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 Table of Contents  
EDITORIAL
Year : 2017  |  Volume : 31  |  Issue : 1  |  Page : 1-6

Role of platelet-rich plasma: The current trend and evidence


Department of Pain Management, Pain Clinic of India Pvt. Ltd. and KEM Hospital, Mumbai, India

Date of Web Publication5-May-2017

Correspondence Address:
Kailash Kothari
2005/A, Cosmic heights, Bhakti Park, Wadala East, Mumbai - 400 037, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijpn.ijpn_31_17

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  Abstract 


Platelets contain many important growth factors, which helps in healing. These lead researchers to inject high concentration of Platelets in plasma (platelet-rich plasma [PRP]) at injury site. There is a variety of PRP preparations produced by the different commercial equipment. The concentration of platelets should be more than 5 times the normal in PRP. PRP can be used for long list of conditions, for example, orthopedic, neurology, musculoskeletal, cardiology, dermatology, and plastic surgery. The research on PRP is still in infancy, and there is no consensus on platelet concentration, amount of PRP, which is the best technology in preparing PRP. There are many animal studies, which are showing encouraging results, but human studies are lacking. PRP is very promising treatment option which is nonsurgical. We need to wait for more concrete evidence to emerge to define its exact clinical role.

Keywords: Healing, injuries, musculoskeletal, osteoarthritis, platelet-rich plasma, regenerative therapy, tendinopathy


How to cite this article:
Kothari K. Role of platelet-rich plasma: The current trend and evidence. Indian J Pain 2017;31:1-6

How to cite this URL:
Kothari K. Role of platelet-rich plasma: The current trend and evidence. Indian J Pain [serial online] 2017 [cited 2017 Oct 17];31:1-6. Available from: http://www.indianjpain.org/text.asp?2017/31/1/1/205719




  Introduction Top


Platelet-rich plasma (PRP) is defined as a portion of the plasma fraction of autologous blood having a platelet concentration above baseline.[1] PRP is becoming a very popular therapy for a variety of conditions including degenerative and musculoskeletal conditions. The balance between degeneration and regeneration is restored in favor of regeneration with the help of PRP.

The initial popularity of PRP grew from its promise as a safe and natural alternative to surgery. PRP advocates promoted the procedure as an organically based therapy that enabled healing through the use of one's own natural growth factors. In recent years, scientific research and technology have provided a new perspective on platelets. Studies suggest that platelets contain an abundance of growth factors and cytokines that can affect inflammation, postoperative blood loss, infection, osteogenesis, wound, muscle tear, and soft tissue healing. Research now shows that platelets also release many bioactive proteins responsible for attracting macrophages, mesenchymal stem cells, and osteoblasts that not only promote removal of degenerated and necrotic tissue but also enhance tissue regeneration and healing.

A typical blood specimen comprises 93% red blood cells, 6% platelets, and 1% white blood cells.[1] French physician Alfred Donné first saw platelets in the blood in 1842.[2] Platelets are small discoid cells with a life span of about 7–10 days. Only in the past two decades, have we learned that platelet activation in the body releases healing proteins called growth factors.[3]

Platelets are vital in preventing acute blood loss, repairing vascular walls, and nearby tissues after the injury take place. PRP also includes three proteins in blood known to act as cell adhesion molecules: fibrin, fibronectin, and vitronectin.[4]

Post injury wound healing takes place; platelets are activated when they get in contact with collagen in the blood stream. Platelets are responsible for storing intercellular mediators and cytokines, release their α-granule content after aggregation. This process is intense in the 1st h and synthesis of cytokines and growth factors continues almost up to 7 days.[3] More than 800 different proteins are secreted into the surrounding media [3],[5],[6] having a paracrine effect on different cell types: myocytes,[3],[6],[7] tendon cells,[3],[7],[8],[9],[10],[11] mesenchymal stem cells from different origins,[2],[12],[13],[14],[15] chondrocytes,[16],[17],[18] osteoblasts,[19],[20] fibroblasts,[21],[22],[23] and endothelial cells.[24] Tissue repair happens with the help of cell regeneration, angiogenesis, and cell migration. Some research suggests that platelets have antibiotic effect by virtue of their ability to secrete antimicrobial peptides.[2],[25] Platelets also have anti-inflammatory [26] and analgesic properties.[2], 18, [27],[28],[29],[30]

PRP has been used since 1970s and they are becoming increasingly popular since then. There are various ways of preparing PRP in the market. Initially, simple centrifugation was used, and later many advances happened in many commercial systems. In newer systems, by adding collagen, calcium, thrombin, by glass contact or by freezing cycles, helps to activate platelets. Some systems use PRP as suspension, and some use it as gel. The technology is going through rapid growth in recent times.[31],[32],[33]

The first use of Autologous PRP injections was reportedly in 1987 in open heart surgery.[34]

The interest in PRP therapy grew intensely in last one decade, especially after 2009. In 2009, it was reported that two of the Pittsburgh Steelers received PRP for their ankle injuries before their triumph at the Super Bowl.[1] Due to the media attention, PRP became an accepted though unproven treatment for sports-related injuries.[35]


  Indications of Platelet-Rich Plasma Top


PRP is being used in various fields:[36],[39]

  1. Orthopedics
  2. Sports medicine
  3. Dentistry
  4. Otolaryngology
  5. Neurosurgery
  6. Ophthalmology
  7. Urology
  8. Wound healing
  9. Cosmetic
  10. Cardiothoracic and
  11. Maxillofacial surgery.


The common indications [36] for which PRP is being used are:

  1. Joint pains (chronic arthritis)
  2. Chronic tendinopathies
  3. Ligament sprains
  4. Muscles strains
  5. Intervertebral discs
  6. Plantar fasciitis
  7. Subacute and chronic sports injuries
  8. Nerve injuries
  9. Bone repair and regeneration
  10. In plastic surgery
  11. Oral surgery.



  Contraindications Top


Absolute contraindications:[36]

  1. Platelet dysfunction syndrome
  2. Critical thrombocytopenia
  3. Hemodynamic instability
  4. Septicemia
  5. Local infection at the site of the procedure
  6. Patient unwilling to accept risks.


Relative contraindications:[36]

  1. Consistent use of nonsteroidal anti-inflammatory drugs within 48 h of procedure
  2. Corticosteroid injection at treatment site within 1 month
  3. Systemic use of corticosteroids within 2 weeks
  4. Tobacco use
  5. Recent fever or illness
  6. Cancer-especially hematopoietic or of bone
  7. Hemoglobin (HGB) <10 g/dl
  8. Platelet count <105/ul.



  Why We Need Regenerative Therapies Like Platelet-Rich Plasma Top


The global impact of musculoskeletal conditions is huge and its continuously growing.[37] The World Health Organization has acknowledged that musculoskeletal injuries affect hundreds of millions of people worldwide and are the most common cause of severe long-term pain and physical disability.[38]

Chronic and degenerative musculoskeletal conditions impose a great challenge to treat and can have major negative impact on an otherwise active lifestyle. Many of these patients might require a surgical intervention and follow-up rehabilitation program. Still, the outcome is not certain. There are very few treatments, which offer repair and healing the injuries. In view of these facts, the researches and case reports that suggest improvement in osteoarthritis (OA) symptoms and in other musculoskeletal injuries with PRP treatment generated huge interest in the PRP therapies for a wide variety of conditions. With more research, if proven effective, this would be a breakthrough nonoperative treatment option for many degenerative and variety of other conditions.


  What Is Ideal Platelet-Rich Plasma? Top


PRP is basically a reversal of ratio between red blood cells and platelets. Red blood cells play minimal role in wound healing. In PRP, the red blood cells are reduced to <5% and platelet concentration is increased to more than 94%. Platelets are storehouse of number of powerful growth factors. In a healthy individual, a normal platelet count is between 150,000 and 450,000 cells/μl of blood. Platelet concentrations of <1000 × 106/ml were not reliable for enhancing wound healing.[1] The general consensus among most studies have suggested that effective concentration of platelet in PRP should be a minimum increase of 5 times the normal concentration of platelets (approximately 1 million platelets/μl).[1],[40] Concentration more than this has not shown any added benefits in wound healing. We do not know the ideal concentration and is yet to be defined.


  Growth Factors in Platelet-Rich Plasma Top


The important growth factors in PRP are 2,[41],[42]

  1. Transforming growth factor-B - stimulates undifferentiated mesenchymal cell proliferation, endothelial chemotaxis, and angiogenesis, inhibits macrophage and lymphocyte proliferation, regulates endothelial, fibroblastic, and osteoblastic mitogenesis, mitogenic effects of other growth factors, collagen synthesis, and collagenase secretion
  2. Platelet-derived growth factors (PDGF-AB and PDGF-BB) - mitogenetic for mesenchymal cells and osteoblasts, stimulates chemotaxis and mitogenesis in fibroblast, glial, or smooth muscle cells, regulates collagenase secretion and collagen synthesis, stimulates macrophage and neutrophil chemotaxis
  3. Insulin-like growth factor (IGF) improves the early healing of tendon defects by over-expression of IGF-1,[43] chemotactic for fibroblasts and stimulates protein synthesis, enhances bone formation
  4. Vascular endothelial growth factors - stimulating new blood vessel formation to bring nutrients and progenitor cells to the injury site, stimulates mitogenesis for endothelial cells
  5. Epidermal growth factor - stimulates endothelial chemotaxis or angiogenesis, regulates collagenase secretion, stimulates epithelial, or mesenchymal mitogenesis
  6. Fibroblast growth factor-2 - stimulating new blood vessel formation to bring nutrients and progenitor cells to the injury site
  7. Platelet factor 4 - stimulate the initial influx of neutrophils into wounds, chemoattractant for fibroblasts
  8. Interleukin 8 - pro-inflammatory mediator, recruitment of inflammatory cells
  9. Keratinocyte growth factor - promote endothelial cell growth, migration, adhesion and survival, angiogenesis.



  How They Help Top


  • Stabilize the damaged tissue during initial stages of tissue repair
  • Direct the local mesenchymal and epithelial cells to migrate, divide, and increase collagen and matrix synthesis
  • Ultimately leading to fibrous connective tissue and scar formation.



  Platelet-Rich Plasma Procedure Top
[44]

PRP therapy has simple three steps:

  1. Collect patients' blood under all aseptic conditions
  2. Centrifuge – 5–20 min (sterile barrier is a must) – recommendation is to have platelets 5 times the normal
  3. Extract PRP and activate them by the addition of thrombin and calcium chloride (Follow the instruction as per the device and Kit of PRP used). Inject in the injury area under all aseptic precautions.



  Problems Top


We do not know:

  1. What is the ideal concentration of PRP
  2. Which technique is better as several techniques and commercial products are used for PRP preparation
  3. Which PRP is better as each commercial technique leads to formation of different product. Each has different biology and efficacy.


PRP preparations (varieties):[44]

  1. Pure PRP OR leukocyte-poor PRP


    • Preparations without leukocytes
    • With a low-density fibrin network after activation.


  2. Pure platelet rich fibrin


    • Without leukocytes
    • With a high-density fibrin network
    • Only exist in a strongly activated gel form
    • Cannot be injected or used like traditional fibrin glues.


  3. Leukocytes and PRP


    • With leukocytes and with a low-density fibrin network after activation
    • Most commercial or experimental systems have this variety
    • Most kits need minimum handling of the blood samples and maximum standardization of the preparations.


  4. Leukocyte and platelet-rich fibrin


    • Second-generation PRP products
    • With leukocytes
    • With a high-density fibrin network.



  Evidence Top


Cochrane review 2015–PRP for musculoskeletal soft tissue injuries[45]

This Cochrane review evaluated:

  • All randomized and quasi-randomized controlled trials
  • 19 trials, 1088 patients
  • PRP versus placebo, autologous whole blood, dry needling, or no PRP therapy across eight clinical indications.


A major confounding factor identified in this review of PRP is the heterogeneity of the included studies, particularly with:

  • Chronicity of injuries
  • Timing of interventions
  • Outcomes reported
  • A lack of standardization in the application of PRP-most important.


More than 40 commercial PRP systems are available [46] and each product may contain differing:

  • Concentrations of platelets
  • Leukocytes, and
  • Growth factors.


Included studies varied in the timespan between:

  • PRP preparation and delivery
  • Method of delivery (image, arthroscope, direct vision, or no guidance)
  • Number of PRP applications, and
  • Postoperative co-interventions.


Variability in the intervention, as identified by the study authors, may bias the results (e.g., comparing preparations with high platelet concentrations versus those with low concentrations).

Overall, the evidence was considered low quality, given the uncertainty related to estimates of effect, according to the GRADE approach.

Of the 19 included trials, 11 did not provide a prior protocol or trial registration details for the study, which may bias results in favor of the intervention.

Cochrane review concludes that:

  1. No benefit attributable to PRP for short-, medium-, or long-term function
  2. Short-term improvements in pain were identified, but the effect sizes were small and unlikely to be clinically important.


Similar results were found in a paper published by Harris.[46]

Sheth et al.[47] published a paper on the efficacy of autologous PRP use for orthopedic indications: a meta-analysis. They concluded that there is a lack of standardization of study protocols, platelet-separation techniques, and outcome measures. There is uncertainty about PRP use as a treatment modality for orthopedic bone and soft-tissue injuries.

Cole et al.[48] published a paper in Sports Health in May 2010. A PubMed search was performed for studies relating to PRP, growth factors, and soft tissue injuries from 1990 to 2010. There has been the widespread anecdotal use of PRP for muscle strains, tendinopathy, and ligament injuries and as a surgical adjuvant to rotator cuff repair, anterior cruciate ligament reconstruction, and meniscal or labral repairs. Although the fascination with this emerging technology has led to a dramatic increase in its use, scientific data supporting this use are still in their infancy. They concluded that despite the promising results of several animal studies, well-controlled human studies are lacking.

Fitzpatrick et al.[4] in 2016 published a meta-analysis of the outcomes of the PRP groups by preparation method and injection technique in tendinopathy. The aim was to determine the clinical effectiveness of the preparations and to evaluate the effect of controls used in the studies reviewed. They included a total of 18 studies, and 1066 participants. Out of that 8 studies were at low risk of bias. The study quality was assessed using Cochrane Collaboration risk-of-bias tool by 2 reviewers. The primary outcome was a change in pain intensity. They found that with the use of leukocyte-rich (LR) PRP, there was a strongly positive effect compared to leukocyte-poor PRP use. There was no significant difference in control groups whether they used saline, local anesthetic, steroid or dry needling. They concluded that there is good evidence to support the use of a single injection of LR-PRP under ultrasound guidance in tendinopathy. They also concluded that method of preparation and technique of injection is of great clinical significance.

Meheux et al.[49] did a systematic review to determine if PRP injection significantly improves outcomes in patients with symptomatic knee OA at 6 and 12 months posttreatment with PRP injection. They also did compare PRP and corticosteroid injections or viscosupplementation or placebo injections at 6 and 12 months post-PRP injection. In addition, they compared similarities and differences in outcomes based on the PRP formulations used in the different studies. They analyzed 6 studies, 739 patients, 817 knees, 39% males, mean age was 59.9 years; average follow-up was 38 weeks. They concluded that in symptomatic OA knee PRP injections results in clinical significant improvement up to 12 months post-PRP injection. PRP treatment is better and the difference, when compared to viscosupplementation, was found to be clinically significant.

Similar results were found by Kon et al.[50],[51] They also found that improvement ceases around 24 months and may need repeat PRP therapy.

Engebretsen et al.[52] in an IOC consensus paper on the use of PRP in sports medicine concluded that in the current scenario, it is advised to proceed with caution in the use of PRP in athletic sporting injuries.


  Conclusion Top


PRP is very promising futuristic therapy. It is a vehicle to deliver large amount of important growth factors, which are biologically active, to the injury site. Its use has increased extensively over the last decade due to advanced technology, availability of newer commercial PRP equipment, manufacturing various PRP products in the market. It is very simple and easy to use, easily available, uses patient own blood (autologous), potential cost-effective, and considered very safe therapy. There are many case series showing positive outcomes. But despite the promising results of several animal studies, well-controlled human studies are lacking. The research is still in its infancy. There is no consensus or protocol for the use of PRP. Even with all the limited evidence available, today PRP is becoming a very popular therapy in various fields of medicine. More research in future will clear the clouds over many questions being raised about the efficacy and evidence for PRP. To conclude, we may say that there are reasonable amount of data which warrant continued research in PRP but currently its role in clinical practice is not completely defined.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Abstract
Introduction
Indications of P...
Contraindications
Why We Need Rege...
What Is Ideal Pl...
Growth Factors i...
How They Help
Problems
Evidence
Conclusion
Platelet-Rich Pl...
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