In shortArticle

Tissue repair by means of autologous platelet-rich plasma?


Autologous platelet-rich plasma (PRP) or autologous conditioned plasma (ACP) is used particularly as a medical treatment in sports and cosmetic medicine. The exact extent of its use is unknown. The presumed tissue regeneration effects of platelet-rich plasma have not been proven in scientific research. There is insufficient evidence for the efficacy of platelet-rich plasma in treating musculoskeletal soft tissue injuries in general and Achilles tendon ruptures in particular. Statutory regulations, surveillance and quality assurance have not been arranged.

  • There is insufficient evidence for the efficacy of platelet-rich plasma. 
  • The unproven efficacy, the lack of statutory regulations, the lack of inspection for quality assurance and the safety risks constitute sufficient arguments against using platelet-rich plasma in medicine.

Treatment with autologous  platelet-rich plasma (PRP) or autologous conditioned plasma (ACP) is used particularly for musculoskeletal soft tissue injuries in spots and cosmetic medicine. It is also used in orthopaedics and maxillary surgery, especially for large bone defects. The volume of platelet-rich plasma treatments is unknown. Platelet-rich plasma is supposed to promote tissue repair and/or the formation of new tissues by delivering high doses of growth factors and other bioactive proteins, such as cytokines, in injured tissues. However, both in vitro research and animal studies have reported contradictory findings in this respect.1 The Health Council of the Netherlands and the Dutch national Health Care Institute doubt the efficacy of platelet-rich plasma2,3,4, and the Dutch Orthopaedic Association NOV) has published a negative judgement on its use for lateral epicondyle tendinopathy (tennis elbow) and osteoarthritis5

This article explores the use of autologous platelet-rich plasma for musculoskeletal soft tissue injuries. The use of heterologous platelet-rich plasma and the use of platelet-rich plasma in treating patients with thrombocytopaenia  or thrombocytopathy with heterologous platelet concentrates are beyond the scope of this article.


Autologous platelet-rich plasma is plasma prepared from a patient’s own whole blood . After the whole blood has been centrifuged and other blood components have been removed, the plasma contains a higher concentration of platelets than the original whole blood. Blood collection, plasma processing and the administration of the platelet-rich plasma are usually carried out in immediate succession. The platelet-rich plasma is normally administered by injection. Injections with 1 to 5 mL platelet-rich plasma can be given once or repeatedly, at intervals of a few weeks. 

Composition not constant 

Due to the use of various initial volumes, the many ways of preparing platelet-rich plasma and the individual differences in the composition of the blood plasma, it is impossible to achieve a constant quality of the platelet-rich plasma. The platelet concentration in the plasma and the presence or absence of a particular concentration of white blood cells differ with the preparation method but also between individuals. Platelet concentrations in autologous platelet-rich plasma ranges from 300 to 1900 x 10³/µL, and the quantity of platelet-rich plasma after preparation ranges from 0.34 to 7.5 mL.3,6,7

Medicine or not?

Surveillance of the use of platelet-rich plasma is as yet not fully organised. According to the definition of a medicine in the Dutch Medicines Act, platelet-rich plasma is a medicine, as it is a substance with therapeutic properties, used with the aim of repairing or improving physiological functions. However, the Medicines Act does not apply to blood, plasma or blood cells of human origin. Hence, platelet-rich plasma is not a medicine. This means that the surveillance of the use of platelet-rich plasma now comes under the Healthcare, Quality, Complaints and Disputes Act (Wkkgz), but no suitable guidelines for this have been established. The guideline entitled Nieuwe Interventies in de Klinische Praktijk (NIKP; new interventions in clinical practice) could be used for this purpose.8 


Insufficient evidence for musculoskeletal soft tissue injuries

A 2014 Cochrane meta-analysis showed that there was insufficient evidence for the efficacy of using platelet-rich plasma for soft-tissue injuries of the tendons and capsules of the shoulder, elbow, hamstring, knee and foot.9 Further research carried out since the publication of the meta-analysis found no evidence of efficacy either and provided no supplementary information.10,11,12,1

The meta-analysis compared platelet-rich plasma treatment with conservative or surgical treatment.9 Conservative treatment meant wait-and-see, pain relief or physiotherapy. Primary outcome measures of the studies included function, pain and adverse effects. Data from 11 studies were used for the primary outcome measures.

The included studies were subject to a high or undefined degree of bias, and the evidence from the studies was of very low quality. In addition, the method used to prepare the platelet-rich plasma was not standardised, which means that the results are hard to compare.

Primary outcomes

The authors concluded that there was no statistically significant difference in terms of improving function in the short term (up to 3 months) between the treatment with platelet-rich plasma and the control treatment. They found a standardised mean difference (SMD ) of 0.26 (95% CI -0.19 to 0.71, based on 162 patients and 4 studies). The same was true for the function in the medium term (3–12 months), with an SMD of -0.09 (95% CI -0.56 to 0.39, 151 patients, 5 studies) and for the function in the longer term (>1 year), with an SMD of 0.25 (95% CI -0.07 to 0.57, 484 patients, 10 studies).

As regards the outcome in terms of pain in the short term, a statistically significant, but not clinically relevant difference was found in favour of the platelet-rich plasma treatment. The researchers found a mean difference (MD ) of -0.95 on a 10-point scale (95% CI -1.41 to -0.48, 175 patients, 4 studies). The data for pain in the medium and longer term were not used in the meta-analysis because of the large heterogeneity. No statistically significant difference in adverse effects was found between the two groups: RR  1.31 (95% CI 0.48 to 3.59;  486 patients, 11 studies).

Primary outcomes in subgroups

A subgroup analysis was carried out to examine the treatment of tendinopathy (tendon injury without tearing) with platelet-rich plasma as monotherapy and as adjunctive therapy to surgery. The analysis showed that the differences with the control treatment were non-significant for the three primary outcome measures. Finally, an analysis for each individual disorder also found that the treatment with platelet-rich plasma offered to significant advantages over conservative treatment. The findings were often not used in the meta-analysis due to a high level of heterogeneity. 

Secondary outcome measures

The meta-analysis combined the results regarding recurrence of rotator cuff rupture obtained in 5 studies. After 1 year (3 studies) and 2 years (2 studies) no statistically significant differences were found regarding recurrent ruptures: after 1 year, 10/101 in the platelet-rich plasma group versus 19/98 in the control group (RR 0.55, 95% VI 0.30 to 1.01; 3 studies), and after 2 years, 19/36 in the platelet-rich plasma group versus 22/37 in the control group (RR 0.88, 95% CI 0.59 to 1.32; 2 studies). Data for the other secondary outcome measures were not used in the meta-analysis, as these were only examined in a very few studies. 

No functional improvement in Achilles tendon rupture 

A recent randomised, placebo-controlled superiority study compared platelet-rich plasma as a treatment for the most common tendon rupture, viz. Achilles tendon rupture, with placebo. After 24 weeks, injections with platelet-rich plasma did not improve the function of the Achilles tendon compared to the placebo.13

Methods

Venous blood (50 mL) was collected from patients with an acute Achilles tendon rupture (having occurred no longer than 12 before), in order to prepare platelet-rich plasma with leukocytes, using a special centrifuge. Shortly afterward (about 17 minutes) an injection needle was placed in the tendon space, under local anaesthetic, with patients in prone position. Subsequently, either 4 mL of the platelet-rich plasma was injected in the locally anaesthetised area, or the injection syringe was held in position for the same period of time without anything being injected. The platelet and leukocyte concentrations were higher than those in the whole blood: 4.1-fold (95% CI 3.6 to 4.5) and 2.2 (95% CI 2.0 to 2.5), respectively.

No functional difference after 24 weeks

In terms of a so-called ‘limb symmetry index’ (see box) there was no difference in Achilles tendon functioning as shown by the ‘heel rise endurance test’ (see box). Twenty-four weeks after the treatment, the group treated with platelet-rich plasma was found to have a 34.7% function, while the placebo group had 38.5%, a mean difference of -3.9% (95% CI -10.5% to 2.7%).

The platelet-rich plasma and placebo did not differ for any of the secondary outcome measures either. Secondary outcome measures included how many times the heel could be lifted, and how high, during the ‘heel rise endurance test’, as well as other, unspecified functional tests and pain scores using a VAS scale. No differences in adverse effects were found either. The main adverse effects included recurring rupture (5%), deep-vein thrombosis (4 to 5%), local skin undermining or ulceration (11%) and persistent discomfort at the injection site (5 to 6%).

Testing Achilles tendon function
‘Limb symmetry index’ is a measure for which a score for the functional outcome measure of the affected limb is divided by the score for the non-affected limb, multiplied by 100%.

‘Heel rise endurance test’ is a validated endurance test for the Achilles tendon function. It primarily measures how long the patient is able to keep raising the heel repeatedly to a specified height.

How is platelet-rich plasma prepared? 

The preparation of platelet-rich plasma starts by collecting 6 to 60 mL of the patient’s blood in a tube. The tube contains sodium citrate, ACD (‘acid-citrate-dextrose’) or CPFD (‘citrate-phosphate-dextrose’) as an anticoagulant. Centrifuging for 3 to 17 minutes at 180 to 3200 g and a temperature of 12 to 26 °C results in 3 layers. The middle layer, the so-called ‘buffy coat’, contains the most platelets, but also still contains many white blood cells. Depending on the requirements for the final product, the white blood cells can be removed. The platelets can then be activated by adding calcium chloride, calcium gluconate, human thrombin, UV irradiation or auto-activation at the site of administration. Various medical devices with their corresponding protocols for blood-taking, centrifuging and ‘harvesting’ the platelet-rich plasma are commercially available.3,6,7

How might platelet-rich plasma work? 

When the platelets in the platelet-rich plasma are activated, the alpha-granules release their growth factors and cytokines within 10 minutes. The growth factors platelet derived growth factor (PDGF), transforming growth factor-β (TGF-β), vascular endothelial growth factor (VEGF), insulin-like growth factor-1 (IGF-1) and epidermal growth factor (EGF) play a part in wound healing and tissue regeneration. They are thought to promote angiogenesis, vasculogenesis, chemotaxis, cell growth, proliferation and differentiation of the target cells.

Further applications

There is a long list of other medical disorders for which the effect of platelet-rich plasma has been investigated. The list includes: bone transplantation in the jaw (first application)14,15, bone fractures, acute and chronic trauma, diabetic ulcers of the feet, epithelial defects in the eye, severe dry eye syndrome, sexual dysfunction, osteoarthritis, infectious defects of the sternum after thorax surgery, IVF failure and carpal tunnel syndrome. In cosmetic medicine, platelet-rich plasma is used to inhibit ageing of the skin and baldness, as an adjunct in lipid transplantation and facial surgery (‘Dracula facelift’).2

Details of the studies described

Moraes et al9
Nature of study: systematic review and meta-analysis.
Funding: Escola Paulista de Medicina, Federal university of Sao Paulo, Brazil.
Conflicts of interests: reported by none of the five authors.
Primary outcome measures: function (repair of injury, assessed by means of subjective questionnaire), pain and adverse effects.
Secondary outcome measure: time to return to work or sports (or non-return), quality of life, recurrence of disorder, need for secondary treatment and patient satisfaction.
Inclusion criteria: randomised or quasi-randomised controlled studies, 2005-2013.
Exclusion criteria: studies of osteoarthritis and studies involving a drug like corticosteroid as control.
Number of studies analysed: 19, 17 randomised and 2 quasi-randomised, involving 8 different disorders (rotator cuff rupture (6 studies), shoulder impingement syndrome (1), anterior cruciate ligament reconstruction (6), patellar tendinopathy (1), lateral epicondylitis (3), Achilles tendinopathy (1) and Achilles tendon rupture (1)). The primary outcome measures were assessed on the basis of 11 studies with a maximum of 486 patients. All studies were conducted at the same research centre.
Interventions: treatment with platelet-rich plasma was compared with placebo, whole blood or conservative treatment, or as an adjunct to conservative treatment.
Number of patients: 1088; 23 to 150 participants per study.
Keene et al13
Study title: PATH-2 trial (Platelet-rich plasma in Achilles Tendon Healing).
Conflict of interests: reported by 2 of the 12 authors.
Funding: the study was funded by the National Institute for Health Research, London, UK, which in turn is primarily funded by the British Ministry of Health and Social Affairs, but also collaborates closely with the pharmaceutical industry.
Nature of study: randomised double-blind placebo-controlled superiority study, carried out in 19 British hospitals.
Primary outcome measure: ‘heel rise endurance test’, its score expressed in a ‘limb symmetry index’.
Power calculation: 230 patients required (115 for each arm) for a power of 80% to enable detection of a standardised difference of 0.5 for the ‘limb symmetry index’ after 24 weeks at 5% significance and a possible loss to follow-up of 20%. 
Inclusion criteria: a clinical diagnosis of complete Achilles tendon rupture, acquired at most 12 days ago.
Main exclusion criteria: Achilles tendon ruptures at the level of the bone or muscle attachment, previous major leg injuries or deformities, diabetes mellitus, haematological or platelet disorders, systemic corticosteroid use, use of anticoagulants, other plausible contra-indications such as peripheral arterial vascular disease, foot ulcers, kidney failure, chemotherapy or severe acute neurological or psychiatric conditions.
Duration of study: 24 weeks.
Randomisation: computer-generated and carried out by external organisation, block randomisation stratified by participating hospitals.
Analysis of results: intention-to-treat.
Number of patients: a total of 230 (114 platelet-rich plasma, 116 placebo), 201 in analysis of primary outcome measure (100 platelet-rich plasma, 101 placebo).
Patient characteristics: average age 46 years, 25% and 32% for platelet-rich plasma and placebo, respectively; on average about 5 days after trauma
Trial registration: ISRCTN54992179.
 

  1. Keene DJ, Alsousou J, Willett K. How effective are platelet rich plasma injections in treating musculoskeletal soft tissue injuries?. BMJ. 2016;352:i517. Published 2016 Feb 17. doi:10.1136/bmj.i517.
  2. Gezondheidsraad. Plaatjesrijk plasma. Den Haag: Gezondheidsraad, 2019: publicatienr. 2019/01. 
  3. Gezondheidsraad. Bereiding, effectiviteit en veiligheid van PRP. Achtergronddocument bij het advies Plaatjesrijk plasma. Den Haag: Gezondheidsraad, 2019: publicatienr. 2019/01A.
  4. Zorginstituut Nederland. Standpunt van Zorginstituut Nederland: Plaatjesrijk plasma injectie(s) bij een laterale epicondylaire tendinopathie. 21 mei 2015. Via: //www.zorginstituutnederland.nl/publicaties/standpunten/2015/05/21/plaatjesrijk-plasma-injecties-bij-een-laterale-epicondylaire-tendinopathie. Geraadpleegd op 22 mei 2020.
  5. Nederlandse Orthopaedische Vereniging. Standpunten en adviezen. Via: //www.orthopeden.org/kwaliteit/kwaliteitsbeleid/standpunten-en-adviezen. Geraadpleegd op 2 mei 2020.
  6. Magalon J, Chateau AL, Bertrand B, et al. DEPA classification: a proposal for standardising PRP use and a retrospective application of available devices. BMJ Open Sport Exerc Med. 2016;2(1):e000060. Published 2016 Feb 4. doi:10.1136/bmjsem-2015-000060.
  7. Michelson AD, Cattaneo M, Frelinger A, Newman P. Platelets. ISBN 978-0-12-813456-6. Academic Press, 4th ed. 2019;1161-5.  
  8. Zorginstituut Nederland. Leidraad NIKP: Nieuwe Interventies in de Klinische Praktijk. 15 oktober 2014. Via: //www.zorginstituutnederland.nl/binaries/zinl/documenten/publicatie/2014/10/15/leidraad-nikp-nieuwe-interventies-in-de-klinische-praktijk/Leidraad+NIKP+%28Nieuwe+Interventies+in+de+Klinische+Praktijk%29.pdf. Geraadpleegd op 22 mei 2020
  9. Moraes VY, Lenza M, Tamaoki MJ, Faloppa F, Belloti JC. Platelet-rich therapies for musculoskeletal soft tissue injuries. Cochrane Database Syst Rev. 2014;2014(4):CD010071. Published 2014 Apr 29. doi:10.1002/14651858.CD010071.pub3. 
  10. Reurink G, Goudswaard GJ, Moen MH, et al. Platelet-rich plasma injections in acute muscle injury. N Engl J Med. 2014;370(26):2546?2547. doi:10.1056/NEJMc1402340.
  11. Holtby R, Christakis M, Maman E, et al. Impact of Platelet-Rich Plasma on Arthroscopic Repair of Small- to Medium-Sized Rotator Cuff Tears: A Randomized Controlled Trial. Orthop J Sports Med. 2016;4(9):2325967116665595. Published 2016 Sep 13. doi:10.1177/2325967116665595.
  12. Miller LE, Parrish WR, Roides B, Bhattacharyya S. Efficacy of platelet-rich plasma injections for symptomatic tendinopathy: systematic review and meta-analysis of randomised injection-controlled trials. BMJ Open Sport Exerc Med. 2017;3(1):e000237. Published 2017 Nov 6. doi:10.1136/bmjsem-2017-000237.
  13. Keene DJ, Alsousou J, Harrison P, et al. Platelet rich plasma injection for acute Achilles tendon rupture: PATH-2 randomised, placebo controlled, superiority trial. BMJ. 2019;367:l6132. Published 2019 Nov 20. doi:10.1136/bmj.l6132.
  14. Esposito M, Grusovin MG, Rees J, et al. Effectiveness of sinus lift procedures for dental implant rehabilitation: a Cochrane systematic review. Eur J Oral Implantol. 2010;3(1):7?26.
  15. Hou X, Yuan J, Aisaiti A, Liu Y, Zhao J. The effect of platelet-rich plasma on clinical outcomes of the surgical treatment of periodontal intrabony defects: A systematic review and meta-analysis. BMC Oral Health. 2016;16(1):71. Published 2016 Aug 17. doi:10.1186/s12903-016-0261-5.

Authors

  • Erik P Schwarz
  • Hein J.E.M. Janssens, dr, general practitioner