports medicine.

Study Methods:

This paper was a narrative review of the literature on PRP. Based on the current state of the literature on this topic, this study design was appropriate.

Additional References:

  1. Mishra A, Pavlenko T. Treatment of chronic elbow tendinosis with buffered platelet-rich plasma. Am J Sports Med 2006; 34(11): 1774-1778.
  2. Peerbooms JC et al. Positive effect of an autologous platelet concentrate in lateral epicondylitis in a double-blind randomized controlled trial: Platelet-Rich Plasma versus corticosteroid injection with a 1-year follow-up. Am J Sports Med 2010; 38(2): 255-262.
  3. de Vos RJ et al. Platelet-rich plasma injection for chronic Achilles tendinopathy: a randomized controlled trial. JAMA 2010; 303(2): 144-149.
  4. Liu Y et al. Fibroblast proliferation due to exposure to a platelet concentrate in vitro is pH dependent. Wound Repair & Regeneration 2002; 10(5): 336-340.